AZAQUINAZOLINE PAN-KRAS INHIBITORS
20260015350 ยท 2026-01-15
Inventors
- Xiaolun Wang (San Diego, CA)
- Svitlana Kulyk (San Diego, CA, US)
- John David Lawson (Carlsbad, CA, US)
- Matthew Arnold Marx (San Diego, CA, US)
- Christopher Ronald Smith (San Diego, CA, US)
Cpc classification
A61K31/519
HUMAN NECESSITIES
A61K31/553
HUMAN NECESSITIES
A61K31/675
HUMAN NECESSITIES
C07F9/6561
CHEMISTRY; METALLURGY
A61K31/547
HUMAN NECESSITIES
A61K31/5355
HUMAN NECESSITIES
A61K31/541
HUMAN NECESSITIES
A61K31/5377
HUMAN NECESSITIES
A61K31/5383
HUMAN NECESSITIES
A61K31/554
HUMAN NECESSITIES
C07D519/00
CHEMISTRY; METALLURGY
A61K31/537
HUMAN NECESSITIES
A61K31/549
HUMAN NECESSITIES
International classification
A61K31/519
HUMAN NECESSITIES
A61K31/5355
HUMAN NECESSITIES
A61K31/537
HUMAN NECESSITIES
A61K31/5377
HUMAN NECESSITIES
A61K31/5383
HUMAN NECESSITIES
A61K31/541
HUMAN NECESSITIES
A61K31/547
HUMAN NECESSITIES
A61K31/549
HUMAN NECESSITIES
A61K31/55
HUMAN NECESSITIES
A61K31/553
HUMAN NECESSITIES
A61K31/554
HUMAN NECESSITIES
A61K31/675
HUMAN NECESSITIES
C07D519/00
CHEMISTRY; METALLURGY
Abstract
The present invention relates to compounds that inhibit at least one of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H, pharmaceutical compositions comprising the compounds and methods of use therefor.
Claims
1. A compound of Formula (I): ##STR00891## or a pharmaceutically acceptable salt thereof, wherein: W is: ##STR00892## A is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted with 1-4 R.sup.1; B is: ##STR00893## Y.sup.1 is hydrogen, L-hydroxy optionally substituted with 1-4 R.sup.8, L-alkoxy optionally substituted with 1-4 R.sup.8, halogen, L-C3-C6 cycloalkyl optionally substituted with 1-4 R.sup.9, L-heteroaryl optionally substituted with 1-4 R.sup.8, L-aryl optionally substituted with 1-4 R.sup.8, L-C(O)NH.sub.2, and L-heterocycle substituted with 1-2 oxo (O) or oxo-containing substituent, and optionally further substituted with 1-2 R.sup.8; Y.sup.2 is hydrogen or C1-C4 alkyl; or Y.sup.1 and Y.sup.2 join to form: ##STR00894## where X is selected from: a bond, S, O, N<bound to a fused ring, CH.sub.2, CH.sub.2N, CH.sub.2NCH.sub.2, CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2, OCH.sub.2 and SCH.sub.2; or Y.sup.2 and Z join to form V, where V is: ##STR00895## optionally substituted with 1-4 R.sup.8; Z is hydrogen or joins with Y.sup.2; each R.sup.1 is independently halogen, cyano, hydroxy, C1-C4 alkyl, SC1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, OC1-C3 haloalkyl, SC1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, CH.sub.2C(O)N(R.sup.5).sub.2, C3-C4 alkynyl(NR.sup.5).sub.2, N(R.sup.5).sub.2, deuteroC2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl-, or C3-C6 cycloalkyl wherein said C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl; each R.sup.2 is independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3-N(R.sup.5).sub.2, O(C1-C3 alkyl), (C1-C3 alkyl)-O(C1-C3 alkyl), (C1-C3 alkyl)-O(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(O), -L-OC(O)N(C1-C10 alkyl).sub.2, CO.sub.2R.sup.5, CO.sub.2N(R.sup.5).sub.2, CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2, or two R.sup.2 join to form a heterocycle or cycloalkyl optionally substituted with C1-C3 alkyl; each R.sup.3 is independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3-N(R.sup.5).sub.2, O(C1-C3 alkyl), (C1-C3 alkyl)-O(C1-C3 alkyl), (C1-C3 alkyl)-O(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(O), -L-OC(O)N(C1-C10 alkyl).sub.2, CO.sub.2R.sup.5, CO.sub.2N(R.sup.5).sub.2, CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2, or two R.sup.2 join to form a heterocycle or cycloalkyl optionally substituted with C1-C3 alkyl; wherein if V is not present at least one of R.sup.2 and R.sup.3 are CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2; each R.sup.4 is independently hydrogen, halogen or C1-C3 alkyl; each R.sup.5 is independently hydrogen or C1-C3 alkyl, or two R.sup.5 join to form cycloalkyl or heterocycle; each R.sup.6 is independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl, or two R.sup.6 join to form C3-C6 cycloalkyl or heterocycle; each R.sup.7 is independently hydrogen, C1-C3 alkyl, C2 alkenyl, hydroxy, halogen, C1-C3 haloalkyl, -L-NH.sub.2, NH(C1-C3 alkyl), N(C1-C3 alkyl).sub.2, oxo (O), L-O(C1-C3 alkyl), L-O(C1-C3 alkyl)-OR.sup.5, (C1-C3 alkyl)-OH, C(O)OH, C(O)O(C1-C3 alkyl), L-C(O)N(R.sup.10).sub.2, NHC(O)H, CN, aryl, (CH.sub.2).sub.1-2S(O).sub.2N(R.sup.10).sub.2, NHS(O).sub.2N(R.sup.10).sub.2, OS(O).sub.2N(R.sup.10).sub.2, S(O).sub.2R.sup.10, P(O)(R.sup.5).sub.2 or L-heteroaryl or L-heterocycle optionally independently substituted with 1-2 substituents independently selected from C1-C3 alkyl, CN and C(O)NH.sub.2, two R.sup.7 on the same atom optionally join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with 1-4 substituents independently selected from oxo (O), halogen, hydroxy, C1-C3 alkyl, cyano and O(C1-C3 alkyl), two R.sup.7 on adjacent atoms optionally join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-4 R.sup.8, heteroaryl optionally substituted with 1-4 R.sup.8, aryl optionally substituted with 1-4 R.sup.8, and heterocycle optionally substituted with 1-4 R.sup.8, and two R.sup.7 on non-adjacent atoms optionally join to form a 1-2 carbon bridge; each R.sup.8 is independently C1-C3 alkyl, hydroxy, halogen, N(R.sup.10).sub.2, N(R.sup.10)C(O)R.sup.10, oxo (O), O(C1-C3 alkyl), (C1-C3 alkyl)-OH, C(O)OH, C(O)N(R.sup.10).sub.2, C(O)O(C1-C3 alkyl), C(O)N(R.sup.10).sub.2, heteroaryl, heterocycle or CN; each R.sup.9 is independently C1-C3 alkyl, hydroxy, halogen, oxo (O), O(C1-C3 alkyl), (C1-C3 alkyl)-OH, C(O)OH, C(O)O(C1-C3 alkyl), C(O)NH.sub.2, C(O)NH(C1-C3 alkyl), C(O)N(C1-C3 alkyl).sub.2 or CN; each R.sup.10 is independently hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and hydroxy, or two R.sup.10 join to form cycloalkyl or heterocycle optionally substituted with 1-2 C1-C3 alkyl; each R.sup.11 is independently halogen or methyl; each L is independently a bond, O, C1-C4 alkyl-, C1-C4 alkyl-NH, NH, N(C1-C3 alkyl)- or cyclopropyl-CH.sub.2; each n is 0-3; o is 1-6; p is 1-8; and q is 1-2.
2. A compound of Formula (IA): ##STR00896## or a pharmaceutically acceptable salt thereof, wherein: W is: ##STR00897## A is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted with 1-4 R.sup.1; B is: ##STR00898## Y.sup.1 is hydrogen, L-hydroxy optionally substituted with 1-4 R.sup.8, L-alkoxy optionally substituted with 1-4 R.sup.8, halogen, L-C3-C6 cycloalkyl optionally substituted with 1-4 R.sup.9, L-heteroaryl optionally substituted with 1-4 R.sup.8, L-aryl optionally substituted with 1-4 R.sup.8, L-C(O)NH.sub.2, and L-heterocycle substituted with 1-2 oxo (O) or oxo-containing substituent, and optionally further substituted with 1-2 R.sup.8; Y.sup.2 is hydrogen or C1-C4 alkyl; or Y.sup.1 and Y.sup.2 join to form: ##STR00899## where X is selected from: a bond, S, O, N<bound to a fused ring, CH.sub.2, CH.sub.2N, CH.sub.2NCH.sub.2, CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2, OCH.sub.2 and SCH.sub.2; each R.sup.1 is independently halogen, cyano, hydroxy, C1-C4 alkyl, SC1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, OC1-C3 haloalkyl, SC1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, CH.sub.2C(O)N(R.sup.5).sub.2, C3-C4 alkynyl(NR.sup.5).sub.2, N(R.sup.5).sub.2, deuteroC2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl-, or C3-C6 cycloalkyl wherein said C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl; each R.sup.2 is independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3-N(R.sup.5).sub.2, O(C1-C3 alkyl), (C1-C3 alkyl)-O(C1-C3 alkyl), (C1-C3 alkyl)-O(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(O), -L-OC(O)N(C1-C10 alkyl).sub.2, CO.sub.2R.sup.5, CO.sub.2N(R.sup.5).sub.2, CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2, or two R.sup.2 join to form a heterocycle or cycloalkyl optionally substituted with C1-C3 alkyl; each R.sup.3 is independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3-N(R.sup.5).sub.2, O(C1-C3 alkyl), (C1-C3 alkyl)-O(C1-C3 alkyl), (C1-C3 alkyl)-O(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(O), -L-OC(O)N(C1-C10 alkyl).sub.2, CO.sub.2R.sup.5, CO.sub.2N(R.sup.5).sub.2, CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2, or two R.sup.2 join to form a heterocycle or cycloalkyl optionally substituted with C1-C3 alkyl; each R.sup.4 is independently hydrogen, halogen or C1-C3 alkyl; each R.sup.5 is independently hydrogen or C1-C3 alkyl, or two R.sup.5 join to form cycloalkyl or heterocycle; each R.sup.6 is independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl, or two R.sup.6 join to form C3-C6 cycloalkyl or heterocycle; each R.sup.7 is independently hydrogen, C1-C3 alkyl, C2 alkenyl, hydroxy, halogen, C1-C3 haloalkyl, -L-NH.sub.2, NH(C1-C3 alkyl), N(C1-C3 alkyl).sub.2, oxo (O), L-O(C1-C3 alkyl), L-O(C1-C3 alkyl)-OR.sup.5, (C1-C3 alkyl)-OH, C(O)OH, C(O)O(C1-C3 alkyl), L-C(O)N(R.sup.10).sub.2, NHC(O)HCN, aryl, (CH.sub.2).sub.1-2S(O).sub.2N(R.sup.10).sub.2, NHS(O).sub.2N(R.sup.10).sub.2, OS(O).sub.2N(R.sup.10).sub.2, S(O).sub.2R.sup.10, P(O)(R.sup.5), or L-heteroaryl or L-heterocycle optionally independently substituted with 1-2 substituents independently selected from C1-C3 alkyl, CN and C(O)NH.sub.2, two R.sup.7 on the same atom optionally join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with 1-4 substituents independently selected from oxo (O), halogen, hydroxy, C1-C3 alkyl, cyano and O(C1-C3 alkyl), two R.sup.7 on adjacent atoms optionally join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-4 R.sup.8, heteroaryl optionally substituted with 1-4 R.sup.8, aryl optionally substituted with 1-4 R.sup.8, and heterocycle optionally substituted with 1-4 R.sup.8, and two R.sup.7 on non-adjacent atoms optionally join to form a 1-2 carbon bridge; each R.sup.8 is independently C1-C3 alkyl, hydroxy, halogen, N(R.sup.10).sub.2, N(R.sup.10)C(O)R.sup.10, oxo (O), O(C1-C3 alkyl), (C1-C3 alkyl)-OH, C(O)OH, C(O)N(R.sup.10).sub.2, C(O)O(C1-C3 alkyl), C(O)N(R.sup.10).sub.2, heteroaryl, heterocycle or CN; each R.sup.9 is independently C1-C3 alkyl, hydroxy, halogen, oxo (O), O(C1-C3 alkyl), (C1-C3 alkyl)-OH, C(O)OH, C(O)O(C1-C3 alkyl), C(O)NH.sub.2, C(O)NH(C1-C3 alkyl), C(O)N(C1-C3 alkyl).sub.2 or CN; each R.sup.10 is independently hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and hydroxy, or two R.sup.10 join to form cycloalkyl or heterocycle optionally substituted with 1-2 C1-C3 alkyl; each R.sup.11 is independently halogen or methyl; each L is independently a bond, O, C1-C4 alkyl-, C1-C4 alkyl-NH, NH, N(C1-C3 alkyl)- or cyclopropyl-CH.sub.2; each n is 0-3; o is 1-6; p is 1-8; and q is 1-2.
3. The compound or salt of claim 2, wherein each R.sup.1 is independently selected from halogen, hydroxy, C1-C3 alkoxy and C1-C4 alkyl.
4. The compound or salt of claim 2, wherein each R.sup.2, if present, is selected from CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2, and wherein each R.sup.3, if present, is selected from CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2.
5. The compound or salt of claim 2, wherein each R.sup.7 is independently selected from hydrogen, C1-C4 alkyl, hydroxy, C1-C3 alkoxy, and wherein two R.sup.7 on non-adjacent atoms optionally join to form a 1-2 carbon bridge.
6. The compound or salt of claim 2, wherein each R.sup.6 is independently hydrogen or hydroxy.
7. The compound or salt of any of claims 1-6, wherein Y.sup.1 and Y.sup.2 join to form: ##STR00900##
8. The compound or salt of any of claims 1-6, wherein Y.sup.1 and Y.sup.2 join to form: ##STR00901##
9. The compound or salt of any of claims 1-6, wherein Y.sup.1 and Y.sup.2 join to form: ##STR00902##
10. The compound or salt of any of claims 1-9, wherein A is naphthyl.
11. The compound or salt of any of claims 1-10, wherein at least one R.sup.1 is C1-C4 alkyl.
12. The compound or salt of any of claims 1-10, wherein at least one R.sup.1 is halogen
13. The compound or salt of claim 12, wherein said halogen is a fluorine.
14. The compound or salt of any of claims 1-10, wherein at least one R.sup.1 is hydroxy.
15. The compound or salt of any of claims 1-14, wherein at least one R.sup.2 is CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2.
16. The compound or salt of claim 15, wherein R.sup.11 is fluorine.
17. The compound or salt of any of claims 1-14, wherein at least one R.sup.2 is halogen.
18. The compound or salt of claim 16, wherein said halogen is a fluorine.
19. The compound or salt of any of claims 1-14, wherein at least one R.sup.2 is hydroxy.
20. The compound or salt of any of claims 1-14, wherein at least one R.sup.3 is CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2.
21. The compound or salt of claim 20, wherein R.sup.11 is fluorine.
22. The compound or salt of any of claims 1-21, wherein at least one R.sup.3 is C1-C4 alkyl.
23. The compound or salt of any of claims 1-21, wherein at least one R.sup.3 is halogen.
24. The compound or salt of claim 23, wherein said halogen is fluorine.
25. The compound or salt of any of claims 1-21, wherein at least one R.sup.3 is hydroxy.
26. The compound or salt of any of claims 1-25, wherein R.sup.4 is halogen.
27. The compound or salt of claim 26, wherein said halogen is fluorine.
28. The compound or salt of any of claims 1-27, wherein at least one R.sup.5 is C1-C4 alkyl.
29. The compound or salt of any of claims 1-27, wherein at least one R.sup.5 is hydrogen.
30. The compound or salt of any of claims 1-29, wherein one or both R.sup.6 are C1-C4 alkyl.
31. The compound or salt of any of claims 1-29, wherein one or both R.sup.6 are hydrogen.
32. The compound or salt of any of claims 1-29, wherein two R.sup.6 join to form C3-C6 cycloalkyl or heterocycle.
33. The compound or salt of any of claims 1-6, wherein Y.sup.1 is L-C3-C6 cycloalkyl, L-heteroaryl, L-aryl, or L-heterocycle, where L is a bond, C1-C4 alkyl, NH or N(C1-C3)alkyl.
34. The compound or salt of claim 33, wherein Y.sup.1 is L-heteroaryl, where said heteroaryl is thietane dioxide, iso-thiazolidine dioxide, imidazopyrazine, pyridine or pyrimidine.
35. The compound or salt of claim 33, wherein Y.sup.1 is L-C3-C6 cycloalkyl.
36. The compound or salt of claim 35, wherein the cycloalkyl is cyclobutane, cyclopentane, cyclohexane or cycloheptane.
37. The compound or salt of claim 33, wherein Y.sup.1 is L-heterocycle.
38. The compound or salt of claim 37, wherein the heterocycle is pyrrolidinone.
39. The compound or salt of claim 1, wherein Y.sup.2 is hydrogen.
40. The compound or salt of any of claims 1-6, wherein Y.sup.2 is C1-C4 alkyl;
41. The compound or salt of any of claims 1-6, wherein at least one R.sup.8 is C1-C4 alkyl.
42. The compound or salt of any of claims 1-6, wherein at least one R.sup.8 is hydroxy or C1-C3 alkyl-hydroxy.
43. The compound or salt of any of claims 1-6, wherein one or two R.sup.8 are oxo (O).
44. The compound or salt of any of claims 1-6, wherein at least one R.sup.8 is aryl or heteroaryl.
45. The compound or salt of any of claims 1-6, wherein at least one R.sup.8 is C(O)OH.
46. The compound or salt of any of claims 1-6, wherein at least one R.sup.8 is C(O)NH.sub.2, C(O)NH(C1-C3 alkyl) or C(O)N(C1-C3 alkyl).sub.2.
47. The compound or salt of any of claims 1-6, wherein at least one R.sup.8 is NH.sub.2, NH(C1-C3 alkyl); N(C1-C3 alkyl).sub.2.
49. The compound or salt of any of claims 1-6, wherein at least one R.sup.9 is C1-C4 alkyl.
50. The compound or salt of any of claims 1-6, wherein at least one R.sup.9 is hydroxy or C1-C3 alkyl-hydroxy.
51. The compound or salt of any of claims 1-6, wherein one or two R.sup.9 is oxo (O).
52. The compound or salt of any of claims 1-6, wherein at least one R.sup.9 is aryl or heteroaryl.
53. The compound or salt of any of claims 1-6, wherein at least one R.sup.9 is C(O)OH.
54. The compound or salt of any of claims 1-6, wherein at least one R.sup.9 is C(O)NH.sub.2, C(O)NH(C1-C3 alkyl) or C(O)N(C1-C3 alkyl).sub.2.
55. The compound or salt of any of claims 1-6, wherein Y.sup.1 and Y.sup.2 join to form piperidine, azepane, azocane, thiazepine, diazepane, oxazepane, azetidine, pyrrolidine, piperazine bound to a fused ring via nitrogen or thiomorpholine.
56. The compound or salt of any of claims 1-6, wherein two R.sup.7 on the same atom join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with one or more substituents selected from oxo (O), halogen, hydroxy, C1-C3 alkyl and O(C1-C3 alkyl).
57. The compound or salt of any of claims 1-6, wherein two R.sup.7 on adjacent atoms join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-4 R.sup.8; heteroaryl optionally substituted with 1-4 R.sup.8; aryl optionally substituted with 1-4 R.sup.8, and heterocycle optionally substituted with 1-4 R.sup.8.
58. The compound or salt of any of claims 1-6, wherein two R.sup.7 on non-adjacent atoms join to form a 1-2 carbon bridge.
59. A compound selected from: ##STR00903## ##STR00904## ##STR00905## ##STR00906## ##STR00907## ##STR00908## ##STR00909## ##STR00910## ##STR00911## ##STR00912## ##STR00913## ##STR00914## ##STR00915## ##STR00916## ##STR00917## ##STR00918## ##STR00919## ##STR00920## ##STR00921## ##STR00922## ##STR00923## ##STR00924## ##STR00925## ##STR00926## ##STR00927## ##STR00928## ##STR00929## ##STR00930## ##STR00931## ##STR00932## ##STR00933## ##STR00934## ##STR00935## ##STR00936## ##STR00937## ##STR00938## ##STR00939## ##STR00940## ##STR00941## ##STR00942## ##STR00943## ##STR00944## ##STR00945## ##STR00946## ##STR00947## ##STR00948## ##STR00949## ##STR00950## ##STR00951## ##STR00952## ##STR00953## ##STR00954## ##STR00955## ##STR00956## ##STR00957## ##STR00958## ##STR00959## ##STR00960## ##STR00961## ##STR00962## ##STR00963## ##STR00964## ##STR00965## ##STR00966## ##STR00967## ##STR00968## ##STR00969## ##STR00970## ##STR00971## ##STR00972## ##STR00973## ##STR00974## ##STR00975## ##STR00976## ##STR00977## ##STR00978## ##STR00979## ##STR00980## ##STR00981## ##STR00982## ##STR00983## ##STR00984## ##STR00985## ##STR00986## ##STR00987## ##STR00988## ##STR00989## ##STR00990## ##STR00991## ##STR00992## ##STR00993## ##STR00994## ##STR00995## ##STR00996## ##STR00997## ##STR00998## ##STR00999## ##STR01000## ##STR01001## ##STR01002## and pharmaceutically acceptable salts thereof.
60. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of any of claims 1-59 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
61. A method for inhibiting the wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H activity in a cell, comprising contacting the cell in which inhibition of KRas activity is desired with an effective amount of a compound of according to any of claims 1-59 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 60.
62. A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound according to any of claims 1-59 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 60.
63. The method of claim 62, wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg/kg per day.
64. The method of claim 63, wherein the therapeutically effective amount of the compound is between about 0.1 to 50 mg/kg per day.
65. The method of claim 62, wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma): Gynecological: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.
66. The method of claim 65, wherein the cancer is a KRas G12A-associated cancer.
67. The method of claim 65, wherein the cancer is a KRas G12C-associated cancer.
68. The method of claim 65, wherein the cancer is a KRas G12D-associated cancer.
69. The method of claim 65, wherein the cancer is a KRas G12R-associated cancer.
70. The method of claim 65, wherein the cancer is a KRas G12S-associated cancer.
71. The method of claim 65, wherein the cancer is a KRas G12V-associated cancer.
72. The method of claim 65, wherein the cancer is a KRas G13D-associated cancer.
73. The method of claim 65, wherein the cancer is a KRas Q61H-associated cancer.
74. The method of claim 65, wherein the cancer is a KRas G12A-associated cancer.
75. The method of claim 65, wherein the cancer is associated with at least one of wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H.
76. The method of any of claims 65-75, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.
77. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with wild type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H mutation; and (b) administering to the patient a therapeutically effective amount of a compound according to any of claims 1-59 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 60.
78. The method of any one of claims 65-77, wherein the administering is done via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.
79. The method of claim 78, wherein the administration route is oral.
80. The method of claim 78, wherein the administration is intravenous injection.
81. The method of claim 78, wherein the administration route is intramuscular injection.
82. The method of claim 78, wherein the administration route utilizes a delivery device.
83. The method of claim 78, wherein administration is done in a hospital setting.
Description
DETAILED DESCRIPTION OF THE INVENTION
[0057] The present invention relates to inhibitors of KRas wild type and/or multiple mutated forms of KRas, for instance KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and/or Q61H mutations. In particular, the present invention relates to compounds that inhibit the activity of KRas wild type and/or KRas mutations such as G12A, G12C, G12D, G12R, G12S, G12V, G13D and/or Q61H, pharmaceutical compositions comprising a therapeutically effective amount of the compounds and methods of use therefor.
Definitions
[0058] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference.
[0059] As used herein, wild type KRas refers to a non-mutant form of a mammalian KRas protein. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a wild type KRas inhibitor refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of wild type KRas G12A. A wild type KRas-associated disease or disorder as used herein refers to diseases or disorders associated with or mediated by or having wild type KRas. A non-limiting example of a wild type KRas-associated disease or disorder is a wild type KRas-associated cancer.
[0060] As used herein, KRas G12A refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an alanine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a KRas G12A inhibitor refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12A. A KRas G12A-associated disease or disorder as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12A mutation. A non-limiting example of a KRas G12A-associated disease or disorder is a KRas G12A-associated cancer.
[0061] As used herein, KRas G12C refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a KRas G12C inhibitor refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C. A KRas G12C-associated disease or disorder as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12CD-associated cancer.
[0062] As used herein, KRas G12D refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a KRas G12D inhibitor refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12D. A KRas G12D-associated disease or disorder as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12D mutation. A non-limiting example of a KRas G12D-associated disease or disorder is a KRas G12D-associated cancer.
[0063] As used herein, KRas G12R refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an arginine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a KRas G12R inhibitor refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12R. A KRas G12R-associated disease or disorder as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12R mutation. A non-limiting example of a KRas G12R-associated disease or disorder is a KRas G12R-associated cancer.
[0064] As used herein, KRas G12S refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a serine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a KRas G12S inhibitor refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12S. A KRas G12S-associated disease or disorder as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12S mutation. A non-limiting example of a KRas G12S-associated disease or disorder is a KRas G12S-associated cancer.
[0065] As used herein, KRas G12V refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a valine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a KRas G12V inhibitor refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12V. A KRas G12V-associated disease or disorder as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12V mutation. A non-limiting example of a KRas G12V-associated disease or disorder is a KRas G12V-associated cancer.
[0066] As used herein, KRas G13D refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 13. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a KRas G13D inhibitor refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G13D. A KRas G13D-associated disease or disorder as used herein refers to diseases or disorders associated with or mediated by or having a KRas G13D mutation. A non-limiting example of a KRas G13D-associated disease or disorder is a KRas G13D-associated cancer.
[0067] As used herein, KRas Q61H refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a histidine for a glutamine at amino acid position 61. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a KRas Q61H inhibitor refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas Q61H. A KRas Q61H-associated disease or disorder as used herein refers to diseases or disorders associated with or mediated by or having a KRas Q61H mutation. A non-limiting example of a KRas Q61H-associated disease or disorder is a KRas Q61H-associated cancer.
[0068] As used herein, the term subject, individual, or patient, used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer having wild type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and/or Q61H mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for wild type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and/or Q61H mutation (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a tumor(s) that is positive for wild type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and/or Q61H mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have wild type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and/or Q61H mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having wild type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H gene-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has wild type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and/or Q61H mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
[0069] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the patient has wild type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and/or Q61H mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having wild type KRas-associated or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and/or Q61H-associated cancer, a patient having one or more symptoms of wild type KRas-associated or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and/or Q61H-associated cancer, and/or a patient that has an increased risk of developing wild type KRas-associated or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and/or Q61H-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.
[0070] The term regulatory agency is a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).
[0071] The term acyl refers to C(O)CH.sub.3.
[0072] The terms C1-C6 alkyl, C1-C4 alkyl and C1-C3 alkyl as employed herein refers to straight and branched chain aliphatic groups having from 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, respectively. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
[0073] The terms C1-C3 haloalkyl and C1-C4 haloalkyl refer to a C1-C3 alkyl chain or C1-C4 alkyl chain, respectively, as defined herein in which one or more hydrogen has been replaced by a halogen. Examples include trifluoromethyl, difluoromethyl and fluoromethyl.
[0074] An C1-C4 alkylene, group is a C1-C4 alkyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Exemplary alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
[0075] The terms C1-C3 alkoxy and C1-C4 alkoxy refer to OC1-C3 alkyl and OC1-C4 alkyl, respectively, wherein the alkyl portion is as defined herein above.
[0076] The term cycloalkyl as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted with one or more R.sup.8 or R groups as defined herein. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term cycloalkyl also includes bridged cycloalkyls, such as bicyclo[1.1.1]pentanyl.
[0077] As used herein, the terms C1-C3 hydroxyalkyl and C1-C4 hydroxyalkyl refer to C1-C3 alkylene-OH and C1-C4 alkylene-OH, respectively.
[0078] As used herein, the term C2-C4 hydroxyalkynyl refers to C2-C4 alkynylene-OH.
[0079] An aryl group is a C.sub.6-C.sub.14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted with one or more R.sup.8 or R.sup.9 groups as defined herein. As one embodiment, the aryl group is a C.sub.6-C.sub.10 aryl group. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. Aryl also refers to bicyclic or tricyclic ring systems in which one or two rings, respectively, of said aryl ring system may be saturated or partially saturated, and wherein if said ring system includes two saturated rings, said saturated rings may be fused or spirocyclic. An example of an aryl ring system comprising two saturated rings wherein the rings are spirocyclic includes the following ring system:
##STR00006##
[0080] An araC1-C6 alkyl or arylalkyl group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted. An example of an aralkyl group is (C6-C10) aryl(C1-C6)alkyl-, including, without limitation, benzyl, phenethyl, and naphthylmethyl. An example of a substituted araC1-C6 alkyl is wherein the alkyl group is substituted with hydroxyalkyl.
[0081] A heterocyclyl or heterocyclic group is a ring structure having from 3 to 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S wherein the ring N atom may be oxidized to NO, and the ring S atom may be oxidized to SO or SO.sub.2, the remainder of the ring atoms being carbon. The heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system. The heterocyclic group is optionally substituted with one or more R.sup.8 or R.sup.9 groups on ring carbon or ring nitrogen at one or more positions, wherein R.sup.6 is as defined for Formula I. The heterocyclic group is also independently optionally substituted on a ring nitrogen atom with alkyl, aralkyl, alkylcarbonyl, or on sulfur with lower alkyl. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1H,3H-spiro[cyclopropane-1,2-pyrrolizine], hexahydro-1H-pyrrolizinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(1H)-oxide, tetrahydro-2H-thiopyranyl 1-oxide and tetrahydro-2H-thiopyranyl 1,1-dioxide. Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms.
[0082] As used herein, the term heteroaryl refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring, or from one to three heteroatoms in at least one ring, selected from the group consisting of N, O, and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Heteroaryl also refers to bicyclic ring systems having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S in which one ring system may be saturated or partially saturated.
[0083] As used herein, an effective amount of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of one or more of wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
[0084] As used herein, a therapeutically effective amount of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of one or more of wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
[0085] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.
[0086] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
Compounds
[0087] In certain embodiments of the invention there are provided compounds of Formula (I):
##STR00007##
or a pharmaceutically acceptable salt thereof, wherein: [0088] W is:
##STR00008## [0089] A is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted with 1-4 R.sup.1; [0090] B is:
##STR00009## [0091] Y.sup.1 is hydrogen, L-hydroxy optionally substituted with 1-4 R.sup.8, L-alkoxy optionally substituted with 1-4 R.sup.8, halogen, L-C3-C6 cycloalkyl optionally substituted with 1-4 R.sup.9, L-heteroaryl optionally substituted with 1-4 R.sup.8, L-aryl optionally substituted with 1-4 R.sup.8, L-C(O)NH.sub.2, and L-heterocycle substituted with 1-2 oxo (O) or oxo-containing substituent, and optionally further substituted with 1-2 R.sup.8, [0092] Y.sup.2 is hydrogen or C1-C4 alkyl; [0093] or Y.sup.1 and Y.sup.2 join to form:
##STR00010##
where X is selected from: a bond, S, O, N<bound to a fused ring, CH.sub.2, CH.sub.2N, CH.sub.2NCH.sub.2, CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2, OCH.sub.2 and SCH.sub.2; [0094] or Y.sup.2 and Z join to form V, where V is:
##STR00011##
optionally substituted with 1-4 R.sup.8, [0095] Z is hydrogen or joins with Y.sup.2; [0096] each R.sup.1 is independently halogen, cyano, hydroxy, C1-C4 alkyl, SC1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, OC1-C3 haloalkyl, SC1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, CH.sub.2C(O)N(R.sup.5).sub.2, C3-C4 alkynyl(NR.sup.5).sub.2, N(R.sup.5).sub.2, deuteroC2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl-, or C3-C6 cycloalkyl wherein said C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl; [0097] each R.sup.2 is independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3-N(R.sup.5).sub.2, O(C1-C3 alkyl), (C1-C3 alkyl)-O(C1-C3 alkyl), (C1-C3 alkyl)-O(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(O), -L-OC(O)N(C1-C10 alkyl).sub.2, CO.sub.2R.sup.5, CO.sub.2N(R.sup.5).sub.2, CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2, or two R.sup.2 join to form a heterocycle or cycloalkyl optionally substituted with C1-C3 alkyl; [0098] each R.sup.3 is independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3-N(R.sup.5).sub.2, O(C1-C3 alkyl), (C1-C3 alkyl)-O(C1-C3 alkyl), (C1-C3 alkyl)-O(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(O), -L-OC(O)N(C1-C10 alkyl).sub.2, CO.sub.2R.sup.5, CO.sub.2N(R.sup.5).sub.2, CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2, or two R.sup.2 join to form a heterocycle or cycloalkyl optionally substituted with C1-C3 alkyl; [0099] wherein if V is not present at least one of R.sup.2 and R.sup.3 are CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2; [0100] each R.sup.4 is independently hydrogen, halogen or C1-C3 alkyl; [0101] each R.sup.5 is independently hydrogen or C1-C3 alkyl, or two R.sup.5 join to form cycloalkyl or heterocycle; [0102] each R.sup.6 is independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl, [0103] or two R.sup.6 join to form C3-C6 cycloalkyl or heterocycle; [0104] each R.sup.7 is independently hydrogen, C1-C3 alkyl, C2 alkenyl, hydroxy, halogen, C1-C3 haloalkyl, -L-NH.sub.2, NH(C1-C3 alkyl), N(C1-C3 alkyl).sub.2, oxo (O), L-O(C1-C3 alkyl), L-O(C1-C3 alkyl)-OR.sup.5, (C1-C3 alkyl)-OH, C(O)OH, C(O)O(C1-C3 alkyl), L-C(O)N(R.sup.10).sub.2, NHC(O)H, CN, aryl, (CH.sub.2).sub.1-2S(O).sub.2N(R.sup.10).sub.2, NHS(O).sub.2N(R.sup.10).sub.2, OS(O).sub.2N(R.sup.10).sub.2, S(O).sub.2R.sup.10, P(O)(R.sup.5).sub.2 or L-heteroaryl or L-heterocycle optionally independently substituted with 1-2 substituents independently selected from C1-C3 alkyl, CN and C(O)NH.sub.2, [0105] two R.sup.7 on the same atom optionally join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with 1-4 substituents independently selected from oxo (O), halogen, hydroxy, C1-C3 alkyl, cyano and O(C1-C3 alkyl), [0106] two R.sup.7 on adjacent atoms optionally join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-4 R.sup.8, heteroaryl optionally substituted with 1-4 R.sup.8, aryl optionally substituted with 1-4 R.sup.8, and heterocycle optionally substituted with 1-4 R.sup.8, and [0107] two R.sup.7 on non-adjacent atoms optionally join to form a 1-2 carbon bridge; [0108] each R.sup.8 is independently C1-C3 alkyl, hydroxy, halogen, N(R.sup.10).sub.2, N(R.sup.10)C(O)R.sup.10, oxo (O), O(C1-C3 alkyl), (C1-C3 alkyl)-OH, C(O)OH, C(O)N(R.sup.10).sub.2, C(O)O(C1-C3 alkyl), C(O)N(R.sup.10).sub.2, heteroaryl, heterocycle or CN; [0109] each R.sup.9 is independently C1-C3 alkyl, hydroxy, halogen, oxo (O), O(C1-C3 alkyl), (C1-C3 alkyl)-OH, C(O)OH, C(O)O(C1-C3 alkyl), C(O)NH.sub.2, C(O)NH(C1-C3 alkyl), C(O)N(C1-C3 alkyl).sub.2 or CN; [0110] each R.sup.10 is independently hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and hydroxy, or two R.sup.10 join to form cycloalkyl or heterocycle optionally substituted with 1-2 C1-C3 alkyl; [0111] each R.sup.11 is independently halogen or methyl; [0112] each L is independently a bond, O, C1-C4 alkyl-, C1-C4 alkyl-NH, NH, N(C1-C3 alkyl)- or cyclopropyl-CH.sub.2; [0113] each n is 0-3; [0114] is 1-6; [0115] p is 1-8; and [0116] q is 1-2.
[0117] In a preferred embodiment, R.sup.11 is fluorine.
[0118] Embodiments of the invention also include compounds of Formula (IA):
##STR00012##
or a pharmaceutically acceptable salt thereof, wherein: [0119] W is:
##STR00013## [0120] A is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted with 1-4R.sup.1; [0121] B is:
##STR00014## [0122] Y.sup.1 is hydrogen, L-hydroxy optionally substituted with 1-4 R.sup.8, L-alkoxy optionally substituted with 1-4 R.sup.8, halogen, L-C3-C6 cycloalkyl optionally substituted with 1-4 R.sup.9, L-heteroaryl optionally substituted with 1-4 R.sup.8, L-aryl optionally substituted with 1-4 R.sup.8, L-C(O)NH.sub.2, and L-heterocycle substituted with 1-2 oxo (O) or oxo-containing substituent, and optionally further substituted with 1-2 R.sup.8, [0123] Y.sup.2 is hydrogen or C1-C4 alkyl; [0124] or Y.sup.1 and Y.sup.2 join to form:
##STR00015## [0125] where X is selected from: a bond, S, O, N [0146] Embodiments also include such compounds or salts wherein each R.sup.1 is independently selected from halogen, hydroxy, C1-C3 alkoxy and C1-C4 alkyl. [0147] Embodiments also include such compounds or salts wherein each R.sup.2, if present, is selected from hydrogen and halogen, and wherein each R.sup.3, if present, is selected from hydrogen and halogen. [0148] Embodiments also include such compounds or salts wherein each R.sup.7 is independently selected from hydrogen, C1-C4 alkyl, hydroxy, C1-C3 alkoxy, and wherein two R.sup.7 on non-adjacent atoms optionally join to form a 1-2 carbon bridge. [0149] Embodiments also include such compounds or salts wherein each R.sup.6 is independently hydrogen or hydroxy. [0150] Embodiments also include such compounds or salts wherein B is: ##STR00016## [0151] Embodiments also include such compounds or salts wherein Y.sup.1 and Y.sup.2 join to form: ##STR00017## [0152] Embodiments also include such compounds or salts wherein Y.sup.1 and Y.sup.2 join to form: ##STR00018## [0153] Embodiments also include such compounds or salts wherein Y.sup.1 and Y.sup.2 join to form: ##STR00019## [0154] Embodiments also include such compounds or salts wherein A is naphthyl. [0155] Embodiments also include such compounds or salts wherein A is indazolyl. [0156] Embodiments also include such compounds or salts wherein A is phenyl. [0157] Embodiments also include such compounds or salts wherein A is pyridyl. [0158] In certain embodiments of the invention at least one R.sup.1 is C1-C4 alkyl. [0159] In certain embodiments of the invention at least one R.sup.1 is halogen, preferably fluorine or chlorine. [0160] In certain embodiments of the invention at least one R.sup.1 is hydroxy [0161] In certain embodiments of the invention at least one R.sup.2 is C1-C4 alkyl. [0162] In certain embodiments of the invention at least one R.sup.2 is halogen, preferably fluorine or chlorine. [0163] In certain embodiments of the invention at least one R.sup.2 is hydroxy. [0164] In certain embodiments of the invention at least one R.sup.2 is CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2. [0165] In certain embodiments of the invention at least one R.sup.3 is C1-C4 alkyl. [0166] In certain embodiments of the invention at least one R.sup.3 is halogen, preferably fluorine or chlorine. [0167] In certain embodiments of the invention at least one R.sup.3 is hydroxy. [0168] In certain embodiments of the invention at least one R.sup.3 is CH.sub.2, CHR.sup.11 or C(R.sup.11).sub.2. [0169] In certain embodiments of the invention R.sup.4 is halogen, preferably fluorine. [0170] In certain embodiments of the invention at least one R.sup.5 is C1-C4 alkyl. [0171] In certain embodiments of the invention at least one R.sup.5 is hydrogen. [0172] In certain embodiments of the invention at least one R.sup.6 is C1-C4 alkyl. [0173] In certain embodiments of the invention, two R.sup.6 join to form C3-C6 cycloalkyl or heterocycle. [0174] In certain embodiments of the invention at least one R.sup.6 is hydrogen. [0175] In certain embodiments of the invention both R.sup.6 are C1-C4 alkyl. [0176] In certain embodiments of the invention both R.sup.6 are hydrogen. [0177] In certain embodiments Y.sup.1 is L-C3-C6 cycloalkyl, L-heteroaryl, L-aryl, or L-heterocycle. In certain of these embodiments, L is a bond. In certain of these embodiments L is C1-C4 alkyl. In certain of these embodiments L is NH or N(C1-C3)alkyl. [0178] In certain embodiments Y.sup.1 is L-heteroaryl where the heteroaryl is thietane dioxide, iso-thiazolidine dioxide, imidazopyrazine, pyridine or pyrimidine. [0179] In certain embodiments Y.sup.1 is L-C3-C6 cycloalkyl where the cycloalkyl is preferably cyclobutane, cyclopentane, cyclohexane or cycloheptane. [0180] In certain embodiments Y.sup.1 is L-heterocycle where the heterocycle is preferably pyrrolidinone. [0181] In certain embodiments of the invention Y.sup.2 is hydrogen. [0182] In certain embodiments of the invention Y.sup.2 is C1-C4 alkyl; [0183] In certain embodiments of the invention at least one R.sup.8 is C1-C4 alkyl, preferably methyl. [0184] In certain embodiments of the invention at least one R.sup.8 is hydroxy or C1-C3 alkyl-hydroxy. [0185] In certain embodiments of the invention one or two R.sup.8 is oxo (O). [0186] In certain embodiments of the invention at least one R.sup.8 is aryl or heteroaryl. [0187] In certain embodiments of the invention at least one R.sup.8 is C(O)OH. [0188] In certain embodiments of the invention at least one R.sup.8 is C(O)NH.sub.2, C(O)NH(C1-C3 alkyl) or C(O)N(C1-C3 alkyl).sub.2. [0189] In certain embodiments of the invention R.sup.8 is NH.sub.2, NH(C1-C3 alkyl); N(C1-C3 alkyl).sub.2. [0190] In certain embodiments of the invention at least one R.sup.9 is C1-C4 alkyl, preferably methyl. [0191] In certain embodiments of the invention at least one R.sup.9 is hydroxy or C1-C3 alkyl-hydroxy. [0192] In certain embodiments of the invention one or two R.sup.9 is oxo (O). [0193] In certain embodiments of the invention at least one R.sup.9 is aryl or heteroaryl. [0194] In certain embodiments of the invention at least one R.sup.9 is C(O)OH. [0195] In certain embodiments of the invention at least one R.sup.9 is C(O)NH.sub.2, C(O)NH(C1-C3 alkyl) or C(O)N(C1-C3 alkyl).sub.2. [0196] In certain embodiments of the invention at least one R.sup.11 is F. [0197] In certain embodiments of the invention Y.sup.1 and Y.sup.2 join to form a piperidine, azepane, azocane, thiazepine, diazepane, oxazepane, azetidine, pyrrolidine, piperazine bound to a fused ring via nitrogen or thiomorpholine. [0198] In certain embodiments of the invention, two R.sup.7 on the same atom join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with oxo (O), halogen, hydroxy, C1-C3 alkyl and O(C1-C3 alkyl). [0199] In certain embodiments of the invention, two R.sup.7 on adjacent atoms optionally join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-4 R.sup.8; heteroaryl optionally substituted with 1-4 R.sup.8; aryl optionally substituted with 1-4 R.sup.8, and heterocycle optionally substituted with 1-4 R.sup.8. [0200] In certain embodiments of the invention, two R.sup.7 on non-adjacent atoms optionally join to form a 1-2 carbon bridge. [0201] Nonlimiting examples of the compounds of the invention include: ##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105## and pharmaceutically acceptable salts thereof. [0202] Non-limiting examples of compounds of Formula (I) are selected from the group consisting of the compounds described in the below Examples, and pharmaceutically acceptable salts thereof. [0203] In one embodiment, the compounds of Formula (I) include bis-hydrochloride, tris-hydrochloride, trifluoroacetic acid, bis-trifluoroacetic acid, and tris-trifluoracetic acid salts of the above compounds. The compounds of Formula (I) or pharmaceutically acceptable salt thereof may be formulated into pharmaceutical compositions. Pharmaceutical Compositions [0204] In another aspect, the invention provides pharmaceutical compositions comprising a wild type Kras, Kras G12A, Kras G12C, Kras G12D, Kras G12R, Kras G12S, Kras G12V, Kras G13D and/or Kras Q61H inhibitor according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intranasal, intratracheal, intrarectal, subcutaneous, and topical administration. In certain embodiments, compounds of the invention are administered intravenously in a hospital setting. In one embodiment, administration may be by the oral route. In some embodiments, the provided pharmaceutical compositions may be administered to a subject in need of treatment by injection systemically, such as by intravenous injection; or by injection or application to the relevant site, such as by direct injection via syringe, or direct application to the site when the site is exposed in surgery; or by topical administration. [0205] Parenteral administration can be by bolus injection or continuous infusion. Pharmaceutical compositions for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. [0206] The provided pharmaceutical compositions can also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the formulations may be modified with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. [0207] The pharmaceutical compositions may, if desired, be presented in a vial, pack or a medical device, including but not limited to a dispenser device which may contain one or more unit dosage forms containing the active ingredient. In one embodiment the dispenser device can comprise a syringe having a single dose of the liquid formulation ready for injection. The syringe can be accompanied by instructions for administration. [0208] The characteristics of the carrier will depend on the route of administration. As used herein, the term pharmaceutically acceptable means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18.sup.th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990. [0209] As used herein, the term pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula NR+Z.sup.2, wherein R is hydrogen, alkyl, or benzyl, and Z.sup.2 is a counterion, including chloride, bromide, iodide, O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate). [0210] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. In one embodiment, a dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, for example 0.1 to 100 mg/kg per day, and as a further example 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art. [0211] The pharmaceutical compositions comprising compounds of the present invention may be used in the methods of use described herein. Methods of Use [0212] In yet another aspect, the invention provides for methods for inhibiting wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V and/or KRas Q61H activity in a cell, comprising contacting the cell in which inhibition of wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V and/or Q61H activity is desired with an effective amount of a compound of Formula (I), pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo. [0213] As used herein, the term contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, contacting wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having wild type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H mutation, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing wild type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H mutation. [0214] In one embodiment, a cell in which inhibition of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H activity is desired is contacted with an effective amount of a compound of Formula (I) or pharmaceutically acceptable salt thereof to negatively modulate the activity of one or more of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H. [0215] By negatively modulating the activity of one or more of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to affect the desired negative modulation of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H. The ability of compounds to bind one or more of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H may be monitored in vitro using well known methods, including those described in Examples A and B below. In addition, the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of one or more of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H activity of the amount of phosphorylated ERK, for example using the method described in Example C below. [0216] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided. [0217] The compositions and methods provided herein may be used for the treatment of a wild type KRas-associated or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H-associated cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided. In one embodiment, the wild type KRas-associated or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H-associated cancer is lung cancer. [0218] The compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In certain embodiments, the cancer is non-small cell lung cancer. [0219] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. [0220] Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in therapy. [0221] Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer. [0222] Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the inhibition of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H. [0223] Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of wild type KRas-associated or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H-associated disease or disorder. [0224] Also provided herein is the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer. [0225] Also provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H. [0226] Also provided herein is the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of wild type KRas-associated or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H-associated disease or disorder. [0227] Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with wild type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and/or KRas Q61H mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [0228] One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and/or animal models are predictive of the ability of a test compound to treat or prevent a given disorder. [0229] One skilled in the art will further recognize that human clinical trials including first-in-human, dose ranging and efficacy trials, in healthy patients and/or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts. REACTION SCHEMES AND EXAMPLES [0230] The compounds of the present invention may be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art. For instance, compounds of the present invention may be prepared according to the reaction schemes and examples outlines below. [0231] The compounds of the present invention may have one or more chiral center and may be synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures or the individual components/isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK (Sigma-Aldrich) or CHIRALCEL (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer's instructions. Alternatively, compounds of the present invention may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Unless otherwise indicated, whenever the specification, including the claims, refers to compounds of the invention, the term compound is to be understood to encompass all chiral (enantiomeric and diastereomeric) and racemic forms. [0232] The compounds of the present invention may be in anhydrous, solvated or hydrated forms, and all such forms are included within the scope of the invention. [0233] The following Intermediates are intended to illustrate further certain embodiments of the invention and are not intended to limit the scope of the invention. Intermediate 1 ##STR00106## 8-fluoro-7-(8-fluoronaphthalen-1-yl)-4-(methylthio)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine ##STR00107## [0234] Step A. 8-fluoro-7-(8-fluoronaphthalen-1-yl)-4-(methylthio)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine: To a solution of 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1.0 equiv) in DCM (8 mL) was added NaSMe (119 mg, 1.8 equiv). The mixture was stirred at 20 C. for 2 hours. The mixture was filtered, concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 0:1) to afford the title compound (260 mg, 58% yield) as a white solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.22 (s, 1H), 8.01 (br d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.67-7.61 (m, 1H), 7.60-7.56 (m, 1H), 7.46 (dt, J=5.2, 8.0 Hz, 1H), 7.16-7.08 (m, 1H), 4.40 (br s, 2H), 3.19 (br s, 2H), 2.79 (s, 3H), 2.75-2.64 (m, 2H), 2.18-2.07 (m, 2H), 1.98-1.86 (m, 4H), 1.77-1.66 (m, 2H). m/z=479.2. Intermediate 2 ##STR00108## 5-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide ##STR00109## [0235] To a solution of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (4.55 g, 1.0 equiv) in DCM (50 mL) was added DIPEA (3.92 g, 3.0 equiv) and N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (2.0 g, 0.95 equiv). The mixture was stirred at 40 C. for 0.5 hr. The reaction mixture was quenched by H.sub.2O (20 mL) and extracted with ethyl acetate (20 mL3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified by reversed-phase flash chromatography (C18, 0.1% FA condition) to afford the title compound (5.00 g, 78% yield) as a white solid. LCMS (ESI, M+1): m/z=622.2. Intermediate 3 ##STR00110## ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate ##STR00111## [0236] Step A. (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizine: To a solution of ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methanol (2.00 g, 1.0 equiv) and TEA (1.24 g, 2.5 equiv) in DCM (20 mL) was added TrtCl (2.72 g, 2.0 equiv) at 0 C. The mixture was stirred at 15 C. for 10 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2100 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 20:1 to 5:1] to afford the title compound (3.40 g, crude) as a colorless oil; LCMS (ESI, M+1): m/z=652.5. [0237] Step B. ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methanol: To a solution of (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizine (3.40 g, 1.0 equiv) in DMF (20 mL) was added CsF (7.92 g, 10 equiv). The mixture was stirred at 25 C. for 6 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (250 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (980 mg, 45% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.53-7.19 (m, 15H), 3.52-3.24 (m, 2H), 2.96-2.60 (m, 5H), 2.03 (m, 1H), 1.93-1.83 (m, 1H), 1.82-1.49 (m, 6H); LCMS (ESI, M+1): m/z=414.2. [0238] Step C. ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methanol (930 mg, 1.0 equiv) in THF (20 mL) was added NaH (360 mg, 60% purity, 4.0 equiv) at 0 C. The mixture was stirred at 0 C. for 10 minutes. To the mixture was added dimethylcarbamic chloride (484 mg, 2.0 equiv) at 0 C. The mixture was stirred at 15 C. for 20 hours. The mixture was quenched by water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (1.00 g, 83% yield) as a yellow oil; LCMS (ESI, M+1): m/z=485.3. [0239] Step D. ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (620 mg, 1.0 equiv) in DCM (5 mL) was added TFA (1.46 g, 10 equiv) at 0 C. The mixture was stirred at 15 C. for 3 hours. The mixture was concentrated. To the residue was added MeOH (5 mL) and NaHCO.sub.3 (300 mg). The mixture was filtered and concentrated to give a residue which was purified by column chromatography [Al.sub.2O.sub.3, Petroleum ether/Ethyl acetate 2:1 to 0:1, ethyl acetate/MeOH 12:1] to afford the title compound (220 mg, 71% yield) as a yellow oil; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =4.00 (dq, J=6.0, 10.8 Hz, 2H), 3.31-3.22 (m, 2H), 3.03-2.96 (m, 2H), 2.95-2.86 (m, 6H), 2.80 (td, J=5.2, 10.8 Hz, 1H), 2.09-1.46 (m, 8H). Intermediate 4 ##STR00112## dimethyl(1,4-oxazepan-6-yl)phosphine oxide ##STR00113## [0240] Step A: tert-butyl 6-(dimethylphosphoryl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate: A mixture of tert-butyl 6-(((trifluoromethyl) sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (350 mg, 1 equiv), methylphosphonoylmethane (86.5 mg, 1.1 equiv), Pd(PPh.sub.3).sub.4 (58.2 mg, 0.05 equiv), Et.sub.3N (204 mg, 2 equiv) and methylphosphonoylmethane (86.5 mg, 1.1 equiv) in MeCN (10 mL) was degassed and stirred at 90 C. for 10 hours under N.sub.2 atmosphere. The reaction mixture was concentrated and purified by prep-HPLC (column: Waters Xbridge 15025 mm5 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 12%-42%, 9 min). .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.51 (d, J=15.6 Hz, 1H), 4.35 (br d, J=7.6 Hz, 2H), 3.99-3.84 (m, 4H), 1.59 (s, 3H), 1.55 (s, 3H), 1.52 (s, 9H) [0241] Step B tert-butyl 6-(dimethylphosphoryl)-1,4-oxazepane-4-carboxylate: A mixture of tert-butyl 6-(dimethylphosphoryl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (100 mg, 1.0 equiv), Pd/C (50 mg, 60% purity, 1.0 equiv) in MeOH (1.0 mL) was degassed and purged with H.sub.2 for 3 times, and then the mixture was stirred at 25 C. for 2 hours under H.sub.2 atmosphere. The reaction mixture was filtered with MeOH (20 mL) and concentrated under reduced pressure to afford the title compound (100 mg) as a white solid. [0242] Step C dimethyl(1,4-oxazepan-6-yl)phosphine oxide: To a solution of tert-butyl 6-(dimethylphosphoryl)-1,4-oxazepane-4-carboxylate (100 mg, 1.0 equiv) in DCM (2.0 mL) was added TFA (411 mg, 10.0 equiv). The mixture was stirred at 25 C. for 1 hour. The reaction mixture was concentrated under reduced pressure to afford the title compound (50 mg) as a yellow oil. Intermediate 5 ##STR00114## [0243] Three isomeric 3-azabicyclo[3.2.1]octane-6,7-diol (stereochemistry was arbitrarily assigned) ##STR00115## [0244] Step A. benzyl 6-hydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate To a mixture of 3-azabicyclo[3.2.1]octan-6-ol (4.50 g, 1.0 equiv) and NaHCO.sub.3 (11.9 g, 4.0 equiv) in EtOAc (54.0 mL) and water (36.0 mL) were added benzyl carbonochloridate (8.45 g, 1.4 equiv) and TBAB (1.14 g, 0.1 equiv) at 0 C. The reaction was stirred at 20 C. for 12 hours. The mixture was extracted with EtOAc (250 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate 3:1 to ethyl acetate/methanol 30:1) to afford the title compound (8.30 g, 90% yield) as a colorless oil. [0245] Step B. benzyl 6-((methylsulfonyl)oxy)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a mixture of benzyl 6-hydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (7.50 g, 1.0 equiv) in pyridine (70 mL) was added methanesulfonyl chloride (5.84 g, 1.8 equiv) drop-wise at 0 C. The reaction was stirred at 20 C. for 0.5 hour. The mixture was diluted with water (300 mL) and extracted with EtOAc (3100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to afford the title compound (10 g, 94% yield) as a light-yellow solid. [0246] Step C. benzyl 3-azabicyclo[3.2.1]oct-6-ene-3-carboxylate: To a mixture of benzyl 6-((methylsulfonyl)oxy)-3-azabicyclo[3.2.1]octane-3-carboxylate (9.00 g, 1.0 equiv) in 2,3,5-trimethylpyridine (25 mL) was added DBU (12.1 g, 3.0 equiv). The reaction was stirred at 170 C. for 3 hours. The mixture was acidified with 1N HCl (15 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with NaHCO.sub.3 (10 mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (3.37 g, 51% yield) as a colorless oil; .sup.1H NMR (400 MHZ, chloroform-d) =7.40-7.28 (m, 5H), 6.02-5.91 (m, 2H), 5.12 (d, J=2.8 Hz, 2H), 3.85-3.70 (m, 2H), 3.09-2.95 (m, 2H), 2.70-2.63 (m, 1H), 2.61-2.54 (m, 1H), 2.10-2.01 (m, 1H), 1.60-1.57 (m, 1H). [0247] Step D. benzyl 3-oxa-7-azatricyclo[3.3.1.02,4]nonane-7-carboxylate: To a mixture of benzyl 3-azabicyclo[3.2.1]oct-6-ene-3-carboxylate (3.47 g, 1.0 equiv) in DCM (70 mL) was added m-CPBA (6.15 g, 2.0 equiv). The reaction was stirred at 20 C. for 5 hours. The mixture was quenched by addition of saturated aqueous Na.sub.2SO.sub.3 (70 mL), neutralized with solid NaHCO.sub.3 and extracted with DCM (270 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated. The mixture was purified by silica gel chromatography (petroleum ether/ethyl acetate 20/1 to 3/1) to afford the title compound (2.50 g, 61% yield) as a light yellow solid; .sup.1H NMR (400 MHZ, chloroform-d) =7.43-7.30 (m, 5H), 5.19-5.08 (m, 2H), 4.02-3.88 (m, 2H), 3.40-3.28 (m, 2H), 3.16-3.04 (m, 2H), 2.45-2.31 (m, 2H), 1.64-1.54 (m, 1H), 1.20-1.13 (m, 1H). [0248] Step E. benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate: To a mixture of benzyl 3-oxa-7-azatricyclo[3.3.1.02,4]nonane-7-carboxylate (2.50 g, 1.0 equiv) in THF (35 mL) was added H.sub.2SO.sub.4 (2 M in water, 72.3 mL, 5.0 equiv). The reaction was stirred at 60 C. for 12 hours. The mixture was basified with 40% NaOH under ice bath and extracted with EtOAc (450 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [Phenomenex luna C18 25050 mm10 m; A: water (TFA); B: ACN; B %: 14%-44% over 20 min]. The desired fractions were neutralized with solid K.sub.2CO.sub.3 and extracted with EtOAc (450 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (1.1 g, 37% yield) as a yellow oil; SFC: Chiralpak AD-3 504.6 mm I.D., 3 m; gradient elution: IPA (0.05% DEA) in CO.sub.2 from 5% to 40%, t.sub.R: 1.411 min, 1.468 min, 1.599 min, 1.707 min; LCMS (ESI, M+23): m/z=278.0. [0249] Step F. Isomers of benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate: benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (1.1 g) was separated by SFC [Daicel Chiralpak AD 250 mm30 mm, 10 um; mobile phase: (0.1% NH.sub.3.Math.H.sub.2O IPA); B %: 30%-30%, C8. 4; 244 min]. The four peaks were obtained. Sufficient purity for peak 2 was not achieved. SFC: Chiralpak AD-3 504.6 mm I.D., 3 m; Gradient elution: 5% to 40% IPA (0.05% DEA) in CO.sub.2, 3 mL/min, 220 nm, t.sub.R: 1.713 min. (stereochemistry was arbitrarily assigned) [0250] (1R,5S,6R,7R)-benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (peak 1, 260 mg, 23% yield) as a colorless oil. [0251] (1R,5S,6S,7S)-benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (peak 3, 260 mg, 23% yield) as a colorless oil. [0252] (1R,5S)-benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (peak 4, 230 mg, 20% yield) as a colorless oil. [0253] Step G. Isomers of 3-azabicyclo[3.2.1]octane-6,7-diol, Intermediate 5 peak 1: To a mixture of (1R,5S,6S,7S)-benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (80.0 mg, 1.0 equiv) in MeOH (1.5 mL) was added Pd/C (30 mg, 10% purity, 1.0 equiv) under nitrogen atmosphere. The reaction was degassed and purged with hydrogen several times. The reaction was stirred under hydrogen (15 psi) at 20 C. for 2 hours. The mixture was filtered and concentrated to afford Intermediate 5 peak 1 (58.0 mg, 94% yield) as a white solid; LCMS (ESI, M+1): m/z=144.2. [0254] Intermediate 5 peak 3 and Intermediate 5 peak 4 were obtained using the same procedure as described in Step G Intermediate 6 ##STR00116## 6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepine ##STR00117## [0255] Step A. (E)-benzyl 3-((dimethylamino)methylene)-4-oxoazepane-1-carboxylate: A mixture of benzyl 4-oxoazepane-1-carboxylate (10 g, 1.0 equiv) in DMF-DMA (50 mL) was stirred at 100 C. for 12 hours. The mixture was concentrated to afford the title compound (12.0 g, crude) as a brown oil and used directly in the next step without further purification. [0256] Step B. benzyl 8,9-dihydro-5H-pyrimido[5,4-c]azepine-6(7H)-carboxylate: To a solution of formimidamide (2.46 g, 1.1 equiv, AcOH) in EtOH (70 mL) was added EtONa (4.39 g, 3.0 equiv). The reaction was stirred at 20 C. for 0.5 hour. The (E)-benzyl 3-((dimethylamino)methylene)-4-oxoazepane-1-carboxylate (6.50 g, 1.0 equiv) was added into the mixture. The reaction was stirred at 80 C. for 2 hours. The mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (320 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC (column: Phenomenex Luna C18 20040 mm10 um; mobile phase: [water (FA)-ACN]; B %: 25%-55%, 10 min) to afford the title compound (5.60 mg, 91% yield) as a yellow oil; LCMS (ESI, M+1): m/z=284.0. [0257] Step C. 6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepine: To a solution of benzyl 8,9-dihydro-5H-pyrimido[5,4-c]azepine-6(7H)-carboxylate (300 mg, 1.0 equiv) in MeOH (0.5 mL) was added Pd/C (300 mg, 10% purity) under nitrogen atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The reaction was stirred under H.sub.2 (15 Psi) at 20 C. for 0.5 hour. The mixture was filtered and concentrated to afford the title compound (150 mg, 94% yield) as a yellow oil and used directly in the next step without further purification. Intermediate 7 ##STR00118## 6,7,8,9-tetrahydro-5H-[1,2,3]triazino[5,4-c]azepine ##STR00119## [0258] Step A. tert-butyl 2-amino-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5 (2H)-carboxylate: To a solution of tert-butyl 4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5 (2H)-carboxylate (2.00 g, 1.0 equiv) in DMF (60 mL) was added t-BuONa (4.05 g, 5.0 equiv) at 0 C. in portions. The mixture was stirred at 0 C. for 0.5 hour. Amino hydrogen sulfate (2.86 g, 3.0 equiv) was added to the mixture at 0 C. in portions. The reaction was stirred at 0 C. for 2 hours. The mixture was quenched with water (200 mL) carefully at 0 C. and extracted with ethyl acetate (380 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC (column: Phenomenex luna C18 25050 mm10 m; mobile phase: [water (FA)-ACN]; B %: 14%-44% over 20 min) to afford the title compound (250 mg, 12% yield) as a yellow solid; LCMS (ESI, M55, M+1): m/z=196.8, 252.9. [0259] Step B. tert-butyl 8,9-dihydro-5H-[1,2,3]triazino[5,4-c]azepine-6(7H)-carboxylate: To a solution of tert-butyl 2-amino-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5 (2H)-carboxylate (200 mg, 1.0 equiv) in DCM (3 mL) and H.sub.2O (3 mL) was added NaIO.sub.4 (254 mg, 1.5 equiv). The reaction was stirred at 20 C. for 2 hours. The mixture was quenched with saturated aqueous Na.sub.2S.sub.2O.sub.3 (10 mL) at 0 C. and extracted with DCM (25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography (C18, 0.1% formic acid condition) to afford the title compound (120 mg, 60% yield) as a yellow solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.15-8.94 (m, 1H), 4.48 (br s, 2H), 3.67 (br s, 2H), 3.31-3.27 (m, 2H), 1.90-1.65 (m, 2H), 1.34-1.22 (m, 9H). [0260] Step C. 6,7,8,9-tetrahydro-5H-[1,2,3]triazino[5,4-c]azepine: A solution of tert-butyl 8,9-dihydro-5H-[1,2,3]triazino[5,4-c]azepine-6(7H)-carboxylate (60.0 mg, 1.0 equiv) in HCOOH (1 mL) was stirred at 20 C. for 0.5 hour. The mixture was concentrated to afford the title compound (50 mg, crude) as a yellow oil and used for the next step directly; LCMS (ESI, M+1): m/z=151.2. Intermediate 8 ##STR00120## 4-methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione ##STR00121## [0261] Step A. 1-((benzyloxy)methyl)-1H-pyrrole-2,5-dione: To a solution of pyrrole-2,5-dione (5.00 g, 1.0 equiv) in THF (100 mL) were added DIPEA (20.0 g, 3.0 equiv) and ((chloromethoxy)methyl)benzene (16.1 g, 2.0 equiv) at 0 C. The reaction was stirred at 0 C. for 2 hours. The reaction mixture was quenched by water (100 mL) and extracted with ethyl acetate (3100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 3:1) to afford the title compound (4.00 g, 36% yield) as a white solid; .sup.1H NMR (400 MHZ, chloroform-d) =7.33-7.28 (m, 3H), 7.27-7.19 (m, 2H), 6.66 (s, 2H), 4.98 (s, 2H), 4.54 (s, 2H). [0262] Step B. 5-benzyl-2-((benzyloxy)methyl)-4-methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione: To a solution of 1-((benzyloxy)methyl)-1H-pyrrole-2,5-dione (1.00 g, 1.0 equiv) in THF (100 mL) was added N-benzyl-1-(trimethylsilyl) methanamine (1.78 g, 2.0 equiv) and acetaldehyde (1.01 g, 40% purity, 2.0 equiv). The reaction was stirred at 70 C. for 7 hours. The reaction mixture was concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 0:1) to afford the title compound (225 mg, 13% yield) as a colorless oil; .sup.1H NMR (400 MHZ, chloroform-d) =7.26-7.09 (m, 10H), 4.93 (s, 2H), 4.53 (s, 2H), 3.69-3.64 (m, 1H), 3.33 (d, J=13.2 Hz, 1H), 3.13-3.03 (m, 2H), 3.01-2.94 (m, 1H), 2.81-2.71 (m, 1H), 2.66-2.60 (m, 1H), 1.14 (d, J=6.4 Hz, 3H). [0263] Step C. 4-methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione: To a mixture of 5-benzyl-2-((benzyloxy)methyl)-4-methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (400 mg, 1.0 equiv) in ethanol (8 mL) were added NH.sub.3.Math.MeOH (12 M, 4 mL, 44 equiv) and Pd(OH).sub.2/C (50.0 mg, 10% purity) under N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The reaction was stirred under H.sub.2 (50 Psi) at 50 C. for 24 hours. The reaction mixture was filtered under N.sub.2. The filtrate was concentrated and purified by prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 1%-25% over 15 min] to afford the title compound (159 mg, 94% yield) as a white solid; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =8.20 (br s, 1H), 3.43-3.11 (m, 3H), 3.06-2.61 (m, 3H), 1.15-0.99 (m, 3H). Intermediate 9 ##STR00122## (1R,5S)-3,7-diazabicyclo[3.3.1]nonane-2,4-dione ##STR00123## [0264] Step A. (3S,5R)-1-(tert-butoxycarbonyl)-5-carbamoylpiperidine-3-carboxylic acid: A solution of tert-butyl (1R,5S)-2,4-dioxo-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate (500 mg, 1.96 mmol, 1.00 eq) in NH.sub.3.Math.H.sub.2O (32.5 g, 260 mmol, 35.7 mL, 28.0% purity, 132 eq), was stirred at 80 C. for 4 hrs under N.sub.2 atmosphere. The solvent was removed under reduced pressure to give the crude (3S,5R)-1-(tert-butoxycarbonyl)-5-carbamoylpiperidine-3-carboxylic acid (450 mg, crude) as a white solid. [0265] Step B. tert-butyl (1R,5S)-6,8-dioxo-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate: To a solution of (3S,5R)-1-(tert-butoxycarbonyl)-5-carbamoylpiperidine-3-carboxylic acid (3.30 g, 12.1 mmol, 1.00 eq) in THF (10.0 mL) was added CDI (7.86 g, 48.5 mmol, 4.00 eq). The reaction was stirred at 75 C. for 12 hrs under N.sub.2. The mixture was poured into ice water (20 mL), and then 1 N HCl was added until pH was adjusted to 4. The mixture was extracted with DCM (10.0 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (3V) at 25 C. for 30 min to give product compound 7 (mmol, 14.6% yield) as a white solid. .sup.1H NMR: (400 MHZ, DMSO) 10.9 (s, 1H), 4.12-4.10 (m, 2H), 3.07-3.04 (m, 2H), 2.62 (s, 2H), 3.30-2.27 (m, 1H), 1.87-1.83 (m, 1H), 1.34 (s, 9H). [0266] Step C. (1R,5S)-3,7-diazabicyclo[3.3.1]nonane-2,4-dione: To a solution of tert-butyl (1R,5S)-6,8-dioxo-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (250 mg, 983 mol, 1.00 eq) in DCM (2.50 mL) was added TFA (673 mg, 5.90 mmol, 437 L, 6.00 eq) at 0 C. The reaction was stirred at 20 C. for 5 hrs. The mixture was concentrated in vacuum. The crude product was triturated with EtOAc (10.0 ml) at 25 C. for 40 min to give (140 mg, 889 mol, 90.4% yield, 98.0% purity) as a white solid. LCMS (ESI, M+1): m/z=155.1 (M+H).sup.+ Intermediate 10 ##STR00124## (R)-6-(methoxymethyl)-6-methyl-1,4-oxazepane ##STR00125## [0267] Step A. (R)-benzyl 6-(hydroxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate: A mixture of [(6R)-6-methyl-1,4-oxazepan-6-yl]methanol (300 mg, 1.0 equiv), CbzCl (881 mg, 2.5 equiv), K.sub.2CO.sub.3 (857 mg, 3.0 equiv) in EtOAc (4 mL) and H.sub.2O (4 mL) was stirred at 28 C. for 5 hours. The mixture was extracted with EtOAc 15 mL (5 mL3), washed with brine, dried over Na.sub.2SO.sub.4, filtered and purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate 20:1 to 3:1) and lyophilized to afford the title compound (300 mg, 44% yield) as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =7.44-7.26 (m, 5H), 5.16-5.11 (m, 2H), 3.80-3.68 (m, 2H), 3.65-3.57 (m, 2H), 3.56-3.50 (m, 1H), 3.46-3.42 (m, 1H), 3.42-3.36 (m, 2H), 3.36-3.32 (m, 1H), 3.32-3.28 (m, 2H), 0.89-0.83 (m, 3H) LCMS (ESI, M+1): m/z=280.2. [0268] Step B. (R)-benzyl 6-(methoxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate: To a solution of benzyl (6R)-6-(hydroxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate (300 mg, 1.0 equiv) in THF (8 mL) was added NaH (85.9 mg, 60% purity, 2.0 equiv) at 0 C. The mixture was stirred for 0.5 hour, then CH.sub.3I (305 mg, 2.0 equiv) was added dropwise and the mixture was stirred at 0 C. for 2 hours. The mixture was quenched by H.sub.2O (3 mL) at 0 C., filtered and purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate 10:1 to 3:1) to afford the title compound (100 mg, 27% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =7.44-7.26 (m, 5H), 5.20-5.08 (m, 2H), 3.77-3.69 (m, 3H), 3.63-3.51 (m, 5H), 3.38-3.32 (m, 2H), 3.21-3.16 (m, 2H), 3.16-3.09 (m, 1H), 0.87 (br d, J=18.0 Hz, 3H) LCMS (ESI, M+1): m/z=294.1 [0269] Step C. (R)-6-(methoxymethyl)-6-methyl-1,4-oxazepane: A mixture of benzyl (6R)-6-(methoxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate (50 mg, 1.0 equiv), Pd/C (10 mg, 0.1 equiv) in MeOH (5 mL) was degassed and purged with H.sub.2 for 3 times, and then the mixture was stirred at 20 C. for 2 hours under H.sub.2 atmosphere (15 psi). The mixture was filtered and concentrated under reduced pressure to afford the title (20 mg, 74% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =3.70-3.40 (m, 5H), 3.34 (s, 3H), 3.18 (br s, 2H), 3.06-2.35 (m, 4H), 0.95-0.88 (m, 3H) Intermediate 11 ##STR00126## 3-(aminomethyl)-3-methyl-1,2,5-thiadiazolidine 1,1-dioxide ##STR00127## [0270] Step A. tert-butyl (2-amino-2-cyanopropyl)carbamate: To a solution of tert-butyl (2-oxopropyl)carbamate (1.00 g, 1.0 equiv) in MeOH (10 mL) were added Ti(i-PrO).sub.4 (1.64 g, 1.0 equiv) and NH.sub.3.Math.MeOH (7.00 M, 2.0 equiv). TMSCN (1.15 g, 2.0 equiv) was added dropwise to the resulting mixture at 0 C. The reaction was stirred at 25 C. for 16 hours. The mixture was diluted with water (50 mL), filtered and extracted with ethyl acetate (3100 mL). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by flash silica gel chromatography (0-100% ethyl acetate/petroleum ether) to afford the title compound (800 mg, 69% yield) as a white solid; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d6) =7.16 (br t, J=5.6 Hz, 1H), 3.10 (br d, J=6.0 Hz, 2H), 2.56 (s, 2H), 1.39 (s, 9H), 1.28 (s, 3H). [0271] Step B. tert-butyl (2,3-diamino-2-methylpropyl)carbamate: To a mixture of tert-butyl (2-amino-2-cyanopropyl)carbamate (200 mg, 1.0 equiv) and in MeOH (2 mL) and NH.sub.3.Math.MeOH (0.5 mL) was added Raney-Ni (257 mg, 3.0 equiv). The reaction was degassed and purged with hydrogen for 3 times. The reaction was stirred at 25 C. for 5 hours under hydrogen (15 psi) atmosphere. The mixture was filtered and concentrated to afford the title compound (80.0 mg, crude) as a yellow oil. [0272] Step C. tert-butyl ((3-methyl-1,1-dioxido-1,2,5-thiadiazolidin-3-yl)methyl)carbamate: To a solution of tert-butyl (2,3-diamino-2-methylpropyl)carbamate (80.0 mg, 1.0 equiv) in pyridine (3 mL) was added a solution of sulfamide (37.8 mg, 1.0 equiv) in pyridine (3 mL) dropwise at 25 C. The reaction was stirred at 115 C. for 20 hours. The mixture was filtered, concentrated, and purified by prep-TLC (dichloromethane/methanol 10:1) to afforded title compound (50 mg, 19% yield) as a yellow oil; 1H NMR (400 MHZ, dimethylsulfoxide-d6) =7.06 (br t, J=7.2 Hz, 1H), 6.92 (br t, J=5.6 Hz, 1H), 6.76 (s, 1H), 3.22 (br dd, J=7.6, 11.6 Hz, 1H), 3.15-3.08 (m, 1H), 3.06-2.97 (m, 1H), 2.96-2.88 (m, 1H), 1.38 (s, 9H), 1.16 (s, 3H). [0273] Step D. 3-(aminomethyl)-3-methyl-1.2.5 thiadiazolidine 1,1-dioxide: To a solution of tert-butyl ((3-methyl-1,1-dioxido-1,2,5-thiadiazolidin-3-yl)methyl)carbamate (40 mg, 1.0 equiv) in dichloromethane (0.5 mL) was added dropwise HCl.Math.dioxane (4 M, 1 mL 1.0 equiv) at 0 C. The reaction was stirred at 25 C. for 1 hour. The mixture was concentrated to afford the title compound (30.0 mg, crude, HCl) as a brown solid. Intermediate 12 ##STR00128## (3aR,8aS)-hexahydropyrrolo[3,4-d]azepine-1,3(2H,3aH)-dione ##STR00129## [0274] Step A. (3aR,8aS)-tert-butyl 2-(2,4-dimethoxybenzyl)-1,3-dioxooctahydropyrrolo[3,4-d]azepine-6 (2H)-carboxylate: To a solution of 1-tert-butoxycarbonylazepane-4,5-dicarboxylic acid (500, 1.0 equiv) in MeCN (5 mL) was added di(1H-imidazol-1-yl) methanone (564 mg, 2.0 equiv) at 20 C. After addition, the mixture was stirred at 50 C. for 1 hour, and (2,4-dimethoxyphenyl) methanamine (291 mg, 1.0 equiv) was added at 20 C. The resulting mixture was stirred at 90 C. for 18 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 1:1) to afford the title compound (500 mg, 69% yield) as a colorless oil; LCMS (ESI, M55): m/z=419.2 [0275] Step B. (3aR,8aS)-tert-butyl 1,3-dioxooctahydropyrrolo[3,4-d]azepine-6 (2H)-carboxylate: To a solution of tert-butyl (3aR,8aS)-2-[(2,4-dimethoxyphenyl)methyl]-1,3-dioxo-3a,4,5,7,8,8a-hexahydropyrrolo[3,4-d]azepine-6-carboxylate (100 mg, 1.0 equiv) in ACN (5 mL) was added CAN (262 mg, 2.0 equiv) in water (0.5 mL) at 0 C. Then the mixture was stirred at 20 C. for 0.5 hour. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (10 mL2). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO.sub.2, petroleum ether/ethyl acetate 1:1) to afford the title compound (25 mg, 39% yield) as a colorless oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.07 (br s, 1H), 3.82-3.66 (m, 1H), 3.61-3.48 (m, 1H), 3.47-3.36 (m, 1H), 3.30 (ddd, J=6.0, 8.0, 14.2 Hz, 1H), 2.76-2.59 (m, 2H), 2.56-2.35 (m, 2H), 1.76-1.62 (m, 2H), 1.50-1.42 (m, 9H). [0276] Step C. (3aR,8aS)-hexahydropyrrolo[3,4-d]azepine-1,3(2H,3aH)-dione: To a solution of tert-butyl (3aR,8aS)-1,3-dioxo-3a,4,5,7,8,8a-hexahydropyrrolo[3,4-d]azepine-6-carboxylate (25 mg, 1.0 equiv) in DCM (1.5 mL) was added trifluoroacetic acid (770 mg, 72.5 equiv). The mixture was stirred at 20 C. for 0.5 hour. The mixture was concentrated under reduced pressure to afford the title compound (25 mg, 95% yield, TFA) as a white solid. The crude product was used for the next step without further purification; LCMS (ESI, M+1): m/z=169.2 Intermediate 13A ##STR00130## (1S,3aS,6aR)-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxamide ##STR00131## [0277] Step A. (2S)-1-tert-butyl 2-ethyl 5-oxo-4-(phenylselanyl)pyrrolidine-1,2-dicarboxylate: To a solution of(S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (2.00 g, 1.0 equiv) in THF (40 mL) was added LiHMDS (1 M, 8.55 mL, 1.1 equiv) dropwise at 78 C. The mixture was stirred at 78 C. for 1 hour under N.sub.2 atmosphere. Then a solution of phenyl hypobromoselenoite (2.20 g, 1.2 equiv) in THF (10 mL) was added dropwise to the mixture at 78 C. The mixture was stirred at 78 C. for 2 hours under N.sub.2 atmosphere. The reaction mixture was quenched with ammonium chloride saturated aqueous solution (50 mL) at 78 C. and extracted with ethyl acetate (20 mL3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase MPLC [C18, 0.1% formic acid condition] to afford the title compound (0.80 g, 25% yield) as a yellow oil. 1H NMR (400 MHZ, CHLOROFORM-d) =7.64 (dd, J=1.2, 8.0 Hz, 2H), 7.35-7.25 (m, 3H), 4.22 (dd, J=5.0, 8.6 Hz, 1H), 4.15 (d, J=7.2 Hz, 2H), 3.98 (dd, J=8.0, 8.6 Hz, 1H), 2.38 (dd, J=7.2, 8.2 Hz, 2H), 1.45-1.43 (m, 9H), 1.22 (t, J=7.2 Hz, 4H). [0278] Step B: (S)-1-tert-butyl 2-ethyl 5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate: To a solution of (2S)-1-tert-butyl 2-ethyl 5-oxo-4-(phenylselanyl)pyrrolidine-1,2-dicarboxylate (2.00 g, 1.0 equiv) in THF (40 mL) was added H2O2 (1.15 g, 30% purity, 2.1 equiv) slowly dropwise. The resulting mixture was stirred at 35 C. for 2 hours. The reaction mixture was quenched with sodium bicarbonate saturated aqueous solution (50 mL) and extracted with ethyl acetate (50 mL3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase MPLC [C18, 0.1% formic acid condition] to afford the title compound (720 mg, 58% yield) as a brown oil. 1H NMR (400 MHZ, CHLOROFORM-d) =7.09 (dd, J=2.4, 6.0 Hz, 1H), 6.24 (dd, J=2.0, 6.0 Hz, 1H), 5.16 (t, J=2.2 Hz, 1H), 4.26 (dq, J=1.2, 7.2 Hz, 2H), 1.53 (s, 9H), 1.31 (t, J=7.2 Hz, 3H). [0279] Step C. (1S,3aS,6aR)-2-tert-butyl 1-ethyl 5-benzyl-3-oxohexahydropyrrolo[3,4-c]pyrrole-1,2(1H)-dicarboxylate: To a solution of (S)-1-tert-butyl 2-ethyl 5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (450 mg, 1.0 equiv) in DCM (3 mL) was added a solution of TFA (80.4 mg, 0.4 equiv) DCM in (5 mL). Then N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl) methanamine (1.26 g, 3.0 equiv) in DCM (2 mL) was added dropwise to the mixture at 0 C. The resulting mixture was allowed to warm to 25 C. and stirred at 25 C. for 3 hours. The reaction mixture was quenched with sodium bicarbonate saturated aqueous solution (50 mL) and extracted with ethyl acetate (50 mL3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase MPLC [C18, 0.1% formic acid condition] to afford the title compound (460 mg, 67% yield). 1H NMR (400 MHZ, METHANOL-d4) =7.34-7.23 (m, 5H), 4.37 (d, J=2.4 Hz, 1H), 4.29-4.19 (m, 2H), 3.69-3.52 (m, 2H), 3.18-3.08 (m, 2H), 2.94 (br d, J=10.0 Hz, 1H), 2.80-2.71 (m, 1H), 2.60 (dd, J=7.8, 9.6 Hz, 1H), 2.48-2.38 (m, 1H), 1.48 (s, 9H), 1.29 (t, J=7.2 Hz, 3H). [0280] Step D. (1S,3aS,6aR)-ethyl 5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate: To a solution of (1S,3aS,6aR)-2-tert-butyl 1-ethyl 5-benzyl-3-oxohexahydropyrrolo[3,4-c]pyrrole-1,2(1H)-dicarboxylate (300 mg, 1.0 equiv) in EtOAc (2 mL) was added HCl/dioxane (4 M, 10 mL, 51.8 equiv). The mixture was stirred at 25 C. for 1 hour. The reaction mixture was concentrated under reduced pressure to afford the title compound (220 mg, 99% yield) as a white solid; LCMS (ESI, M+1): m/z=289.0. [0281] Step E. (1S,3aS,6aR)-5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylic acid: To a solution of (1S,3aS,6aR)-ethyl 5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (220 mg, 1.0 equiv) in MeOH (9 mL) was added NaOH aqueous solution (1 M, 3.05 mL, 4.0 equiv). The mixture was stirred at 40 C. for 1 hour. The reaction mixture was poured into water (10 mL) and then pH of the mixture was adjusted to 5 with formic acid. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (110 mg, 55% yield) as a white solid. 1H NMR (400 MHZ, METHANOL-d4) =7.45-7.37 (m, 5H), 4.06 (s, 2H), 3.89 (d, J=2.2 Hz, 1H), 3.07 (s, 6H); LCMS (ESI, M+1): m/z=261.0. [0282] Step F. (1S,3aS,6aR)-5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxamide: To a mixture of (1S,3aS,6aR)-5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylic acid (90.0 mg, 1.0 equiv, FA salt) and NH.sub.4Cl (47.2 mg, 3.0 equiv) in DMAc (1 mL) was added PYBROP (164 mg, 1.2 equiv) and TEA (89.2 mg, 3.0 equiv), then the mixture was stirred at 40 C. for 12 hours under N.sub.2 atmosphere. MeOH (1 mL) was added into the mixture. The mixture was directly purified by prep-HPLC [C18, 0.1% NH3.Math.H2O condition] to afford the title compound (21.0 mg, 28% yield). 1H NMR (400 MHZ, CHLOROFORM-d) =7.53-7.28 (m, 5H), 6.56 (br s, 1H), 6.29 (br s, 1H), 5.75-5.48 (m, 1H), 3.88 (s, 1H), 3.70 (br d, J=13.0 Hz, 1H), 3.64-3.48 (m, 1H), 3.22 (br d, J=9.2 Hz, 1H), 3.06-2.86 (m, 3H), 2.61-2.38 (m, 2H). [0283] Step G. (1S,3aS,6aR)-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxamide: To a solution of (1S,3aS,6aR)-5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxamide (21.0 mg, 1.0 equiv) in MeOH (0.5 mL) was added Pd/C (10.0 mg, 10% purity) under N.sub.2 atmosphere. The suspension was degassed under vacuum and purged with H.sub.2 several times. The mixture was stirred at 40 C. for 12 hours under H2 (15 Psi) atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to afford the tittle compound (9.79 mg, crude), which was used directly in next step. Intermediate 13B ##STR00132## (1R,3aS,6aR)-tert-butyl 1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate ##STR00133## [0284] Step A. (S)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one: To a mixture of (5S)-5-(hydroxymethyl)pyrrolidin-2-one (10.0 g, 1.0 equiv) and imidazole (8.80 g, 1.5 equiv) in dichloromethane (100 mL) was added tert-butyldimethylsilyl chloride (15.7 g, 1.2 equiv) portionwise at 0-5 C. After completing the addition, the resulting mixture was allowed to warm to 25-30 C. and stirred for 12 hours. The mixture was diluted with water (150 mL) and separated. The aqueous phase was extracted with dichloromethane (250 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by flash silica gel chromatography [50-100% Ethyl acetate/Petroleum ether] to afford the title compound (17.5 g, 83% yield) as a colorless liquid; 1H NMR (400 MHZ, CDCl3-d4) =5.98 (br s, 1H), 3.81-3.71 (m, 1H), 3.62 (dd, J=4.0, 10.0 Hz, 1H), 3.44 (dd, J=7.6, 10.0 Hz, 1H), 2.40-2.30 (m, 2H), 2.22-2.11 (m, 1H), 1.81-1.69 (m, 1H), 0.88 (s, 9H), 0.06 (s, 6H); LCMS (ESI, M+1): m/z=230.2. [0285] Step B. tert-butyl(S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxopyrrolidine-1-carboxylate: To a solution of (5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-one (2.0 g, 1.0 equiv) in dichloromethane (20 mL) was added tert-butyldicarbonate (2.8 g. 1.5 equiv), triethylamine (1.7 g, 2.0 equiv) and 4-dimethylaminopyridine (106 mg, 0.1 equiv). The resulting mixture was stirred at 25 C. for 12 hours. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography [ISCOR; 80 g SepaFlash Silica Flash Column, Eluent of 20% Ethyl acetate/Petroleum ethergradient@100 mL/min] to afford the title compound (2.25 g, 78% yield) as a colorless oil; 1H NMR (400 MHZ, CDCl3-d4) =4.22-4.13 (m, 1H), 3.92 (dd, J=4.0, 10.4 Hz, 1H), 3.69 (dd, J=2.0, 10.4 Hz, 1H), 2.78-2.64 (m, 1H), 2.38 (ddd, J=2.0, 9.6, 17.6 Hz, 1H), 2.16-1.96 (m, 2H), 1.54 (s, 9H), 0.88 (s, 9H), 0.04 (d, J=5.2 Hz, 6H). [0286] Step C. tert-butyl (5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxo-3-(phenylselanyl)pyrrolidine-1-carboxylate: To a solution of tert-butyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-oxo-pyrrolidine-1-carboxylate (1.0 g, 1.0 equiv) in tetrahydrofuran (25 mL) was added lithium hexamethyldisilazide (1 M, 3.3 mL, 1.1 equiv) dropwise at 60 C. under nitrogen. The solution was stirred at 60 C. for 0.5 hour and then a solution of phenyl selenohypochlorite (1.0 g, 1.75 equiv) in tetrahydrofuran (5.0 mL) was added at 60 C. The resulting mixture was stirred at 60 C. for additional 1 hour and then warmed to 25 C. and stirred at 25 C. for 12 hours. The mixture was quenched by saturated ammonium chloride (40 mL) at 0-5 C. under nitrogen, and allowed to warm to 25 C. stirred for 0.5 hour. The mixture was extracted with ethyl acetate (325 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered concentrated and purified with flash silica gel chromatography [10-15% Ethyl acetate/Petroleum ether] to afford the title compound (740 mg, 50% yield) as a yellow oil. [0287] Step D. tert-butyl(S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate: To a solution of tert-butyl (5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-oxo-3-phenylselanyl-pyrrolidine-1-carboxylate (740 mg, 1.0 equiv) in dichloromethane (10.0 mL) was added pyridine (362 mg, 3.0 equiv) at 70 C., followed by slowly addition of hydrogen peroxide (606 mg, 30% purity, 3.5 equiv). The resulting mixture was allowed to warm to 25 C. and stirred at 25 C. for 12 hours. The mixture was diluted with water (20 mL) and extracted with dichloromethane (210 mL). The combined organic layers were washed with saturated sodium sulfite and brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography [10-15% Ethyl acetate/Petroleum] to afford the title compound (230 mg, 34% yield) as a colorless oil. [0288] Step E. tert-butyl (1S,3aS,6aR)-5-benzyl-1-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solution of tert-butyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-oxo-2H-pyrrole-1-carboxylate (180 mg, 1.0 equiv) and N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl) methanamine (391 mg, 3.0 equiv) in dichloromethane (5.0 mL) was added TFA (25 mg, 0.4 equiv) at 0 C. After addition, the resulting mixture was stirred at 25 C. for 12 hours. Another batch of N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl) methanamine (391 mg, 3.0 equiv) was added, followed by TFA (25 mg, 0.4 equiv). The resulting mixture was stirred at 25 C. for another 12 hours. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC [3_Phenomenex Luna C18 7530 mm3 um; A: water (HCl), B: CH3CN, B %: 39%-59% over 6 min], followed by lyophilization. The title compound (102 mg, 37% yield) was obtained as a yellow solid; LCMS (ESI, M+1): m/z=461.4. [0289] Step F. (1S,3aS,6aR)-tert-butyl 5-benzyl-1-(hydroxymethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: A mixture of (1S,3aS,6aR)-tert-butyl 5-benzyl-1-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10 g, 1.0 equiv) and 4-methylbenzenesulfonic acid; hydrate (4.54 g, 1.1 uiv eq) in THF (120 mL) was stirred at 30 C. for 16 hours. The mixture was concentrated and purified by Prep-HPLC (column: Kromasil Eternity XT 250*80 mm*10 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 30%-60%, 16 min) to afford the title compound (6.2 g, 80% yield) as white solid; LCMS (ESI, M+1): m/z=347.1. [0290] Step G. tert-butyl (1R,3aS,6aR)-5-benzyl-1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solution of tert-butyl (3aS,6S,6aR)-2-benzyl-6-(hydroxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (1.00 g, 1.0 equiv) in THF (10 mL) were added 2-hydroxy-2-methyl-propanenitrile (737 mg, 1.0 equiv) and tributylphosphine (2.04 g, 3.5 equiv). Then ADDP (2.55 g, 3.5 equiv) was added to the mixture at 0 C. The mixture was stirred at 50 C. for 2 hours. The reaction mixture was poured into saturated NH.sub.4Cl aqueous solution (50 mL) and extracted with EtOAc (20 mL3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (060% ethyl acetate/petroleum ether) and concentrated under vacuum to afford the title compound (600 mg, 58% yield) as a yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.32-7.23 (m, 5H), 7.13-7.13 (m, 1H), 4.07 (ddd, J=2.1, 4.0, 6.1 Hz, 1H), 3.67 (d, J=13.2 Hz, 1H), 3.50 (d, J=13.2 Hz, 1H), 3.25-3.18 (m, 2H), 2.90-2.80 (m, 2H), 2.77 (dd, J=2.0, 9.2 Hz, 1H), 2.64 (br d, J=8.8 Hz, 1H), 2.61-2.52 (m, 2H), 1.57 (s, 9H) [0291] Step H. (1R,3aS,6aR)-tert-butyl 1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solution of (1R,3aS,6aR)-tert-butyl 5-benzyl-1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (70.0 mg, 1.0 equiv) in MeOH (2 mL) was added Pd/C (50.0 mg, 5% purity, wet). The suspension was degassed and purged with H.sub.2 for three times. The mixture was stirred under hydrogen atmosphere (15 Psi) at 25 C. for 16 hours. The reaction mixture was filtered and concentrated to afford the title compound (50.0 mg, 96% yield) as a yellow oil; [0292] Step I. (1S,3aS,6aR)-tert-butyl 5-benzyl-1-(hydroxymethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solution of (1S,3aS,6aR)-tert-butyl 5-benzyl-1-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10.0 g, 1.0 equiv) in THF (120 mL) was added 4-methylbenzenesulfonic acid; hydrate (4.54 g, 1.1 equiv). The mixture was stirred at 45 C. for 5 hours. The mixture was concentrated and purified with prep-HPLC [column: Kromasil Eternity XT 25080 mm10 um; mobile phase: water (ammonia hydroxide v/v)-CAN; B %: 30%-60%, 16 min] to afford the title compound as a white solid (6.20 g, 80% yield); 1H NMR (400 MHZ, CHLOROFORM-d) =7.27 (br s, 5H), 3.96 (br s, 1H), 3.84 (dd, J=3.6, 11.2 Hz, 1H), 3.73-3.61 (m, 2H), 3.56-3.48 (m, 1H), 3.18-3.11 (m, 1H), 3.07 (dd, J=2.4, 9.6 Hz, 1H), 2.65-2.59 (m, 2H), 1.55 (s, 9H); LCMS (ESI, M+1): m/z=347.2. Intermediate 13C ##STR00134## 2-((1R,3aS,6aR)-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetamide ##STR00135## [0293] Step A. tert-butyl (1R,3aS,6aR)-5-benzyl-1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solution of tert-butyl (3aS,6S,6aR)-2-benzyl-6-(hydroxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (1.00 g, 1.0 equiv) in THF (10 mL) were added 2-hydroxy-2-methyl-propanenitrile (737 mg, 1.0 equiv) and tributylphosphane (2.04 g, 3.5 equiv). Then ADDP (2.55 g, 3.5 equiv) was added to the mixture at 0 C. The mixture was stirred at 50 C. for 2 hours. The reaction mixture was poured into saturated NH.sub.4Cl aqueous solution (50 mL) and extracted with EtOAc (20 mL3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (060% ethyl acetate/petroleum ether) and concentrated under vacuum to afford the title compound (600 mg, 58% yield) as a yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.32-7.23 (m, 5H), 7.13-7.13 (m, 1H), 4.07 (ddd, J=2.1, 4.0, 6.1 Hz, 1H), 3.67 (d, J=13.2 Hz, 1H), 3.50 (d, J=13.2 Hz, 1H), 3.25-3.18 (m, 2H), 2.90-2.80 (m, 2H), 2.77 (dd, J=2.0, 9.2 Hz, 1H), 2.64 (br d, J=8.8 Hz, 1H), 2.61-2.52 (m, 2H), 1.57 (s, 9H) [0294] Step B. tert-butyl (1R,3aS,6aR)-1-(2-amino-2-oxoethyl)-5-benzyl-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solution of tert-butyl (3aS,6aR)-2-benzyl-6-(cyanomethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (500 mg, 79.7% purity, 1.0 equiv) in EtOH (9 mL) and H.sub.2O (1 mL) was added dimethylphosphinite dimethylphosphinous acid platinum (2+) (479 mg, 1.0 equiv). The mixture was stirred at 60 C. for 2 hours. The reaction mixture was filtered, concentrated and purified by reversed phase flash chromatography (C18, 0.1% ammonium hydroxide) to afford the title compound (420 mg, 90% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =7.37-7.28 (m, 5H), 4.23 (dd, J=2.8, 8.0 Hz, 1H), 3.67-3.53 (m, 2H), 3.29-3.23 (m, 1H), 2.95 (br d, J=9.6 Hz, 1H), 2.82-2.56 (m, 6H), 1.52 (s, 9H) [0295] Step C. 2-((1R,3aS,6aR)-5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetamide: To a solution of tert-butyl (3aS,6aR)-6-(2-amino-2-oxo-ethyl)-2-benzyl-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (100 mg, 90.2% purity, 1.0 equiv) in MeOH (1 mL) was added HCl/dioxane (4 M, 3 mL, 49.7 equiv). The mixture was stirred at 20 C. for 0.5 hour. The reaction mixture was concentrated under reduced pressure to afford the title compound (70.0 mg, 93% yield, HCl) as a white solid. [0296] Step D. 2-((1R,3aS,6aR)-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetamide: To a solution of 2-((1R,3aS,6aR)-5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetamide (50.0 mg, 1.0 equiv, HCl) in MeOH (2 mL) was added Pd/C (50.0 mg, 5% purity, wet). The suspension was degassed and purged with H.sub.2 for three times. The mixture was stirred under H.sub.2 atmosphere (15 Psi) at 25 C. for 2 hours. The reaction mixture was filtered and concentrated to afford the title compound (40.0 mg, crude, HCl) as a white solid. Intermediate 13D ##STR00136## 1-[(3aS,6S,6aR)-4-oxo-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-6-yl]methanesulfonamide ##STR00137## [0297] Step A. tert-butyl (3aS,6S,6aR)-2-benzyl-6-(methylsulfonyloxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate: To a solution of tert-butyl (3aS,6S,6aR)-2-benzyl-6-(hydroxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (1.20 g, 1.0 equiv) and Ms.sub.2O (1.81 g, 3.0 equiv) in DCM (10 mL) was added TEA (1.75 g, 5.0 equiv) and DMAP (4.23 mg, 0.01 equiv) at 0 C. The mixture was stirred at 25 C. for 2 hours. The mixture was diluted with H.sub.2O (20 mL) and was extracted with DCM (25 mL2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (1030% EtOAc/PE) to afford the title compound (1.30 g, 79% yield) as a yellow oil; LCMS (ESI, M+1): m/z=425.2 [0298] Step B. tert-butyl (3aS,6S,6aR)-6-(acetylsulfanylmethyl)-2-benzyl-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate: To a solution of tert-butyl (3aS,6S,6aR)-2-benzyl-6-(methylsulfonyloxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (1.30 g, 1.0 equiv) and TEA (1.55 g, 5.0 equiv) in DMF (10 mL) was added ethanethioic S-acid (699 mg, 3.0 equiv) at 0 C. The mixture was stirred at 25 C. for 2 hours. The mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (25 mL2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (1030% EtOAc/PE) to afford the title compound (1.10 g, 88% yield) as a yellow oil; LCMS (ESI, M+1): m/z=405.2 [0299] Step C. 1-[(1S,3aS,6aR)-5-benzyl-3-oxo-1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-1-yl]methanesulfonamide); To a solution of NCS (495 mg, 5.0 equiv) in ACN (18 mL) and HCl (2 M, 0.5 mL, 1.5 equiv) was added dropwise a solution of tert-butyl (3aS,6S,6aR)-6-(acetylsulfanylmethyl)-2-benzyl-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (300 mg, 1.0 equiv) in ACN (12 mL) at 0 C. The mixture was stirred at 25 C. for 1 hour. Then NH.sub.3.Math.H.sub.2O (18 mL) was added and the resulting mixture was stirred at 25 C. for 12 hours. The mixture was concentrated. The crude was purified by prep-HPLC [Phenomenex Synergi Polar-RP 10025 mm4 um; A: water (TFA), B: ACN, B %: 18%-38% over 7 min] and lyophilized to afford the title compound (100 mg, 32% yield, TFA) as a white solid; LCMS (ESI, M+1): m/z=310.1 [0300] Step D. 1-[(3aS,6S,6aR)-4-oxo-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-6-yl]methanesulfonamide: To a solution of 1-[(1S,3aS,6aR)-5-benzyl-3-oxo-1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-1-yl]methanesulfonamide (100 mg, 1.0 equiv, TFA) in MeOH (2 mL) was added Pd/C (50.0 mg, 10% purity, wet). The mixture was stirred at 25 C. under H.sub.2 atmosphere for 2 hours. The mixture was filtered to remove the insoluble material. The filtrate was concentrated to afford the title compound (70.0 mg, 89% yield, TFA) as a white solid; LCMS (ESI, M+1): m/z=220.1. Intermediate 14 ##STR00138## azepan-3-yldimethylphosphine oxide ##STR00139## [0301] Step A. tert-butyl 6-(((trifluoromethyl) sulfonyl)oxy)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate: To a solution of tert-butyl 3-oxoazepane-1-carboxylate (5 g, 1.0 equiv) in THF (15 mL) was slowly added LiHMDS (1.0 M, 28.1 mL, 1.2 equiv) at 78 C., and the resulting mixture was stirred at 78 C. for 1 hour. The reaction mixture was concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=1/0 to 10/1) to afford the title compound (6.6 g, 78% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.14-6.79 (m, 1H), 3.70 (br t, J=5.6 Hz, 2H), 2.65-2.55 (m, 2H), 1.92-1.75 (m, 4H), 1.50 (s, 9H). [0302] Step B. tert-butyl 6-(dimethylphosphoryl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate: A mixture of tert-butyl 6-(((trifluoromethyl) sulfonyl)oxy)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (500 mg, 1.0 equiv), methylphosphonoylmethane (136 mg, 1.2 equiv), TEA (220 mg, 302 L, 1.5 equiv) and Pd(PPh.sub.3).sub.4 (50.2 mg, 0.03 equiv) in ACN (5 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 90 C. for 3 hours under N.sub.2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated and purified by prep-HPLC [C18, 0.1% TFA condition] to afford the title compound (180 mg, 43.1% yield, 94.8% purity) as a yellow gum. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.37 (d, J=16.0 Hz, 1H), 3.80 (br s, 2H), 2.33 (br d, J=4.0 Hz, 2H), 1.88 (br s, 4H), 1.64 (d, J=12.8 Hz, 6H), 1.51 (s, 9H); LCMS (ESI, M+1): m/z=274.3. [0303] Step C. tert-butyl 3-(dimethylphosphoryl)azepane-1-carboxylate: To a solution of tert-butyl 6-(dimethylphosphoryl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (180 mg, 1.0 equiv) in MeOH (2 mL) was added Pd/C (10%, 20 mg) under N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The mixture was stirred under H.sub.2 (15 Psi) at 25 C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound (160 mg) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =4.02-3.85 (m, 1H), 3.33-3.24 (m, 1H), 3.21-3.06 (m, 1H), 2.58-2.28 (m, 4H), 2.19-1.89 (m, 4H), 1.64-1.57 (m, 6H), 1.49-1.44 (m, 9H). [0304] Step D. azepan-3-yldimethylphosphine oxide: To a solution of tert-butyl 3-(dimethylphosphoryl)azepane-1-carboxylate (160 mg, 1.0 equiv) in DCM (1.0 mL) was added HCl/dioxane (4 M, 1 mL, 6.9 equiv). The mixture was stirred at 25 C. for 2 hours. The reaction mixture was concentrated under reduce pressure to afford the title compound (120 mg, HCl salt) as a yellow oil. Intermediate 15 ##STR00140## 3-amino-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide Intermediate 15A ##STR00141## 5-amino-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide ##STR00142## [0305] Step A. 3-amino-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a mixture of 3-amino-1H-pyrazole-4-carbonitrile (10.0 g, 1.0 equiv), DIPEA (35.9 g, 3.0 equiv) in THF (200 mL) was added DMAP (2.26 g, 0.2 equiv) and dimethylcarbamic chloride (14.9 g, 1.5 equiv). The reaction was stirred at 60 C. for 12 hours. The mixture was quenched with water (100 ml) and extracted with EtOAc (3100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified with silica gel chromatography (petroleum ether/ethyl acetate 1:0 to 0:1) to afford Intermediate 15 (5.40 g, 32% yield) as white solid; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =8.62 (s, 1H), 5.99 (s, 2H), 3.07 (br s, 6H); LCMS (ESI, M1): m/z=178.1, and Intermediate 15A (4.44 g, 26% yield) as light pink solid; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =7.76 (s, 1H), 7.19 (s, 2H), 3.02 (s, 6H). Intermediate 16 ##STR00143## (4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocin-2-yl)(morpholino)methanone ##STR00144## [0306] Step A: tert-butyl 2-(morpholine-4-carbonyl)-6,7,8,9-tetrahydropyrazolo[1,5-a][1,4]diazocine-5(4H)-carboxylate: To a solution of 5-tert-butoxycarbonyl-6,7,8,9-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazocine-2-carboxylic acid (50.0 mg, 1.00 equiv) in DMF (1.00 mL) were added morpholine (14.8 mg, 1.00 equiv), HATU (193 mg, 3.00 equiv) and DIPEA (219 mg, 10.0 equiv). The mixture was stirred at 20 C. for 1 hour. After the reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL2). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified with prep-TLC [SiO.sub.2, PE/EA=0/1] to afford the title compound (25.0 mg, 40% yield, 99% purity) as a brown oil; .sup.1H NMR (400 MHZ, CDCl.sub.3) =6.57 (s, 1H), 4.69-4.50 (m, 2H), 4.31 (br s, 2H), 4.05 (br d, J=18.8 Hz, 2H), 3.76 (br s, 4H), 3.70 (br s, 2H), 3.48-3.24 (m, 2H), 1.89 (br s, 2H), 1.69-1.57 (m, 2H), 1.47 (s, 9H). LCMS (ESI, M+1): m/z=365.2 [0307] Step B: (4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocin-2-yl)(morpholino)methanone: A solution of tert-butyl 2-(morpholine-4-carbonyl)-6,7,8,9-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazocine-5-carboxylate (240 mg, 1.00 equiv) in MeCN (5.00 mL) and HCl/dioxane (4 M, 5.00 mL, 30.37 equiv) was stirred at 20 C. for 1 hour. The reaction mixture was concentrated under reduced pressure to remove solvent and afford the title compound (330 mg, crude) as a colorless oil. LCMS (ESI, M+1): m/z=265.1 Intermediate 16A ##STR00145## N,N-dimethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide Intermediate 16B ##STR00146## N-ethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide [0308] Intermediates 16A and 16B were synthesized following the 2-step procedure described for Intermediate 16. Intermediate 17 ##STR00147## 2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine ##STR00148## [0309] To a solution of CF.sub.3CH.sub.2OH (2.57 g, 1.05 equiv) in THF (50 mL) was added t-BuONa (2 M, 12.8 mL, 1.05 equiv). The mixture was stirred at 20 C. for 1 hour. To the mixture was added dropwise a solution of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (11.0 g, 1.0 equiv) in THF (100 mL) at 40 C. The reaction was stirred at 40 C. for 0.5 hour. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford the title compound (12.0 g, 92% yield) as a yellow solid; LCMS (ESI, M+1, M+3): m/z=514.2, 516.2. Intermediate 18 ##STR00149## (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00150## [0310] Step A. (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution 2,4-dichloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidine (10.0 g, 1.0 equiv) and (R)-3-methylpiperidin-3-ol (4.04 g, 1.2 equiv, HCl) in dichloromethane (200 mL) was added DIPEA (11.5 g, 4.0 equiv) and 4 molecular sieves (1.0 g, 1.0 equiv). The mixture was stirred at 40 C. for 15 minutes. The reaction mixture was filtered, washed with EtOAc (100 mL) and extracted with EtOAc (2100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (10.0 g, 84% yield) as yellow liquid; LCMS (ESI, M+1): m/z=529.2. [0311] Step B. (R)-1-(2-(((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (4.26 g, 1.1 equiv) and 4 molecular sieves (150 mg, 1.0 equiv) in toluene (50 mL) was added t-BuONa (2.73 g, 3.0 equiv) at 0 C. The mixture was stirred at 0 C. for 10 minutes. Then (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (5.0 g, 1.0 equiv) was added to the mixture and the mixture was stirred at 0 C. for 1 hour. The reaction mixture was filtered, washed with EtOAc (100 mL). The filtrate was quenched with water (30 mL) and extracted with EtOAc (250 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (6.60 g, 76% yield) as yellow liquid; LCMS (ESI, M+1): m/z=902.6. [0312] Step C. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(2-(((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (6.60 g, 1.0 equiv) in DMF (66 mL) was added CsF (16.7 g, 15 equiv). The mixture was stirred at 40 C. for 12 hours. The reaction mixture was filtered, washed with EtOAc (30 mL). The filtrate was concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (4.0 g, 80% yield) as yellow liquid; LCMS (ESI, M+1): m/z=664.4 Intermediate 19 ##STR00151## 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine ##STR00152## [0313] Step A. 4-bromo-5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole: To a solution of 4-bromo-5,6-dimethyl-1H-indazole (4.5 g, 1.0 equiv) and TsOH (104 mg, 0.03 equiv) in DCM (100 mL) was added 3,4-dihydro-2H-pyran (2.56 g, 1.5 equiv) dropwise at 0 C. The mixture was stirred at 25 C. for 6 hours. The mixture was diluted with H.sub.2O (30 mL) and saturated NaHCO.sub.3 aqueous (30 mL), extracted with DCM (320 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified by column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 15:1 to 4:1] to afford the title compound (5.7 g, 91% yield) as a yellow oil; .sup.1H NMR (400 MHZ, methanol-d.sub.4) =7.88 (s, 1H), 7.46 (s, 1H), 5.74 (dd, J=2.8, 9.6 Hz, 1H), 4.04-3.95 (m, 1H), 3.84-3.76 (m, 1H), 2.48 (s, 3H), 2.44 (s, 3H), 2.16-2.08 (m, 1H), 2.05-1.95 (m, 1H), 1.90-1.72 (m, 2H), 1.64-1.49 (m, 2H). [0314] Step B. 5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole: To a mixture of 4-bromo-5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5.7 g, 1.0 equiv), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi (1,3,2-dioxaborolane) (7.49 g, 1.6 equiv) in DMSO (60 mL) were added AcOK (5.43 g, 3.0 equiv) and Pd(dppf)Cl.sub.2 (809 mg, 0.06 equiv) under N.sub.2 atmosphere. The mixture was stirred at 110 C. for 0.75 hours. The mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate (200 mL). The mixture was diluted with H.sub.2O (200 mL) and extracted with ethyl acetate (430 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 20:1 to 15:1] to afford the title compound (3.3 g, 50% yield) as a light yellow oil; .sup.1H NMR (400 MHZ, methanol-d.sub.4) =8.21 (s, 1H), 7.53 (s, 1H), 5.72 (dd, J=2.4, 10.0 Hz, 1H), 4.04-3.95 (m, 1H), 3.80 (dt, J=2.8, 11.2 Hz, 1H), 2.54 (s, 3H), 2.52-2.44 (m, 1H), 2.42 (s, 3H), 2.16-2.06 (m, 1H), 2.00-1.92 (m, 1H), 1.87-1.61 (m, 3H), 1.42 (s, 12H). [0315] Step C. 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of 7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1 g, 1.0 equiv), 5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.00 g, 1.2 equiv) in methoxycyclopentane (15 mL) were added Cs.sub.2CO.sub.3 (1 M in H.sub.2O, 3.0 equiv) and CataCXium A Pd G3 (173 mg, 0.1 equiv) under N.sub.2 atmosphere. The mixture was stirred at 80 C. for 6 hours. The mixture was diluted with H.sub.2O (10 mL) and extracted with ethyl acetate (510 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified with reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile=3/1 to 2/1] to afford the title compound (0.66 g, 44% yield) as a light red solid; LCMS (ESI, M+1): m/z=615.4. Intermediate 20 ##STR00153## 4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole ##STR00154## [0316] Step A. ethyl 5-benzyl-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate: To a mixture of ethyl 1-(dimethylsulfamoyl) pyrazole-4-carboxylate (150 g, 1.0 equiv) in THF (1000 mL) were added HMPA (130 g, 1.2 equiv) and LDA (2 M, 1.2 equiv) at 65 C. under nitrogen atmosphere. After stirring at 65 C. for 0.5 hour, bromomethylbenzene (124 g, 1.2 equiv) was added. The reaction was stirred at 65 C. for 0.5 hour under nitrogen atmosphere. The mixture was quenched with water (500 mL) and extracted with ethyl acetate (500 mL2). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile] to afford the title compound (130 g, 45% yield) as a yellow solid. [0317] Step B. 5-benzyl-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid: A mixture of ethyl 5-benzyl-1-(dimethylsulfamoyl) pyrazole-4-carboxylate (110 g, 1.0 equiv) and NaOH (195 g, 15 equiv) in dioxane (600 mL) and H.sub.2O (600 mL) was stirred at 25 C. for 1 hour. The mixture was extracted with ethyl acetate (21000 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (95 g, crude) as a yellow solid. LCMS (ESI, M1): m/z=310.0. [0318] Step C. 1H-benzo[f]indazol-4-ol: A mixture of 5-benzyl-1-(dimethylsulfamoyl) pyrazole-4-carboxylic acid (30.0 g, 1.0 eq) in CF.sub.3SO.sub.3H (150 mL) was stirred at 90 C. for 2 hours. The mixture was poured into ice water (1000 mL) and extracted with ethyl acetate (21000 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (43.5 g, crude) as a yellow solid. LCMS (ESI, M+1): m/z=184.9. [0319] Step D. 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol: To a mixture of 1H-benzo[f]indazol-4-ol (12.0 g, 1.0 equiv) and TsOH.Math.H.sub.2O (123 mg, 0.01 equiv) in THF (120 mL) was added DHP (10.9 g, 2.0 equiv). The reaction was stirred at 20 C. for 1 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2500 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile] to afford the title compound (16 g, 74% yield) as a yellow solid. [0320] Step E. 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate: To a mixture of 1-tetrahydropyran-2-ylbenzo[f]indazol-4-ol (9.2 g, 1.0 equiv), DIEA (17.3 g, 4.0 equiv) and 4 molecular sieves (1.00 g) in DCM (100 mL) was added trifluoromethanesulfonic anhydride (19.3 g, 2.0 equiv) at 40 C. The reaction was stirred at 40 C. for 0.5 hour. The mixture was quenched with H.sub.2O (200 mL) and extracted with DCM (3100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated and purified with reversed-phase HPLC (0.1% FA condition) to afford the title compound (2.8 g, 20% yield) as a black solid; [0321] Step F. 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole: To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (2.80 g, 1.0 equiv), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.95 g, 10 equiv) and TEA (2.12 g, 3.0 equiv) in MeCN (30 mL) was added (1,1-bis(diphenylphosphino)ferrocene)palladium (II) dichloride (511 mg, 0.10 equiv). The reaction was stirred at 80 C. for 5 hours. The mixture was concentrated, dissolved in water (20 mL) and extracted with ethyl acetate (320 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified with reversed-phase HPLC (0.1% FA condition) to afford the title compound (800 mg, 30% yield) as a brown solid. [0322] Step G. 4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2.2.2 trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole: To a solution of 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole (200 mg, 1.0 equiv) 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (232 mg, 1.0 equiv) and Cs.sub.2CO.sub.3 (517 mg, 1.5 M, 3.0 equiv) in methoxycyclopentane (2 mL) was added [2-(2-aminophenyl)phenyl]palladium bis(1-adamantyl)butylphosphane methanesulfonate (38.5 mg, 0.10 equiv). The reaction was stirred at 90 C. for 2 hours. The mixture was filtered and purified with reversed-phase HPLC (0.1% FA condition) to afford the title compound (320 g, 92% yield) as a brown solid; LCMS (ESI, M+1): m/z=655.3. Intermediate 21 ##STR00155## 4-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole ##STR00156## [0323] To a solution of 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole (250 mg, 1.0 equiv), 7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (278 mg, 1.0 equiv) and Cs.sub.2CO.sub.3 (646 mg, 1.5 M, 3.0 equiv) in methoxycyclopentane (2 mL) was added [2-(2-aminophenyl)phenyl]palladium bis(1-adamantyl)butylphosphane methanesulfonate (48.1 mg, 0.10 equiv). The reaction was stirred at 90 C. for 2 hours. The mixture was filtered and purified by reversed-phase HPLC (0.1% FA condition) to afford the title compound (120 mg, 28% yield) as a yellow solid; LCMS (ESI, M+1): m/z=637.3. Intermediate 22 ##STR00157## 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole ##STR00158## ##STR00159## [0324] Step A. ethyl 1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate: To a solution of ethyl 1H-pyrazole-4-carboxylate (20.0 g, 1.0 equiv) and DABCO (17.6 g, 1.1 equiv) in MeCN (200 mL) was added N,N-dimethylsulfamoyl chloride (22.5 g, 1.1 equiv). The mixture was stirred at 25 C. for 1 hour. The mixture was concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 8:1] to afford the title compound (29.0 g, 82% yield) as a white solid; .sup.1H NMR (400 MHZ, DMSO-d6) =8.66 (s, 1H), 8.22 (s, 1H), 4.28-4.23 (m, 2H), 2.90 (s, 6H), 1.30-1.26 (m, 3H); LCMS (ESI, M+1): m/z=248.2. [0325] Step B. ethyl 2-chloro-5-ethylbenzoate: A mixture of ethyl 5-bromo-2-chlorobenzoate (66.0 g, 1.0 equiv), triethylborane (1 M, 501 mL, 2.0 equiv), K.sub.2CO.sub.3 (69.2 g, 2.0 equiv) and Pd(PPh.sub.3).sub.4 (28.9 g, 0.1 equiv) in DMF (600 mL) and THF (600 mL) was degassed and purged with N.sub.2 for 3 times. The mixture was stirred at 70 C. for 12 hours under N.sub.2 atmosphere. The mixture was filtered and diluted with ethyl acetate (3000 mL). The organic layer was washed by brine (52000 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 10:1] to afford the title compound (98.0 g, 92% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.58 (d, J=2.0 Hz, 1H), 7.30-7.20 (m, 1H), 7.19-7.16 (m, 1H), 4.36 (dd, J=7.2, 14.4 Hz, 2H), 2.63-2.57 (m, 2H), 1.38-1.34 (m, 3H), 3.00 (s, 6H), 1.21-1.17 (m, 3H). [0326] Step C. (2-chloro-5-ethylphenyl)methanol: To a solution of ethyl 2-chloro-5-ethylbenzoate (73.0 g, 1.0 equiv) in THF (500 mL) was added DIBAL-H (1 M, 700 mL, 2.0 equiv) at 0 C. under N.sub.2 atmosphere. The solution was stirred at 0-25 C. for 12 hours. The mixture was quenched by ice water (1000 mL) and extracted with ethyl acetate (3500 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 10:1] to afford the title compound (49.0 g, 82% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.32 (d, J=1.6 Hz, 1H), 7.29-7.22 (m, 1H), 7.07 (dd, J=2.0, 8.0 Hz, 1H), 4.74 (br d, J=3.6 Hz, 2H), 2.64 (q, J=7.6 Hz, 2H), 1.26-1.21 (m, 3H) [0327] Step D. 2-(bromomethyl)-1-chloro-4-ethylbenzene: To a solution of (2-chloro-5-ethylphenyl)methanol (98.0 g, 1.0 equiv) in DCM (600 mL) was added PBr.sub.3 (171 g, 1.1 equiv) at 0 C. slowly. The mixture was stirred at 0 C. for 2 hours. The mixture was added into saturated NaHCO.sub.3 solution (2 L) at 0 C. and extracted with ethyl acetate (3500 mL). The organic layer was dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 1:0] to afford the title compound (78.0 g, 58% yield) as a colorless oil. [0328] Step E. ethyl 5-(2-chloro-5-ethylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate: To a mixture of ethyl 1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate (52.9 g, 1.0 equiv) and HMPA (46.0 g, 1.2 equiv) in THF (550 mL) was added LDA (2 M, 128 mL, 1.2 equiv) at 60 C. The mixture was stirred at 60 C. for 1 hour. To the mixture was added 2-(bromomethyl)-1-chloro-4-ethylbenzene (60.0 g, 1.2 equiv) at 60 C. The mixture was stirred at 60 C. for 1 hour and warmed to 15 C. for 12 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2300 mL). The organic layer was washed with brine (100 ml) and dried over Na.sub.2SO.sub.4. The organic phase was concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 50:1 to 8:1] to afford the title compound (35.0 g, 38% yield) as a white solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.12 (s, 1H), 7.34-7.22 (m, 1H), 6.97 (dd, J=1.2, 8.0 Hz, 1H), 6.43 (s, 1H), 4.77 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 3.00 (s, 6H), 2.47 (q, J=7.6 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.09 (t, J=7.6 Hz, 3H); LCMS (ESI, M+1): m/z=400.1. [0329] Step F. 5-(2-chloro-5-ethylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid: A mixture of ethyl 5-(2-chloro-5-ethylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate (5.00 g, 1.0 equiv) and NaOH (10.0 g, 20 equiv) in dioxane (30 mL) and H.sub.2O (30 mL) was stirred at 90 C. for 2 hours. The mixture was diluted with ethyl acetate (100 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to to afford the title compound (6.00 g, crude) as a yellow solid; LCMS (ESI, M+1): m/z=372.1. [0330] Step G. 8-chloro-5-ethyl-1H-benzo[f]indazol-4(9H)-one: A mixture of 5-(2-chloro-5-ethylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid (6.00 g. 1.0 equiv) in CF.sub.3SO.sub.3H (102 g, 42 equiv) was stirred at 90 C. for 1.5 hours. The mixture was quenched by ice water (200 mL) and filtered. The filter cake was partitioned between ethyl acetate (100 mL) and sat. NaHCO.sub.3 (100 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford the title compound (3.20 g, 74 yield) as a yellow solid; LCMS (ESI, M+1): m/z=247.0. [0331] Step H. 8-chloro-5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4(9H)-one: To a solution of 8-chloro-5-ethyl-1H-benzo[f]indazol-4(9H)-one (12.0 g, 1.0 equiv) and TsOH (838 mg, 0.1 equiv) in THF (120 mL) was added DHP (5.32 g, 1.3 equiv) at 0 C. The mixture was stirred at 15 C. for 0.5 hour. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2100 mL). The organic layer was dried and concentrated to give a residue. The residue was purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 8:1 to 2:1] to afford the title compound (8.00 g, 42% yield) as a yellow solid. [0332] Step I. 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol: To a suspension of Pd/C (500 mg, 10% purity) and NaHCO.sub.3 (1.02 g, 1.0 equiv) in MeOH (40 mL) was added 8-chloro-5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4(9H)-one (4.00 g, 1.0 equiv) under N.sub.2. The suspension was degassed under vacuum and purged with H.sub.2 several times. The mixture was stirred under H.sub.2 (15 psi) at 15 C. for 20 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 30:1 to 4:1] to afford the title compound (2.40 g, 55% yield) as a yellow oil: LCMS (ESI, M+1): m/z=297.2. [0333] Step J. 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate: To a solution of 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol (2.40 g, 1.0 equiv) and DIPEA (3.14 g, 3.0 equiv) in DCM (30 mL) was added Tf.sub.2O (4.57 g, 2.0 equiv) at 40 C. The mixture was stirred at 40 C. for 15 minutes. The mixture was concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 100:1 to 20:1] to afford the title compound (1.00 g, 26% yield) as a yellow solid; LCMS (ESI, M+1): m/z=429.1. [0334] Step K. 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole: To the mixture of 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (1.00 g, 1.0 equiv), Pd(dppf)Cl.sub.2 (171 mg, 0.1 equiv) and TEA (945 mg, 4.0 equiv) in ACN (20 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.19 g, 4.0 equiv) under N.sub.2. The mixture was stirred at 80 C. for 2 hours. The mixture was quenched by MeOH (3 mL) and concentrated to give a residue. The residue was purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 80:1 to 10:1] to afford the title compound (190 mg, 18% yield) as a yellow oil; LCMS (ESI, M+1): m/z=407.2. [0335] Step L. 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole: To a mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (142 mg, 1.2 equiv), 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole (110 mg, 1.0 equiv) and Cs.sub.2CO.sub.3 (1.5 M, 3.0 equiv) in methoxycyclopentane (2 mL) was added CataCXium A Pd G3 (19.7 mg, 0.1 equiv) under N.sub.2. The mixture was stirred at 90 C. for 2 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 10 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (60.0 mg, 28% yield) as a yellow solid; LCMS (ESI, M+1): m/z=683.4. Intermediate 23 ##STR00160## 5-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide ##STR00161## [0336] Step A. 5-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.3 g, 1.0 equiv) and DIPEA (307 mg, 2.0 equiv) in DCM (6 mL) was added N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (223 mg, 0.9 equiv) and DIPEA (614 mg, 4.0 equiv) in DMF (2 mL) dropwise at 40 C. The mixture was stirred at 40 C. for 0.5 hour. The mixture was quenched with H.sub.2O (30 mL) at 40 C. The mixture was extracted with DCM (310 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was dispersed in petroleum ether/ethyl acetate 2:1 (30 mL). The mixture was stirred for 0.5 hour. The mixture was filtered and the solid was dried under reduced pressure to afford the title compound (0.48 g, 94% yield) as a yellow solid; LCMS (ESI, M+1, M+3, M+5): m/z=424.1, 426.1, 428.1. [0337] Step B. 5-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a mixture of 5-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (240 mg, 1.0 equiv) and (hexahydro-1H-pyrrolizin-7a-yl)methanol (88 mg, 1.1 equiv) in dioxane (1 mL) and DMSO (1 mL) was added DIPEA (183 mg, 2.5 equiv) and 4A MS (30 mg). The mixture was stirred at 90 C. for 14 hours under N.sub.2 atmosphere. The mixture was filtered and purified with reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile 4:1] to afford the title compound (60 mg, 19% yield) as light yellow solid; LCMS (ESI, M+1, M+3): m/z=529.3, 531.3. Intermediate 24 ##STR00162## 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00163## [0338] Step A. (5-chloro-6-fluoro-4-trimethylstannyl-2-naphthyl)oxy-triisopropyl-silane: A mixture of (8-chloro-7-fluoro-3-triisopropylsilyloxy-1-naphthyl)trifluoromethanesulfonate (800 mg, 1.0 equiv), trimethyl(trimethylstannyl) stannane (8.0 g, 15 equiv), Pd(PPh.sub.3).sub.4 (184 mg, 0.1 equiv) and LiCl (203 mg, 3.0 equiv) in toluene (10 mL) was degassed and purged with N.sub.2 for 3 times. And the mixture was stirred at 105 C. for 12 hours under N.sub.2 atmosphere. The reaction was filtered and concentrated, purified by prep-HPLC [C18, 0.1% formic acid condition] and lyophilized to afford the title compound (150 mg, 18% yield) as a colorless liquid; .sup.1H NMR (400 MHz, CHLOROFORM-d) =7.62-7.57 (m, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.19 (d, J=2.4 Hz, 1H), 1.37-1.27 (m, 5H), 1.15 (d, J=7.2 Hz, 18H), 0.50-0.36 (m, 9H). [0339] Step B. 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: A mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv), (5-chloro-6-fluoro-4-trimethylstannyl-2-naphthyl)oxy-triisopropyl-silane (423 mg, 1.2 equiv), CuI (39.1 mg, 0.3 equiv), Pd(dppf)Cl.sub.2 (50.0 mg, 0.1 equiv) and BINAP (85.2 mg, 0.2 equiv) in toluene (4.0 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 20 C. for 12 hours under N.sub.2 atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to remove solvent. The crude product was purified by prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (80 mg, 15.5% yield) as a white solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.25 (s, 1H), 7.70 (dd, J=5.4, 9.1 Hz, 1H), 7.37-7.30 (m, 2H), 7.24 (d, J=2.0 Hz, 1H), 5.41-5.19 (m, 1H), 5.17-4.95 (m, 2H), 4.45-4.25 (m, 2H), 4.13 (q, J=7.2 Hz, 1H), 3.31-3.18 (m, 2H), 3.04-2.96 (m, 1H), 2.32-2.22 (m, 1H), 2.18-2.11 (m, 1H), 2.02-1.93 (m, 2H), 1.83-1.51 (m, 3H), 1.36-1.30 (m, 3H), 1.13 (d, J=7.2 Hz, 17H), 0.91-0.78 (m, 2H). Intermediate 25 ##STR00164## 7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine ##STR00165## [0340] Step A. 6-chloro-4-fluoro-1H-indazole: To a solution of 4-chloro-2,6-difluoro-benzaldehyde (100 g, 1.0 equiv) in dioxane (1.0 L) was added N.sub.2H.sub.4.Math.H.sub.2O (58.1 g, 2.0 equiv) in dropwise at 25 C. for 10 minutes. The mixture was stirred at 25 C. for 0.5 hour, and 95 C. for 15.5 hours. The reaction mixture was diluted with H.sub.2O (500 mL) and extracted with EtOAc (2500 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (95.0 g, crude) as a white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =14.08-12.38 (m, 1H), 8.23 (d, J=0.4 Hz, 1H), 7.51 (s, 1H), 7.06 (dd, J=1.2, 9.6 Hz, 1H); LCMS (ESI, M+1): m/z=171.0. [0341] Step B. 6-chloro-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole: To a solution of 6-chloro-4-fluoro-1H-indazole (40.0 g, 1.0 equiv) in THF (200 mL) was added NaH (14.1 g, 60% purity 1.5 equiv) portionwise at 0 C. for 30 minutes. The mixture was stirred at 25 C. for 0.5 hour. Then SEM-Cl (46.9 g, 1.2 equiv) was added to the mixture in dropwise at 0 C. for 20 minutes. The mixture was stirred at 25 C. for 1 hour. The mixture was quenched by slow addition of H.sub.2O (300 mL) at 0 C. over the course of 30 minutes. The mixture was extracted with EtOAc (2300 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 10:1] to afford the title compound (42.0 g, 60% yield) as a yellow solid; .sup.1H NMR (400 MHZ, CDCl.sub.3-d) =8.09-8.00 (m, 1H), 7.45-7.37 (m, 1H), 6.88 (dd, J=1.2, 9.6 Hz, 1H), 5.70 (s, 2H), 3.63-3.46 (m, 2H), 0.96-0.84 (m, 2H), 0.04 (s, 9H); LCMS (ESI, M+1): m/z=301.3. [0342] Step C. 6-chloro-4-fluoro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole: To a solution of 2-[(6-chloro-4-fluoro-indazol-1-yl)methoxy]ethyl-trimethyl-silane (20.0 g, 1.0 equiv) in THF (100 mL) was added LDA (43.2 mL, 1.3 equiv) in dropwise at 65 C. for 5 minutes. The mixture was stirred at 65 C. for 55 minutes. Then solution of 12 (21.9 g, 1.3 equiv) in THF (50.0 mL) was added to the mixture slowly at 15 minutes and stirred at 65 C. for 1 hour. The mixture was quenched with H.sub.2O (100 mL) at 0 C. for 15 minutes. The mixture was extracted with EtOAc (2100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [0.1% formic acid condition] to afford the title compound (12.0 g, 42% yield) as a yellow solid; .sup.1H NMR (400 MHz, CDCl.sub.3-d) =8.03 (s, 1H), 7.61 (s, 1H), 5.70 (s, 2H), 3.58-3.50 (m, 2H), 0.93-0.86 (m, 2H), 0.04 (s, 9H). LCMS (ESI, M+1): m/z=427.2. [0343] Step D. 6-chloro-5-cyclopropyl-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole: To a solution of 2-[(6-chloro-4-fluoro-5-iodo-indazol-1-yl)methoxy]ethyl-trimethyl-silane (8.0 g, 1.0 equiv) and cyclopropylboronic acid (3.22 g, 2.0 equiv) in dioxane (80 mL) was added Pd(dppf)Cl.sub.2 (1.37 g, 0.1 equiv) and K.sub.3PO.sub.4 (1.5 M, 37.5 mL, 3.0 equiv). The mixture was degassed and purged with N.sub.2 three times and stirred at 100 C. for 12 hours under N.sub.2. The mixture was diluted with H.sub.2O (80 mL) and extracted with EtOAc (260 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 10:1] to afford the title compound (4.10 g, 58% yield) as a yellow oil. 1H NMR (400 MHZ, CDCl.sub.3-d) =8.00 (d, J=0.8 Hz, 1H), 7.44 (s, 1H), 5.79-5.55 (m, 2H), 3.62-3.48 (m, 2H), 1.90-1.75 (m, 1H), 1.16-1.02 (m, 2H), 0.96-0.80 (m, 4H), 0.01 (s, 9H); LCMS (ESI, M+1): m/z=341.1. [0344] Step E. 6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-ol: To a solution of 2-[(6-chloro-5-cyclopropyl-4-fluoro-indazol-2-yl)methoxy]ethyl-trimethyl-silane (4.10 g, 1.0 equiv) and 2-methylsulfonylethanol (2.20 g, 1.5 equiv) in DMF (50 mL) was added NaH (2.40 g, 60% purity, 5.0 equiv) portionwise at 0 C. for 15 minutes. Then the mixture was stirred at 25 C. for 0.5 hour and 40 C. for 11.5 hours. The mixture was quenched by slow addition of H.sub.2O (50 mL) at 0 C. over the course of 15 minutes. The mixture was extracted with EtOAc (210 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [0.1% formic acid condition] to afford the title compound (2.0 g, 50% yield) as a yellow oil. 1H NMR (400 MHZ, CDCl.sub.3-d) =8.12-7.98 (m, 1H), 7.20 (s, 1H), 6.54 (s, 1H), 5.80-5.58 (m, 2H), 3.66-3.41 (m, 2H), 1.78-1.60 (m, 1H), 1.27-1.14 (m, 2H), 0.98-0.83 (m, 2H), 0.80-0.69 (m, 2H), 0.04 (s, 9H); LCMS (ESI, M+1): m/z=339.3. [0345] Step F. 6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl trifluoromethanesulfonate: To a solution of 6-chloro-5-cyclopropyl-1-(2-trimethylsilylethoxymethyl) indazol-4-ol (0.80 g, 1.0 equiv) 4 molecular sieves (100 mg), DIPEA (915 mg, 3.0 equiv) in DCM (8 mL) was added Tf.sub.2O (999 mg, 1.5 equiv). The mixture was degassed and purged with N.sub.2 three times, and stirred at 40 C. for 0.5 hour. The mixture was diluted with H.sub.2O (3 mL) and extracted with EtOAc (25 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 10:1] to afford the title compound (740 mg, 62% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CDCl.sub.3-d) =7.98 (s, 1H), 7.70 (s, 1H), 5.70 (s, 2H), 3.55 (t, J=8.4 Hz, 2H), 1.94-1.82 (m, 1H), 1.31-1.19 (m, 2H), 0.90 (t, J=8.4 Hz, 2H), 0.81-0.70 (m, 2H), 0.05 (s, 9H); LCMS (ESI, M+1): m/z=471.1. [0346] Step G. 6-chloro-5-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole: To a solution of 6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl trifluoromethanesulfonate (300 mg, 1.0 equiv) and Pin.sub.2B.sub.2 (243 mg, 1.5 equiv) in ACN (6 mL) were added KOAc (125 mg, 2.0 equiv), P(Cy.sub.3)-Pd-G3 (46.8 mg, 0.1 equiv) under N.sub.2. The mixture was stirred at 90 C. for 12 hours. The mixture was filtered, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (150 mg, 51% yield) as a yellow liquid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =8.13 (d, J=0.8 Hz, 1H), 7.65 (d, J=0.4 Hz, 1H), 5.67 (s, 2H), 3.55-3.50 (m, 2H), 2.19-2.10 (m, 1H), 1.47 (s, 12H), 1.10-1.04 (m, 2H), 0.9-0.86 (m, 2H), 0.62-0.56 (m, 2H), 0.05 (s, 9H); LCMS (ESI, M+1): m/z=449.2. [0347] Step H. 7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (150 mg, 1.0 equiv) and 6-chloro-5-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (192 mg, 1.2 equiv) in toluene (3 mL) were added K.sub.3PO.sub.4 (1.5 M, 713 L, 3.0 equiv) and APhos-Pd-G3 (22.6 mg, 0.1 equiv). The mixture was stirred at 60 C. for 12 hours under N.sub.2. The reaction mixture was diluted with H.sub.2O (10 mL) and extracted with EtOAc (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 10:1 to 1:0] and reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (70.0 mg, 28% yield) as yellow liquid. Intermediate 26 ##STR00166## tert-butyl 2-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate ##STR00167## [0348] Step A. methyl 3-bromo-1-(3-((tert-butoxycarbonyl)amino) propyl)-1H-pyrazole-5-carboxylate: To a solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (1.0 g, 1.0 equiv) in ACN (10.0 mL) were added Cs.sub.2CO.sub.3 (3.2 g, 2.0 equiv) and tert-butyl N-(3-bromopropyl)carbamate (1.4 g, 1.2 equiv). The reaction was stirred at 15 C. for 2 hours. The mixture was filtered and purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 030% Ethyl acetate/Petroleum ethergradient @36 mL/min) to afford the title compound (1.3 g, 68.3% yield, 95% purity) as a colorless clear liquid. 1H NMR (400 MHz, CHLOROFORM-d) =6.81 (s, 1H), 4.88 (br s, 1H), 4.67-4.57 (m, 2H), 3.96-3.85 (m, 3H), 3.10 (br d, J=5.6 Hz, 2H), 2.09-1.98 (m, 3H), 1.45 (s, 10H) [0349] Step B. methyl 1-(3-aminopropyl)-3-bromo-1H-pyrazole-5-carboxylate: To a solution methyl 3-bromo-1-(3-((tert-butoxycarbonyl)amino) propyl)-1H-pyrazole-5-carboxylate (1.3 g, 1.0 equiv) in dioxane (5.0 mL) was added HCl.Math.dioxane (4 M, 15 mL, 17.1 equiv). The reaction was stirred at 20 C. for 12 hours. The mixture was concentrated under reduced pressure to afford the title compound (1.1 g, HCl) as a white solid. [0350] Step C. 2-bromo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one; A solution of methyl 1-(3-aminopropyl)-3-bromo-1H-pyrazole-5-carboxylate hydrochloride (1.1 g, 1.0 equiv) in saturated Na.sub.2CO.sub.3 (20 mL) solution was stirred at 20 C. for 12 hours. The reaction was diluted with H.sub.2O (30 mL) and extracted with DCM 100 mL (20 mL5). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated, and triturated with DCM/PE at 20 C. for 5 minutes to afford the title compound (690 mg. 79.3% yield). .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.00-6.93 (m, 1H), 6.84 (s, 1H), 4.49 (t, J=6.8 Hz, 2H), 3.43-3.38 (m, 3H), 2.32-2.22 (m, 3H); LCMS (ESI, M+1): m/z=232.0. [0351] Step D. 2-bromo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine: A mixture of 2-bromo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one (610 mg, 1.0 equiv) in THF (5.0 mL) was degassed and purged with N.sub.2 3 times. BH.sub.3.Math.Me.sub.2S (10 M, 3.0 equiv) was added at 0 C. and the reaction was stirred at 20 C. for 30 minutes then at 60 C. for 12 hours. The mixture was concentrated under reduced pressure to afford the title compound (650 mg, 97% yield, HCl) as a white solid. .sup.1H NMR (400 MHZ, DMSO-d6) =6.55 (s, 1H), 4.48-4.34 (m, 5H), 3.38 (br dd, J=6.0, 12.0 Hz, 3H), 2.01 (br d, J=4.0 Hz, 2H). [0352] Step E. tert-butyl 2-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 2-bromo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (650 mg, 1.0 equiv, HCl) in DCM (8 mL) were added TEA (520 mg, 716 L 2.0 equiv) and Boc.sub.2O (842 mg, 1.5 equiv). The mixture was stirred at 25 C. for 2 hours. The reaction was concentrated and purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 030% Ethyl acetate/Petroleum ethergradient @ 30 mL/min) to afford the title compound (250 mg, 28.9% yield, 94.0% purity) as a white solid. 1H NMR (400 MHZ, CHLOROFORM-d) =6.32-6.12 (m, 1H), 4.48-4.35 (m, 4H), 3.78-3.65 (m, 2H), 1.91 (br d, J=4.4 Hz, 2H), 1.51-1.40 (m, 9H); LCMS (ESI, M+1): m/z=318.0. Intermediate 27 ##STR00168## 5-bromo-N,N,1-trimethyl-1H-pyrazole-3-carboxamide ##STR00169## [0353] Step A. methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate: To a solution of methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (25.0 g, 1.0 equiv) in acetonitrile (250 mL) was added POBr.sub.3 (184 g, 4.0 equiv) in portions under N.sub.2 at 0 C. The reaction was stirred at 80 C. for 12 hours. The mixture was diluted with ethyl acetate (500 mL) and washed with 5% NaHCO.sub.3 solution (3300 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=1/0 to 4/1) to afford the title compound (13.0 g, 34% yield) as yellow solid. [0354] Step B. 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid: To a solution of methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate (13.0 g, 1.0 equiv) in THF (237 mL) was added NaOH (2 M in water, 119 mL, 4.0 equiv) in one portion. The reaction was stirred at 25 C. for 2 hours. The mixture was quenched with conc. HCl (150 mL) and extracted with ethyl acetate (350 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (5.00 g, crude) as white solid; LCMS (ESI, M+1, M+3): m/z=204.9, 206.9. [0355] Step C. 5-bromo-N,N,1-trimethyl-1H-pyrazole-3-carboxamide: To a mixture of 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (5.00 g, 1.0 equiv) in THF (50 mL) was added dimethylamine (2 M in THF, 24.4 mL, 2.0 equiv) and DIEA (15.8 g, 5.0 equiv) at 0 C. HATU (18.5 g, 2.0 equiv) was added. The reaction was stirred at 25 C. 0.5 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (350 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=I/O to 2/1) to afford the title compound (4.10 g, 72% yield) as yellow solid; LCMS (ESI, M+1, M+3): m/z=232.0, 234.0. Intermediate 28 ##STR00170## tert-butyl ((5-(dimethylcarbamoyl)-1H-pyrazol-3-yl)methyl)carbamate ##STR00171## [0356] Step A. methyl 3-cyano-1H-pyrazole-5-carboxylate: To a solution of methyl prop-2-ynoate (5.00 g, 1.0 equiv) and 2-aminoacetonitrile (9.91 g, 1.8 equiv, HCl) in CHCl.sub.3 (500 mL) and H.sub.2O (16 mL) was added NaNO.sub.2 (12.3 g, 3.0 equiv) at 25 C. slowly. The reaction was stirred at 25 C. for 3 hours and warmed to 60 C. for 12 hours. The reaction mixture was filtered, concentrated, and purified by flash silica gel chromatography [ISCO; 80 g Sepaflash silica flash column, eluent of 3050% EtOAc/PE gradient] to afford the title compound (5.00 g, 54% yield) as yellow solid; 1H NMR (400 MHZ, CHLOROFORM-d) =11.59 (br s, 1H), 7.23 (s, 1H), 4.01 (s, 3H). [0357] Step B. methyl 3-(aminomethyl)-1H-pyrazole-5-carboxylate: To a solution of methyl 3-cyano-1H-pyrazole-5-carboxylate (500 mg, 1.0 equiv) in MeOH (10 mL) were added HCl (0.5 mL) and Pd/C (50.0 mg, 10% purity, wet). The reaction was stirred at 25 C. under H.sub.2 atmosphere for 2 hours. The mixture was filtered and concentrated to afford the title compound (513 mg, 99% yield) as yellow oil. [0358] Step C. methyl 3-[(tert-butoxycarbonylamino)methyl]-1H-pyrazole-5-carboxylate: To a solution of methyl 3-(aminomethyl)-1H-pyrazole-5-carboxylate (400 mg, 79.7% purity, 1.0 equiv) in DCM (10 mL) were added TEA (424 mg, 3.0 equiv) and Boc.sub.2O (336 mg, 1.1 equiv). The reaction was stirred at 25 C. for 1 hour. The mixture was filtered, concentrated, and purified by flash silica gel chromatography [ISCOR; 20 g Sepaflash silica flash column, eluent of 065% PE/EtOAc gradient @20 mL/min] to afford the title compound (300 mg, 83% yield) as white solid; LCMS (ESI, M+1): m/z=256.2. [0359] Step D. 3-[(tert-butoxycarbonylamino)methyl]-1H-pyrazole-5-carboxylic acid: To a solution of methyl 3-[(tert-butoxycarbonylamino)methyl]-1H-pyrazole-5-carboxylate (300 mg, 1.0 equiv) in MeOH (10 mL) was added NaOH (1 M, 3.5 mL, 3.0 equiv) in water. The reaction was stirred at 60 C. for 2 hours. The mixture was poured into water (20 mL) and the pH was adjusted to 5 with HCl (1 M). The mixture was extracted with EtOAc (320 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (280 mg, 99% yield) as white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =13.32-12.96 (m, 1H), 7.35-7.26 (m, 1H), 6.53 (br s, 1H), 4.11 (br d, J=5.2 Hz, 2H), 1.39 (s, 9H). [0360] Step E. tert-butyl N-[[5-(dimethylcarbamoyl)-1H-pyrazol-3-yl]methyl]carbamate: To a solution of 3-[(tert-butoxycarbonylamino)methyl]-1H-pyrazole-5-carboxylic acid (260 mg, 1.0 equiv) and N-methylmethanamine (439 mg, 5.0 equiv, HCl) in DMAc (10 mL) was added dropwise TEA (240 mg, 2.2 equiv). Then bromo(tripyrrolidin-1-yl)phosphonium;hexafluorophosphate (653 mg, 1.3 equiv) was added to the mixture. The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified with prep-HPLC [Waters Xbridge 15025 mm5 um; A: water (NH.sub.3.Math.H.sub.2O), B: ACN, B %: 10%-40% over 10 min] to afford the title compound (170 mg, 59% yield) as yellow gum; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =6.56-6.43 (m, 1H), 4.28 (br s, 2H), 3.27 (s, 3H), 3.09 (s, 3H), 1.45 (s, 9H). Intermediate 29 ##STR00172## 3-cyano-N,N-dimethyl-1H-pyrazole-5-carboxamide ##STR00173## [0361] Step A. 3-cyano-1H-pyrazole-5-carboxylic acid: To a solution of methyl 3-cyano-1H-pyrazole-5-carboxylate (500 mg, 1.0 equiv) in water (15.0 mL) and tetrahydrofuran (15.0 mL) was added lithium hydroxide (158 mg, 2.0 equiv). The reaction was stirred at 50 C. for 2 hours. The mixture was quenched with water (20.0 mL) and extracted with ethyl acetate (320.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (400 mg, 88% yield) as yellow oil; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ppm 7.27-7.51 (m, 1H). [0362] Step B. 3-cyano-N,N-dimethyl-1H-pyrazole-5-carboxamide: To a solution of 3-cyano-N,N-dimethyl-1H-pyrazole-5-carboxamide (500 mg, 1.0 equiv) and N-methylmethanamine (2 M, 2.0 equiv, tetrahydrofuran) in N,N-dimethylformamide (25 mL) were added N,N-diisopropylethylamine (1.41 g, 3.0 equiv) and [dimethylamino (triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium; hexafluorophosphate (2.08 g, 1.50 equiv). The reaction was stirred at 25 C. for 1 hour. The mixture was concentrated and purified with prep-HPLC [neutral condition; column: Waters Xbridge C18 15050 mm10 um; mobile phase: [water (NH.sub.4HCO.sub.3)-ACN]; B %: 1%-26%, 10 min] to afford the title compound (500 mg, 84% yield) as yellow solid; .sup.1HNMR (400 MHz, CHLOROFORM-d) =2.82 (s, 3H) 2.91 (s, 3H) 7.95 (s, 1H). Intermediate 30 ##STR00174## ((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methanol Intermediate 31 ##STR00175## ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methanol ##STR00176## [0363] Step A. methyl cis-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate methyl and trans-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate: To a solution of methyl 3-(hydroxymethyl)tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (10 g, 1 equiv) and imidazole (10.2 g, 3 equiv) in DCM (150 mL) were added TBDPSCl (20.7 g, 1.5 equiv) and DMAP (613 mg, 0.1 equiv). The reaction was stirred at 25 C. for 2 hours. The mixture was washed with H.sub.2O (250 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified with column chromatography (SiO.sub.2, Petroleum ether: Ethyl acetate=50:1-1:1) and reversed phase flash chromatography (C18, 0.1% formic acid condition) to afford the two title compounds: Peak 1 (3.4 g, 12% yield) as yellow oil; LCMS (ESI, M+1): m/z=438.3. Peak 2 (4 g, 13% yield) as yellow oil; LCMS (ESI, M+1): m/z=438.3. [0364] Step B. ((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol: To a solution of methyl cis-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (5.0 g, 1.0 equiv) in THF (60 mL) was added LiAlH.sub.4 (1.30 g, 3.0 equiv) in portions at 40 C. The reaction was stirred at 40 C. for 1 hour. The mixture was quenched with saturated anhydrous sodium sulfate aqueous solution (4 mL), filtered, concentrated and purified with reversed phase flash chromatography (C18, 0.1% formic acid condition) followed with SFC [column: Phenomenex-Cellulose-2 (250 mm30 mm, 10 um); mobile phase: (0.1% NH.sub.3H.sub.2O IPA); B %: 50%-50%, 7.7 min; 470 min] to afford the two title compounds: [0365] Intermediate 30 (900 mg, 19% yield) as yellow oil; .sup.1H NMR (400 MHZ, chloroform-d) =7.70 (br t, J=5.6 Hz, 4H), 7.50-7.32 (m, 6H), 3.73-3.52 (m, 2H), 3.33-3.11 (m, 2H), 2.98-2.71 (m, 3H), 1.98-1.84 (m, 2H), 1.83-1.73 (m, 2H), 1.71-1.64 (m, 2H), 1.63-1.54 (m, 2H), 1.07 (s, 9H). [0366] Intermediate 31 (900 mg, 19% yield) as yellow oil; .sup.1H NMR (400 MHZ, chloroform-d) =7.74-7.67 (m, 4H), 7.46-7.37 (m, 6H), 3.74-3.52 (m, 2H), 3.37-3.11 (m, 2H), 3.03-2.71 (m, 3H), 2.01-1.88 (m, 2H), 1.87-1.78 (m, 2H), 1.74-1.65 (m, 2H), 1.63-1.52 (m, 2H), 1.07 (s, 9H). Intermediate 32 ##STR00177## ((3R,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methanol Intermediate 33 ##STR00178## ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methanol ##STR00179## [0367] Step A. ((3R,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol: To a solution of methyl trans-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (3.0 g, 1.0 equiv) in THF (40 mL) was added LiAlH.sub.4 (781 mg, 3.0 equiv) at 40 C. in portions. The reaction was stirred at 40 C. for 1 hour. The mixture was quenched with saturated anhydrous sodium sulfate aqueous solution (3 mL), filtered, concentrated and purified with reversed phase flash chromatography (C18, 0.1% formic acid condition) followed by SFC [column: DAICEL CHIRALPAK IG (250 mm30 mm, 10 um); mobile phase: (0.1% NH.sub.3H.sub.2O MeOH); B %: 30%-30%, 3; 800 min] to afford the two title compounds: [0368] Intermediate 32 (1.0 g, 36% yield) as yellow oil; 1H NMR (400 MHZ, chloroform-d) =7.68 (td, J=1.6, 8.0 Hz, 4H), 7.49-7.35 (m, 6H), 3.84-3.65 (m, 2H), 3.33 (br s, 2H), 3.26-3.15 (m, 1H), 2.93-2.89 (m, 1H), 2.77 (br d, J=6.4 Hz, 1H), 2.03-1.95 (m, 1H), 1.84-1.72 (m, 4H), 1.71-1.59 (m, 3H), 1.07 (s, 9H). [0369] Intermediate 33 (1.0 g, 36% yield) as yellow oil; .sup.1H NMR (400 MHZ, chloroform-d) =7.67 (br d, J=7.6 Hz, 4H), 7.48-7.37 (m, 6H), 3.95-3.88 (m, 1H), 3.80 (br dd, J=5.6, 10.8 Hz, 1H), 3.34 (br s, 2H), 3.29-3.19 (m, 1H), 3.00-2.88 (m, 1H), 2.85-2.72 (m, 1H), 2.04-1.95 (m, 1H), 1.84-1.72 (m, 4H), 1.71-1.57 (m, 3H), 1.07 (s, 9H). Intermediate 34 ##STR00180## ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate ##STR00181## [0370] Step A. (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizine: To a solution of ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (6.44 g, 1.0 equiv) and TEA (3.98 g, 2.5 equiv) in DCM (64.4 mL) was added TrtCl (8.77 g, 2.0 equiv) at 0 C. The reaction was stirred at 15 C. for 12 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (350 mL). The combined organic layers were washed with brine (2 40 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to afford the title compound (10.3 g, crude) as a yellow oil; LCMS (ESI, M+1): m/z=652.8. [0371] Step B. ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methanol: To a solution of (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizine (10.3 g, 1.0 equiv) in DMF (20.3 mL) was added CsF (23.9 g, 10 equiv). The reaction was stirred at 25 C. for 12 hours. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (320 mL). The combined organic layers were washed with brine (220 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with reversed-phase flash chromatography (0.1% FA condition) to afford the title compound (4.15 g, 57% yield) as a yellow oil; .sup.1H NMR (400 MHz, CDCl.sub.3) =7.49-7.38 (m, 6H), 7.29-7.17 (m, 9H), 3.44 (dd, J=4.4, 10.4 Hz, 1H), 3.27 (br dd, J=3.6, 10.8 Hz, 1H), 2.95-2.83 (m, 3H), 2.82-2.73 (m, 1H), 2.62 (td, J=6.0, 11.2 Hz, 1H), 2.02 (s, 1H), 1.89-1.81 (m, 1H), 1.78-1.48 (m, 6H). [0372] Step C. ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methanol (4.15 g, 1.0 equiv) and TEA (3.05 g, 3.0 equiv) in DCM (42 mL) was added (4-nitrophenyl) carbonochloridate (3.03 g, 1.5 equiv) at 0-5 C. under N.sub.2. The reaction was stirred at 20 C. for 2 hours. N-methylmethanamine (2.0 M, 7.5 mL, 1.5 equiv) was added to the mixture at 0 C. under N.sub.2. The reaction was stirred at 0 C. for 0.5 hour. The mixture was diluted with water (50 mL) and extracted with DCM (350 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reversed-phase flash chromatography (0.1% FA condition) to afford the title compound (2.03 g, 41% yield) as a yellow oil; LCMS (ESI, M+1): m/z=485.7. [0373] Step D. ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (2.03 g, 1.0 equiv) in DCM (20 mL) was added TFA (4.78 g, 10 equiv). The reaction was stirred at 0-25 C. for 12 hours. The mixture was concentrated, dissolved in MeOH (10 mL), neutralized with solid NaHCO.sub.3 and purified by column chromatography [Al.sub.2O.sub.3, petroleum ether/ethyl acetate=10/1 to 1/1, dichloromethane/methanol=15:1] to afford the title compound (834 mg, 82% yield) as a yellow oil; .sup.1H NMR (400 MHZ, METHANOL-d4) =4.03-3.93 (m, 2H), 3.41-3.18 (m, 3H), 3.04-2.97 (m, 1H), 2.97-2.84 (m, 6H), 2.80 (td, J=4.8, 10.4 Hz, 1H), 2.09-1.93 (m, 2H), 1.91-1.82 (m, 1H), 1.82-1.71 (m, 2H), 1.69-1.47 (m, 3H). Intermediate 35 ##STR00182## ((3S,7aS)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate [0374] Synthesized according to Intermediate 34 from ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methanol. The title compound was obtained as yellow oil; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =4.00 (dq, J=6.0, 10.8 Hz, 2H), 3.31-3.22 (m, 2H), 3.03-2.96 (m, 2H), 2.95-2.86 (m, 6H), 2.80 (td, J=5.2, 10.8 Hz, 1H), 2.09-1.46 (m, 8H). Intermediate 36 ##STR00183## 5-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide ##STR00184## [0375] Step A. cis-3-(benzyloxy)cyclobutyl methanesulfonate: To a solution of cis-3-(benzyloxy)cyclobutan-1-ol (1.0 g, 1.0 equiv), DMAP (68.6 mg, 0.1 equiv) and TEA (1.7 g, 3.0 equiv) in DCM (10 mL) was added methylsulfonyl methanesulfonate (2.0 g, 11.2 mmol, 2.0 equiv) drop-wise at 0 C. under N.sub.2. The reaction was stirred at 25 C. for 2 hours. The mixture was quenched by ice slowly and then extracted with DCM (20 mL3). The combined organic phases were washed with brine (25 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated, and purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 5/1) to afford the title compound (1.4 g, 97.4% yield) as yellow liquid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.39-7.28 (m, 5H), 4.66 (quin, J=7.2 Hz, 1H), 4.44 (s, 2H), 3.75 (quin, J=6.8 Hz, 1H), 2.99 (s, 3H), 2.89-2.79 (m, 2H), 2.39-2.30 (m, 2H). [0376] Step B. tert-butyl ((1-(trans-3-(benzyloxy)cyclobutyl)-3-(dimethylcarbamoyl)-1H-pyrazol-5-yl)methyl)carbamate: To a mixture of tert-butyl N-[[3-(dimethylcarbamoyl)-1H-pyrazol-5-yl]methyl]carbamate (100 mg, 1.0 equiv) and cis-3-(benzyloxy)cyclobutyl methanesulfonate (143 mg, 1.5 equiv) in DMF (2 mL) was added Cs.sub.2CO.sub.3 (364 mg, 3.0 equiv) in one portion at 25 C. under N.sub.2. The reaction was heated to 90 C. and stirred for 12 hours. The mixture was poured into ice-water (3 mL) and extracted with ethyl acetate (4 mL3). The combined organic phases were washed with brine (5 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and purified by prep-TLC (SiO.sub.2, PE/EA=3:1) to afford the title compound (38 mg, 20% yield) as yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.28-7.21 (m, 5H), 6.49 (s, 1H), 4.93 (br s, 1H), 4.70 (brs, 1H), 4.42-4.39 (m, 3H), 4.26 (br d, J=5.6 Hz, 2H), 3.27 (s, 3H), 3.02 (s, 3H), 2.71-2.66 (m, 2H), 2.54-2.50 (m, 2H), 1.37 (s, 9H). The other regioisomer was also observed. [0377] Step C. tert-butyl ((3-(dimethylcarbamoyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)methyl)carbamate: To a solution of tert-butyl ((1-(trans-3-(benzyloxy)cyclobutyl)-3-(dimethylcarbamoyl)-1H-pyrazol-5-yl)methyl)carbamate (175 mg, 1.0 equiv) in MeOH (3 mL) was added Pd/C (100 mg, 10% purity) under N.sub.2. The suspension was degassed under vacuum and purged with H.sub.2 several times. The reaction was stirred under H.sub.2 (15 psi) at 25 C. for 1 hour. The mixture was filtered, and the filtrate was concentrated to afford the title compound (100 mg, crude) as white solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =6.48 (s, 1H), 5.01-4.89 (m, 1H), 4.60 (br s, 1H), 4.22 (br s, 2H), 4.12-3.92 (m, 3H), 3.35 (s, 2H), 3.32-3.15 (m, 3H), 3.13-2.98 (m, 3H), 2.71 (td, J=6.0, 12.0 Hz, 2H), 2.47-2.32 (m, 2H), 1.36 (s, 9H). [0378] Step D. 5-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: To a solution of tert-butyl ((3-(dimethylcarbamoyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)methyl)carbamate (100 mg, 1.0 equiv) in dioxane (1 mL) was added HCl/dioxane (4 M, 4.0 equiv) at 25 C. The reaction was stirred at 25 C. for 1 hour. The mixture was concentrated to give the crude product (70 mg, crude, HCl) as yellow solid. LCMS (ESI, M+1): m/z=239.2. Intermediate 37 ##STR00185## 3-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide ##STR00186## ##STR00187## [0379] Step A. cis-3-(benzyloxy)cyclobutanol: To a solution of 3-(benzyloxy)cyclobutanone (7.00 g, 1.0 equiv) in MeOH (120 mL) was added NaBH.sub.4 (1.80 g, 1.2 equiv) in portions at 0 C. under nitrogen atmosphere. The reaction was stirred at 0 C. for 1 hour. The mixture was quenched with saturated ammonium chloride solution (300 mL) slowly at 0-5 C., concentrated to remove MeOH, and extracted with EtOAc (70 mL3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated to afford the title compound (6.88 g, 94% yield) as colorless liquid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.39-7.29 (m, 5H), 4.49-4.38 (m, 2H), 3.96-3.87 (m, 1H), 3.64 (t, J=6.8 Hz, 1H), 2.76-2.68 (m, 2H), 1.98-1.92 (m, 2H). [0380] Step B. methyl 1-(trans-3-(benzyloxy)cyclobutyl)-3-cyano-1H-pyrazole-5-carboxylate: To a mixture of methyl 5-cyano-1H-pyrazole-3-carboxylate (1.80 g, 1.0 equiv), cis-3-(benzyloxy)cyclobutanol (2.12 g, 1.0 equiv) and PPh.sub.3 (6.25 g, 2.0 equiv) in THF (40 mL) was added DIAD (4.82 g, 4.6 mL, 2.0 equiv). The reaction was stirred at 0 C. for 0.5 hours and 25 C. for 12 hours. The mixture was concentrated and purified with flash silica gel chromatography (ISCO; 80 g Sepaflash silica flash column, eluent of 30% ethyl acetate/petroleum ether gradient @ 100 mL/min) to afford the title compound (3.00 g, 71% yield) as yellow oil; 1H NMR (400 MHZ, CHLOROFORM-d) o=7.37 (d, J=4.4 Hz, 4H), 7.34-7.29 (m, 1H), 7.20 (s, 1H), 5.95-5.78 (m, 1H), 4.49 (s, 2H), 4.45 (ddd, J=2.4, 4.4, 6.8 Hz, 1H), 3.91 (s, 3H), 2.88-2.76 (m, 2H), 2.74-2.62 (m, 2H). [0381] Step C. methyl 3-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylate: To a solution of methyl 1-(trans-3-(benzyloxy)cyclobutyl)-3-cyano-1H-pyrazole-5-carboxylate (600 mg, 1.0 equiv) in MeOH (20 mL) and HCl solution (1 mL, 2 M in MeOH) was added Pd/C (100 mg, 10% purity, wet). The reaction was degassed and purged with H.sub.2 3 times. The reaction was stirred at 25 C. under H.sub.2 atmosphere (15 psi) for 2 hours. The mixture was filtered and concentrated to afford the title compound (500 mg, 99% yield, HCl) as white solid. [0382] Step D. methyl 3-(((tert-butoxycarbonyl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylate: To a mixture of methyl 3-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylate (500 mg, 1.0 equiv, HCl) and TEA (580 mg, 0.8 mL, 3.0 equiv) in dichloromethane (10 mL) was added BoczO (625 mg, 0.6 mL, 1.5 equiv). The reaction was stirred at 30 C. for 2 hours. The mixture was concentrated and purified with flash silica gel chromatography (ISCO; 40 g Sepaflash silica flash column, eluent of 50-70% EtOAc/PE gradient @ 50 mL/min) to afford the title compound (200 mg, 31% yield, 95% purity) as white solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =6.76 (s, 1H), 5.82 (br s, 1H), 5.06-4.92 (m, 1H), 4.81-4.69 (m, 1H), 4.34 (br d, J=4.4 Hz, 2H), 3.86 (s, 3H), 2.93-2.81 (m, 2H), 2.50 (ddd, J=4.0, 8.4, 13.2 Hz, 2H), 1.48 (s, 9H); LCMS (ESI, M+1): m/z=326.1. [0383] Step E: 3-(((tert-butoxycarbonyl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylic acid: To a solution of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylate (200 mg, 1 equiv) in MeOH (2 mL) and H.sub.2O (1 mL) was added KOH (51.7 mg, 1.5 equiv). The mixture was stirred at 40 C. for 2 hours. The reaction was quenched by ice slowly and then extracted with DCM (5 mL3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to afford the title compound (166 mg, crude) as white solid; 1H NMR (400 MHZ, DMSO-d6) =13.43-13.08 (m, 1H), 7.29 (br t, J=5.6 Hz, 1H), 6.63 (s, 1H), 5.76-5.66 (m, 1H), 5.15 (br d, J=4.4 Hz, 1H), 4.40 (br d, J=3.6 Hz, 1H), 4.09 (br d, J=5.6 Hz, 2H), 2.70-2.57 (m, 2H), 2.29 (ddd, J=4.0, 8.5, 12.6 Hz, 2H), 1.39 (s, 9H). [0384] Step F. tert-butyl ((5-(dimethylcarbamoyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)methyl)carbamate: To a solution of 3-(((tert-butoxycarbonyl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylic acid (143 mg, 1.0 equiv) and N-methylmethanamine (93.6 mg, 2.5 equiv, HCl) in DMF (2 mL) were added DIEA (297 mg, 5.0 equiv) and HATU (524 mg, 3.0 equiv). The reaction was stirred at 25 C. for 12 hours. The residue was poured into ice-water (5 mL) and extracted with ethyl acetate (5 mL3). The combined organic phases were washed with brine (5 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum to afford the tittle compound (155 mg, 94.7% yield,) as yellow liquid. [0385] Step G. 3-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide: To a solution of tert-butyl ((5-(dimethylcarbamoyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)methyl)carbamate (155 mg, 1.0 equiv) in dioxane (1 mL) was added HCl/dioxane (4 M, 1 mL). The reaction was stirred at 25 C. for 2 hours. The mixture was concentrated to afford the title compound (100 mg, crude, HCl) as yellow solid. LCMS (ESI, M+1): m/z=239.0. Example 524 ##STR00188## 4-(cyclohex-1-en-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine ##STR00189## [0386] A mixture of Intermediate 1 (60 mg, 1 equiv), tributyl(cyclohexen-1-yl) stannane (93.1 mg, 2 equiv), cuprous; 2-hydroxy-3-methyl-benzoate (80.8 mg, 3 equiv), Pd(PPh.sub.3).sub.4 (14.5 mg, 0.1 equiv) in THF (2 mL) was degassed and purged with N.sub.2 for 3 times. The mixture was stirred at 60 C. for 15 hours under N.sub.2 atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated and purified by prep-HPLC (column: Phenomenex Luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 23%-53%, 10 min) to afford the title compound (1.27 mg, 2.45 mol, 1.95% yield) as an off-white solid (0.23 formic acid salt). 1H NMR (400 MHZ, METHANOL-d.sub.4) =9.27 (s, 1H), 8.67-8.47 (m, 1H), 8.14 (br d, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.74-7.69 (m, 1H), 7.65-7.62 (m, 1H), 7.54 (dt, J=5.0, 8.0 Hz, 1H), 7.20 (dd, J=7.0, 13.2 Hz, 1H), 6.49 (br t, J=3.6 Hz, 1H), 4.45 (s, 2H), 3.19 (br dd, J=5.8, 10.8 Hz, 2H), 2.81 (td, J=6.5, 10.8 Hz, 2H), 2.70 (br s, 2H), 2.51-2.39 (m, 2H), 2.13 (br dd, J=6.5, 12.4 Hz, 2H), 2.00-1.81 (m, 10H). LCMS (ESI, M+1): m/z=513.3. Example 525 ##STR00190## 5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,6a-dihydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione ##STR00191## [0387] Step A. 2-[(2,4-dimethoxyphenyl)methyl]-5-methylene-3a,4,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3-dione: To a solution of 1-[(2,4-dimethoxyphenyl)methyl]pyrrolidine-2,5-dione (12.0 g, 1.0 equiv) in THF (200 mL) was added LDA (2 M, 144 mL, 6.0 equiv) at 78 C. under nitrogen atmosphere. The mixture was stirred at 78 C. for 15 min and stirred at 0 C. for 1 hour. The mixture was cooled to 78 C. and a solution of 3-chloro-2-(chloromethyl) prop-1-ene (24.1 g, 4.0 equiv) in THF (100 mL) was added dropwise. The mixture was allowed to warm to 20 C. and stirred at 20 C. for 24 hours. The mixture was quenched with saturated ammonium chloride solution (500 mL) and water (500 mL). The mixture was extracted with EtOAc (300 mL2). The organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 1:1) to afford the title compound (5.50 g, 21% yield, 55% purity) as a light yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =6.97 (d, J=8.4 Hz, 1H), 6.44-6.34 (m, 2H), 4.93 (s, 2H), 4.61 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.28-3.20 (m, 2H), 2.79-2.69 (m, 2H), 2.69-2.61 (m, 2H) [0388] Step B. 2-[(2,4-dimethoxyphenyl)methyl]-3a,4,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3,5-trione: To a solution of 2-[(2,4-dimethoxyphenyl)methyl]-5-methylene-3a,4,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3-dione (2.00 g, 1.0 equiv) in THF (20 mL) and H.sub.2O (20 mL) was added NaIO.sub.4 (5.68 g, 4.0 equiv) and K.sub.2OsO.sub.4.Math.2H.sub.2O (122 mg, 0.05 equiv). The mixture was stirred at 20 C. for 3 hours. The mixture was diluted with water (200 mL) and extracted with EtOAc (50 mL3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 20:1 to 1:1) to afford the title compound (850 mg, 42% yield) as a light yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.14 (d, J=8.0 Hz, 1H), 6.46-6.41 (m, 2H), 4.66 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.56-3.49 (m, 2H), 2.84-2.73 (m, 2H), 2.62-2.51 (m, 2H) [0389] Step C. [2-[(2,4-dimethoxyphenyl)methyl]-1,3-dioxo-6,6a-dihydro-3aH-cyclopenta[c]pyrrol-5-yl]trifluoromethanesulfonate: To a solution of 2-[(2,4-dimethoxyphenyl)methyl]-3a,4,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3,5-trione (850 mg, 1.0 equiv) in THF (12 mL) was added LDA (2 M, 1.7 mL, 1.2 equiv) at 78 C. under nitrogen atmosphere. The mixture was stirred at 78 C. for 0.5 hour. A solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.00 g, 1.0 equiv) in THF (6 mL) was added. The reaction mixture was stirred at 20 C. for 16 hours. The mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (30 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 20:1 to 3:1) to afford the title compound (410 mg, 34% yield) as a light yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.04 (d, J=9.2 Hz, 1H), 6.44-6.39 (m, 2H), 5.81 (d, J=2.0 Hz, 1H), 4.73-4.57 (m, 2H), 3.89 (qd, J=2.8, 8.1 Hz, 1H), 3.79 (s, 6H), 3.46 (ddd, J=2.8, 7.8, 10.5 Hz, 1H), 3.16-3.06 (m, 1H), 3.03-2.93 (m, 1H) [0390] Step D. 2-[(2,4-dimethoxyphenyl)methyl]-5-trimethylstannyl-6,6a-dihydro-3aH-cyclopenta[c]pyrrole-1,3-dione: To a solution of [2-[(2,4-dimethoxyphenyl)methyl]-1,3-dioxo-6,6a-dihydro-3aH-cyclopenta[c]pyrrol-5-yl]trifluoromethanesulfonate (100 mg, 1.0 equiv) and trimethyl(trimethylstannyl) stannane (90.3 mg, 1.2 equiv) in THF (2 mL) were added LiCl (29.2 mg, 3.0 equiv) and Pd(PPh.sub.3).sub.4 (53.1 mg, 0.2 equiv). The mixture was stirred at 60 C. for 16 hours under nitrogen atmosphere. The mixture was filtered and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 2:1) to afford the title compound (50.0 mg, 48% yield) as a light yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =6.93 (d, J=8.0 Hz, 1H), 6.43-6.35 (m, 2H), 5.86 (d, J=2.4 Hz, 1H), 4.59 (d, J=3.6 Hz, 2H), 3.95 (dt, J=2.4, 5.0 Hz, 1H), 3.78 (d, J=1.6 Hz, 6H), 3.50-3.41 (m, 1H), 2.97-2.91 (m, 2H), 0.18 (s, 9H) [0391] Step E. 2-(3,4-dimethoxybenzyl)-5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,6a-dihydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione: To a solution of Intermediate 1 (40.0 mg, 1.0 equiv) and 2-[(2,4-dimethoxyphenyl)methyl]-5-trimethylstannyl-6,6a-dihydro-3aH-cyclopenta[c]pyrrole-1,3-dione (48.9 mg, 1.3 equiv) in THF (1 mL) were added thiophene-2-carbonyloxy copper (23.9 mg, 1.5 equiv), Pd.sub.2(dba) 3 (7.65 mg, 0.1 equiv) and tris(2-furyl)phosphine (5.82 mg, 0.3 equiv). The mixture was stirred at 60 C. for 12 hours under nitrogen atmosphere. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 0:1 and ethyl acetate/MeOH 10:1) to afford the title compound (50.0 mg, 76% yield) as a light yellow solid; .sup.1H NMR (400 MHz, CHLOROFORM-d) =9.23 (d, J=2.8 Hz, 1H), 8.03 (br d, J=8.4 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.69-7.63 (m, 1H), 7.62-7.57 (m, 1H), 7.47 (dt, J=5.2, 8.0 Hz, 1H), 7.17-7.08 (m, 2H), 6.66 (br s, 1H), 6.46-6.38 (m, 2H), 4.68 (s, 2H), 4.54-4.31 (m, 2H), 4.29-4.22 (m, 1H), 3.82-3.77 (m, 3H), 3.71 (d, J=16.0 Hz, 4H), 3.67-3.59 (m, 2H), 3.58-3.48 (m, 1H), 3.36-3.02 (m, 2H), 2.86-2.59 (m, 3H), 2.22-2.09 (m, 2H), 2.00-1.86 (m, 4H), 1.82-1.68 (m, 2H); [0392] Step F. 5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,6a-dihydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione: To a solution of 2-(3,4-dimethoxybenzyl)-5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,6a-dihydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (40.0 mg, 1.0 equiv) in ACN (1 mL) was added a solution of CAN (153 mg, 5.0 equiv) in H.sub.2O (1 mL) at 0 C. The mixture was stirred at 20 C. for 12 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL5). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 0:1 and ethyl acetate/MeOH 10:1) and prep-HPLC [Phenomenex luna C18 15025 mm10 um; A: water (FA), B: ACN, B %: 12%-42% over 10 min] to afford the title compound (0.80 mg, 2.2% yield) as a yellow solid (0.40 formic acid salt); .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.34 (s, 1H), 8.30-8.23 (m, 1H), 8.03 (br d, J=8.4 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.69-7.64 (m, 1H), 7.63-7.59 (m, 1H), 7.47 (dt, J=5.2, 8.0 Hz, 1H), 7.18-7.09 (m, 1H), 6.73 (br s, 1H), 4.95-4.85 (m, 1H), 4.84-4.75 (m, 1H), 4.39-4.26 (m, 1H), 3.94-3.82 (m, 2H), 3.75-3.67 (m, 1H), 3.67-3.54 (m, 2H), 3.04-2.91 (m, 2H), 2.41 (br dd, J=6.0, 13.6 Hz, 2H), 2.33-2.26 (m, 2H), 2.12 (br dd, J=6.4, 12.8 Hz, 2H), 2.01 (br dd, J=6.4, 13.2 Hz, 2H); LCMS (ESI, M+1): m/z=568.2. Example 526 ##STR00192## 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydro-2,6-naphthyridine-1,3(2H,4H)-dione ##STR00193## [0393] Step A. methyl 2-(4-cyanopyridin-3-yl)acetate: To a mixture of 3-methylisonicotinonitrile (2.2 g, 1.0 equiv) and dimethyl carbonate (2.52 g, 1.5 equiv) in THF (20 mL) was added dropwise KHMDS (1 M, 37.2 mL, 2.0 equiv) at 60 C. The reaction was stirred at 60 C. for 0.5 hour. The mixture was quenched with saturated NH.sub.4Cl solution (50 ml) and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 20:1 to 2:1) to afford the title compound (600 mg, 17% yield) as a yellow oil; LCMS (ESI, M+1): m/z=177.1. [0394] Step B. 2,6-naphthyridine-1,3(2H,4H)-dione: To a mixture of methyl 2-(4-cyanopyridin-3-yl)acetate (300 mg, 1.0 equiv) in toluene (6 mL) were added tris(triphenylphosphine) rhodium (I) chloride (78.8 mg, 0.05 equiv) and (E)-acetaldehyde oxime (503 mg, 5 equiv). The mixture was degassed and purged with nitrogen 3 times. The reaction was stirred at 110 C. for 6 hours under nitrogen atmosphere. The mixture was concentrated and triturated with methanol (5 ml) at 25 C. for 1 hour to afford the title compound (170 mg, 45% yield) as a brown solid; LCMS (ESI, M+1): m/z=163.0. [0395] Step C. tert-butyl 5,7-dioxooctahydro-2,6-naphthyridine-2(1H)-carboxylate: To a mixture of 2,6-naphthyridine-1,3(2H,4H)-dione (170 mg, 1.0 equiv) and (Boc).sub.2O (333 mg, 2.0 equiv) in MeOH (10 mL) was added Pd/C (30 mg, 10% purity). The reaction was degassed and purged with hydrogen 3 times. The reaction was stirred at 40 C. for 20 hours under H.sub.2 (50 psi) atmosphere. The mixture was filtered and concentrated to afford the title compound (147 mg, 45% yield) as a brown solid, LCMS (ESI, M55): m/z=213.0. [0396] Step D. hexahydro-2,6-naphthyridine-1,3(2H,4H)-dione: To a mixture of tert-butyl 5,7-dioxooctahydro-2,6-naphthyridine-2(1H)-carboxylate (147 mg, 1.0 equiv) in dichloromethane (2 mL) was added TFA (770 mg, 12 equiv). The reaction was stirred at 25 C. for 0.5 hour. The mixture was concentrated to afford the title compound (160 mg, crude, TFA salt) as a brown oil. [0397] Step E. 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydro-2,6-naphthyridine-1,3(2H,4H)-dione: To a mixture of hexahydro-2,6-naphthyridine-1,3(2H,4H)-dione (160 mg, 5.0 equiv, TFA) and 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (60 mg, 1.0 equiv) in DMF (0.05 mL) were added DIPEA (223 mg, 15 equiv) and 4 molecular sieves (50 mg). The reaction was stirred at 40 C. for 16 hours. The mixture was filtered and purified with prep-HPLC [Phenomenex Luna C18 7530 mm3 m; A: water (FA), B: ACN, B %: 5%-35% over 10 min] and lyophilized to afford the title compound (7.54 mg, 9.3% yield over two steps,) as a brown solid (0.95 formic acid salt); .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.18-9.10 (m, 1H), 8.18-8.11 (m, 1H), 7.91-7.85 (m, 1H), 7.76-7.69 (m, 1H), 7.67-7.60 (m, 1H), 7.59-7.52 (m, 1H), 7.27-7.16 (m, 1H), 4.67 (s, 2H), 4.30-3.89 (m, 3H), 3.74-3.62 (m, 2H), 3.32-3.06 (m, 4H), 2.92-2.78 (m, 1H), 2.77-2.42 (m, 3H), 2.40-2.31 (m, 2H), 2.30-2.15 (m, 4H), 2.12 (br dd, J=6.4, 12.4 Hz, 3H); LCMS (ESI, M+1): m/z=599.2. Example 527 ##STR00194## (R)-1-(2-(3-aminoazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00195## [0398] Step A. (R)-tert-butyl (1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl) azetidin-3-yl)carbamate: To a mixture of (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 1.0 equiv), tert-butyl N-(azetidin-3-yl)carbamate (130 mg, 2.0 equiv) in dioxane (2 mL) was added DIPEA (244 mg, 5.0 equiv), and then the mixture was stirred at 90 C. for 12 hours under N.sub.2 atmosphere. The reaction mixture was diluted (40 mL) and extracted with ethyl acetate (230 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate and concentrated to afford the title compound (200 mg, 80% yield) as a yellow solid; LCMS (ESI, M+1): m/z=665.3. [0399] Step B. (R)-1-(2-(3-aminoazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of tert-butyl N-[1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]azetidin-3-yl]carbamate (150 mg, 1.0 equiv) in dioxane (1.5 mL) was added HCl/dioxane (4 M, 564 L, 10.0 equiv) at 0 C. The mixture was stirred at 0 C. for 2 hours. The reaction was quenched with saturated sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (330 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, concentrated and purified with prep-HPLC (C18, A: water [(0.1% FA)-ACN]; B: ACN, B %: 45%-65%, over 25 min) to afford the title compound (96.3 mg, 82% yield) as a white solid (0.52 formic acid salt); 1H NMR (400 MHZ, METHANOL-d4) =8.98 (d, J=1.6 Hz, 1H), 8.51 (br s, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.24 (t, J=9.2 Hz, 1H), 7.04 (s, 1H), 4.58-4.48 (m, 2H), 4.31 (br d, J=13.2 Hz, 1H), 4.18-4.01 (m, 4H), 3.64-3.50 (m, 1H), 3.47-3.39 (m, 1H), 2.59-2.42 (m, 1H), 2.33-2.19 (m, 1H), 2.18-2.05 (m, 1H), 1.89-1.68 (m, 3H), 1.26 (d, J=13.6 Hz, 3H), 0.82 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=521 Example 528 ##STR00196## 7-(2-(3-aminoazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione [0400] The title compound was synthesized from 7-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione according to the 2-step procedure described for example 527 as a white solid. (0.54 formic acid salt) .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =8.87 (d, J=1.2 Hz, 1H), 8.68 (d, J=2.0 Hz, 1H), 7.74 (dd, J=6.0, 9.2 Hz, 1H), 7.39-7.27 (m, 2H), 6.99 (dd, J=2.4, 6.0 Hz, 1H), 4.35-4.16 (m, 4H), 3.93-3.69 (m, 4H), 3.55-3.25 (m, 3H), 2.39-2.30 (m, 1H), 2.25-2.12 (m, 1H), 2.10-1.96 (m, 2H), 1.94-1.77 (m, 2H), 0.81-0.68 (m, 3H); LCMS (ESI, M+1): m/z=575.3. Example 529 ##STR00197## 5-(2-(3-aminoazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [0401] The title compound was synthesized from 5-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide according to the 2-step procedure described for example 527 as a white solid. (0.40 formic acid salt) .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =8.95 (s, 1H), 7.66 (dd, J=6.0, 9.2 Hz, 1H), 7.31-7.19 (m, 2H), 7.04 (d, J=2.4 Hz, 1H), 6.65 (s, 1H), 5.22-5.01 (m, 2H), 4.57-4.43 (m, 4H), 4.33 (td, J=5.6, 14.4 Hz, 2H), 4.15-4.06 (m, 3H), 3.32 (s, 3H), 2.56-2.44 (m, 1H), 2.34 (br s, 2H), 2.28-2.14 (m, 1H), 0.79 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=614.4. Example 530 ##STR00198## (R)-1-(2-(3-amino-3-methylazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol [0402] The title compound was synthesized from (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol and tert-butyl N-(3-methylazetidin-3-yl)carbamate according to the 2-step procedure described for example 527 except for HCl.Math.MeOH was used in Step B to produce the desired compound as as a white solid. (0.37 formic acid salt) .sup.1H NMR (400 MHZ, METHANOL-d4) =8.99 (d, J=2.0 Hz, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.27-7.20 (m, 1H), 7.03 (s, 1H), 4.32 (br d, J=13.2 Hz, 1H), 4.18 (s, 4H), 4.08 (br dd, J=8.4, 13.2 Hz, 1H), 3.46 (br s, 2H), 2.50 (ddd, J=2.0, 7.2, 14.4 Hz, 1H), 2.34-2.19 (m, 1H), 2.17-2.03 (m, 1H), 1.90-1.70 (m, 3H), 1.60 (s, 3H), 1.26 (d, J=13.2 Hz, 3H), 0.88-0.78 (m, 3H); LCMS (ESI, M+1): m/z=535.3. Example 531 ##STR00199## 7-(2-(3-amino-3-methylazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione [0403] The title compound was synthesized from 7-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione and tert-butyl N-(3-methylazetidin-3-yl)carbamate according to the 2-step procedure described for example 527 to produce the desired compound as as a white solid. (0.7 formic acid salt) .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =8.87 (s, 1H), 8.25 (s, 1H), 7.74 (dd, J=6.0, 8.8 Hz, 1H), 7.39-7.26 (m, 2H), 6.99 (dd, J=2.4, 6.4 Hz, 1H), 4.39-4.15 (m, 3H), 3.97-3.89 (m, 4H), 3.51-3.29 (m, 3H), 2.31-1.96 (m, 4H), 1.93-1.76 (m, 2H), 1.41 (s, 3H), 0.81-0.67 (m, 3H); LCMS (ESI, M+1): m/z=589.3 Example 532 ##STR00200## 5-(2-(3-amino-3-methylazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [0404] The title compound was synthesized from 5-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide and tert-butyl N-(3-methylazetidin-3-yl)carbamate according to the 2-step procedure described for example 527 to produce the desired compound as as a white solid. (0.31 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =8.95 (s, 1H), 7.66 (dd, J=6.0, 9.2 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.24 (t, J=9.2 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.65 (s, 1H), 5.25-5.03 (m, 2H), 4.56-4.48 (m, 2H), 4.35 (br d, J=15.6 Hz, 2H), 4.12 (s, 4H), 3.33 (s, 3H), 3.32-3.30 (m, 6H), 3.08 (s, 3H), 2.62-2.45 (m, 1H), 2.40-2.30 (m, 2H), 2.27-2.16 (m, 1H), 1.56 (s, 3H), 0.80 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=628.4. Example 533 ##STR00201## (R)-1-(2-(3-(dimethylamino) azetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol [0405] The title compound was synthesized from (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol and N,N-dimethylazetidin-3-amine dihydrochloride according to the 2-step procedure described for example 527 to produce the desired compound as as a white solid. (0.28 formic acid salt) .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =8.97 (d, J=2.4 Hz, 1H), 8.35 (br s, 1H), 7.66 (dd, J=5.9, 9.0 Hz, 1H), 7.29 (d, J=2.6 Hz, 1H), 7.24 (t, J=9.4 Hz, 1H), 7.08-7.01 (m, 1H), 4.41-4.25 (m, 3H), 4.15-4.02 (m, 3H), 3.64-3.48 (m, 1H), 3.47-3.36 (m, 2H), 3.31 (s, 2H), 2.56-2.46 (m, 1H), 2.36 (s, 6H), 2.24 (dqd, J=4.6, 7.4, 14.5 Hz, 1H), 2.17-2.03 (m, 1H), 1.82 (br s, 1H), 1.79-1.69 (m, 2H), 1.26 (d, J=13.4 Hz, 3H), 0.89-0.77 (m, 3H); LCMS (ESI, M+1): m/z=: 549.2. Example 534 ##STR00202## 7-(2-(3-(dimethylamino) azetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione [0406] The title compound was synthesized from 7-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione and N,N-dimethylazetidin-3-amine dihydrochloride according to the 2-step procedure described for example 527 to produce the desired compound as a white solid. (0.32 formic acid salt) .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.87-10.62 (m, 1H), 10.17-9.53 (m, 1H), 8.87 (s, 1H), 8.66 (1H), 7.75 (dd, J=6.0, 9.2 Hz, 1H), 7.40-7.26 (m, 2H), 6.99 (dd, J=2.4, 6.0 Hz, 1H), 4.37-4.09 (m, 4H), 3.99-3.87 (m, 2H), 3.46-3.38 (m, 2H), 3.18-3.10 (m, 1H), 2.47-2.17 (m, 2H), 2.13 (s, 6H), 2.09-1.94 (m, 2H), 1.83 (br t, J=9.6 Hz, 2H), 0.80-0.68 (m, 3H); LCMS (ESI, M+1): m/z=603.4. Example 535 ##STR00203## 5-(2-(3-(dimethylamino) azetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [0407] The title compound was synthesized from 5-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide and N,N-dimethylazetidin-3-amine dihydrochloride according to the 2-step procedure described for example 527 to produce the desired compound as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =8.94 (s, 1H), 7.66 (dd, J=6.0, 8.8 Hz, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.24 (t, J=9.2 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.69 (s, 1H), 5.28-5.02 (m, 2H), 4.52 (br d, J=5.6 Hz, 2H), 4.41-4.27 (m, 4H), 4.16-4.01 (m, 2H), 3.44-3.36 (m, 1H), 3.36-3.32 (m, 3H), 3.08 (s, 3H), 2.57-2.47 (m, 1H), 2.41-2.28 (m, 8H), 2.27-2.16 (m, 1H), 0.80 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=642.4. Example 536 ##STR00204## (R)-1-(2-((1-(aminomethyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00205## [0408] Step A. (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropanecarbonitrile: To a solution of t-BuONa (2 M, 3.40 mL, 2.0 equiv) in THF was added 1-(hydroxymethyl)cyclopropanecarbonitrile (661 mg, 2.0 equiv). The reaction was stirred at 0 C. for 0.5 hour under N.sub.2 atmosphere. The mixture was added into a solution of (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1.80 g, 1.0 equiv) in THF (10 mL) at 0 C. The reaction was stirred at 25 C. for 2 hours. The reaction mixture was quenched by addition of H.sub.2O (10 mL) at 0 C. The mixture was extracted with EtOAc (320 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (900 mg, 45% yield) as a white solid; LCMS (ESI, M+1): m/z=590.2. [0409] Step B. (R)-1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropanecarbonitrile: To a solution of (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropanecarbonitrile (400 mg, 1.0 equiv) in DCM (4 mL) was added TFA (6.16 g, 4.00 mL) at 0 C. The mixture was stirred at 25 C. for 0.5 hour. The reaction mixture was quenched with saturated NaHCO.sub.3 solution (8 mL) at 0 C. The mixture was extracted with EtOAc (35 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (15.4 mg, 11% yield) as a white solid; LCMS (ESI, M+1): m/z=546.3. [0410] Step C. (R)-1-(2-((1-(aminomethyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of PtO.sub.2 (83.2 mg, 1.0 equiv) in MeOH (2.5 mL) were added (R)-1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropanecarbonitrile (200 mg, 1.0 equiv) and HCl.Math.MeOH (4 M, 1 mL) under N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The mixture was stirred under H.sub.2 (15 Psi) at 25 C. for 3 hours. The reaction mixture was filtered, concentrated and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (10 mM FA), B: ACN, B %: 13%-43% over 10 min] to afford the title compound (14.3 mg, 6.9% yield) as a light yellow solid (0.9 formic acid salt); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.23 (s, 1H), 8.38 (s, 1H), 7.77-7.73 (m, 1H), 7.40-7.25 (m, 2H), 7.10-6.97 (m, 1H), 4.43-4.00 (m, 4H), 3.69-3.43 (m, 1H), 3.41-3.25 (m, 1H), 2.82 (d, J=1.6 Hz, 1H), 2.53-2.51 (m, 2H), 2.44-2.26 (m, 3H), 2.25-1.92 (m, 2H), 1.74-1.61 (m, 3H), 1.17 (d, J=9.6 Hz, 3H), 0.81-0.53 (m, 7H); LCMS (ESI, M+1): m/z=550.2. Example 537 ##STR00206## (1R,5R,6R)-3-(7-(4-bromo-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00207## [0411] Step A. 1-bromo-5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (340 mg, 1.0 equiv) in DMF (5.0 mL) was added a solution of NBS (112 mg, 1.1 equiv) in DMF (1.5 mL). The mixture was stirred at 20 C. for 2 hours. The reaction mixture was diluted with NazSO.sub.3 (25 mL) and extracted with EtOAc (325 mL). The combined organic layers were washed with NaHCO.sub.3 (220 mL) and brine (20 mL). The organic was dried over Na.sub.2SO.sub.4, concentrated and purified with prep-HPLC [Phenomenex Synergi Polar-RP 10025 mm4 m; A: water (TFA), B: ACN; B %: 44%-64% over 7 min] to afford the title compound (140 mg, 34% yield) as a yellow solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.85 (br s, 1H), 9.22 (s, 1H), 8.21 (dd, J=6.0, 9.6 Hz, 1H), 7.56 (t, J=9.6 Hz, 1H), 7.23 (s, 1H), 5.47-5.17 (m, 3H), 4.34-4.14 (m, 2H), 3.18-3.05 (m, 2H), 3.03 (s, 1H), 2.91-2.78 (m, 1H), 2.39-2.31 (m, 1H), 2.17-2.01 (m, 4H), 1.88-1.77 (m, 3H), 0.71 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+3): m/z=673.0. [0412] Step B. (1R,5R,6R)-3-(7-(4-bromo-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 1-bromo-5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50 mg, 1.0 equiv) and (1S,5S,6R)-3-azabicyclo[3.2.1]octan-6-ol (18.3 mg, 1.5 equiv, HCl) in DMF (0.15 mL) was added DIPEA (48.1 mg, 5.0 equiv) and 4 molecular sieves (20 mg). Then the mixture was stirred at 60 C. for 12 hours. The mixture was filtered, concentrated and purified by prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN; B %: 18%-48% over 10 min] to afford the title compound (22 mg, 39% yield, FA) as a yellow solid (0.19 formic acid salt); .sup.1H NMR (400 MHz, DMSO-d.sub.6) =10.83 (br s, 1H), 9.39-9.24 (m, 1H), 8.20 (dd, J=6.0, 9.6 Hz, 1H), 8.16 (s, 1H), 7.55 (dt, J=2.8, 9.6 Hz, 1H), 7.23 (d, J=16.0 Hz, 1H), 5.39-5.18 (m, 1H), 4.93-4.66 (m, 2H), 4.64-4.50 (m, 1H), 4.20-4.11 (m, 2H), 4.08-3.95 (m, 1H), 3.80-3.68 (m, 1H), 3.37 (br d, J=13.2 Hz, 1H), 3.10 (br d, J=8.8 Hz, 2H), 3.03 (br s, 1H), 2.84 (br d, J=6.4 Hz, 1H), 2.43-2.31 (m, 2H), 2.20-1.99 (m, 6H), 1.89-1.74 (m, 4H), 1.67 (br s, 1H), 1.30-1.21 (m, 1H), 0.73 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+3): m/z=698.0, 700.0. Example 538 ##STR00208## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00209## [0413] A mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (350 mg, 1.00 equiv), 1-oxa-8-azaspiro[3.5]nonane oxalate (305 mg, 1.5 equiv), K.sub.3PO.sub.4 (1.25 g, 10 equiv) and 4 molecular sieves (100 mg) in DMF (2 mL) and ACN (2 mL) was stirred at 60 C. for 2 hours under N.sub.2 atmosphere. The mixture was filtered and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: [water (ammonia hydroxide)-ACN]; B %: 41%-71%, 9 min] to afford the title compound (140 mg, 36% yield) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.29-9.21 (m, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.24 (t, J=9.6 Hz, 1H), 7.08 (d, J=2.8 Hz, 1H), 5.44-5.16 (m, 1H), 4.68-4.52 (m, 3H), 4.49-4.36 (m, 1H), 4.35-4.29 (m, 1H), 4.28-4.20 (m, 1H), 3.82 (ddd, J=2.4, 13.6, 19.4 Hz, 1H), 3.54-3.37 (m, 1H), 3.25-3.13 (m, 3H), 3.00 (dt, J=6.0, 9.2 Hz, 1H), 2.54-2.44 (m, 3H), 2.37-2.12 (m, 5H), 2.02-1.76 (m, 6H), 0.87-0.69 (m, 3H). LCMS (ESI, M+1): m/z=620.1 Example 539 ##STR00210## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((R)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol Example 540 ##STR00211## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00212## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol was separated by SFC [condition: column: REGIS (S,S) WHELK-01 (250 mm25 mm, 10 um); mobile phase: [0.1% NH.sub.3H.sub.2O ETOH]; B %: 40%-40%, 5.5 min] to afford [0414] Example 539 (51.3 mg, 36% yield) as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.26 (d, J=4.4 Hz, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.08 (d, J=2.8 Hz, 1H), 5.40-5.20 (m, 1H), 4.70-4.53 (m, 3H), 4.50-4.37 (m, 1H), 4.37-4.29 (m, 1H), 4.29-4.20 (m, 1H), 3.84 (dd, J=13.6, 17.6 Hz, 1H), 3.57-3.37 (m, 1H), 3.25-3.12 (m, 3H), 3.05-2.96 (m, 1H), 2.56-2.43 (m, 3H), 2.38-2.12 (m, 5H), 2.03-1.79 (m, 6H), 0.81 (q, J=7.6 Hz, 3H), LCMS (ESI, M+1): m/z=620.3. [0415] Example 540 (49.5 mg, 34.7% yield,) as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.26 (d, J=4.0 Hz, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.24 (t, J=9.6 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 5.39-5.22 (m, 1H), 4.69-4.52 (m, 3H), 4.50-4.39 (m, 1H), 4.36-4.31 (m, 1H), 4.29-4.23 (m, 1H), 3.84 (dd, J=13.6, 18.0 Hz, 1H), 3.52-3.39 (m, 1H), 3.26-3.18 (m, 3H), 3.05-2.96 (m, 1H), 2.54-2.44 (m, 3H), 2.34-2.13 (m, 5H), 2.03-1.82 (m, 6H), 0.81 (dt, J=3.6, 7.6 Hz, 3H), LCMS (ESI, M+1): m/z=620.3. Example 541 ##STR00213## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((S)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00214## [0416] To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (100 mg, 1 equiv) and(S)-3-methylpiperidine (25.1 mg, 1.5 equiv) in DMF (0.8 mL) was added DIPEA (109 mg, 5 equiv) and 4 molecular sieves (20 mg). The mixture was stirred at 40 C. for 12 hours. The mixture was diluted with H.sub.2O (10 mL) and extracted with ethyl acetate (45 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified with prep-HPLC [column: Phenomenex Synergi C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 20%-50%, 10 minutes] to afford the title compound (44.5 mg, 41% yield, 0.2FA) as a white solid (1 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.02 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.35-7.19 (m, 2H), 7.06 (s, 1H), 5.48-5.24 (m, 1H), 4.68-4.49 (m, 2H), 4.44-4.27 (m, 2H), 3.56-3.32 (m, 4H), 3.18-3.04 (m, 2H), 2.49-1.75 (m, 12H), 1.40 (br d, J=11.2 Hz, 1H), 1.03 (br d, J=6.4 Hz, 3H), 0.80 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=592.3 Example 542 ##STR00215## 4-(4-((1,2-oxazinan-4-yl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ##STR00216## [0417] Step A tert-butyl 4-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)-1,2-oxazinane-2-carboxylate: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30.0 mg, 1.0 equiv) in dimethyl formamide (1.0 mL) were added K.sub.3PO.sub.4 (107 mg, 10.0 equiv) and tert-butyl 4-aminooxazinane-2-carboxylate (20.5 mg, 2.0 equiv). The mixture was stirred at 60 C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound (40.0 mg, crude), LCMS (ESI, M+1): m/z=695.3. [0418] Step B. 4-(4-((1,2-oxazinan-4-yl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a solution of tert-butyl tert-butyl 4-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)-1,2-oxazinane-2-carboxylate (30.0 mg, 1.0 equiv) in DCM (1.0 mL) was added TFA (0.2 mL). The mixture was stirred at 25 C. for 1 hours. The reaction mixture was concentrated to give a residue which was purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; mobile phase: [water (NH4HCO3)-ACN]; B %: 35%-65%, 10 minutes] and lyophilized to afford the title compound (8.04 mg, 30% yield, 97% purity) as a white solid; 1H NMR (400 MHZ, DMSO-d6) =9.96 (s, 1H), 9.43 (s, 1H), 7.77 (dd, J=6.0, 9.2 Hz, 1H), 7.42-7.31 (m, 2H), 7.2-6.94 (m, 2H), 5.70-5.23 (m, 1H), 4.55-4.41 (m, 2H), 4.11-3.98 (m, 1H), 3.80 (br t, J=10.8 Hz, 1H), 3.26-3.11 (m, 3H), 3.06-2.96 (m, 1H), 2.96-2.84 (m, 1H), 2.81-2.59 (m, 1H), 2.41-2.26 (m, 4H), 2.15-1.84 (m, 7H), 0.71 (t, J=7.2 Hz, 3H), LCMS (ESI, M+1): m/z=595.4. Example 543 ##STR00217## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((E)-2-(1-methyl-1H-pyrazol-5-yl) vinyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00218## [0419] Step A. (E)-1-methyl-5-(2-(tributylstannyl) vinyl)-1H-pyrazole: To a solution of 5-ethynyl-1-methyl-pyrazole (477 mg, 1.0 equiv) and Bu.sub.3SnH (1.7 g, 1.3 equiv) in toluene (7 mL) was added AIBN (36.9 mg, 0.05 equiv). The mixture was stirred at 80 C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (035% Ethyl acetate/Petroleum ether) to afford the title compound (150 mg, 5.4% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.44 (d, J=1.6 Hz, 1H), 6.49-6.45 (m, 1H), 6.37 (d, J=1.6 Hz, 1H), 5.71 (d, J=2.8 Hz, 1H), 3.79 (s, 3H), 1.56-1.52 (m, 6H), 1.49-1.43 (m, 6H), 1.34-1.31 (m, 6H), 0.92-0.90 (m, 9H). [0420] Step B. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((E)-2-(1-methyl-1H-pyrazol-5-yl) vinyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: A mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (35 mg, 1.0 equiv), (E)-1-methyl-5-(2-(tributylstannyl) vinyl)-1H-pyrazole (33.4 mg, 1.3 equiv), thiophene-2-carbonyloxycopper (18.5 mg, 1.5 equiv), tris(2-furyl)phosphane (1.5 mg, 0.1 equiv) and Pd.sub.2(dba).sub.3 (17.8 mg, 0.3 equiv) in THF (1 mL) was stirred at 60 C. for 12 hours under N.sub.2 atmosphere. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL3). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and purified by prep-TLC (SiO.sub.2, DCM/MeOH 10:1), followed by prep-HPLC [C18, 0.1% formic acid condition] and lyophilized to afford the title compound (4 mg, 10.0% yield) as a yellow solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.31 (d, J=6.0 Hz, 1H), 8.26-8.12 (m, 1H), 7.63 (dd, J=11.2, 15.2 Hz, 1H), 7.57-7.48 (m, 2H), 7.23-7.16 (m, 2H), 7.10-6.86 (m, 1H), 6.78 (dd, J=1.6, 14.0 Hz, 1H), 5.48-5.24 (m, 1H), 4.67-4.46 (m, 2H), 4.05 (d, J=6.0 Hz, 3H), 3.64-3.48 (m, 2H), 3.44-3.25 (m, 2H), 3.14-3.07 (m, 1H), 2.50-2.17 (m, 6H), 0.85-0.67 (m, 4H); LCMS (ESI, M+1): m/z=601.2. Example 544 ##STR00219## 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile ##STR00220## [0421] To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (60.0 mg, 1.0 equiv) and piperidine-4-carbonitrile;hydrochloride (55.6 mg, 3.0 equiv, HCl) in DMF (2 mL) was added potassium phosphate (214 mg, 10 equiv) and 4 molecular sieves (10 mg). The mixture was stirred at 60 C. for 2 hours. The mixture was filtered and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 m; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 43%-73%, 9 minutes] and lyophilized to afford the title compound (16.0 mg, 25% yield,) as a yellow solid; .sup.1H NMR (400 MHz, CD.sub.3OD) =9.04 (s, 1H), 7.65 (dd, J=6.0, 8.8 Hz, 1H), 7.27 (d, J=2.4 Hz, 1H), 7.23 (t, J=9.6 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 5.40-5.21 (m, 1H), 4.34-4.24 (m, 4H), 3.96-3.87 (m, 2H), 3.28-3.17 (m, 4H), 3.04-2.98 (m, 1H), 2.93 (s, 1H), 2.53-2.43 (m, 1H), 2.29-2.04 (m, 8H), 2.02-1.95 (m, 2H), 1.92-1.84 (m, 1H), 0.79 (t, J=6.8 Hz, 3H); LCMS (ESI, M+1): m/z=603.2. Example 545 ##STR00221## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2-(1-methyl-1H-pyrazol-5-yl)ethyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00222## [0422] To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((E)-2-(1-methyl-1H-pyrazol-5-yl) vinyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (10 mg, 1 equiv) in THF (0.5 mL) was added Pd/C (5 mg, 10% purity). The mixture was degassed and purged with H.sub.2 for 3 times, and then the mixture was stirred at 20 C. for 12 hours under H.sub.2 atmosphere (15 Psi). The reaction mixture was filtered and purified by prep-HPLC [C18, 0.1% NH.sub.4HCO.sub.3 condition] and lyophilized to afford the title compound (1.4 mg, 12.8% yield) as a white solid. 1H NMR (400 MHZ, CHLOROFORM-d) =7.14 (d, J=8.0 Hz, 1H), 6.48-6.34 (m, 2H), 4.66 (s, 2H), 3.78 (d, J=8.4 Hz, 6H), 3.58-3.46 (m, 2H), 2.86-2.73 (m, 2H), 2.65-2.50 (m, 2H); LCMS (ESI, M+1): m/z=603.1. Example 546 ##STR00223## [0423] (1S,5R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.0]heptan-1-ol The title compound was synthesized according to the procedure described for example 538 as a yellow solid (0.38 formic acid salt). .sup.1H NMR (400 MHZ, CD.sub.3OD) =9.29 (d, J=2.8 Hz, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.06 (dd, J=2.4, 4.8 Hz, 1H), 5.50-5.32 (m, 1H), 4.57-4.46 (m, 2H), 4.45-4.37 (m, 1H), 4.36-4.24 (m, 1H), 4.23-4.12 (m, 2H), 3.63-3.41 (m, 3H), 3.22-3.14 (m, 1H), 3.05-2.96 (m, 1H), 2.52-2.39 (m, 2H), 2.38-2.30 (m, 2H), 2.29-2.21 (m, 2H), 2.19-2.07 (m, 4H), 2.06-1.97 (m, 1H), 1.50-1.36 (m, 1H), 0.83-0.77 (m, 3H); LCMS (ESI, M+1): m/z=606.3. Example 547 ##STR00224## 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-3-carbonitrile [0424] The title compound was synthesized according to the procedure described for example 538 except for heating of the reaction mixture was carried out at 40 C. for 15 hours to afford the desired compound as a yellow solid. .sup.1HNMR (400 MHZ, methanol-d4) =9.21-9.24 (m, 1H), 8.50 (s, 1H), 7.68 (dd, J=9.2, 6.0 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.02-7.08 (m, 1H), 5.28-5.51 (m, 1H), 4.43-4.58 (m, 3H), 4.03-4.35 (m, 3H), 3.39-3.65 (m, 4H), 3.13-3.23 (m, 1H), 2.04-2.59 (m, 11H), 1.94-2.01 (m, 1H), 1.81-1.92 (m, 1H), 1.48-1.65 (m, 1H), 0.75-0.84 ppm (m, 3H); LCMS (ESI, M+1): m/z=617.4. Example 548 ##STR00225## ((3S,7aR)-7a-(((7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate ##STR00226## [0425] Step A ((3S,7aR)-7a-(((7-chloro-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (165 mg, 1.1 equiv) in toluene (5.0 mL) were added ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (110 mg, 1.0 equiv), t-BuONa (131 mg, 3.0 equiv) and 4 molecular sieves (20.0 mg). The mixture was stirred at 0 C. for 1 hour. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic phase was separated and concentrated under reduced pressure to give a residue. The residue was purified with prep-TLC (SiO.sub.2, dichloromethane/methyl alcohol 10:1) to afford the title compound (70.0 mg, 29% yield), LCMS (ESI, M+1): m/z=537.1 [0426] Step B ((3S,7aR)-7a-(((7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-(((7-chloro-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate) (140 mg, 1.0 equiv) in dioxane (2.00 mL) and H.sub.2O (0.50 mL) was added K.sub.3PO.sub.4 (166 mg, 3.0 equiv) CataCXium A Pd G3 (19.0 mg, 0.1 equiv) and 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 1.1 equiv). The mixture was stirred at 90 C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM/MeOH 10:1) to afford the title compound (80.0 mg, 42% yield) as a yellow solid. LCMS (ESI, M+1): m/z=725.4 [0427] Step C ((3S,7aR)-7a-(((7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-(((7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (70.0 mg, 1.0 equiv) in EtOAc (3.00 mL) was added HCl/MeOH (4 M, 3.00 mL). The mixture was stirred at 0 C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified with prep-HPLC (column: Phenomenex C18 7530 mm3 um; mobile phase: [water (FA)-ACN]; B %: 15%-45%, 7 min) to afford the title compound (5.15 mg, 7% yield,) as a white solid (1 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d4) =9.22 (d, J=4.4 Hz, 1H), 8.53 (s, 1H), 7.61 (dd, J=4.4, 8.8 Hz, 1H), 7.44-7.35 (m, 1H), 7.33 (s, 1H), 7.24 (dd, J=2.4, 6.4 Hz, 1H), 4.61-4.53 (m, 1H), 4.40-4.26 (m, 3H), 4.16 (td, J=5.2, 10.4 Hz, 1H), 4.03 (ddd, J=4.0, 6.8, 10.8 Hz, 1H), 3.65-3.59 (m, 1H), 3.48-3.39 (m, 1H), 3.25-3.13 (m, 2H), 3.02-2.94 (m, 1H), 2.93-2.84 (m, 6H), 2.28 (td, J=6.4, 12.6 Hz, 1H), 2.21 (br d, J=2.8 Hz, 1H), 2.12-1.90 (m, 5H), 1.89-1.76 (m, 5H), 1.31-1.27 (m, 3H), LCMS (ESI, M+1): m/z=681.4 Example 549 ##STR00227## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0428] The title compound was synthesized according to the procedure described for example 541 to produce the desired compound as a yellow solid (0.21 formic acid salt); .sup.1H NMR (400 MHZ, methanol-d4) =9.08 (s, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 5.35 (d, J=54.0 Hz, 1H), 4.42-4.32 (m, 2H), 4.17 (br d, J=12.8 Hz, 1H), 4.13-4.05 (m, 1H), 4.00 (br d, J=12.8 Hz, 1H), 3.91-3.81 (m, 1H), 3.36-3.33 (m, 3H), 3.15-3.05 (m, 1H), 2.54-2.26 (m, 3H), 2.24-2.13 (m, 2H), 2.11-2.00 (m, 2H), 1.99-1.89 (m, 3H), 1.88-1.73 (m, 8H), 1.74-1.73 (m, 1H), 0.80 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=618.3. Example 550 ##STR00228## 4-(4-(3-azabicyclo[4.2.1]nonan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ##STR00229## [0429] To a solution of 3-azabicyclo[4.2.1]nonane (20.5 mg, 3.0 equiv, HCl) in DMF (0.1 mL) was added K.sub.3PO.sub.4 (44.8 mg, 5.0 equiv). The mixture was stirred at 25 C. for 0.5 hour. Then 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (25.0 mg, 1.0 equiv) and ACN (0.1 mL) was added. The mixture was stirred at 40 C. for 11.5 hours. The resulting mixture was filtered and purified by prep-HPLC [Waters Xbridge 15025 mm5 um; A: water (0.1% NH.sub.4HCO.sub.3), B: ACN, B %: 56%-86% over 8 min] and lyophilized to afford the title compound (6.07 mg, 23% yield) as a white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.19-9.66 (m, 1H), 9.11 (s, 1H), 7.77 (dd, J=6.0, 9.2 Hz, 1H), 7.38-7.32 (m, 2H), 7.04 (d, J=2.8 Hz, 1H), 5.38-5.21 (m, 1H), 4.32-3.76 (m, 6H), 3.70-3.62 (m, 1H), 3.09 (br d, J=6.4 Hz, 2H), 3.01 (s, 1H), 2.83 (br d, J=6.0 Hz, 1H), 2.65-2.61 (m, 1H), 2.13 (br d, J=4.8 Hz, 2H), 2.03-1.71 (m, 10H), 1.67-1.54 (m, 2H), 1.46-1.38 (m, 1H), 1.24 (s, 1H), 0.77-0.70 (m, 3H); LCMS (ESI, M+1): m/z=618.3. Example 551 ##STR00230## 4-(4-(3-azabicyclo[3.3.1]nonan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0430] The title compound was synthesized according to the procedure described for example 550 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.95 (br s, 1H), 9.16 (s, 1H), 7.77 (dd, J=6.0, 9.2 Hz, 1H), 7.39-7.31 (m, 2H), 7.04 (d, J=2.4 Hz, 1H), 5.39-5.21 (m, 1H), 4.74-4.64 (m, 2H), 4.19-4.08 (m, 2H), 3.78-3.65 (m, 4H), 3.12-3.07 (m, 2H), 2.83 (br d, J=6.0 Hz, 2H), 2.07 (br d, J=10.8 Hz, 5H), 1.91-1.72 (m, 8H), 1.67 (br s, 2H), 1.48-1.41 (m, 1H), 0.73 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=618.5. Example 552 ##STR00231## 4-(4-(2-azabicyclo[3.3.1]nonan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0431] The title compound was synthesized according to the procedure described for example 550 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.03-9.86 (m, 1H), 9.16 (d, J=5.2 Hz, 1H), 7.76 (dd, J=6.0, 9.0 Hz, 1H), 7.38-7.32 (m, 2H), 7.03-6.99 (m, 1H), 5.36-5.20 (m, 1H), 5.04 (br d, J=9.9 Hz, 1H), 4.38-4.27 (m, 1H), 4.19-3.93 (m, 4H), 3.13-3.00 (m, 4H), 2.82 (br d, J=6.4 Hz, 1H), 2.33 (br s, 2H), 2.12 (br d, J=3.5 Hz, 4H), 2.02-1.86 (m, 5H), 1.83-1.72 (m, 6H), 0.73 (br t, J=6.8 Hz, 3H); LCMS (ESI, M+1): m/z=618.5. Example 553 ##STR00232## 5-ethyl-4-(4-(4-ethynyl-4-fluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol [0432] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.08 (s, 1H), 7.67 (dd, J=5.8, 9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.24 (t, J=9.6 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 5.47-5.14 (m, 1H), 4.37-4.22 (m, 3H), 4.22-4.07 (m, 4H), 3.28-3.16 (m, 3H), 3.01 (dt, J=5.6, 9.2 Hz, 1H), 2.57-2.40 (m, 1H), 2.33-2.09 (m, 8H), 2.03-1.85 (m, 3H), 0.79 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=620.3. Example 554 ##STR00233## 4-(4-(5-oxaspiro[3.4]octan-2-ylamino)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0433] The title compound was synthesized according to the procedure (except for no 4A Molecular sieves were added) described for example 538 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.31-9.19 (m, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.04 (d, J=2.8 Hz, 1H), 5.62-5.31 (m, 1H), 4.62-4.35 (m, 4H), 3.84 (t, J=6.4 Hz, 2H), 3.69-3.49 (m, 3H), 2.70-2.61 (m, 2H), 2.52-2.39 (m, 5H), 2.36-2.27 (m, 1H), 2.23-2.12 (m, 3H), 2.07-1.98 (m, 5H), 0.78 (t, J=7.6 Hz, 3H); LCMS [ESI, M+1]: m/z=620.3. Example 555 ##STR00234## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,4-b][1,4]oxazin-6 (2H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00235## [0434] Step A. tert-butyl (4aR,7aS)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate: A mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (20.0 mg, 1.0 equiv), tert-butyl (4aS,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylate (9.80 mg, 1.1 equiv, HCl), K.sub.3PO.sub.4 (35.8 mg, 5.0 equiv) in DMF (0.5 mL) was degassed and stirred at 40 C. for 2 hours under N.sub.2 atmosphere. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 mL3). The combined organic layers were washed with brine (8 mL), dried over Na.sub.2SO.sub.4, filtered and purified with prep-HPLC [C18, 0.1% formic acid condition] to afford the tittle compound (20 mg, 82.0% yield) as a white solid; 1H NMR (400 MHZ, CHLOROFORM-d) =9.22-9.03 (m, 1H), 7.51 (br d, J=4.4 Hz, 1H), 7.21-7.09 (m, 2H), 7.07-6.95 (m, 1H), 5.41-5.16 (m, 1H), 4.81-4.49 (m, 1H), 4.35-4.02 (m, 6H), 4.01-3.72 (m, 3H), 3.66-3.50 (m, 1H), 3.40-3.13 (m, 4H), 3.05-2.95 (m, 1H), 2.53-2.36 (m, 1H), 2.34-2.20 (m, 2H), 2.19-2.07 (m, 2H), 2.01-1.88 (m, 3H), 0.87-0.74 (m, 3H). [0435] Step B. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((4aR,7aS)-hexahydropyrrolo[3,4-b][1.4]oxazin-6 (2H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of tert-butyl (4aR,7aS)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate (20.0 mg, 1.0 equiv) in DCM (0.3 mL) was added HCl.Math.dioxane (0.3 mL). The mixture was stirred at 20 C. for 1 hour. The reaction mixture was concentrated under reduced pressure to afford the title compound (17 mg, HCl salt) as a yellow solid. .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.54-9.34 (m, 1H), 7.74 (dd, J=6.0, 9.2 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.32 (t, J=9.2 Hz, 1H), 7.19 (br d, J=2.8 Hz, 1H), 5.72-5.48 (m, 1H), 5.05-4.91 (m, 2H), 4.74-4.50 (m, 3H), 4.48-4.24 (m, 3H), 4.20-4.02 (m, 2H), 4.02-3.84 (m, 4H), 3.71-3.62 (m, 1H), 3.60 (s, 1H), 3.49 (dt, J=6.0, 10.4 Hz, 1H), 2.83-2.62 (m, 2H), 2.58-2.44 (m, 2H), 2.42-2.33 (m, 2H), 2.29-2.15 (m, 2H), 0.91-0.82 (m, 3H); .sup.19F NMR (376 MHz, methanol-d.sub.4) =120, 136, 174; LCMS (ESI, M+1): m/z=621.4. Example 556 ##STR00236## 6-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl) morpholin-3-one [0436] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =0.79 (t, J=7.2 Hz, 3H) 1.96-2.07 (m, 1H) 2.09-2.20 (m, 3H) 2.25 (br d, J=8.8 Hz, 1H) 2.30-2.54 (m, 3H) 3.16-3.25 (m, 1H) 3.33-3.41 (m, 1H) 3.43-3.54 (m, 4H) 3.78-3.99 (m, 2H) 4.13-4.29 (m, 3H) 4.40-4.53 (m, 2H) 5.32-5.52 (m, 1H) 7.04 (d, J=2.4 Hz, 1H) 7.25 (t, J=9.2 Hz, 1H) 7.31 (d, J=2.8 Hz, 1H) 7.68 (dd, J=9.2, 5.6 Hz, 1H) 8.49 (br s, 1H) 9.22 (s, 1H); LCMS (ESI, M+1): m/z=623.2 The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid (0.34 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d4) =0.79 (t, J=7.2 Hz, 3H) 1.96-2.07 (m, 1H) 2.09-2.20 (m, 3H) 2.25 (br d, J=8.8 Hz, 1H) 2.30-2.54 (m, 3H) 3.16-3.25 (m, 1H) 3.33-3.41 (m, 1H) 3.43-3.54 (m, 4H) 3.78-3.99 (m, 2H) 4.13-4.29 (m, 3H) 4.40-4.53 (m, 2H) 5.32-5.52 (m, 1H) 7.04 (d, J=2.4 Hz, 1H) 7.25 (t, J=9.2 Hz, 1H) 7.31 (d, J=2.8 Hz, 1H) 7.68 (dd, J=9.2, 5.6 Hz, 1H) 8.49 (br s, 1H) 9.22 (s, 1H). Example 557 ##STR00237## 5-ethyl-6-fluoro-4-(8-fluoro-4-((3R,5R)-3-fluoro-5-methoxypiperidin-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0437] The title compound was synthesized according to the procedure (except for no 4A Molecular sieves were added) described for example 538 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.22 (d, J=5.6 Hz, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.07 (dd, J=2.8, 10.8 Hz, 1H), 5.55-5.39 (m, 1H), 5.15-4.99 (m, 1H), 4.61-4.43 (m, 3H), 4.34-4.15 (m, 2H), 3.90-3.65 (m, 3H), 3.65-3.54 (m, 2H), 3.42 (s, 1H), 3.37 (s, 2H), 2.63-2.39 (m, 3H), 2.37-2.26 (m, 2H), 2.25-1.95 (m, 6H), 0.78 (t, J=7.6 Hz, 3H); LCMS (ESI, M+1): m/z=626.4 Example 558 ##STR00238## 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1-oxide ##STR00239## [0438] To a solution of NaIO.sub.4 (33.2 mg, 1.1 equiv) in water (1 mL) was added a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (90.0 mg, 1.0 equiv) in MeOH (0.8 mL) and dioxane (0.6 mL) at 0 C. and the reaction was stirred at 15 C. for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The organic layer was washed with brine (10 mL) and dried over Na.sub.2SO.sub.4. The solvent was concentrated to and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (10 mM NH.sub.4HCO.sub.3), B: ACN, B %: 33%-63% over 8 minutes] to afford the title compound (45.1 mg, 49% yield) as a yellow oil. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.21 (s, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.40-7.17 (m, 2H), 7.04 (dd, J=2.4, 17.2 Hz, 1H), 5.43-5.21 (m, 1H), 4.51 (br d, J=1.8 Hz, 1H), 4.43-4.04 (m, 5H), 3.40 (br s, 2H), 3.35 (br s, 1H), 3.29-3.09 (m, 3H), 3.08-2.77 (m, 3H), 2.59-2.41 (m, 1H), 2.39-2.09 (m, 5H), 2.08-1.78 (m, 3H), 0.87-0.72 (m, 3H); LCMS (ESI, M+1): m/z=626.3. Example 559 ##STR00240## 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carbonitrile [0439] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid (0.31 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d4) =9.17-9.03 (m, 1H), 8.51 (br s, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.05 (br s, 1H), 5.54-5.22 (m, 1H), 4.77-4.68 (m, 2H), 4.47-4.33 (m, 2H), 3.99-3.85 (m, 1H), 3.73-3.59 (m, 1H), 3.56-3.36 (m, 3H), 3.25-3.02 (m, 2H), 2.80-2.63 (m, 2H), 2.51-2.30 (m, 3H), 2.24-2.03 (m, 5H), 2.00-1.83 (m, 2H), 1.75 (br t, J=8.4 Hz, 2H), 0.79 (br t, J=7.2 Hz, 3H); LCMS [ESI, M+1]: m/z=629.3. Example 560 ##STR00241## (1R,5S,8R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carbonitrile Example 561 ##STR00242## (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carbonitrile ##STR00243## [0440] 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carbonitrile was purified by SFC (column: DAICEL CHIRALCEL OJ (250 mm30 mm, 10 um); mobile phase: [0.1% NH.sub.3H.sub.2O ETOH]; B %: 50%-50%, 4.0 minutes) to afford Example 560 (5.41 mg, 13% yield) as a yellow solid. .sup.1H NMR (400 MHZ, CD.sub.3OD) =9.11 (s, 1H), 7.64 (dd, J=6.0, 9.2 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.22 (t, J=9.6 Hz, 1H), 7.04 (d, J=2.8 Hz, 1H), 5.39-5.21 (m, 1H), 4.79-4.62 (m, 2H), 4.36-4.17 (m, 2H), 3.98-3.86 (m, 2H), 3.29-3.13 (m, 3H), 3.05-2.97 (m, 2H), 2.68 (br s, 2H), 2.54-2.42 (m, 1H), 2.38-2.20 (m, 2H), 2.19-2.07 (m, 2H), 2.07-1.90 (m, 3H), 1.89-1.82 (m, 2H), 1.80-1.67 (m, 2H), 0.79 (br t, J=6.0 Hz, 3H). LCMS ([ESI, M+1):]: m/z=629.3. and Example 561 (13.8 mg, 33.8% yield) as a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) =9.04 (s, 1H), 7.67 (dd, J=6.0, 9.6 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.05 (d, J=2.8 Hz, 1H), 5.41-5.22 (m, 1H), 4.79-4.69 (m, 2H), 4.35-4.22 (m, 2H), 3.70-3.59 (m, 2H), 3.29-3.16 (m, 4H), 3.07-2.99 (m, 1H), 2.75 (br s, 2H), 2.54-2.42 (m, 1H), 2.40-2.20 (m, 2H), 2.19-2.10 (m, 2H), 2.06-1.96 (m, 4H), 1.95-1.87 (m, 1H), 1.81-1.73 (m, 2H), 0.79 (dt, J=2.0, 6.8 Hz, 3H). LCMS ([ESI, M+1):]: m/z=629.3. Example 562 ##STR00244## 4-(4-(7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0441] The title compound was synthesized according to the procedure described for example 541 to produce the desired compound as a white solid as white solid (0.09 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.27-9.15 (m, 1H), 7.94-7.82 (m, 1H), 7.74-7.60 (m, 1H), 7.39-7.20 (m, 2H), 7.11-6.96 (m, 1H), 5.66-5.48 (m, 1H), 5.46 (s, 2H), 4.82-4.72 (m, 2H), 4.70-4.45 (m, 4H), 4.06-3.75 (m, 3H), 3.53-3.36 (m, 1H), 2.40 (br s, 6H), 2.38-2.25 (m, 2H), 2.23-2.07 (m, 2H), 0.84-0.70 (m, 3H); LCMS (ESI, M+1): m/z=631.3. Example 563 ##STR00245## 4-(4-(6,7-dihydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepin-8 (9H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ##STR00246## [0442] Step A. 8-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepine: A mixture of 2,4-dichloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidine (146 mg, 0.80 equiv) and 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepine (56.0 mg, 1.0 equiv) in DMF (1.0 mL) was added DIPEA (157 mg, 3.0 equiv) and 4 molecular sieves (22.81 mg). The mixture was stirred at 40 C. for 0.2 hour. The mixture was purified by column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 1:1] to afford the tittle compound (200 mg, 89% yield) as a white solid. LCMS (ESI, M+1): m/z=552.1. [0443] Step B. 8-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepine: A mixture of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (115 mg, 2.0 equiv) and 8-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepine (200 mg, 1.0 equiv) in dioxane (5.0 mL) was added DIPEA (140 mg, 3.0 equiv) and 4 molecular sieves (200 mg, 11 equiv). The mixture was stirred at 100 C. for 12 hours. The mixture was concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; phase: [water (ammonia hydroxide v/v)-ACN]; B %: 36%-66%, 9 minutes] to afford the title compound (50 mg, 20% yield) as a white solid. LCMS (ESI, M+1): m/z=675.2. [0444] Step C. 4-(4-(6,7-dihydro-5H-[1.2.4]triazolo[4,3-a][1,4]diazepin-8 (9H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a solution of 8-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepine (20.0 mg, 1.0 equiv) in dichloromethane (5.0 mL) was added HCl/MeOH (0.5 mL). The mixture was stirred at 0 C. for 1 hour. The mixture was concentrated and purified by prep-HPLC [column: waters Xbridge 15025 mm5 m; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 27%-57%, 9 minutes] and lyophilized to afford the title compound (4.0 mg, 21% yield, 99% purity,) as a white oil (0.26 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.17 (s, 1H), 8.41 (br s, 1H), 8.34 (s, 1H), 7.57 (dd, J=6.0, 9.2 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.15 (t, J=9.2 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 5.41-5.18 (m, 3H), 4.43-4.33 (m, 2H), 4.30-4.18 (m, 4H), 3.52-3.24 (m, 3H), 3.11-2.99 (m, 1H), 2.38-1.90 (m, 11H), 0.67 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=631.2. Example 564 ##STR00247## 4-(4-(3-(4H-1,2,4-triazol-4-yl)pyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0445] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.16 (s, 1H), 8.67 (s, 2H), 7.50 (dd, J=6.0, 8.8 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H), 6.92 (d, J=2.8 Hz, 1H), 5.38-5.04 (m, 2H), 4.59-4.39 (m, 1H), 4.31-4.05 (m, 5H), 3.17-3.03 (m, 3H), 2.90 (dt, J=6.0, 9.2 Hz, 1H), 2.64 (br dd, J=4.8, 6.8 Hz, 1H), 2.55-2.32 (m, 2H), 2.29-2.07 (m, 2H), 2.02 (br dd, J=8.0, 9.6 Hz, 2H), 1.93-1.70 (m, 3H), 0.68 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=631.3. Example 565 ##STR00248## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(1-(hydroxymethyl)-5-methyl-3-azabicyclo[3.1.1]heptan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0446] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.49 (s, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.35-7.20 (m, 2H), 7.06 (d, J=2.4 Hz, 1H), 5.57-5.25 (m, 1H), 4.65-4.37 (m, 3H), 4.28-3.98 (m, 4H), 3.72-3.38 (m, 4H), 3.25-3.04 (m, 1H), 2.55-2.25 (m, 4H), 2.20-1.96 (m, 4H), 1.75 (br d, J=6.8 Hz, 2H), 1.64 (br d, J=6.4 Hz, 2H), 1.27 (s, 3H), 0.80 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=634.5 Example 566 ##STR00249## 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-3-methylpyrrolidine-2,5-dione ##STR00250## [0447] To a solution of 3-(aminomethyl)-3-methyl-pyrrolidine-2,5-dione (11.0 mg, 1.01 equiv, 2HCl) in DMF (1 mL) was added K.sub.3PO.sub.4 (53.7 mg, 5.0 equiv) and 4 molecular sieves (30 mg). The mixture was stirred at 40 C. for 0.5 hour. A solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30.0 mg, 1.0 equiv) in ACN (0.4 mL) was added. The mixture was stirred at 40 C. for 15.5 hours. The reaction mixture was diluted with DMF (1 mL) and filtered. The filtrate was purified by prep-HPLC [Phenomenex Luna C18 15025 mm10 um; A: water (FA), B: ACN, B %: 12%-42% over 11 min] and further re-purified by prep-HPLC [Waters Xbridge 15025 mm5 um; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 33%-63% over 9 min] and lyophilized to afford the title compound (3.95 mg, 12% yield) as an off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.23 (s, 1H), 7.70 (dd, J=5.9, 9.0 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.27 (t, J=9.4 Hz, 1H), 7.08-7.05 (m, 1H), 5.63-5.39 (m, 1H), 4.67-4.48 (m, 2H), 4.17 (dd, J=13.8, 15.7 Hz, 1H), 3.91-3.83 (m, 1H), 3.80 (br s, 3H), 3.08 (d, J=18.0 Hz, 1H), 2.66 (br d, J=18.0 Hz, 1H), 2.61-2.42 (m, 3H), 2.41-2.08 (m, 6H), 1.47 (s, 3H), 0.80 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=635.4. Example 567 ##STR00251## (7S,8aS)-2-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) octahydropyrrolo[1,2-a]pyrazin-7-ol [0448] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.07 (s, 1H), 7.67 (dd, J=6.0, 8.8 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.04 (dd, J=2.4, 6.8 Hz, 1H), 5.41-5.17 (m, 1H), 4.77 (br d, J=12.4 Hz, 1H), 4.68 (br d, J=13.2 Hz, 1H), 4.41-4.34 (m, 1H), 4.33-4.19 (m, 2H), 3.66 (br t, J=12.4 Hz, 1H), 3.43-3.34 (m, 1H), 3.28-3.14 (m, 4H), 3.03 (br d, J=10.0 Hz, 2H), 2.50-2.36 (m, 4H), 2.33-2.10 (m, 5H), 2.03-1.87 (m, 3H), 1.56-1.41 (m, 1H), 0.79 (dt, J=2.4, 7.2 Hz, 3H); LCMS (ESI, M+1): m/z=635.4 Example 568 ##STR00252## (1R,5S,6R,7S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6,7-diol ##STR00253## [0449] To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (100 mg, 1.0 equiv) in DMF (0.5 mL) and DCM (0.5 mL) were added K.sub.3PO.sub.4 (107 mg, 3.0 equiv), (1S,5R,6S,7R)-3-azabicyclo[3.2.1]octane-6,7-diol (purchased from Enamine Ltd) (46 mg, 1.5 eq, HCl) and 4 molecular sieves (20 mg). The mixture was stirred at 40 C. for 12 hours. The reaction mixture was filtered and purified by prep-HPLC [Phenomenex Synergi C18 15025 mm10 m; A: water (10 mM FA); B: ACN; B %: 11%-41% over 10 min] to afford the title compound (25.9 mg, 24% yield) as a white solid (0.2 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.27 (s, 1H), 7.69-7.66 (m, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 5.55-5.35 (m, 1H), 4.58-4.42 (m, 2H), 4.21-4.13 (m, 2H), 3.59 (d, J=6.4 Hz, 6H), 3.30-3.19 (m, 2H), 2.62-2.49 (m, 1H), 2.48-2.37 (m, 4H), 2.33-2.25 (m, 1H), 2.23-2.12 (m, 3H), 2.10-2.02 (m, 1H), 1.93 (d, J=12.4 Hz, 1H), 1.73-1.63 (m, 1H), 0.83-0.76 (m, 3H); LCMS (ESI, M+1): m/z=636.3. Example 569 ##STR00254## (1R,5S,6S,7S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6,7-diol (stereochemistry was arbitrarily assigned) [0450] The title compound was synthesized from Intermediate 5 peak 3 and 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol according to the procedure described for example 568 to produce the desired compound as a yellow solid. .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =9.43-9.14 (m, 1H), 7.70 (dd, J=6.2, 8.8 Hz, 1H), 7.30 (br t, J=9.6 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 7.06-6.93 (m, 1H), 5.41-5.16 (m, 1H), 5.02-4.69 (m, 3H), 4.52-4.42 (m, 1H), 4.22-4.08 (m, 1H), 4.01 (dd, J=4.0, 10.4 Hz, 1H), 3.82 (br t, J=5.2 Hz, 1H), 3.76-3.63 (m, 2H), 3.24 (br d, J=13.2 Hz, 1H), 3.09 (br d, J=9.2 Hz, 2H), 3.01 (br s, 1H), 2.86-2.79 (m, 1H), 2.25 (br s, 1H), 2.20-1.90 (m, 7H), 1.89-1.74 (m, 3H), 1.69 (br dd, J=4.8, 11.6 Hz, 1H), 0.70 (t, J=7.2 Hz, 3H); .sup.1H NMR (400 MHZ, chloroform-d) =9.22-8.84 (m, 1H), 7.58-7.41 (m, 1H), 7.21-7.02 (m, 2H), 6.98-6.57 (m, 1H), 5.38-5.08 (m, 1H), 4.87-4.10 (m, 5H), 4.00-3.65 (m, 2H), 3.55-3.37 (m, 1H), 3.29 (br s, 2H), 3.23-2.92 (m, 4H), 2.52-2.02 (m, 8H), 1.91-1.74 (m, 3H), 1.61-1.51 (m, 1H), 1.17-1.05 (m, 3H); .sup.19F NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =139.353, 172.075; LCMS (ESI, M+1): m/z=636.4. Example 570 ##STR00255## (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6,7-diol (Stereochemistry was Arbitrarily Assigned) [0451] The title compound was synthesized from Intermediate 5 peak 4 and 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol according to the procedure described for example 568 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =9.97-9.90 (m, 1H), 9.11-9.06 (m, 1H), 7.80-7.73 (m, 1H), 7.39-7.30 (m, 2H), 7.04-7.00 (m, 1H), 5.38-5.19 (m, 1H), 4.91-4.84 (m, 1H), 4.71-4.62 (m, 1H), 4.47-4.38 (m, 1H), 4.28-4.18 (m, 1H), 4.17-4.10 (m, 1H), 4.07-4.02 (m, 2H), 4.01-3.94 (m, 1H), 3.61-3.44 (m, 2H), 3.15-3.05 (m, 2H), 3.02-2.99 (m, 1H), 2.88-2.79 (m, 1H), 2.26-2.20 (m, 1H), 2.20-2.11 (m, 2H), 2.11-1.96 (m, 3H), 1.95-1.85 (m, 2H), 1.85-1.73 (m, 4H), 0.75-0.69 (m, 3H); .sup.19F NMR (400 MHz, dimethylsulfoxide-d.sub.6) =119.629, 139.308, 172.150; LCMS (ESI, M+1): m/z=636.1. Example 571 ##STR00256## (1R,5S,6R,7R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6,7-diol (Stereochemistry was Arbitrarily Assigned) [0452] The title compound was synthesized from Intermediate 5 peak 1 and 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol according to the procedure described for example 568 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =9.93-9.86 (m, 1H), 9.33-9.24 (m, 1H), 7.79-7.73 (m, 1H), 7.38-7.30 (m, 2H), 7.05-6.99 (m, 1H), 5.37-5.18 (m, 1H), 5.02-4.69 (m, 3H), 4.52-4.42 (m, 1H), 4.15-4.09 (m, 1H), 4.07-4.00 (m, 1H), 3.86-3.79 (m, 1H), 3.75-3.65 (m, 2H), 3.28-3.22 (m, 1H), 3.15-3.06 (m, 2H), 3.03-2.99 (m, 1H), 2.86-2.79 (m, 1H), 2.34-2.31 (m, 1H), 2.28-2.22 (m, 1H), 2.15-2.04 (m, 4H), 2.02-1.91 (m, 2H), 1.89-1.74 (m, 3H), 1.72-1.65 (m, 1H), 0.75-0.68 (m, 3H); .sup.19F NMR (400 MHz, dimethylsulfoxide-d.sub.6) =119.622, 139.405, 172.127; LCMS (ESI, M+1): m/z=636.7. Example 572 ##STR00257## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(1-(hydroxymethyl)-2-oxa-6-azabicyclo[3.2.1]octan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0453] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a yellow solid (0.34 formic acid salt). .sup.1H NMR (400 MHZ, CD.sub.3OD) =9.56-9.11 (m, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.05 (s, 1H), 5.57-5.27 (m, 2H), 4.50-4.30 (m, 3H), 4.28-4.13 (m, 1H), 4.05-3.95 (m, 1H), 3.92-3.80 (m, 1H), 3.78-3.69 (m, 2H), 3.46-3.38 (m, 2H), 3.20-3.09 (m, 1H), 2.58-2.39 (m, 2H), 2.38-2.25 (m, 2H), 2.24-2.18 (m, 2H), 2.15-2.03 (m, 4H), 2.02-1.90 (m, 2H), 1.89-1.77 (m, 1H), 0.84-0.77 (m, 3H); LCMS (ESI, M+1): m/z=636.3. Example 573 ##STR00258## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0454] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid (0.22 formic acid salt). .sup.1H NMR (400 MHZ, CD.sub.3OD) =9.56 (s, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.34-7.21 (m, 2H), 7.06 (dd, J=2.4, 8.8 Hz, 1H), 5.46-5.24 (m, 1H), 4.70-4.51 (m, 4H), 4.44-3.95 (m, 8H), 3.92-3.81 (m, 1H), 3.14-3.07 (m, 1H), 2.76-2.66 (m, 1H), 2.63-2.37 (m, 3H), 2.35-2.13 (m, 4H), 2.11-2.03 (m, 2H), 1.99-1.88 (m, 1H), 0.86-0.75 (m, 3H); LCMS (ESI, M+1): m/z=636.4. Example 574 ##STR00259## 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-3-carboxamide ##STR00260## [0455] Step A. tert-butyl 3-carbamoyl-3-hydroxypiperidine-1-carboxylate: To a solution of tert-butyl 3-cyano-3-hydroxy-piperidine-1-carboxylate (4.00 g, 1 equiv) in DCM (50 mL) was added H.sub.2SO.sub.4 (9.54 g, 5.5 equiv) at 0 C. The reaction mixture was stirred at 0 C. for 2 hours. The pH of the mixture was adjusted with aq. NaOH (7.00 g, 9.9 equiv, 40% in water) to 7. (Boc).sub.2O (19.3 g, 5.0 equiv) was added. The reaction mixture was stirred at 20 C. for 16 hours. The reaction mixture was diluted with DCM (50 mL) and water (50 mL), extracted with DCM (50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [water (0.1% FA)/acetonitrile] to afford the title compound (3.9 g, 43% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =6.86 (br s, 1H), 4.04-3.84 (m, 2H), 3.27 (br d, J=14.0 Hz, 1H), 3.10 (br d, J=6.4 Hz, 1H), 2.83 (br t, J=12.6 Hz, 1H), 2.12-1.96 (m, 1H), 1.81-1.62 (m, 2H), 1.61-1.52 (m, 1H), 1.47 (s, 9H), 1.35 (s, 9H); LCMS (ESI, M+1): m/z=245.3. [0456] Step B. 3-hydroxypiperidine-3-carboxamide: To a solution of tert-butyl 3-carbamoyl-3-hydroxy-piperidine-1-carboxylate (1.00 g, 1.0 equiv) in MeCN (5 mL) was added HCl.Math.dioxane (4 M, 10 mL). The reaction mixture was stirred at 20 C. for 1 hour. The mixture was concentrated under vacuum to afford the title compound (590 mg, crude, HCl) as a yellow solid. [0457] Step C. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-3-carboxamide: To a solution of 3-hydroxypiperidine-3-carboxamide (157 mg, 2 equiv, HCl), 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (257 mg, 1.0 equiv) and DIEA (280 mg, 5.0 equiv) in DMF (1 mL) was added 4 molecular sieve (10 mg). The reaction mixture was stirred at 40 C. for 16 hours. The mixture was filtered and the filtrate was purified by prep-HPLC [column: Unisil 3-100 C18 Ultra 15050 mm3 um; A: water (FA), B: ACN, B %: 8%-38% over 7 min], followed by prep-HPLC [column: Welch Ultimate XB-SiOH 2505010 um; A: Hexane, B: EtOH, B %: 10%-50% over 15 min] and lyophilized to afford the title compound (8.91 mg, 3.2% yield) as a white solid (0.50 formic acid salt); .sup.1HNMR (400 MHZ, METHANOL-d4) =9.23 (t, J=2.8 Hz, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.4 Hz, 1H), 7.06 (t, J=2.8 Hz, 1H), 5.49-5.24 (m, 1H), 4.71 (br d, J=13.2 Hz, 1H), 4.61-4.29 (m, 3H), 3.94-3.84 (m, 1H), 3.52-3.33 (m, 4H), 3.17-3.04 (m, 1H), 2.52-2.27 (m, 4H), 2.26-2.13 (m, 3H), 2.11-2.02 (m, 2H), 2.01-1.83 (m, 3H), 0.85-0.73 (m, 3H); LCMS (ESI, M+1): m/z=637.3. Example 575 ##STR00261## 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-5-(hydroxymethyl)pyrrolidin-2-one ##STR00262## [0458] Step A. tert-butyl ((5-oxo-3-phenyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl)methyl)carbamate: A mixture of tert-butyl N-(benzenesulfonylmethyl)carbamate (293.71 mg, 1.1 equiv) in THF (15 mL) was degassed and purged with N.sub.2 for 3 times, and then LiHMDS (1 M, 2.07 mL, 2.1 equiv) was added to the mixture before it was stirred at 78 C. for 30 min under N.sub.2 atmosphere. 3-phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (200 mg, 1.0 equiv) in THF (3 mL) was added to the mixture and the resulting was stirred at 78 C. for 30 min under N.sub.2 atmosphere. The reaction mixture was quenched by addition of aqueous NH.sub.4Cl (5 mL) at 78 C., and then diluted with water 30 mL, extracted with ethyl acetate 60 mL (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate 1:1) to afford the title compound (100 mg, 30.6% yield) as a yellow oil. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =1.38 (s, 9H) 1.59-1.76 (m, 1H) 2.44 (br s, 2H) 2.95-3.06 (m, 2H) 3.43-3.50 (m, 1H) 4.07-4.16 (m, 1H) 4.17-4.24 (m, 1H) 6.04-6.10 (m, 1H) 6.77-6.91 (m, 1H) 7.30-7.44 (m, 5H). [0459] Step B. 3-(aminomethyl)-5-(hydroxymethyl)pyrrolidin-2-one: To a solution of tert-butyl ((5-oxo-3-phenyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl)methyl)carbamate (100 mg, 1.0 equiv) in dioxane (3.0 mL) was added HCl/dioxane (4 M, 1.13 mL, 15.0 equiv). The mixture was stirred at 25 C. for 2 hours. The reaction mixture was filtered to give a white solid, which was used into the next step without further purification. [0460] Step C. 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-5-(hydroxymethyl)pyrrolidin-2-one: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (80 mg, 1.0 equiv), 3-(aminomethyl)-5-(hydroxymethyl)pyrrolidin-2-one (40 mg, 1.6 equiv) and CH.sub.3CN (1.0 mL) in DMF (1 mL) was added K.sub.3PO.sub.4 (286 mg, 1.35 mmol, 10 equiv) and 4 molecular sieves (100 mg, 25 equiv). The mixture was stirred at 60 C. for 2 hours. The reaction mixture was filtered and purified by prep-HPLC [Waters Xbridge 15025 mm5 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 44%-74%, 9 min] to afford the title compound (6.1 mg, 6.71% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =0.81 (br t, J=7.6 Hz, 3H) 1.77-1.90 (m, 1H) 1.92-2.07 (m, 3H) 2.11-2.29 (m, 4H) 2.37 (br d, J=4.4 Hz, 1H) 2.40-2.54 (m, 2H) 2.99-3.13 (m, 2H) 3.15-3.29 (m, 3H) 3.47-3.58 (m, 2H) 3.67 (dd, J=11.2, 4.4 Hz, 1H) 3.77 (br d, J=4.4 Hz, 1H) 3.86-3.98 (m, 1H) 3.99-4.08 (m, 1H) 4.29-4.39 (m, 2H) 5.26 (br s, 1H) 7.06 (s, 1H) 7.23-7.35 (m, 2H) 7.69 (dd, J=9.2, 6.0 Hz, 1H) 9.16 (s, 1H); LCMS (ESI, M+1): m/z=637.3. Example 576 ##STR00263## (3S,5R)-3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-5-(hydroxymethyl)pyrrolidin-2-one ##STR00264## [0461] Step A. (((3S,6S,7aR)-5-oxo-3-phenyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl)methyl)carbamate: A mixture of tert-butyl N-(p-tolylsulfonylmethyl)carbamate (232 mg, 1.1 equiv) in THF (3.0 mL) was degassed and purged with nitrogen for 3 times, and then LDA (2 M, 2.0 equiv) was added. Then the mixture was stirred at 78 C. for 30 minutes under nitrogen atmosphere. And then (3S,7aR)-3-phenyltetrahydropyrrolo[1,2-c]oxazol-5 (3H)-one (150 mg, 1.0 equiv) in THF (3.0 mL) was added to the mixture and stirred at 78 C. for 30 minutes under nitrogen atmosphere. The mixture was quenched with aqueous NH.sub.4Cl (5.0 mL) at 78 C. and extracted with ethyl acetate (320 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated and purified with column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 1:1] to afford the title compound (30.0 mg, 12% yield) as a yellow oil; LCMS (ESI, M55): m/z=277.0 [0462] Step B. (3S,5R)-3-(aminomethyl)-5-(hydroxymethyl)pyrrolidin-2-one: To a solution of (((3S,6S,7aR)-5-oxo-3-phenyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl)methyl)carbamate (30.0 mg, 1.0 equiv) in ACN (1.0 mL) was added HCl/dioxane (4.0 M, 1.0 mL). The mixture was stirred at 25 C. for 6 hours. The reaction mixture was concentrated and purified by prep-TLC [SiO.sub.2, DCM/MeOH 10/1] to afford the title compound (10.0 mg, 76% yield) as a yellow solid. [0463] Step C. (3S,5R)-3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-5-(hydroxymethyl)pyrrolidin-2-one: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (10.0 mg, 1.0 equiv) in dimethyl formamide (1.0 mL) were added K.sub.3PO.sub.4 (20.0 mg, 1.0 equiv), (3S,5R)-3-(aminomethyl)-5-(hydroxymethyl)pyrrolidin-2-one (5.00 mg, 2.5 equiv) and 4 molecular sieves (10.0 mg). The mixture was stirred at 60 C. for 2 hours. The mixture was filtered, concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: water (ammonia hydroxide v/v)-ACN; B %: 22%-52%, 9 min] and lyophilized to afford a title compound (2.70 mg, 24% yield) as yellow solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.92 (br s, 1H), 9.30 (s, 1H), 7.83-7.73 (m, 2H), 7.38-7.31 (m, 2H), 7.00 (d, J=1.2 Hz, 1H), 5.48-5.09 (m, 1H), 4.94-4.71 (m, 1H), 4.21-4.03 (m, 2H), 3.97-3.86 (m, 1H), 3.62-3.50 (m, 2H), 3.15-2.99 (m, 3H), 2.91-2.77 (m, 2H), 2.73-2.62 (m, 1H), 2.36-2.30 (m, 2H), 2.15-1.99 (m, 4H), 1.88-1.75 (m, 3H), 1.66-1.56 (m, 1H), 1.23 (s, 1H), 1.05 (t, J=7.2 Hz, 1H), 0.71 (br t, J=7.2 Hz, 3H), LCMS (ESI, M+1): m/z=637.2 Example 577 ##STR00265## 1-((R)-2-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino) propyl)-3-methylazetidin-3-ol [0464] The title compound was synthesized according to the procedure (except for no 4A Molecular sieves were added) described for example 544 to produce the desired compound as a white solid (1 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.24 (s, 1H), 8.40 (br s, 1H), 7.69 (dd, J=6.0, 8.8 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.29-7.22 (m, 1H), 7.09-7.02 (m, 1H), 5.65-5.25 (m, 1H), 4.83-4.70 (m, 1H), 4.65-4.53 (m, 2H), 4.19-3.51 (m, 8H), 3.24-3.12 (m, 1H), 2.71-2.31 (m, 4H), 2.39-2.20 (m, 1H), 2.29-2.04 (m, 4H), 1.49 (d, J=5.6 Hz, 3H), 1.42 (dd, J=4.4, 6.6 Hz, 3H), 0.90-0.66 (m, 3H); LCMS (ESI, M+1): m/z=637.4. Example 578 ##STR00266## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((S)-2-(2-hydroxyethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0465] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a brown solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.14 (d, J=4.4 Hz, 1H), 7.67 (dd, J=5.6, 9.2 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.06 (dd, J=2.8, 9.6 Hz, 1H), 5.45-5.14 (m, 1H), 4.56 (br t, J=14.8 Hz, 1H), 4.37-4.20 (m, 4H), 4.17-4.03 (m, 2H), 3.75 (br t, J=5.2 Hz, 2H), 3.70-3.56 (m, 2H), 3.28-3.12 (m, 3H), 3.08-2.96 (m, 1H), 2.55-2.42 (m, 1H), 2.35-2.08 (m, 6H), 2.04-1.77 (m, 5H), 0.85-0.71 (m, 3H); LCMS (ESI, M+1): m/z=638.3. Example 579 ##STR00267## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepin-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0466] The title compound was synthesized according to the procedure described for example 541 to produce the desired compound as a white solid (0.88 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d4) =9.17 (s, 1H), 8.37 (dd, J=1.2, 4.0 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.36-7.29 (m, 2H), 7.25 (t, J=9.2 Hz, 1H), 7.04 (d, J=2.8 Hz, 1H), 5.57-5.37 (m, 1H), 5.25-5.21 (m, 2H), 4.51-4.33 (m, 4H), 3.81-3.56 (m, 3H), 3.30-3.19 (m, 3H), 2.60-2.06 (m, 10H), 0.77 (t, J=7.6 Hz, 3H). LCMS (ESI, M+1): m/z=641.4. Example 580 ##STR00268## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy) 4-(3-(S-methylsulfonimidoyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0467] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as an off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.26 (s, 1H), 7.62 (br dd, J=6.0, 8.8 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 7.19 (t, J=9.6 Hz, 1H), 7.04 (br d, J=2.4 Hz, 1H), 5.41-5.20 (m, 1H), 4.45 (br s, 2H), 4.34 (br dd, J=4.0, 10.4 Hz, 2H), 4.30-4.24 (m, 1H), 4.22-4.04 (m, 2H), 3.27-3.15 (m, 3H), 3.12 (s, 3H), 3.04-2.97 (m, 1H), 2.61 (br d, J=4.0 Hz, 2H), 2.45 (br d, J=4.8 Hz, 1H), 2.39-2.19 (m, 2H), 2.17-2.07 (m, 2H), 2.02-1.85 (m, 3H), 0.78 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=641.3. Example 581 ##STR00269## 4-(4-(4,4-difluoro-5-methylazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0468] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.16 (s, 1H), 7.67 (dd, J=5.6, 8.8 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (s, 1H), 7.05 (br s, 1H), 5.50-5.15 (m, 1H), 4.44-3.89 (m, 7H), 3.17-2.98 (m, 1H), 2.64-2.41 (m, 3H), 2.37-1.67 (m, 12H), 1.12-1.00 (m, 3H), 0.84-0.75 (m, 3H); LCMS (ESI, M+1): m/z=642.3. Example 582 ##STR00270## 4-(4-(8,9-dihydro-5H-pyrimido[5,4-c]azepin-6(7H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0469] The title compound was synthesized using Intermediate 6 according to the procedure described for Example 541 to produce the desired compound as a white solid (0.3 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.19 (s, 1H), 8.95 (s, 1H), 8.89 (s, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.33-7.21 (m, 2H), 7.04 (d, J=2.8 Hz, 1H), 5.48-5.30 (m, 1H), 5.27-5.13 (m, 2H), 4.54-4.38 (m, 2H), 4.35-4.19 (m, 2H), 3.56-3.38 (m, 3H), 3.27-3.10 (m, 3H), 2.54-2.27 (m, 5H), 2.26-2.07 (m, 4H), 2.05-1.91 (m, 1H), 0.78 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=642.3. Example 583 ##STR00271## 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1,1-dioxide [0470] The title compound was synthesized according to the procedure described for example 541 to produce the desired compound as a white solid (0.3 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.20 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.26 (t, J=9.2 Hz, 1H), 7.05 (d, J=2.8 Hz, 1H), 5.51-5.26 (m, 1H), 4.54-4.20 (m, 6H), 3.73 (brt, J=5.2 Hz, 2H), 3.61-3.34 (m, 5H), 3.24-3.12 (m, 1H), 2.56-2.45 (m, 3H), 2.44-2.29 (m, 2H), 2.27-2.05 (m, 4H), 2.05-1.95 (m, 1H), 0.86-0.71 (m, 3H); (ESI, M+1): m/z=642.3. Example 584 ##STR00272## 4-(4-(8,9-dihydro-5H-[1,2,3]triazino[5,4-c]azepin-6(7H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0471] The title compound was synthesized using Intermediate 7 according to the procedure described for example 541 to produce the desired compound as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.32 (s, 1H), 9.19 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (s, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.07-7.01 (m, 1H), 5.42-5.22 (m, 1H), 5.22-5.10 (m, 1H), 4.60-4.13 (m, 3H), 4.10-3.95 (m, 1H), 3.49-3.33 (m, 2H), 3.13 (br s, 4H), 3.09-2.95 (m, 1H), 2.55-2.41 (m, 2H), 2.39 (br s, 1H), 2.22-2.10 (m, 3H), 2.08-1.95 (m, 3H), 1.94-1.80 (m, 1H), 0.84-0.73 (m, 3H); LCMS (ESI, M+1): m/z=643.1. Example 585 ##STR00273## 4-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-1-carbonitrile ##STR00274## [0472] Step A. 4-((2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-1-carbonitrile: To a solution of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (15 mg, 1.0 equiv) and excess 4-aminobicyclo[2.2.2]octane-1-carbonitrile in DMF (3.0 mL) was added DIPEA (38.7 mg, 3.0 equiv) and 4 molecular sieves (45 mg, 9.0 equiv). The mixture was stirred at 40 C. for 0.2 hour. The mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was washed with brine (30 mL2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (70 mg, crude). The crude product was used for the next step without further purification; LCMS (ESI, M+1): m/z=564.2 [0473] Step B. 4-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-1-carbonitrile: To a solution of 4-((2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-1-carbonitrile (55 mg, 1.0 equiv) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (46.6 mg, 3.0 equiv) in THF (3 mL) were added DIPEA (63 mg, 5.0 equiv) and 4 molecular sieves (10 mg, 2.1 equiv). The mixture was stirred at 60 C. for 12 hours and then at 70 C. for 5 hours. The mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was washed with brine (20 mL3). The organic phase was filtered, concentrated and purified by prep-HPLC (column: Phenomenex C18 7530 mm3 um; mobile phase: [water (FA)-ACN]; B %: 20%-50%, 7 min) to afford the title compound (25 mg, 35% yield) as a white solid; LCMS (ESI, M+1): m/z=687.2 [0474] Step C. 4-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-1-carbonitrile: To a solution of 4-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-1-carbonitrile (20 mg, 1.0 equiv) in MeOH (1.5 mL) was added HCl/MeOH (4 M, 1.5 mL, 206 equiv). The mixture was stirred at 0 C. for 0.5 hour. The mixture was concentrated and purified by prep-HPLC (column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 16%-46%, 10 min) and lyophilized to afford the title compound (3.8 mg, 20% yield,) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.27 (s, 1H), 7.67 (dd, J=5.6, 9.2 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.24 (t, J=9.2 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 5.54-5.26 (m, 1H), 4.52-4.26 (m, 2H), 3.58-3.38 (m, 3H), 3.16 (dt, J=6.4, 9.6 Hz, 1H), 2.48-2.42 (m, 1H), 2.41-2.31 (m, 8H), 2.25-2.07 (m, 11H), 2.05-1.91 (m, 1H), 0.77 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=643.4 Example 586 ##STR00275## 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-4-ol [0475] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =0.74-0.86 (m, 3H) 1.44 (t, J=7.2 Hz, 2H) 1.89 (br s, 1H) 2.00 (br s, 2H) 2.11-2.28 (m, 4H) 2.31-2.41 (m, 2H) 2.42-2.54 (m, 1H) 2.70-2.90 (m, 1H) 2.96-3.05 (m, 1H) 3.16-3.26 (m, 2H) 3.43 (q, J=7.2 Hz, 1H) 3.87-3.96 (m, 1H) 4.06 (br s, 1H) 4.20-4.34 (m, 4H) 5.18-5.41 (m, 1H) 7.06 (dd, J=7.6, 2.4 Hz, 1H) 7.18-7.34 (m, 2H) 7.66 (dd, J=8.8, 5.6 Hz, 1H) 9.17 (d, J=4.0 Hz, 1H); LCMS (ESI, M+1): m/z=644.2. Example 587 ##STR00276## 4-(4-(3-((1H-pyrazol-1-yl)methyl)pyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0476] The title compound was synthesized according to the procedure described for example 541 to produce the desired compound as a white solid (0.44 formic acid salt). .sup.1H NMR (400 MHZ, DMSO-d6) 0.73 (br t, J=6.8 Hz, 3H) 1.76-1.88 (m, 4H) 1.99-2.16 (m, 6H) 2.31-2.36 (m, 1H) 2.80-2.91 (m, 3H) 3.10 (br d, J=8.4 Hz, 2H) 4.06 (br d, J=10.4 Hz, 2H) 4.16 (br dd, J=10.4, 2.44 Hz, 2H) 4.25-4.36 (m, 3H) 5.19-5.38 (m, 1H) 6.27 (br d, J=2.0 Hz, 1H) 7.01 (br d, J=2.8 Hz, 1H) 7.30-7.40 (m, 2H) 7.48 (br s, 1H) 7.73-7.86 (m, 2H) 8.18 (s, 1H) 9.26 (s, 1H); LCMS (ESI, M+1): m/z=644.6. Example 588 ##STR00277## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxamide ##STR00278## [0477] Step A 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid: To a solution of 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid (25.0 mg, 1.1 equiv) in dimethyl formamide (1.0 mL) were added K.sub.3PO.sub.4 (94.5 mg, 3.0 equiv), 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (87.9 mg, 1.0 equiv) and 4 molecular sieves (10.0 mg). The mixture was stirred at 60 C. for 2 hours. The reaction mixture was partitioned between ethyl acetate (40 mL) and water (30 mL). The organic phase was separated and dried over Na.sub.2SO.sub.4. Then it was filtered and concentrated under reduced pressure to give a yellow solid; LCMS (ESI, M+1): m/z=646.1. [0478] Step B 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxamide: To a solution of 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid (30 mg, 1 equiv) in DMF (1 mL) were added DIPEA (12.01 mg, 2 equiv) NH.sub.4Cl (24.8 mg, 10 equiv) and HATU (53.0 mg, 3 equiv). The mixture was stirred at 25 C. for 1 hr. The reaction mixture was concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 28%-58%, 8.5 min] to afford the title compound (5.6 mg, 18% yield) as a gray solid (0.6 formic acid salt); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.73-9.28 (m, 1H), 8.24 (s, 1H), 7.82-7.57 (m, 3H), 7.41-7.30 (m, 2H), 7.03 (d, J=1.6 Hz, 1H), 5.49-5.20 (m, 3H), 5.15-4.90 (m, 2H), 4.25-4.10 (m, 2H), 3.13-3.06 (m, 2H), 2.84 (br d, J=6.0 Hz, 2H), 2.40-2.33 (m, 1H), 2.20-2.02 (m, 4H), 1.88-1.75 (m, 3H), 0.74 (br t, J=7.2 Hz, 3H), LCMS (ESI, M+1): m/z=645.3 Example 589 ##STR00279## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-8-azaspiro[5.5]undec-3-en-8-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0479] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.24-9.14 (m, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.06 (dd, J=2.8, 8.0 Hz, 1H), 5.83-5.67 (m, 2H), 5.42-5.24 (m, 1H), 4.79-4.47 (m, 4H), 4.37-4.23 (m, 2H), 4.06 (br d, J=18.0 Hz, 1H), 3.94-3.82 (m, 1H), 3.70-3.58 (m, 1H), 3.23-3.18 (m, 1H), 3.09-2.97 (m, 1H), 2.54-2.31 (m, 2H), 2.29-2.18 (m, 2H), 2.17-2.05 (m, 5H), 2.04-1.98 (m, 2H), 1.95-1.87 (m, 1H), 1.80-1.64 (m, 2H), 1.39-1.23 (m, 1H), 0.80 (br t, J=7.2 Hz, 3H). LCMS (ESI, M+1): m/z=646.4, Example 590 ##STR00280## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione [0480] The title compound was synthesized using Intermediate 8 according to the procedure described for example 541 to produce the desired compound as a white solid; (0.10 formic acid salt). SFC: Chiralcel OD-3 504.6 mm I.D., 3 m, Isocratic elution: 40% methanol+ACN (0.05% DEA) in CO.sub.2, 3 mL/min, t.sub.R=0.553 min, 1.073 min; .sup.1H NMR (400 MHz, methanol-d.sub.4) =9.18 (d, J=2.4 Hz, 1H), 7.76-7.59 (m, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.08-7.04 (m, 1H), 5.55-5.22 (m, 1H), 4.75-4.43 (m, 3H), 4.38-4.24 (m, 2H), 3.90-3.50 (m, 2H), 3.43-3.34 (m, 2H), 3.07-2.98 (m, 1H), 2.54-2.11 (m, 7H), 1.96-1.86 (m, 1H), 1.66-1.50 (m, 4H), 0.84-0.76 (m, 3H); .sup.19F NMR (400 MHZ, methanol-d.sub.4) =121.084, 138.457, 73.675; LCMS (ESI, M+1): m/z=647.3. Example 591 ##STR00281## (1R,5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,7-diazabicyclo[3.3.1]nonane-2,4-dione [0481] The title compound was synthesized using Intermediate 9 according to the procedure described for example 541 to produce the desired compound as an off-white solid (0.1 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.04 (s, 1H), 7.70-7.66 (m, 1H), 7.34-7.19 (m, 2H), 7.07-7.06 (m, 1H), 5.45-5.31 (m, 1H), 5.01-4.97 (m, 1H), 4.42-4.25 (m, 2H), 4.01-3.78 (m, 2H), 3.55-3.33 (m, 3H), 3.16-3.07 (m, 1H), 2.95-2.93 (m, 2H), 2.58-2.36 (m, 3H), 2.35-2.15 (m, 4H), 2.10-2.01 (m, 4H), 0.79-0.75 (m, 3H); LCMS (ESI, M+1): m/z=647.4. Example 592 ##STR00282## 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydropyrido[3,4-d]pyrimidin-2(1H)-one [0482] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.05 (s, 1H), 7.65 (dd, J=6.0, 8.8 Hz, 1H), 7.30-7.19 (m, 2H), 7.04 (d, J=2.8 Hz, 1H), 5.45-5.13 (m, 1H), 4.56-4.37 (m, 2H), 4.36-4.21 (m, 2H), 3.93-3.70 (m, 3H), 3.44 (dd, J=4.2, 12.4 Hz, 1H), 3.28-3.13 (m, 4H), 3.05-2.96 (m, 1H), 2.57-2.43 (m, 1H), 2.41-2.26 (m, 2H), 2.23-2.09 (m, 3H), 2.08-1.94 (m, 3H), 1.93-1.78 (m, 2H), 0.85-0.72 (m, 3H). LCMS (ESI, M+1): m/z=648.2. Example 593 ##STR00283## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(1-hydroxycyclobutyl) piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0483] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.05 (s, 1H), 7.66 (dd, J=6.0, 8.8 Hz, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.23 (t, J=9.2 Hz, 1H), 7.06 (dd, J=2.8, 4.4 Hz, 1H), 5.45-5.16 (m, 1H), 4.82-4.65 (m, 2H), 4.38-4.18 (m, 2H), 3.27-2.92 (m, 6H), 2.62-2.41 (m, 2H), 2.37-2.14 (m, 6H), 2.10-2.01 (m, 4H), 1.89-1.58 (m, 7H), 1.41-1.24 (m, 1H), 0.87-0.70 (m, 3H); LCMS (ESI, M+1): m/z=648.2. Example 594 ##STR00284## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-8-azaspiro[5.5]undecan-8-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0484] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a yellow solid (0.29 formic acid salt); .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.38-9.12 (m, 1H), 8.57 (s, 1H), 7.69 (dd, J=6.0, 8.8 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.26 (t, J=9.2 Hz, 1H), 7.09 (br dd, J=2.4, 5.2 Hz, 1H), 5.49-5.13 (m, 1H), 4.74-4.49 (m, 2H), 4.39-4.19 (m, 2H), 3.69-3.55 (m, 2H), 3.50-3.41 (m, 1H), 3.22 (br d, J=20.0 Hz, 2H), 3.09-2.95 (m, 1H), 2.57-2.21 (m, 5H), 2.17-1.88 (m, 6H), 1.77-1.42 (m, 9H), 0.82 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=648.3. Example 595 ##STR00285## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-(tetrahydrofuran-3-yl) piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0485] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.02 (dd, J=1.6, 6.0 Hz, 1H), 7.67 (dd, J=6.0, 8.8 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.24 (t, J=9.2 Hz, 1H), 7.14-6.98 (m, 1H), 5.39-5.22 (m, 1H), 4.71-4.47 (m, 2H), 4.36-4.20 (m, 2H), 4.02-3.95 (m, 1H), 3.92-3.83 (m, 2H), 3.77-3.71 (m, 1H), 3.55-3.49 (m, 1H), 3.43-3.36 (m, 1H), 3.24-3.18 (m, 2H), 3.08-2.95 (m, 2H), 2.69-2.53 (m, 1H), 2.50-2.34 (m, 2H), 2.26-2.18 (m, 2H), 2.14-2.10 (m, 2H), 1.96 (br dd, J=8.8, 16.8 Hz, 3H), 1.79-1.68 (m, 3H), 1.60-1.47 (m, 2H), 1.34-1.14 (m, 1H), 0.89-0.73 (m, 3H). LCMS (ESI, M+1): m/z=648.2. Example 596 ##STR00286## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-((tetrahydrofuran-3-yl)methyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0486] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid (0.1 formic acid salt); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.29 (d, J=5.6 Hz, 1H), 7.77 (dd, J=6.0, 8.8 Hz, 1H), 7.49-7.29 (m, 2H), 7.08 (m, 1H), 5.10 (m, 1H), 4.28-3.99 (m, 5H), 3.92-3.57 (m, 5H), 3.16-2.95 (m, 4H), 2.83 (br d, J=6.2 Hz, 3H), 2.45-1.94 (m, 11H), 1.89-1.37 (m, 8H), 0.73 (q, J=7.6 Hz, 3H); LCMS (ESI, M+1): m/z=648.4. Example 597 ##STR00287## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-((tetrahydrofuran-2-yl)methyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0487] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as an off-white solid (0.2 formic acid salt); .sup.1HNMR (400 MHZ, METHANOL-d.sub.4) ppm=0.80 (q, J=7.6 Hz, 3H) 1.48-1.60 (m, 1H) 1.68-1.85 (m, 3H) 1.94 (br d, J=6.4 Hz, 3H) 1.99-2.06 (m, 2H) 2.07-2.20 (m, 3H) 2.20-2.41 (m, 3H) 2.41-2.60 (m, 2H) 3.00-3.11 (m, 1H) 3.20-3.31 (m, 3H) 3.33-3.46 (m, 1H) 3.68-3.74 (m, 1H) 3.68-3.92 (m, 3H) 3.92-4.02 (m, 1H) 4.03-4.25 (m, 2H) 4.26-4.33 (m, 1H) 4.34-4.43 (m, 1H) 5.23-5.44 (m, 1H) 7.05 (dd, J=6.8, 2.32 Hz, 1H) 7.25 (t, J=9.4 Hz, 1H) 7.30 (d, J=2.4 Hz, 1H) 7.68 (dd, J=9.2, 5.6 Hz, 1H) 8.49-8.59 (m, 1H) 9.26 (d, J=4.4 Hz, 1H). LCMS (ESI, M+1): m/z=648.4 Example 598 ##STR00288## 2-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-oxa-2,9-diazaspiro[4.5]decan-8-one [0488] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, CD.sub.3OD) =9.26 (s, 1H), 7.67 (dd, J=6.0, 8.8 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.24 (t, J=9.6 Hz, 1H), 7.04 (d, J=2.8 Hz, 1H), 5.41-5.19 (m, 1H), 4.35-4.22 (m, 6H), 4.12-3.98 (m, 2H), 3.45-3.39 (m, 2H), 3.27-3.12 (m, 3H), 3.05-2.97 (m, 1H), 2.56-2.29 (m, 2H), 2.28-2.08 (m, 6H), 2.01-1.86 (m, 3H), 0.79 (t, J=6.8 Hz, 3H). LCMS (ESI, M+1): m/z=649.1. Example 599 ##STR00289## 10-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3,10-diazabicyclo[4.3.1]decan-4-one [0489] The title compound was synthesized using according to the 3-step procedure described for example 585, except for in Step B the mixture was stirred at 100 C. for 1 hour, to produce the desired compound as a yellow solid (0.12 formic acid salt). 1H NMR (400 MHZ, CD.sub.3OD) =9.02 (s, 1H), 7.68 (dd, J=5.6, 8.8 Hz, 1H), 7.39-7.17 (m, 2H), 7.04 (dd, J=2.4, 6.0 Hz, 1H), 5.42-5.27 (m, 1H), 5.14-4.91 (m, 4H), 4.45-4.27 (m, 2H), 4.11-3.93 (m, 4H), 3.86-3.74 (m, 2H), 3.20-3.01 (m, 3H), 2.61-1.88 (m, 9H), 0.79 (br t, J=6.8 Hz, 3H); LCMS (ESI, M+1): m/z=649.3. Example 600 ##STR00290## 8-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-8-azaspiro[4.5]decan-4-ol [0490] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid (0.41 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d4) =0.73-0.86 (m, 3H) 1.75 (br d, J=12.8 Hz, 1H) 1.87-2.06 (m, 5H) 2.09-2.26 (m, 4H) 2.32-2.42 (m, 2H) 2.45-2.54 (m, 1H) 3.14-3.25 (m, 1H) 3.42-3.66 (m, 3H) 3.78-3.95 (m, 3H) 3.99-4.10 (m, 2H) 4.37-4.56 (m, 4H) 5.19-5.63 (m, 1H) 7.06 (d, J=2.4 Hz, 1H) 7.25 (t, J=9.2 Hz, 1H) 7.31 (d, J=2.4 Hz, 1H) 7.68 (dd, J=8.8, 6.0 Hz, 1H) 8.50 (br s, 1H) 9.08 (s, 1H); LCMS (ESI, M+1): m/z=650.3. Example 601 ##STR00291## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2-(2-methoxyethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0491] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.15 (d, J=7.6 Hz, 1H), 7.75-7.58 (m, 1H), 7.36-0.17 (m, 2H), 6.99 (dd, J=2.0, 9.6 Hz, 1H), 5.37-5.17 (m, 1H), 4.46 (br t, J=12.4 Hz, 1H), 4.23-3.95 (m, 6H), 3.65-3.41 (m, 6H), 3.15-2.96 (m, 4H), 2.87-2.78 (m, 1H), 2.33 (br s, 1H), 2.19-1.99 (m, 6H), 1.93-1.64 (m, 6H), 0.73 (td, J=7.2, 12.4 Hz, 3H), LCMS (ESI, M+1): m/z=652.4. Example 602 ##STR00292## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-6-(methoxymethyl)-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0492] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a yellow solid (1.05 formic acid salt); 1H NMR (400 MHZ, METHANOL-d4) =9.28-9.15 (m, 1H), 8.50 (br s, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.05 (dd, J=2.4, 6.0 Hz, 1H), 5.51-5.33 (m, 1H), 4.67-4.54 (m, 1H), 4.51-4.36 (m, 3H), 4.34-4.20 (m, 2H), 4.19-4.08 (m, 3H), 3.71 (br dd, J=3.2, 12.8 Hz, 1H), 3.66-3.53 (m, 2H), 3.52-3.42 (m, 2H), 3.19 (br d, J=9.6 Hz, 4H), 2.54-2.32 (m, 3H), 2.27-2.11 (m, 4H), 2.06-1.97 (m, 1H), 1.44-1.24 (m, 1H), 0.98 (d, J=14.8 Hz, 3H), 0.86-0.76 (m, 3H) LCMS [ESI, M+1]: m/z=652.4 Example 603 ##STR00293## 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-thia-7-azaspiro[3.5]nonane 1-oxide [0493] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a yellow solid. .sup.1H NMR (400 MHZ, CD.sub.3OD) =9.07 (s, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.05 (s, 1H), 5.42-5.20 (m, 1H), 4.37-4.20 (m, 4H), 4.14-3.94 (m, 2H), 3.65 (ddd, J=2.8, 8.0, 11.6 Hz, 1H), 3.29-3.09 (m, 4H), 3.06-2.98 (m, 9.2 Hz, 1H), 2.74-2.65 (m, 1H), 2.57-2.44 (m, 2H), 2.39-2.26 (m, 2H), 2.25-2.12 (m, 6H), 2.04-1.88 (m, 3H), 0.80 (br t, J=7.6 Hz, 3H). LCMS (ESI, M+1): m/z=652.3. Example 604 ##STR00294## 7-(7-(8-chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide ##STR00295## [0494] Step A. 7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1.0 eqniv) and (8-chloro-3-(methoxymethoxy)naphthalen-1-yl)trimethylstannane (528 mg, 1.2 eqniv) in toluene (5 mL) was added AdanBup-Pd-G3 (83.2 mg, 0.10 eqniv) under N.sub.2. The reaction mixture was stirred at 90 C. for 12 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (410 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 5:1 to 1:1] and reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (50.0 mg, 7.0% yield) as a yellow oil; LCMS (ESI, M+1): m/z=625.3. [0495] Step B. 7-(7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide: To a solution of 7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (70.0 mg, 1.0 equiv) and 2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide (25.6 mg, 1.2 equiv) in dimethyl formamide (0.3 mL) were added DIEA (43.4 mg, 3.0 equiv) and 4 molecular sieves (30 mg). The reaction mixture was stirred at 40 C. for 12 hours. The reaction mixture was filtered and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (30.0 mg, 37% yield) as a white solid. [0496] Step C. 7-(7-(8-chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide: To a solution of 7-(7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide (30.0 mg, 1.0 equiv) in acetonitrile (0.5 mL) was added HCl.Math.dioxane (4 M, 1.0 mL). The reaction mixture was stirred at 0 C. for 0.5 hours. The reaction mixture was quenched with saturated aqueous NaHCO.sub.3 (5 mL) at 0 C. and extracted with ethyl acetate (45 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Waters Xbridge C18 15050 mm10 m; A: water (NH.sub.4HCO.sub.3), B: ACN; B %: 34%-64% over 10 min] to afford the title compound (5.92 mg, 21% yield) as a yellow gum; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.42-10.09 (m, 1H), 9.09 (d, J=4.8 Hz, 1H), 7.85-7.82 (m, 1H), 7.44-7.33 (m, 4H), 7.14-7.12 (m, 1H), 5.43-5.11 (m, 1H), 4.21-3.98 (m, 4H), 3.83-3.71 (m, 1H), 3.67-3.52 (m, 1H), 3.25-3.16 (m, 2H), 3.14 (br s, 2H), 3.02-2.98 (m, 1H), 2.86-2.77 (m, 1H), 2.30-2.10 (m, 3H), 2.07-2.03 (m, 1H), 2.02-1.91 (m, 3H), 1.87-1.74 (m, 5H); LCMS (ESI, M+1): m/z=671.1. Example 605 ##STR00296## 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoro-4-methylazepan-4-ol [0497] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =0.72-0.86 (m, 3H) 1.34 (br s, 3H) 1.93-2.07 (m, 4H) 2.11-2.40 (m, 7H) 2.43-2.54 (m, 1H) 3.03 (br d, J=5.6 Hz, 1H) 3.18-3.28 (m, 3H) 3.89 (br d, J=1.2 Hz, 1H) 4.11-4.41 (m, 6H) 5.38 (br s, 1H) 7.07 (br d, J=9.6 Hz, 1H) 7.21-7.33 (m, 2H) 7.68 (br dd, J=8.4, 6.0 Hz, 1H) 9.17 (d, J=4.0 Hz, 1H). LCMS (ESI, M+1): m/z=658.3. Example 606 ##STR00297## 2-((1R,3aS,6aR)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl) acetonitrile [0498] The title compound was synthesized using Intermediate 13B ((1R,3aS,6aR)-tert-butyl 1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate) according to the procedure described for example 566 to produce the desired compound as a white solid (0.5 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.34 (d, J=4.8 Hz, 1H), 8.51-8.45 (m, 1H), 7.71 (dd, J=6.0, 9.2 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.28 (t, J=9.2 Hz, 1H), 7.07 (t, J=3.2 Hz, 1H), 5.56-5.41 (m, 1H), 4.63-4.58 (m, 2H), 4.55-4.48 (m, 2H), 4.38-4.28 (m, 1H), 4.08-3.95 (m, 2H), 3.77-3.56 (m, 4H), 3.30-3.26 (m, 2H), 2.92 (d, J=5.6 Hz, 2H), 2.59-2.43 (m, 3H), 2.36-2.29 (m, 1H), 2.25-2.16 (m, 3H), 2.04 (br s, 1H), 0.81 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=658.2. Example 607 ##STR00298## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0499] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.27 (d, J=2.4 Hz, 1H), 7.67 (dd, J=6.0, 8.8 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.24 (t, J=9.2 Hz, 1H), 7.04 (s, 1H), 5.44-5.16 (m, 1H), 4.77-4.46 (m, 3H), 4.39-4.18 (m, 3H), 3.27-3.11 (m, 3H), 3.01 (dt, J=5.6, 9.2 Hz, 1H), 2.64 (br s, 1H), 2.55-2.42 (m, 1H), 2.39-2.35 (m, 3H), 2.31-2.09 (m, 4H), 2.05-1.80 (m, 5H), 1.32-1.28 (m, 1H), 0.79 (q, J=7.2 Hz, 3H). LCMS (ESI, M+1): m/z=658.3. Example 608 ##STR00299## 6-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyridazin-3 (2H)-one [0500] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid; 1H NMR (400 MHZ, METHANOL-d4) =9.32 (s, 1H), 7.70 (dd, J=6.0, 9.2 Hz, 1H), 7.63 (d, J=9.6 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.27 (t, J=9.2 Hz, 1H), 7.09-7.00 (m, 2H), 5.57-5.31 (m, 1H), 4.55-4.33 (m, 4H), 3.79-3.56 (m, 2H), 3.55-3.42 (m, 3H), 3.26-3.11 (m, 2H), 2.59-2.46 (m, 2H), 2.43-2.31 (m, 2H), 2.29-2.22 (m, 1H), 2.21-2.09 (m, 3H), 2.03-1.87 (m, 1H), 1.41-1.31 (m, 1H), 0.82 (br t, J=7.6 Hz, 3H). LCMS (ESI, M+1): m/z=658.3. Example 609 ##STR00300## 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-3-methyl-1,2,5-thiadiazolidine 1,1-dioxide [0501] The title compound was synthesized using Intermediate 11 according to the procedure described for example 541 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =9.94 (br s, 1H), 9.36 (s, 1H), 8.92 (br d, J=5.2 Hz, 1H), 7.77 (dd, J=2.4, 8.8 Hz, 1H), 7.40-7.30 (m, 2H), 7.22-7.09 (m, 2H), 6.99 (d, J=2.4 Hz, 1H), 5.41-5.17 (m, 1H), 4.21-4.05 (m, 2H), 3.92-3.80 (m, 1H), 3.78-3.66 (m, 1H), 3.49 (dt, J=3.6, 7.6 Hz, 1H), 3.15-3.03 (m, 4H), 2.88-2.81 (m, 1H), 2.39-2.34 (m, 1H), 2.18-1.99 (m, 4H), 1.88-1.71 (m, 3H), 1.34 (s, 3H), 0.72 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=658.2. Example 610 ##STR00301## 4-(4-(3-((1H-pyrazol-1-yl)methyl) piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0502] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, CD.sub.3OD) =8.93-8.84 (m, 1H), 7.70-7.64 (m, 2H), 7.52 (s, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.04 (t, J=2.4 Hz, 1H), 6.30-6.28 (m, 1H), 5.41-5.20 (m, 1H), 4.62-4.50 (m, 1H), 4.42-4.31 (m, 1H), 4.27-4.12 (m, 4H), 3.56-3.43 (m, 1H), 3.23-3.16 (m, 2H), 3.03-2.97 (m, 1H), 2.66-2.04 (m, 8H), 2.02-1.90 (m, 4H), 1.86-1.62 (m, 2H), 1.55-1.46 (m, 1H), 0.77 (br t, J=7.6 Hz, 3H); LCMS (ESI, M+1): m/z=658.2. Example 611 ##STR00302## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-((1-methyl-1H-pyrazol-3-yl)methyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0503] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.22 (br s, 1H), 7.66 (dd, J=6.0, 9.2 Hz, 1H), 7.49 (s, 1H), 7.31-7.20 (m, 2H), 7.04 (dd, J=2.4, 4.8 Hz, 1H), 6.18 (br s, 1H), 5.42-5.21 (m, 1H), 4.35-4.29 (m, 1H), 4.26-4.21 (m, 1H), 4.20-4.06 (m, 2H), 3.89-3.78 (m, 4H), 3.23-3.16 (m, 2H), 3.04-2.96 (m, 1H), 2.92-2.59 (m, 4H), 2.56-2.42 (m, 1H), 2.40-1.82 (m, 10H), 0.79 (br d, J=3.6 Hz, 3H); LCMS (ESI, M+1): m/z=658.3 Example 612 ##STR00303## 8-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-8-azaspiro[4.5]decane-4-carbonitrile [0504] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.08 (s, 1H), 7.68 (br dd, J=6.0, 8.8 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (brt, J=9.2 Hz, 1H), 7.10-7.03 (m, 1H), 5.48-5.16 (m, 1H), 4.72-4.49 (m, 2H), 4.41-4.22 (m, 2H), 4.18-3.95 (m, 2H), 3.80 (br t, J=10.4 Hz, 2H), 3.31-3.14 (m, 4H), 3.08-2.94 (m, 1H), 2.69-2.44 (m, 2H), 2.41-2.12 (m, 6H), 2.11-1.97 (m, 4H), 1.91 (br d, J=12.4 Hz, 2H), 0.82 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=659.3 Example 613 ##STR00304## 4-(4-(1-cyclopropyl-5-(hydroxymethyl)-3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0505] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.94 (s, 1H), 9.51 (s, 1H), 8.14 (s, 1H), 7.77 (dd, J=6.0, 9.2 Hz, 1H), 7.43-7.24 (m, 2H), 7.02 (d, J=2.4 Hz, 1H), 5.46-5.19 (m, 1H), 4.78 (br s, 1H), 4.36-4.08 (m, 4H), 3.41 (br s, 2H), 3.22-3.10 (m, 2H), 2.98-2.89 (m, 1H), 2.79-2.53 (m, 1H), 2.40-2.32 (m, 1H), 2.24-2.03 (m, 4H), 1.97-1.80 (m, 3H), 1.46 (br d, J=8.4 Hz, 2H), 1.32 (br d, J=7.6 Hz, 2H), 0.95 (br d, J=4.8 Hz, 1H), 0.74 (t, J=7.2 Hz, 3H), 0.47-0.35 (m, 2H), 0.25 (q, J=5.2 Hz, 2H), LCMS (ESI, M+1): m/z=660.4. Example 614 ##STR00305## (3aR,8aS)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-d]azepine-1,3(2H,3aH)-dione [0506] The title compound was synthesized using Intermediate 12 according to the procedure described for example 538 to produce the desired compound as a white solid; 1H NMR (400 MHZ, DMSO+D2O) =9.18-8.98 (m, 1H), 7.75 (dd, J=6.0, 8.8 Hz, 1H), 7.39-7.30 (m, 2H), 7.02 (d, J=2.4 Hz, 1H), 5.49-5.11 (m, 1H), 4.24-4.00 (m, 5H), 3.96-3.80 (m, 1H), 3.21-2.95 (m, 5H), 2.82 (br d, J=6.0 Hz, 1H), 2.40-2.28 (m, 3H), 2.26-2.10 (m, 3H), 2.07-1.90 (m, 3H), 1.88-1.72 (m, 3H), 0.72 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=661.4 Example 615 ##STR00306## 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-[1,3-bipyrrolidine]-2,5-dione [0507] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, DMSO-d6) ppm 0.66-0.79 (m, 3H) 1.70-1.90 (m, 3H) 1.95-2.18 (m, 4H) 2.20-2.40 (m, 3H) 2.60-2.68 (m, 5H) 2.79-2.87 (m, 1H) 2.99-3.14 (m, 4H) 4.00-4.19 (m, 4H) 4.79-4.91 (m, 1H) 5.18-5.37 (m, 1H) 7.01 (s, 1H) 7.31-7.39 (m, 2H) 7.76 (dd, J=8.8, 6.0 Hz, 1H) 8.15 (s, 1H) 9.24 (br d, J=8.0 Hz, 1H); LCMS (ESI, M+1): m/z=661.6. Example 616 ##STR00307## 3-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-3-yl)pyrrolidin-2-one [0508] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid. 1H NMR (400 MHZ, METHANOL-d4) =9.21-9.01 (m, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.09-7.03 (m, 1H), 5.48-5.19 (m, 1H), 5.11 (br d, J=13.2 Hz, 1H), 4.69 (br d, J=10.0 Hz, 1H), 4.47-4.18 (m, 2H), 3.41-3.35 (m, 2H), 3.31 (br s, 1H), 3.28-3.13 (m, 3H), 3.08-2.95 (m, 1H), 2.60-2.39 (m, 2H), 2.36-2.14 (m, 6H), 2.10-1.53 (m, 9H), 0.88-0.73 (m, 3H); LCMS (ESI, M+1): m/z=661.3. Example 617 ##STR00308## [0509] Peak 1 stereoisomer of 3-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-3-yl)pyrrolidin-2-one Example 618 ##STR00309## [0510] Peak 2 stereoisomer of 3-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-3-yl)pyrrolidin-2-one Example 619 ##STR00310## [0511] Peak 3 stereoisomer of 3-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-3-yl)pyrrolidin-2-one ##STR00311## [0512] 3-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-3-yl)pyrrolidin-2-one (30 mg, 1.0 equiv) was purified by chiral SFC (column: REGIS (S,S) WHELK-O1 (250 mm25 mm, 10 um); mobile phase: [0.1% NH.sub.3H.sub.2O MEOH]; B %: 40%-40%, 5.0 min) and lyophilized to afford peak 1, Example 617 (6 mg, 9.08 mol, 20% yield) as a white solid; 1H NMR (400 MHz, METHANOL-d4) =9.09 (d, J=1.2 Hz, 1H), 7.69 (dd, J=6.0, 8.8 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H), 7.26 (t, J=9.2 Hz, 1H), 7.12-7.03 (m, 1H), 5.50-5.22 (m, 1H), 4.79-4.57 (m, 2H), 4.41 (d, J=10.8 Hz, 1H), 4.26 (d, J=10.4 Hz, 1H), 3.32-3.14 (m, 3H), 3.13-2.96 (m, 1H), 2.61-2.43 (m, 2H), 2.40 (br d, J=1.6 Hz, 8H), 2.10-1.82 (m, 7H), 1.79-1.53 (m, 3H), 1.43-1.36 (m, 1H), 0.82 (q, J=6.8 Hz, 3H); LCMS (ESI, M+1): m/z=661.4, peak 2, Example 618 (6 mg, 20.0% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.11 (s, 1H), 7.67 (dd, J=6.0, 8.8 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.06 (dd, J=2.4, 4.8 Hz, 1H), 5.51-5.26 (m, 1H), 5.15 (br d, J=13.6 Hz, 1H), 4.68 (br d, J=12.4 Hz, 1H), 4.38 (d, J=3.2 Hz, 2H), 3.56-3.38 (m, 3H), 3.16-3.03 (m, 1H), 2.54-2.42 (m, 2H), 2.39-2.05 (m, 8H), 2.02-1.86 (m, 4H), 1.84-1.50 (m, 3H), 1.34-1.27 (m, 2H), 1.21-1.12 (m, 1H), 0.84-0.73 (m, 3H); LCMS (ESI, M+1): m/z=661.4, and peak 3, Example 619 (5 mg, 50% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.11 (s, 1H), 7.69 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.26 (t, J=9.6 Hz, 1H), 7.09-7.04 (m, 1H), 5.41-5.23 (m, 1H), 5.11 (br d, J=11.6 Hz, 1H), 4.79-4.51 (m, 2H), 4.41-4.21 (m, 2H), 3.29-3.15 (m, 3H), 3.09-2.98 (m, 1H), 2.57-2.42 (m, 2H), 2.39-2.09 (m, 8H), 2.08-1.88 (m, 7H), 1.86-1.53 (m, 3H), 1.28 (s, 1H), 0.87-0.77 (m, 3H); LCMS (ESI, M+1): m/z=661.4. Example 620 ##STR00312## 5-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-3-yl)pyrrolidin-2-one [0513] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid (0.24 formic acid salt). .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.08 (d, J=14.2 Hz, 1H), 8.13-7.98 (m, 1H), 7.77 (dd, J=6.0, 8.8 Hz, 1H), 7.44-7.30 (m, 2H), 7.03 (s, 1H), 5.45-5.09 (m, 1H), 4.70-4.46 (m, 2H), 4.07 (s, 2H), 3.16-3.05 (m, 3H), 3.02 (br s, 2H), 2.83 (br d, J=6.0 Hz, 2H), 2.23-1.94 (m, 9H), 1.93-1.58 (m, 10H), 1.48-1.14 (m, 2H), 0.73 (br d, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=661.3 Example 621 ##STR00313## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(5-(oxetan-3-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0514] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.26 (s, 1H), 7.68-7.61 (m, 1H), 7.27 (br s, 1H), 7.23 (br t, J=9.6 Hz, 1H), 7.04 (d, J=2.8 Hz, 1H), 5.43-5.19 (m, 1H), 4.73 (t, J=6.4 Hz, 2H), 4.66-4.55 (m, 2H), 4.43-4.22 (m, 4H), 4.14-4.00 (m, 2H), 3.71 (quin, J=6.0 Hz, 1H), 3.25-3.12 (m, 4H), 3.08-2.93 (m, 1H), 2.80-2.63 (m, 4H), 2.57-2.43 (m, 1H), 2.41-2.09 (m, 4H), 2.04-1.84 (m, 3H), 0.80 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=661.3. Example 622 ##STR00314## (3aS,6aR)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxamide ##STR00315## [0515] A mixture of (1S,3aS,6aR)-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxamide, Intermediate 13A (13.0 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (54.6 mg, 1.2 equiv), K.sub.3PO.sub.4 (48.9 mg, 230.5 mol, 3.0 equiv) in DMF (0.5 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 40 C. for 12 hours under N.sub.2 atmosphere. The mixture was filtered and purified by prep-HPLC [C18, 0.1% formic acid condition] and lyophilized to afford the title compound (10 mg, 19.5% yield) as a white solid. .sup.1H NMR (400 MHZ, DMSO-d6) =9.32 (d, J=5.6 Hz, 1H), 8.20 (s, 2H), 7.77 (dd, J=6.0, 9.2 Hz, 1H), 7.66-7.53 (m, 1H), 7.39-7.32 (m, 2H), 7.27 (br s, 1H), 7.03 (t, J=2.8 Hz, 1H), 5.39-5.17 (m, 1H), 4.52-4.39 (m, 1H), 4.17 (td, J=4.8, 10.0 Hz, 3H), 4.11-4.05 (m, 1H), 4.02 (s, 1H), 3.95-3.85 (m, 1H), 3.23-3.05 (m, 5H), 3.03 (s, 1H), 2.88-2.80 (m, 1H), 2.40-2.28 (m, 1H), 2.18-1.97 (m, 4H), 1.92-1.73 (m, 3H), 0.83-0.63 (m, 3H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) =119.67 (br d, J=14.0 Hz, 1F), 134.92-141.96 (m, 1F), 169.38-176.42 (m, 1F). LCMS (ESI, M+1): m/z=662.5. Example 623 ##STR00316## 1-(6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-b][1,4]oxazin-4(4aH)-yl) ethan-1-one ##STR00317## [0516] To a solution of acetyl chloride (1.70 mg, 1.2 equiv) in a mixed solvent of DCM (0.5 mL) and MeOH (0.1 mL) were added TEA (5.50 mg, 3.0 equiv) and 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,4-b][1,4]oxazin-6 (2H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (12.0 mg, 1.0 equiv, HCl). The mixture was stirred at 0 C. for 0.5 hour. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 mL3). The combined organic layers were washed with brine (8 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified with prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (2.00 mg, 16% yield) as a white solid. .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.27 (br d, J=6.4 Hz, 1H), 8.50 (s, 1H), 7.68 (dd, J=5.6, 8.8 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.09-6.99 (m, 1H), 5.52-5.31 (m, 1H), 5.16-5.05 (m, 1H), 4.53-4.44 (m, 1H), 4.44-4.37 (m, 1H), 4.33-4.18 (m, 3H), 4.13 (ddd, J=6.0, 9.2, 13.6 Hz, 1H), 4.05-3.98 (m, 1H), 3.76-3.66 (m, 1H), 3.65-3.54 (m, 2H), 3.52-3.34 (m, 4H), 3.23-3.12 (m, 1H), 2.54-2.31 (m, 3H), 2.24 (br s, 2H), 2.21-2.15 (m, 3H), 2.14-2.07 (m, 2H), 2.06-1.92 (m, 1H), 0.84-0.74 (m, 3H); .sup.19F NMR (376 MHz, methanol-d.sub.4) =121, 139, 174; LCMS (ESI, M+1): m/z=663.3. Example 624 ##STR00318## (2S,5R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2-oxide (Stereochemistry was Arbitrarily Assigned) Example 625 ##STR00319## (2S,5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2-oxide (Stereochemistry was Arbitrarily Assigned) ##STR00320## [0517] Step A: 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2-oxide: To a solution of NaIO.sub.4 (69.1 mg, 1.0 equiv) in H.sub.2O (1.5 mL) was added a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2-thia-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (0.20 g, 1.0 equiv) in MeOH (1.2 mL) and dioxane (0.9 mL) at 0 C. The reaction was stirred at 15 C. for 12 hours. The mixture was diluted with H.sub.2O (10 mL) and extracted with EtOAc (330 mL). The combined organic layer was washed with brine (350 mL), dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC; column: Unisil 3-100 C18 Ultra 15050 mm3 m, mobile phase: A: water (10 mM formic acid), B: ACN, B %: 13%-43% over 7 min to afford peak 1, Example 625 (24.4 mg, 10% yield). White solid; .sup.1HNMR (400 MHZ, MeOH-d4) 9.11 (s, 1H), 7.71 (dd, J=6.0, 9.2 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.31-7.25 (m, 1H), 7.08 (d, J=2.4 Hz, 1H), 5.51-5.27 (m, 1H), 4.46-4.25 (m, 2H), 4.21-4.05 (m, 2H), 4.01-3.88 (m, 2H), 3.52-3.36 (m, 4H), 3.19-3.10 (m, 2H), 2.78 (br d, J=14.4 Hz, 1H), 2.56-2.47 (m, 2H), 2.45-2.29 (m, 3H), 2.25-2.16 (m, 2H), 2.14-2.07 (m, 4H), 2.03-1.83 (m, 4H), 0.83 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=666.4. and peak 2, Example 624 (42.2 mg, 19% yield) as a white solid; .sup.1HNMR (400 MHZ, MeOH-d.sub.4) 9.11 (s, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.06 (dd, J=2.8, 4.4 Hz, 1H), 5.61-5.22 (m, 1H), 4.62-4.46 (m, 4H), 4.22-3.99 (m, 2H), 3.67-3.36 (m, 3H), 3.26-3.03 (m, 4H), 2.92-2.79 (m, 1H), 2.71-2.56 (m, 1H), 2.54-2.24 (m, 4H), 2.22-1.99 (m, 5H), 1.99-1.77 (m, 4H), 0.80 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=666.3. Example 626 ##STR00321## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,7,7-tetramethyl-1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0518] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.12 (s, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.26 (t, J=9.6 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 5.47-5.21 (m, 1H), 4.65-4.48 (m, 2H), 4.43-4.33 (m, 2H), 4.32-4.18 (m, 3H), 3.50-3.33 (m, 2H), 3.15-3.03 (m, 1H), 2.58-2.31 (m, 4H), 2.30-2.12 (m, 3H), 2.10-1.84 (m, 3H), 1.50-1.40 (m, 12H), 0.81 (br t, J=6.8 Hz, 3H); LCMS [ESI, M+1]: m/z=666.4 Example 627 ##STR00322## (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) azepan-3-yl)dimethylphosphine oxide [0519] The title compound was synthesized using intermediate 14 according to the procedure described for example 544 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.39 (br s, 1H), 7.74 (dd, J=6.0, 8.8 Hz, 1H), 7.40 (br s, 1H), 7.31 (t, J=9.2 Hz, 1H), 7.21-7.07 (m, 1H), 5.72-5.52 (m, 1H), 5.51-5.28 (m, 1H), 5.24-5.05 (m, 1H), 4.76-4.56 (m, 1H), 4.48-4.17 (m, 2H), 4.09-3.92 (m, 2H), 3.91-3.77 (m, 2H), 3.45 (br d, J=7.6 Hz, 1H), 2.70 (br s, 5H), 2.40-2.23 (m, 5H), 2.17-1.98 (m, 3H), 1.73 (br d, J=12.4 Hz, 3H), 1.61 (br d, J=12.0 Hz, 3H), 1.58-1.40 (m, 2H), 0.93-0.83 (m, 3H); LCMS (ESI, M+1): m/z=668.3. Example 628 ##STR00323## 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-thia-6-azaspiro[3.5]nonane 1,1-dioxide [0520] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.13 (br d, J=4.4 Hz, 1H), 7.75-7.62 (m, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (dt, J=2.8, 9.6 Hz, 1H), 7.12-7.01 (m, 1H), 5.54-5.35 (m, 1H), 5.24-4.98 (m, 2H), 4.59 (s, 1H), 4.56-4.38 (m, 2H), 4.07-3.95 (m, 3H), 3.55-3.40 (m, 4H), 3.27-3.11 (m, 1H), 2.76-2.62 (m, 1H), 2.54-2.34 (m, 3H), 2.31-2.23 (m, 1H), 2.16-2.08 (m, 4H), 2.06-1.90 (m, 4H), 0.84-0.75 (m, 3H); LCMS (ESI, M+1): m/z=668.3. Example 629 ##STR00324## (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)dimethylphosphine oxide [0521] The title compound was synthesized using Intermediate 4 according to the procedure described for example 541 to produce the desired compound as a yellow solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.15 (d, J=2.0 Hz, 1H), 7.77 (dd, J=6.0, 8.8 Hz, 1H), .sup.1H NMR (400 MHz, DMSO-d.sub.6) =9.21 (d, J=2.4 Hz, 1H), 7.76 (dd, J=6.0, 8.8 Hz, 1H), 7.39-7.31 (m, 2H), 7.02 (dd, J=2.0, 11.6 Hz, 1H), 5.36-5.18 (m, 1H), 4.78-4.62 (m, 1H), 4.19-4.02 (m, 6H), 3.88-3.75 (m, 2H), 3.15-2.97 (m, 4H), 2.83 (br d, J=6.8 Hz, 2H), 2.14-1.99 (m, 4H), 1.90-1.71 (m, 4H), 1.60-1.51 (m, 6H), 0.76-0.68 (m, 3H), LCMS (ESI, M+1): m/z=670.1. Example 630 ##STR00325## (2R,4s,6S)-4-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)-2,6-dimethyltetrahydro-2H-thiopyran 1,1-dioxide [0522] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.41 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 5.40-5.22 (m, 1H), 4.72 (br d, J=2.8 Hz, 1H), 4.38-4.23 (m, 2H), 3.75-3.54 (m, 2H), 3.24-3.17 (m, 2H), 3.06-2.97 (m, 1H), 2.60-2.42 (m, 3H), 2.28-2.10 (m, 6H), 2.06-1.84 (m, 4H), 1.35 (dd, J=4.8, 6.5 Hz, 6H), 0.79 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=670.3. Example 631 ##STR00326## 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-sulfonamide [0523] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid (0.38 formic acid salt); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =0.73 (dt, J=10.8, 7.2 Hz, 3H) 1.54-1.67 (m, 1H) 1.73-1.90 (m, 3H) 1.97-2.21 (m, 6H) 2.26-2.43 (m, 2H) 2.67 (br d, J=1.6 Hz, 1H) 2.78-2.94 (m, 1H) 3.02-3.10 (m, 2H) 3.10-3.16 (m, 2H) 3.90 (br s, 1H) 4.07-4.34 (m, 4H) 5.23 (br s, 1H) 5.36 (br s, 1H) 6.80 (s, 1H) 6.95-7.05 (m, 1H) 7.27-7.41 (m, 2H) 7.76 (dd, J=8.8, 6.0 Hz, 1H) 8.14 (s, 1H) 8.97 (s, 1H) 9.16 (s, 1H) 9.94 (br s, 1H); LCMS (ESI, M+1): m/z=671.3. Example 632 ##STR00327## N-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-sulfonamide [0524] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a a white solid; (0.49 formic acid salt) .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =0.71 (t, J=7.2 Hz, 3H) 1.71-1.94 (m, 4H) 2.02-2.26 (m, 7H) 2.30-2.41 (m, 3H) 2.58-2.76 (m, 1H) 2.85-2.95 (m, 1H) 3.12 (br s, 3H) 3.17-3.26 (m, 3H) 3.61 (br d, J=4.4 Hz, 1H) 4.06-4.19 (m, 2H) 5.22-5.41 (m, 1H) 6.97 (s, 1H) 7.28-7.36 (m, 2H) 7.75 (dd, J=8.8, 6.0 Hz, 1H) 8.13-8.16 (m, 1H) 8.14 (s, 1H) 9.04 (s, 1H) 9.88 (br s, 1H); LCMS (ESI, M+1): m/z=671.3. Example 633 ##STR00328## 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-3-sulfonamide [0525] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a a white solid (0.49 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.18-9.15 (m, 1H), 9.16 (s, 1H), 8.52 (s, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.24 (t, J=9.2 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 5.41-5.41 (m, 1H), 5.55-5.39 (m, 1H), 4.73-4.66 (m, 1H), 4.65-4.58 (m, 1H), 4.04-3.83 (m, 3H), 3.74-3.57 (m, 3H), 3.24-3.12 (m, 1H), 2.60-2.39 (m, 5H), 2.32-2.19 (m, 2H), 2.18-2.05 (m, 3H), 2.04-1.86 (m, 3H), 1.81-1.64 (m, 1H), 0.78 (br t, J=6.8 Hz, 3H); LCMS (ESI, M+1): m/z=671.4. Example 634 ##STR00329## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-4-(1-methyl-1H-pyrazol-5-yl) azepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0526] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.17 (br s, 1H), 8.19 (s, 1H), 7.76 (br dd, J=6.0, 8.5 Hz, 1H), 7.45-7.17 (m, 3H), 7.01 (br d, J=11.2 Hz, 1H), 6.03 (br d, J=14.8 Hz, 1H), 5.45-5.13 (m, 1H), 4.34-3.89 (m, 5H), 3.76 (s, 3H), 3.15-2.97 (m, 4H), 2.87-2.64 (m, 2H), 2.28-1.96 (m, 8H), 1.91-1.44 (m, 5H), 0.88-0.61 (m, 3H), LCMS (ESI, M+1): m/z=672.4. Example 635 ##STR00330## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxamide ##STR00331## [0527] To a solution of 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid (30 mg, 1 equiv) in DMF (1 mL) was added DIPEA (12.0 mg, 2 equiv) dimethylamine (24.8 mg, 3 equiv) and HATU (53.0 mg, 3 equiv). The mixture was stirred at 25 C. for 1 hr. The reaction mixture was concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 33%-63%, 8.5 min] to afford the title compound (5.6 mg, 18.5% yield) as a gray solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.42 (s, 1H), 7.73 (dd, J=6.0, 8.9 Hz, 1H), 7.35-7.27 (m, 2H), 7.04 (br d, J=2.0 Hz, 1H), 5.39-5.19 (m, 3H), 4.97 (br d, J=1.6 Hz, 2H), 4.28-4.03 (m, 3H), 3.37 (br d, J=2.4 Hz, 6H), 3.12 (br s, 2H), 3.03 (br s, 2H), 2.19-2.04 (m, 4H), 1.94-1.69 (m, 4H), 0.73 (br t, J=7.2 Hz, 3H), LCMS (ESI, M+1): m/z=673.1. Example 636 ##STR00332## 1-((R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) morpholin-2-yl)methanesulfonamide [0528] The title compound was synthesized according to the procedure described for example 541 to produce the desired compound as a yellow solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.15 (d, J=2.0 Hz, 1H), 7.77 (dd, J=6.0, 8.8 Hz, 1H), 7.42-7.26 (m, 2H), 7.08-6.85 (m, 3H), 5.42-5.14 (m, 1H), 4.62 (br d, J=13.2 Hz, 1H), 4.40 (br d, J=14.0 Hz, 1H), 4.23-4.12 (m, 2H), 4.11-4.01 (m, 2H), 3.79 (br t, J=11.2 Hz, 1H), 3.61-3.50 (m, 1H), 3.47-3.39 (m, 2H), 3.11-2.98 (m, 3H), 2.82 (br d, J=5.6 Hz, 1H), 2.33 (br s, 2H), 2.18-1.95 (m, 5H), 1.86-1.75 (m, 3H), 0.72 (br t, J=7.2 Hz, 3H), LCMS (ESI, M+1): m/z=673.3. Example 637 ##STR00333## N-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((R)-morpholin-2-yl)methanesulfonamide [0529] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid (0.53 formic acid salt); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.02 (s, 1H), 8.15 (s, 1H), 7.75 (dd, J=6.0, 9.2 Hz, 1H), 7.41-7.25 (m, 2H), 6.98 (d, J=2.4 Hz, 1H), 5.45-5.19 (m, 1H), 4.16-4.12 (m, 2H), 3.91 (br dd, J=2.4, 12.4 Hz, 2H), 3.73-3.64 (m, 3H), 3.51 (br s, 2H), 3.33-3.26 (m, 2H), 3.14 (br s, 2H), 3.00-2.79 (m, 4H), 2.69 (s, 1H), 2.25-2.05 (m, 4H), 1.93-1.78 (m, 3H), 0.72 (t, J=7.2 Hz, 3H), LCMS (ESI, M+1): m/z=673.3. Example 638 ##STR00334## 1-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-3-yl)pyrrolidine-2,5-dione [0530] The title compound was synthesized according to the procedure described for example 544, except for the heating of the mixture was conducted at 40 C. for 15 hours, to produce the desired compound as a yellow solid. .sup.1HNMR (400 MHZ, methanol-d4) =9.08 (s, 1H), 7.68 (dd, J=9.2, 5.6 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.05 (dd, J=6.0, 2.4 Hz, 1H), 5.23-5.40 (m, 1H), 4.58-4.71 (m, 2H), 4.32-4.48 (m, 2H), 4.20 (dd, J=16.4, 10.4 Hz, 1H), 3.93-4.04 (m, 1H), 3.49-3.62 (m, 1H), 3.12-3.27 (m, 3H), 2.98-3.05 (m, 1H), 2.71 (s, 4H), 2.56-2.66 (m, 1H), 2.42-2.54 (m, 1H), 2.07-2.36 (m, 4H), 1.77-2.02 (m, 6H), 0.75-0.84 (m, 3H); LCMS (ESI, M+1): m/z=675.2. Example 639 ##STR00335## 3-amino-4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide ##STR00336## [0531] Step A. tert-butyl ((3-amino-1-(dimethylcarbamoyl)-1H-pyrazol-4-yl)methyl)carbamate: To a mixture of Intermediate 15 (500 mg, 1.0 equiv) in MeOH (5.00 mL) was added (Boc).sub.2O (1.83 g, 3.0 equiv) and Pd/C (150 mg, 10 equiv) under nitrogen atmosphere. The mixture was degassed and purged with hydrogen 3 times. The reaction was stirred under hydrogen (15 psi) at 25 C. for 13 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (460 mg, 58% yield) as a white solid; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =7.68 (s, 1H), 5.19 (s, 2H), 3.84 (br d, J=6.0 Hz, 2H), 3.08 (s, 6H), 1.38 (s, 9H); LCMS (ESI, M+1): m/z=284.0. [0532] Step B. 3-amino-4-(aminomethyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a mixture of tert-butyl ((3-amino-1-(dimethylcarbamoyl)-1H-pyrazol-4-yl)methyl)carbamate (400 mg, 1.0 equiv) in DCM (4.00 mL) was added TFA (6.44 g, 40 equiv) drop-wise at 0 C. The reaction was stirred at 25 C. for 0.5 hour. The mixture was concentrated to afford the title compound (250 mg, 91% yield) as a yellow oil; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =8.00 (s, 1H), 3.82 (br d, J=5.2 Hz, 2H), 3.10 (s, 8H). [0533] Step C. 3-amino-4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv) and 3-amino-4-(aminomethyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (155 mg, 10 equiv) in DMF (2.0 mL) were added DIPEA (109 mg, 10 equiv) and 4 molecular sieves (50.0 mg). The reaction was stirred at 40 C. for 18 hours. The mixture was filtered and purified with prep-HPLC [Phenomenex Luna C18 15025 mm10 m; A: water (FA), B: ACN; B %: 18%-48% over 15 min] to afford the title compound (6.45 mg, 11% yield) as a white solid; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =9.93 (s, 1H), 9.36-9.24 (m, 2H), 7.93 (s, 1H), 7.76 (dd, J=6.0, 9.2 Hz, 1H), 7.39-7.30 (m, 2H), 6.99 (d, J=2.4 Hz, 1H), 5.50-5.40 (m, 2H), 5.39-5.20 (m, 1H), 4.58-4.41 (m, 2H), 4.25-4.00 (m, 2H), 3.19-2.76 (m, 10H), 2.37-2.30 (m, 1H), 2.22-1.95 (m, 4H), 1.92-1.74 (m, 3H), 0.70 (t, J=7.2 Hz, 3H); .sup.19F NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =119.672, 139.430, 172.020; LCMS (ESI, M+1): m/z=676.2. Example 640 ##STR00337## 5-amino-4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide ##STR00338## [0534] Step A. tert-butyl ((5-amino-1-(dimethylcarbamoyl)-1H-pyrazol-4-yl)methyl)carbamate; To a mixture of 5-amino-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide (500 mg, 1.0 equiv) in MeOH (5.00 mL) was added (Boc).sub.2O (1.83 g, 3.0 equiv) and Pd/C (150 mg, 10 equiv) under nitrogen atmosphere. The mixture was degassed and purged with hydrogen 3 times. The reaction was stirred under hydrogen (15 psi) at 25 C. for 13 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (460 mg, 58% yield) as a white solid. [0535] Step B. 5-amino-4-(aminomethyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a mixture of tert-butyl ((5-amino-1-(dimethylcarbamoyl)-1H-pyrazol-4-yl)methyl)carbamate (130 mg, 1.0 equiv) in ACN (1.30 mL) was added HCl.Math.dioxane (1.15 mL, 10 equiv) drop-wise at 0 C. The reaction was stirred at 25 C. for 1 hour. The mixture was filtered and concentrated to afford the title compound (90.0 mg, 98% yield) as a yellow oil; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =7.46 (s, 1H), 3.76 (q, J=5.6 Hz, 2H), 3.04 (br s, 8H). [0536] Step C. 5-amino-4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv) and 5-amino-4-(aminomethyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (77.3 mg. 5.0 equiv) in DMF (2.0 mL) were added DIPEA (109 mg, 10 equiv) and 4 molecular sieves (50.0 mg). The reaction was stirred at 40 C. for 18 hours. The mixture was filtered and purified with prep-HPLC [Phenomenex Luna C18 15025 mm10 m; A: water (FA), B: ACN; B %: 15%-45% over 10 min] to afford the title compound (8.83 mg, 15% yield) as a white solid (0.77 formic acid salt); .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) =9.34 (br d, J=3.2 Hz, 1H), 9.29 (s, 1H), 7.76 (dd, J=6.0, 8.8 Hz, 1H), 7.41 (s, 1H), 7.40-7.27 (m, 2H), 6.99 (d, J=2.0 Hz, 1H), 6.08 (s, 2H), 5.40-5.16 (m, 1H), 4.44 (br d, J=5.2 Hz, 2H), 4.25-4.01 (m, 2H), 3.18-2.98 (m, 10H), 2.89-2.79 (m, 1H), 2.36-2.29 (m, 1H), 2.12-1.99 (m, 3H), 1.88-1.75 (m, 3H), 0.70 (br t, J=7.2 Hz, 3H). LCMS (ESI, M+1): m/z=676.3 Example 641 ##STR00339## 2-((1R,3aS,6aR)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetamide [0537] The title compound was synthesized using Intermediate 13C according to the procedure described for example 566, except for heating of the mixture was conducted at 60 C., to produce the desired compound as a white solid (0.1 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.30 (d, J=5.2 Hz, 1H), 8.53 (s, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.32-7.22 (m, 2H), 7.05 (dd, J=2.8, 5.2 Hz, 1H), 5.46-5.27 (m, 1H), 4.60-4.50 (m, 1H), 4.48-4.27 (m, 4H), 4.02-3.95 (m, 2H), 3.46-3.36 (m, 2H), 3.18-3.07 (m, 2H), 2.66 (s, 2H), 2.60 (d, J=7.0 Hz, 2H), 2.53-2.52 (m, 1H), 2.54-2.34 (m, 1H), 2.33-2.26 (m, 1H), 2.22-2.13 (m, 2H), 2.09-2.03 (m, 2H), 1.99-1.91 (m, 1H), 0.79 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=676.5. Example 642 ##STR00340## (3R,4S)-8-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-8-azaspiro[5.5]undecane-3,4-diol [0538] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a yellow solid; .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.23 (d, J=5.2 Hz, 1H), 7.78-7.65 (m, 1H), 7.34 (s, 1H), 7.28 (t, J=9.2 Hz, 1H), 7.14-7.03 (m, 1H), 5.72-5.41 (m, 1H), 4.77-4.51 (m, 5H), 4.01-3.38 (m, 11H), 2.61-2.29 (m, 6H), 2.27-2.06 (m, 4H), 1.89-1.70 (m, 4H), 0.82 (br t, J=6.8 Hz, 3H); LCMS (ESI, M+1): m/z=680.3. Example 643 ##STR00341## 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide ##STR00342## [0539] Step A. 1-benzyl 3-methyl 3-allylpiperidine-1,3-dicarboxylate: A solution of 1-benzyl 3-methyl piperidine-1,3-dicarboxylate (50.0 g, 1.0 equiv) in THF (500 mL) was cooled to 78 C. under argon atmosphere. Following that LiHMDS (1 M, 234 mL, 1.3 equiv) was added over a period of 30 minutes. The reaction was stirred at 78 C. for 1 hour. To the reaction mixture was added 3-bromoprop-1-ene (26.2 g, 1.2 equiv) at 78 C. The reaction was stirred at 20 C. for 5 hours. The reaction was quenched by saturated aqueous NH.sub.4Cl (200 mL) and water (100 mL). The mixture was extracted with ethyl acetate (3200 mL) and washed with 10% aqueous citric acid (2200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. The residue was concentrated to afford the title compound (55.0 g, 96% yield) as a brown oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.47-7.28 (m, 5H), 5.81-5.54 (m, 1H), 5.19-5.00 (m, 4H), 4.00 (br d, J=13.2 Hz, 1H), 3.70-3.53 (m, 4H), 3.21 (br d, J=13.4 Hz, 2H), 2.40-2.27 (m, 1H), 2.27-2.16 (m, 1H), 2.05 (s, 1H), 1.60 (br d, J=4.0 Hz, 3H) [0540] Step B. 3-allyl-1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid: A solution of 1-benzyl 3-methyl 3-allylpiperidine-1,3-dicarboxylate (55.0 g, 1.0 equiv) and LiOH.Math.H.sub.2O (29.1 g, 4.0 equiv) in MeOH (300 mL) and H.sub.2O (100 mL) was stirred at 60 C. for 12 hours under N.sub.2 atmosphere. pH of the mixture was adjusted to 2 by adding 2M HCl and extracted with ethyl acetate (500 mL). The organic layer was concentrated to afford the title compound (49.0 g, 93% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.43-7.27 (m, 5H), 5.87-5.51 (m, 1H), 5.28-4.98 (m, 5H), 3.68-3.52 (m, 1H), 3.37-3.06 (m, 3H), 2.46-2.13 (m, 4H), 2.08-1.98 (m, 2H), 1.68-1.61 (m, 2H), 1.60-1.48 (m, 2H) [0541] Step C. benzyl 3-allyl-3-aminopiperidine-1-carboxylate: To a solution of 3-allyl-1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid (49.0 g, 1.0 equiv), DPPA (48.9 g, 1.1 equiv) and TEA (32.7 g, 2.0 equiv) in toluene (500 mL) was stirred at 80 C. for 4 hours. To the mixture was added 4M HCl.Math.dioxane to adjust pH to 2. The mixture was diluted with water (150 mL) and the layers were separated. To the aqueous layer was added solid NaHCO.sub.3 to adjust pH to 9 and the resulting was extracted with ethyl acetate (230 mL). The combined organic layer was washed with brine (40 mL) and dried over sodium sulfate. The residue was concentrated to afford the title compound (43.0 g, 97% yield) as a yellow oil; LCMS (ESI, M99): m/z=275.2. [0542] Step D. benzyl 3-allyl-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate: A solution of benzyl 3-allyl-3-aminopiperidine-1-carboxylate (42.0 g, 1.0 equiv) and (Boc).sub.2O (334 g, 10 equiv) was stirred at 60 C. for 4 hours under N.sub.2 atmosphere. The mixture was concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 12:1] to afford the title compound (36.0 g, 62% yield) as a white solid; LCMS (ESI, M99): m/z=319.1. [0543] Step E. benzyl 3-((tert-butoxycarbonyl)amino)-3-(2-oxoethyl)piperidine-1-carboxylate: To a solution of benzyl 3-allyl-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (4.00 g, 1.0 equiv) in THF (40 mL) and H.sub.2O (40 mL) was added NaIO.sub.4 (4.57 g, 2.0 equiv) and K.sub.2OsO.sub.42H.sub.2O (197 mg, 0.05 equiv) portionwise at 0 C. The mixture was stirred at 20 C. for 2 hours. The mixture was quenched by adding saturated Na.sub.2S.sub.2O.sub.3 aqueous solution (250 mL). The mixture was extracted with ethyl acetate (350 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 10:1 to 2:1] to afford the title compound (1.70 g, 41% yield) as a white solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.79 (br s, 1H), 7.40-7.35 (m, 4H), 7.34-7.30 (m, 1H), 5.29-5.04 (m, 2H), 4.16-3.85 (m, 2H), 3.20-2.71 (m, 4H), 1.78-1.47 (m, 4H), 1.41 (s, 9H); LCMS (ESI, M99): m/z=277.2. [0544] Step F. benzyl 3-((tert-butoxycarbonyl)amino)-3-(2-hydroxyethyl)piperidine-1-carboxylate: To a solution of benzyl 3-((tert-butoxycarbonyl)amino)-3-(2-oxoethyl)piperidine-1-carboxylate (5.60 g, 1.0 equiv) in EtOH (30 mL) and THF (30 mL) was added NaBH.sub.4 (1.18 g, 2.1 equiv) portionwise at 0 C. The mixture was stirred at 0 C. for 1 hour. The mixture was quenched by adding sat. aq. NH.sub.4Cl (30 mL) slowly and extracted with ethyl acetated (100 mL). The organic layer was concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 10:1 to 1:1] to afford the title compound (5.30 g, 93% yield) as a white solid; .sup.1H NMR (400 MHz, CHLOROFORM-d) =7.41-7.35 (m, 4H), 7.35-7.29 (m, 1H), 5.28-5.05 (m, 2H), 4.98-4.65 (m, 1H), 4.11-3.96 (m, 1H), 3.90-3.63 (m, 3H), 3.14-2.94 (m, 2H), 2.65-2.33 (m, 1H), 1.74-1.45 (m, 4H), 1.42 (s, 9H); LCMS (ESI, M99): m/z=279.1. [0545] Step G. benzyl 3-(2-(acetylthio)ethyl)-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate: To a solution of PPh.sub.3 (3.05 g. 2.0 equiv) in THF (40 mL) was added DIAD (2.35 g, 2.0 equiv) at 0 C. The mixture was stirred at 0 C. for 0.5 hour. To the mixture was added a solution of benzyl 3-((tert-butoxycarbonyl)amino)-3-(2-hydroxyethyl)piperidine-1-carboxylate (2.20 g, 1.0 equiv) and ethanethioic S-acid (885 mg, 2.0 equiv) in THF (20 mL) slowly at 0 C. The mixture was stirred at 0 C. for 1 hour and then at 15 C. for 1 hour. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 20:1 to 7:1] to afford the title compound (5.00 g, crude) as a white solid; LCMS (ESI, M99): m/z=337.1. [0546] Step H. benzyl 3-((tert-butoxycarbonyl)amino)-3-(2-(chlorosulfonyl)ethyl)piperidine-1-carboxylate: To a solution of benzyl 3-(2-(acetylthio)ethyl)-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (1.00 g, 1.0 equiv) in AcOH (6 mL) and H.sub.2O (0.6 mL) was added NCS (918 mg, 3.0 equiv). The mixture was stirred at 15 C. for 0.5 hour. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to afford the title compound (1.5 g, crude) as a yellow oil. [0547] Step I. benzyl 3-amino-3-(2-(chlorosulfonyl)ethyl)piperidine-1-carboxylate: To a solution of benzyl 3-((tert-butoxycarbonyl)amino)-3-(2-(chlorosulfonyl)ethyl)piperidine-1-carboxylate (1.50 g, 1.0 equiv) in DCM (2 mL) was added TFA (7.70 g, 21 equiv) at 0 C. The mixture was stirred at 0 C. for 15 minutes. The mixture was concentrated to afford the title compound (1.2 g, crude) as a yellow oil. [0548] Step J. benzyl 2-thia-1,7-diazaspiro[4.5]decane-7-carboxylate 2,2-dioxide: To a solution of benzyl 3-amino-3-(2-(chlorosulfonyl)ethyl)piperidine-1-carboxylate (1.2 g, crude) in THF (12 mL) was added K.sub.2CO.sub.3 (2.00 g, 14.5 mmol). The mixture was stirred at 15 C. for 2 hours. The mixture was added water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] and column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 5:1 to 1:2] to afford the title compound (100 mg, 26% yield over four steps) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.42-7.29 (m, 5H), 5.23-5.06 (m, 2H), 4.55-4.24 (m, 1H), 3.72-3.29 (m, 4H), 3.18 (br s, 2H), 2.37-2.09 (m, 2H), 1.89 (br s, 1H), 1.78-1.63 (m, 3H); LCMS (ESI, M+1): m/z=325.2. [0549] Step K. 2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide: To a suspension of Pd/C (30.0 mg, 10% purity) in MeOH (2 mL) was added benzyl 2-thia-1,7-diazaspiro[4.5]decane-7-carboxylate 2,2-dioxide (100 mg, 1.0 equiv) under N.sub.2. The suspension was degassed under vacuum and purged with H.sub.2 several times. The mixture was stirred under H.sub.2 (15 psi) at 15 C. for 3 hours. The mixture was filtered and concentrated to afford the title compound (70 mg, crude) as a yellow gum. [0550] Step L. 7-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide: To a mixture of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (130 mg, 1.0 equiv), 2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide (57.9 mg, 1.5 equiv) and 4 molecular sieves (20.0 mg) in DMF (0.6 mL) was added DIPEA (79.2 mg, 3.0 equiv). The mixture was stirred at 40 C. for 10 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (110 mg, 74% yield) as a white solid; LCMS (ESI, M+1): m/z=727.3. [0551] Step M. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide: To a solution of 7-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide (100 mg, 1.0 equiv) in ACN (1 mL) was added HCl.Math.dioxane (4 M, 2 mL, 58 equiv) at 0 C. The mixture was stirred at 0 C. for 15 minutes. The mixture was concentrated and diluted with sat. NaHCO.sub.3 to adjust the pH to 9. The mixture was extracted with ethyl acetate (220 mL). The organic layer was concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 36%-66% over 9 min] to afford the title compound (30.7 mg, 32% yield) as a white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.92 (br s, 1H), 9.11 (d, J=3.6 Hz, 1H), 7.76 (ddd, J=3.2, 6.0, 9.2 Hz, 1H), 7.41-7.36 (m, 1H), 7.35-7.29 (m, 2H), 7.03-6.98 (m, 1H), 5.42-5.15 (m, 1H), 4.27-3.97 (m, 4H), 3.89-3.44 (m, 2H), 3.31-3.05 (m, 5H), 3.04-2.99 (m, 1H), 2.88-2.76 (m, 1H), 2.41-2.27 (m, 1H), 2.25 (m, 3H), 2.07 (m, 4H), 1.89-1.70 (m, 5H), 0.72 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=683.3. Example 644 ##STR00343## 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-3,7-diazaspiro[4.5]decane 2,2-dioxide ##STR00344## [0552] Step A. benzyl 3-(chloromethyl)-3-cyanopiperidine-1-carboxylate: To a solution of benzyl 3-cyanopiperidine-1-carboxylate (5.00 g, 1.0 equiv) in tetrahydrofuran (250 mL) was added dropwise LiHMDS (22.5 mL, 1.0 M, 1.1 equiv) at 78 C. and the resulting was stirred for 1 hour. Then chloro(iodo) methane (4.69 g, 1.3 equiv) in tetrahydrofuran (30 mL) was added dropwise at 78 C. and the mixture was stirred at 78 C. for 1 hour. The reaction mixture was allowed to warm up to 20 C. and stirred for 12 hours. The reaction mixture was quenched with aq. ammonium chloride (6 mL) at 0 C. and diluted with water (200 mL). The mixture was extracted with ethyl acetate (2200 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 50:1 to 10:1] to afford the title compound (5.00 g, 76% yield) as a colorless oil. LCMS (ESI, M+1): m/z=293.2. [0553] Step B. benzyl 3-((acetylthio)methyl)-3-cyanopiperidine-1-carboxylate: To a solution of acetylsulfanylpotassium (2.73 g, 1.4 equiv) in DMF (90 mL) was added benzyl 3-(chloromethyl)-3-cyanopiperidine-1-carboxylate (5.00 g, 1.0 equiv). The mixture was stirred at 85 C. for 12 hours. The reaction mixture was quenched with water (200 mL) at 0 C., and then diluted with water (200 mL) and extracted with ethyl acetate (2200 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified by column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 0:1] to afford the title compound (5.20 g, 89% yield) as a red oil. LCMS (ESI, M+1): m/z=333.1. [0554] Step C. benzyl 3-((chlorosulfonyl)methyl)-3-cyanopiperidine-1-carboxylate: To a solution of NCS (8.03 g, 4.0 equiv) in HCl (7.52 mL, 2.0 M, 1.0 equiv) was added dropwise benzyl 3-(acetylsulfanylmethyl)-3-cyano-piperidine-1-carboxylate (5.00 g, 1.0 equiv) in MeCN (15 mL) at 10 C. The mixture was stirred at 25 C. for 0.5 hour. The residue was diluted with water (10 mL) and extracted with ethyl acetate (320 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (6.20 g, 95% yield) as white solid. LCMS (ESI, M+1): m/z=356.0. [0555] Step D. benzyl 3-cyano-3-((fluorosulfonyl)methyl)piperidine-1-carboxylate: To a solution of benzyl 3-((chlorosulfonyl)methyl)-3-cyanopiperidine-1-carboxylate (6.20 g, 1.0 equiv) in MeCN (10 mL) were added KF (1.67 g, 2.0 equiv) and 18-CROWN-6 (1.14 g, 0.3 equiv). The mixture was stirred at 25 C. for 14 hours. The residue was diluted with water (10 mL) and extracted with ethyl acetate (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 2:1] to afford the title compound (4.10 g, 84% yield) as a white solid. .sup.1H NMR (400 MHz, methanol-d.sub.4) =7.27-7.44 (m, 6H), 5.14 (br d, J=5.6 Hz, 3H), 4.84 (s, 3H), 4.18-4.33 (m, 1H), 3.64-3.78 (m, 1H), 3.37-3.58 (m, 1H), 2.76-3.05 (m, 2H), 2.45-2.64 (m, 1H), 2.14-2.37 (m, 1H), 2.10-2.13 (m, 1H), 1.75-1.93 (m, 2H). [0556] Step E. benzyl 2-thia-3,7-diazaspiro[4.5]decane-7-carboxylate 2,2-dioxide: A mixture of benzyl 3-cyano-3-((fluorosulfonyl)methyl)piperidine-1-carboxylate (3.60 g, 1.0 equiv) and NiCl.sub.2.Math.6H.sub.2O (2.77 g, 1.1 equiv) in MeOH (5 mL) was cooled to 20 C. Then NaBH.sub.4 (1.56 g, 3.9 equiv) was added portionwise at 20 C. The reaction mixture was warmed up to 25 C. and stirred for 14 hours. The reaction mixture was quenched with anhydrous ammonium chloride (10 mL). The residue was diluted with water (100 mL) and extracted with ethyl acetate (250.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [neutral condition, column: Waters X bridge 15025 mm5 m; mobile phase: water(NH.sub.4HCO.sub.3)-ACN]; B %: 25%-55%, 10 minutes] to afford the title compound (140 mg, 3.8% yield) as a white solid. LCMS (ESI, M+1): m/z=325.2. [0557] Step F. 2-thia-3,7-diazaspiro[4.5]decane 2,2-dioxide: To a solution of benzyl 2-thia-3,7-diazaspiro[4.5]decane-7-carboxylate 2,2-dioxide (140 mg, 1.0 equiv) in MeOH (2 mL) was added Pd/C (30.0 mg, 0.6 equiv.). The reaction mixture was degassed and purged with H.sub.2 for three times. The mixture was stirred under H.sub.2 (15 Psi) at 20 C. for 2 hours. The reaction mixture was filtered, concentrated and purified by prep-HPLC [neutral condition, column: Waters X bridge 15025 mm5 m; mobile phase: water (NH.sub.4HCO.sub.3)-ACN]; B %: 1%-10%, 10 minutes] to afford the title compound (33.0 mg, 40% yield) as a white solid. LCMS (ESI, M): m/z=190.7. [0558] Step G. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-3,7-diazaspiro[4.5]decane 2,2-dioxide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (25.0 mg, 1.0 equiv) and 2-thia-3,7-diazaspiro[4.5]decane 2,2-dioxide (24.1 mg, 3.0 equiv) in DMF (1 mL) was added 4 molecular sieves (20.0 mg) and DIPEA (54.5 mg, 10 equiv). The mixture was stirred at 40 C. for 24 hours. The mixture was filtered and purified with prep-HPLC [neutral condition, column: Waters X bridge 15025 mm5 m; mobile phase: water (NH.sub.4HCO.sub.3)-ACN]; B %: 28%-58%, 10 minutes] to afford the title compound (5.13 mg, 17.3% yield) as a yellow solid. .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.09 (s, 1H), 7.67 (dd, J=8.8, 6.0 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 6.99-7.09 (m, 1H), 5.21-5.41 (m, 1H), 4.50-4.69 (m, 1H), 4.39 (dd, J=10.8, 5.6 Hz, 1H), 4.18-4.35 (m, 2H), 3.86-4.02 (m, 1H), 3.67-3.86 (m, 1H), 3.33-3.41 (m, 1H), 3.13-3.28 (m, 3H), 2.96-3.12 (m, 3H), 2.32-2.55 (m, 2H), 2.11-2.25 (m, 3H), 1.94-2.04 (m, 4H), 1.75-1.93 (m, 4H), 0.80 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=683.5. Example 645 ##STR00345## 4-(4-(9,9-difluoro-1-(hydroxymethyl)-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0559] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.21 (s, 1H), 7.69 (dd, J=6.0, 9.2 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.26 (t, J=9.6 Hz, 1H), 7.05 (br d, J=1.6 Hz, 1H), 5.42-5.27 (m, 1H), 4.75 (br d, J=2.4 Hz, 2H), 4.48-4.40 (m, 3H), 4.23 (br dd, J=3.2, 11.6 Hz, 1H), 4.10-4.02 (m, 2H), 3.67 (td, J=4.2, 13.2 Hz, 1H), 3.45-3.33 (m, 3H), 3.29-3.21 (m, 3H), 3.08 (dt, J=6.4, 9.6 Hz, 1H), 2.45-2.32 (m, 2H), 2.31-2.26 (m, 1H), 2.25-2.08 (m, 4H), 2.03-1.88 (m, 2H), 0.76 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=686.2. Example 646 ##STR00346## 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide [0560] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid (0.90 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d4) =9.21 (s, 1H), 8.55 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.61 (s, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 5.39-5.23 (m, 3H), 4.55-4.47 (m, 2H), 4.45 (br s, 2H), 4.40-4.31 (m, 2H), 3.41-3.35 (m, 3H), 3.12-3.02 (m, 4H), 2.52-2.43 (m, 1H), 2.35-2.09 (m, 5H), 2.07-1.85 (m, 4H), 0.80 (t, J=7.4 Hz, 3H); LCMS (ESI, M+1): m/z=687.3 Example 647 ##STR00347## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((1R,5R,6S)-1-(hydroxymethyl)-6-(trifluoromethyl)-3-azabicyclo[3.2.0]heptan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0561] The title compound was synthesized according to the procedure described for example 550 except for 4 molecular sieves (10.0 mg) were added to the mixture, to produce the desired compound as a yellow solid (0.31 formic acid salt); .sup.1H NMR (400 MHZ, methanol-d4) =9.31 (s, 1H), 8.50 (s, 1H), 7.68 (dd, J=9.2, 6.0 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 5.31-5.51 (m, 1H), 4.38-4.56 (m, 4H), 4.04-4.25 (m, 2H), 3.69 (s, 2H), 3.40-3.64 (m, 3H), 3.09-3.23 (m, 2H), 2.99 (dt, J=16.8, 8.4 Hz, 1H), 2.09-2.54 (m, 9H), 1.94-2.06 (m, 1H), 0.80 ppm (q, J=6.0 Hz, 3H); LCMS (ESI, M+1): m/z=688.4. Example 648 ##STR00348## 4-(4-(1-cyclopentyl-5-(hydroxymethyl)-3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0562] The title compound was synthesized according to the procedure described for example 544 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, DMSO-d6) =9.46 (s, 1H), 7.73 (dd, J=6.0, 8.9 Hz, 1H), 7.40-7.22 (m, 2H), 7.01 (d, J=2.4 Hz, 1H), 5.37-5.17 (m, 1H), 4.23-4.05 (m, 4H), 3.43 (s, 3H), 3.14-2.95 (m, 4H), 2.82 (br d, J=6.0 Hz, 1H), 2.21-2.10 (m, 2H), 2.08-1.99 (m, 2H), 1.95-1.74 (m, 6H), 1.68 (br s, 4H), 1.60-1.49 (m, 4H), 1.41-1.26 (m, 4H), 0.73 (br t, J=7.2 Hz, 3H), LCMS (ESI, M+1): m/z=688.5. Example 649 ##STR00349## N-(4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1H-pyrazol-3-yl) oxetane-3-carboxamide ##STR00350## [0563] Step A. 3-amino-4-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a mixture of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (730 mg, 1.0 equiv) and K.sub.3PO.sub.4 (730 mg, 3 equiv) in ACN (3.5 mL) and DMF (3.5 mL) was added 3-amino-4-(aminomethyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (420 mg, 2.0 equiv) and 4 molecular sieves (100 mg). The reaction was stirred at 40 C. for 12 hrs. The mixture was filtered, diluted with water (10 mL) and extracted with ethyl acetate (315 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (640 mg, 74% yield) as a yellow oil; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =9.32-9.29 (m, 2H), 7.94-7.86 (m, 2H), 7.68-7.65 (m, 1H), 7.48-7.38 (m, 1H), 7.19 (d, J=2.0 Hz, 1H), 5.47-5.30 (m, 4H), 5.24-5.18 (m, 1H), 4.57-4.43 (m, 2H), 4.21-4.14 (m, 1H), 4.13-4.06 (m, 1H), 3.47-3.38 (m, 3H), 3.14-3.06 (m, 7H), 3.04-3.00 (m, 1H), 2.87-2.79 (m, 1H), 2.43-2.30 (m, 1H), 2.09 (br s, 2H), 2.08-2.03 (m, 1H), 2.03-1.99 (m, 1H), 1.88-1.73 (m, 3H), 0.77 (br s, 3H); LCMS (ESI, M+1): m/z=720.3. [0564] Step B. 4-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-3-(oxetane-3-carboxamido)-1H-pyrazole-1-carboxamide: To a mixture of oxetane-3-carboxylic acid (125 mg, 2.0 equiv) in DMF (6 mL) were added HOBt (124 mg, 1.5 equiv) and EDCI (176 mg, 1.5 equiv). After stirring at 20 C. for 2 hours, 3-amino-4-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (440 mg, 1.0 equiv) was added. The reaction was stirred at 20 C. for 16 hours. The mixture was diluted with water (10 ml) and extracted with EtOAc (320 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (102 mg, 20% yield) as a yellow oil; LCMS (ESI, M+1): m/z=804.3. [0565] Step C N-(4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1H-pyrazol-3-yl) oxetane-3-carboxamide: To a mixture of 4-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-3-(oxetane-3-carboxamido)-1H-pyrazole-1-carboxamide (92 mg, 1.0 equiv) in DCM (0.2 mL) was added TFA (196 mg, 15 equiv). The reaction was stirred at 20 C. for 0.5 hour. The pH of the mixture was adjusted to 6 with sodium bicarbonate, filtered, and purified with prep-HPLC [Waters xbridge C18 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 27%-57% over 8 min] and lyophilized to afford the title compound (1.71 mg, 2.0% yield) as an off-white solid (0.67 formic acid salt); SFC: >99% ee, Chiralpak IC-3 504.6 mm I.D., 3 m, Isocratic elution: 50% MeOH (0.05% DEA) in CO.sub.2, 3 mL/min; 220 nm, t.sub.R: 0.662 min; .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.11 (s, 1H), 8.55 (s, 1H), 7.71-7.63 (m, 1H), 7.50 (s, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.24 (t, J=9.2 Hz, 1H), 7.03 (d, J=2.8 Hz, 1H), 5.43-5.37 (m, 0.5H), 5.23 (br d, J=4.8 Hz, 0.5H), 4.67-4.54 (m, 3H), 4.39-4.25 (m, 3H), 3.97-3.82 (m, 2H), 3.28-3.12 (m, 4H), 3.11-2.99 (m, 2H), 2.50-2.37 (m, 2H), 2.10-1.94 (m, 5H), 0.95-0.84 (m, 3H); .sup.19F NMR (400 MHZ, methanol-d.sub.4) =76.948, 121.228, 138.977, 173.771; LCMS (ESI, M+1): m/z=689.1. Example 650 ##STR00351## 5-((S)-1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)ethyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide ##STR00352## [0566] Step A. 5-(1-ethoxyvinyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide: To a mixture of 5-bromo-N,N,1-trimethyl-1H-pyrazole-3-carboxamide (0.3 g, 1.0 equiv) and tributyl(1-ethoxyvinyl) stannane (700 mg, 1.5 equiv) in toluene (5.0 mL) was added Pd(PPh.sub.3).sub.2Cl.sub.2 (90.7 mg, 0.1 equiv) in one portion under N.sub.2. The mixture was degassed and stirred at 100 C. for 12 hours. The reaction mixture was diluted by water (10 mL) extracted with ethyl acetate (310 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (288 mg, 99% yield) as a black oil; LCMS (ESI, M+1): m/z=224.0. [0567] Step B. 5-acetyl-N,N,1-trimethyl-1H-pyrazole-3-carboxamide: To a mixture of 5-(1-ethoxyvinyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide (280 mg, 1.0 equiv) in THF (9.4 mL) was added HCl (4 N, 6.0 equiv) at 25 C. under nitrogen. The mixture was degassed and purged with nitrogen 3 times. The reaction was stirred at 25 C. for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (330 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by reversed phase flash chromatography [water (0.1% formic acid)/acetonitrile)] to afford the title compound (60 mg, 24% yield) as a white solid; LCMS (ESI, M+1): m/z=196.1. [0568] Step C. (R,E)-5-(1-((tert-butylsulfinyl)imino)ethyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide: To a mixture of 5-acetyl-N,N,1-trimethyl-1H-pyrazole-3-carboxamide (60.0 mg, 1.0 equiv) and (R)-2-methylpropane-2-sulfinamide (44.7 mg, 1.2 equiv) in THF (10 mL) was added tetraisopropoxytitanium (262 mg, 3.0 equiv) at 25 C. under nitrogen. The mixture was degassed and purged with nitrogen 3 times. The reaction was heated to 80 C. and stirred for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (35 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (90 mg, 98% yield) as a white solid; LCMS (ESI, M+1): m/z=299.1. [0569] Step D. 5-((S)-1-((R)-1,1-dimethylethylsulfinamido)ethyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide: To a mixture of (R,E)-5-(1-((tert-butylsulfinyl)imino)ethyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide (330 mg, 1.0 equiv) in THF (3 mL) was added NaBH.sub.4 (83.7 mg, 2.0 equiv) portionwise at 15 C. under N.sub.2. The reaction was degassed and stirred at 0 C. for 2 hours. The reaction mixture was acidified with HCl (2 N) to pH=5 and extracted with ethyl acetate (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated and purified by reversed phase flash chromatography [water (0.1% formic acid)/acetonitrile)] followed by SFC [DAICEL Chiralpak IC 250 mm30 mm, 10 m; A: (0.1% NH.sub.3.Math.H.sub.2O MeOH); B %: 30%-30% over 8.1; 113 min] to afford the title compound (60 mg, 18% yield) as a yellow oil; LCMS (ESI, M+1): m/z=300.9. [0570] Step E. (S)-5-(1-aminoethyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide: To a mixture of 5-((S)-1-((R)-1,1-dimethylethylsulfinamido)ethyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide (50 mg, 1.0 equiv) in ACN (0.5 mL) was added HCl.Math.dioxane (4 M, 0.5 mL, 12 equiv) at 0 C. under N.sub.2. The reaction was degassed and stirred at 20 C. for 1 hour. The reaction mixture was concentrated to afford the title compound (50 mg, 98% yield) as a white solid; LCMS (ESI, M+1): m/z=197.0. [0571] Step F. 5-((S)-1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)ethyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50 mg, 1.0 equiv) and(S)-5-(1-aminoethyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide (30 mg, 1.16 equiv) in DMF (0.01 mL) was added DIPEA (218 mg, 1.69 mmol, 20 equiv) under nitrogen. The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 40 C. for 24 hours. The mixture was purified by prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 18%-48% over 10 min] and lyophilized to afford the title compound (7.73 mg, 12% yield) as a yellow solid (0.96 formic acid salt); .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =9.40 (d, J=4.0 Hz, 1H), 9.30-9.18 (m, 1H), 7.82-7.70 (m, 1H), 7.34 (s, 1H), 7.32 (d, J=2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.65 (d, J=13.2 Hz, 1H), 5.71 (br t, J=7.2 Hz, 1H), 5.42-5.16 (m, 1H), 4.17-4.04 (m, 2H), 4.00-3.90 (m, 3H), 3.30 (br s, 3H), 3.08 (br s, 2H), 2.99 (br s, 1H), 2.95 (br s, 3H), 2.86-2.79 (m, 1H), 2.38-2.31 (m, 1H), 2.16-1.96 (m, 4H), 1.87-1.72 (m, 3H), 1.66 (br t, J=6.4 Hz, 3H), 0.75-0.67 (m, 3H); .sup.19F NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =119.694, 139.400, 171.990; LCMS (ESI, M+1): m/z=689.3. Example 651 ##STR00353## 5-((R)-1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)ethyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide [0572] The title compound was synthesized according to the 6-step procedure described for example 650 except for(S)-2-methylpropane-2-sulfinamide was used in step C instead of (R)-2-methylpropane-2-sulfinamide to produce the desired compound as a white solid (0.37 formic acid salt); .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) =10.0-9.85 (m, 1H), 9.39 (d, J=4.0 Hz, 1H), 9.25 (br t, J=8.4 Hz, 1H), 7.80-7.71 (m, 1H), 7.39-7.34 (m, 1H), 7.32 (d, J=2.0 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.65 (d, J=13.2 Hz, 1H), 5.77-5.65 (m, 1H), 5.39-5.17 (m, 1H), 4.20-4.11 (m, 1H), 4.10-4.00 (m, 1H), 3.94 (d, J=15.6 Hz, 3H), 3.28 (br s, 3H), 3.12-3.01 (m, 3H), 2.99-2.92 (m, 3H), 2.86-2.79 (m, 1H), 2.17-1.96 (m, 5H), 1.88-1.75 (m, 3H), 1.66 (t, J=6.4 Hz, 3H), 0.76-0.64 (m, 3H); .sup.19F NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =119.667, 139.414, 171.986; LCMS (ESI, M+1): m/z=689.4. Example 652 ##STR00354## 4-(4-(3-((difluoromethyl) sulfonyl) piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [0573] The title compound was synthesized according to the procedure described for example 550 except for heating of the mixture was conducted at 80 C. for 5 hours, to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =0.79 (q, J=7.2 Hz, 3H) 1.87 (br s, 2H) 1.96-2.04 (m, 2H) 2.07-2.30 (m, 6H) 2.34-2.50 (m, 3H) 2.96-3.05 (m, 1H) 3.18-3.27 (m, 4H) 3.71-3.88 (m, 1H) 3.90-4.01 (m, 1H) 4.30-4.37 (m, 2H) 4.97 (br d, J=14.0 Hz, 1H) 5.31 (br d, J=53.2 Hz, 1H) 6.86 (td, J=52.0, 7.6 Hz, 1H) 7.06 (dd, J=11.2, 2.4 Hz, 1H) 7.21-7.28 (m, 1H) 7.30 (d, J=2.4 Hz, 1H) 7.68 (dd, J=8.8, 6.0 Hz, 1H) 9.10 (d, J=3.2 Hz, 1H); LCMS (ESI, M+1): m/z=692.3. Example 653 ##STR00355## 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thio)methyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide ##STR00356## [0574] Step A. 5-(chloromethyl)-1-methyl-1H-pyrazole-3-carbonyl chloride: A solution of 5-(hydroxymethyl)-1-methyl-1H-pyrazole-3-carboxylic acid (480 mg, 1.0 equiv) in SOCl.sub.2 (7.87 g, 4.80 mL, 5.0 equiv) was stirred at 80 C. for 1 hour. The mixture was concentrated to afford the title compound (500 mg, crude) as a yellow oil. [0575] Step B. 5-(chloromethyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide: To a solution of 5-(chloromethyl)-1-methyl-1H-pyrazole-3-carbonyl chloride (500 mg, 1.0 equiv) in DCM (4 mL) was added N-methylmethanamine (2 M in THF, 7.77 mL, 6.0 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hour. The mixture was concentrated and purified by silica gel chromatography (petroleum ether/ethyl acetate 50/1 to 1/1) to afford the title compound (350 mg, 66% yield) as a white solid; LCMS (ESI, M+1): m/z=201.9. [0576] Step C. (3-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-5-yl)methyl carbamimidothioate: To a solution of 5-(chloromethyl)-N,N,1-trimethyl-pyrazole-3-carboxamide (100 mg, 1.0 equiv) in DMSO (1 mL) was added thiourea (113 mg, 3.0 equiv). The reaction was stirred at 25 C. for 6 hours and then concentrated to afford the title compound (100 mg, crude) as a yellow solid. [0577] Step D. 5,5-(disulfanediylbis(methylene)bis(N,N, 1-trimethyl-1H-pyrazole-3-carboxamide): A solution of (3-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-5-yl)methyl carbamimidothioate (250 mg, 1.0 equiv), K.sub.2CO.sub.3 (430 mg, 3.0 equiv) in DMSO (1 mL) was stirred at 25 C. for 2 hours. The reaction mixture was filtered and concentrated. The residue was purified by reversed phase flash chromatography [water (0.1% FA)/acetonitrile] to afford the title compound (55 mg, 12% yield) as white solid; LCMS (ESI, M+1): m/z=397.3. [0578] Step E. 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thio)methyl)-N,N, 1-trimethyl-1H-pyrazole-3-carboxamide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (40.0 mg, 1.0 equiv) and 5,5-(disulfanediylbis(methylene))bis(N,N, 1-trimethyl-1H-pyrazole-3-carboxamide) (53.5 mg, 2.0 equiv) in DMF (0.1 mL) were added tributylphosphine (27.3 mg, 2.0 equiv), 4 molecular sieves (5 mg, 1.0 equiv) and DIPEA (175 mg, 20.0 equiv). The reaction was stirred at 40 C. for 16 hours. The reaction mixture was concentrated and purified by prep-HPLC [Welch Xtimate C18 15025 mm5 m; A: water (NH.sub.3.Math.H.sub.2O), B: ACN, B %: 38%-68% over 8 min] to afford the title compound (7.89 mg, 16% yield) as a yellow solid; SFC: Chiralpak AS-3 504.6 mm I.D., 3 m, Gradient elution: MeOH (0.05% DEA) in CO.sub.2 from 5% to 40%, 3 mL/min, 220 nm, t.sub.R: 1.808 min, 2.018 min; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6+deuterium oxide-d.sub.2) =9.23 (s, 1H), 7.76 (dd, J=6.0, 9.2 Hz, 1H), 7.40-7.32 (m, 2H), 7.03 (d, J=2.4 Hz, 1H), 6.65 (s, 1H), 5.40-5.20 (m, 1H), 4.78 (s, 2H), 4.27-4.17 (m, 2H), 4.00 (s, 3H), 3.23 (s, 2H), 3.08 (br d, J=6.8 Hz, 2H), 3.01 (s, 1H), 2.93 (s, 3H), 2.86-2.79 (m, 1H), 2.57-2.55 (m, 1H), 2.3-2.24 (m, 1H), 2.22-2.12 (m, 1H), 2.11-1.96 (m, 3H), 1.89-1.70 (m, 3H), 0.67 (t, J=7.6 Hz, 3H); .sup.19F NMR (400 MHZ, dimethylsulfoxide-d.sub.6+deuterium oxide-d.sub.2) =119.262, 138.040, 171.834; LCMS (ESI, M+1): m/z=692.2. Example 654 ##STR00357## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0579] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.06 (s, 1H), 7.65 (dd, J=5.9, 9.2 Hz, 1H), 7.27 (d, J=2.4 Hz, 1H), 7.22 (t, J=9.2 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 5.39-5.22 (m, 1H), 4.36-4.19 (m, 4H), 4.12-3.96 (m, 2H), 3.82 (dd, J=7.0, 13.6 Hz, 2H), 3.71 (dd, J=2.1, 8.0 Hz, 2H), 3.28-3.11 (m, 3H), 2.97 (s, 3H), 2.54-2.42 (m, 1H), 2.40-2.27 (m, 1H), 2.27-2.22 (m, 1H), 2.22-2.11 (m, 3H), 2.04-1.92 (m, 5H), 1.85-1.77 (m, 2H), 0.80 (dt, J=1.7, 7.2 Hz, 3H). LCMS (ESI, M+1): 697.3. Example 655 ##STR00358## 2-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-1,2-thiazinane 1,1-dioxide [0580] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.26 (d, J=7.2 Hz, 1H), 8.53 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.05 (t, J=2.4 Hz, 1H), 5.51-5.21 (m, 1H), 4.65 (br d, J=6.8 Hz, 1H), 4.44-4.38 (m, 1H), 4.36-4.31 (m, 1H), 4.28-3.90 (m, 4H), 3.48-3.34 (m, 4H), 3.17-3.07 (m, 3H), 2.48-1.89 (m, 13H), 1.74 (br d, J=3.6 Hz, 2H), 0.78 (td, J=7.2, 10.8 Hz, 3H). LCMS (ESI, M+1): 697.3. Example 656 ##STR00359## 8-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,8-triazaspiro[5.5]undecane 2,2-dioxide ##STR00360## [0581] Step A. (Z)-tert-butyl 3-(cyanomethylene)piperidine-1-carboxylate: NaH (2.41 g, 60% purity, 1.2 equiv) was added portionwise to 2-diethoxyphosphorylacetonitrile (10.7 g, 1.2 equiv) in anhydrous THF (200 mL) under hydrogen at 25 C. and stirred for 30 minutes. Following that was added tert-butyl 3-oxopiperidine-1-carboxylate (10 g, 1.0 equiv). The reaction was stirred at 25 C. for 12 hours. The mixture was quenched with water (200 mL) and concentrated to remove THE, extracted with EtOAc (2300 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate 30:1 to 1:1) to afford the title compound (10 g, 81% yield) as a colorless oil; 1H NMR (400 MHZ, chloroform-d) =5.28-5.13 (m, 1H), 4.28-4.22 (m, 1H), 4.02-3.95 (m, 1H), 3.55-3.45 (m, 2H), 2.67-2.58 (m, 1H), 2.46-2.36 (m, 1H), 1.82-1.68 (m, 2H), 1.53-1.41 (m, 9H). [0582] Step B. tert-butyl 3-amino-3-(cyanomethyl)piperidine-1-carboxylate: To a mixture of tert-butyl (3Z)-3-(cyanomethylene)piperidine-1-carboxylate (3 g, 1.0 equiv) in MeOH (9 mL) was added NH.sub.3.Math.MeOH (36 mL, 20% purity). The reaction was heated to 100 C. with stirring for 16 hours in a sealed tube. The mixture was concentrated and purified by Al.sub.2O.sub.3 chromatography (petroleum ether/ethyl acetate 10:1 to 0:1) to afford the title compound (1.08 g, 30% yield) as a yellow oil; 1H NMR (400 MHZ, chloroform-d) =3.65-3.03 (m, 4H), 2.64-2.32 (m, 2H), 1.86-1.67 (m, 2H), 1.66-1.58 (m, 2H), 1.48 (s, 9H); LCMS (ESI, M55): m/z=184.1. [0583] Step C. tert-butyl 3-amino-3-(2-aminoethyl)piperidine-1-carboxylate: To a mixture of tert-butyl 3-amino-3-(cyanomethyl)piperidine-1-carboxylate (1.25 g, 1.0 equiv) in methanol (20 mL) was added Raney-Ni (1.34 g, 3.0 equiv) and NH.sub.3.Math.MeOH (5 mL, 20% purity) under nitrogen. The reaction was degassed under vacuum and purged with hydrogen several times. The reaction was stirred under hydrogen (15 psi) at 20 C. for 16 hours. The mixture was filtered and concentrated to afford the title compound (1.4 g, 99% yield) as a light blue oil; .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) =3.75-3.19 (m, 4H), 3.14-2.72 (m, 4H), 2.52 (br s, 2H), 1.64-1.11 (m, 15H); LCMS (ESI, M+1): m/z=244.1. [0584] Step D. tert-butyl 2-thia-1,3,8-triazaspiro[5.5]undecane-8-carboxylate 2,2-dioxide: To a mixture of tert-butyl 3-amino-3-(2-aminoethyl)piperidine-1-carboxylate (1.49 g, 1.0 equiv) in pyridine (15 mL) was added sulfuric diamide (706 mg, 1.2 equiv) at 25 C. The reaction was stirred at 125 C. for 12 hours. The mixture was concentrated and purified by prep-TLC (dichloromethane/methanol 10:1) to afford the title compound (443 mg, 23% yield) as a yellow oil; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =6.54-6.42 (m, 1H), 6.42-6.30 (m, 1H), 4.26-4.16 (m, 1H), 3.78-3.60 (m, 1H), 3.45-3.34 (m, 1H), 3.30-3.21 (m, 1H), 2.93-2.69 (m, 2H), 1.75-1.66 (m, 1H), 1.60-1.42 (m, 4H), 1.42-1.35 (m, 9H), 1.33-1.21 (m, 1H); LCMS (ESI, M55): m/z=250.2. [0585] Step E. 2-thia-1,3,8-triazaspiro[5.5]undecane 2,2-dioxide; To a mixture of tert-butyl 2-thia-1,3,8-triazaspiro[5.5]undecane-8-carboxylate 2,2-dioxide (200 mg, 1.0 equiv) in ACN (1.23 mL) was added dropwise HCl.Math.dioxane (4 M, 2.46 mL, 15 equiv) at 0 C. The reaction was stirred at 25 C. for 1 hour. The mixture was concentrated to afford the title compound (150 mg, HCl) as a yellow solid; LCMS (ESI, M+1): m/z=206.2. [0586] Step F. 8-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,8-triazaspiro[5.5]undecane 2,2-dioxide: The title compound was synthesized according to the procedure described for example 541 to produce the desired compound as an off-white solid; SFC: Chiralpak IC-3 504.6 mm I.D., 3 m; Gradient elution: 40% MeOH+ACN (0.05% DEA) in CO.sub.2, 3 mL/min, 220 nm, t.sub.R: 1.207 mim, 1.996 min; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =9.96 (s, 1H), 9.14-9.05 (m, 1H), 7.81-7.68 (m, 1H), 7.40-7.25 (m, 2H), 7.04-6.95 (m, 1H), 6.73-6.60 (m, 1H), 6.46-6.35 (m, 1H), 5.37-5.18 (m, 1H), 4.56-3.98 (m, 4H), 3.98-3.66 (m, 2H), 3.36 (br s, 1H), 3.12-2.97 (m, 4H), 2.91-2.51 (m, 1H), 2.39-2.31 (m, 1H), 2.22-1.90 (m, 6H), 1.88-1.70 (m, 5H), 1.65-1.54 (m, 1H), 1.48-1.32 (m, 1H), 0.82-0.65 (m, 3H); .sup.19F NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =119.619, 139.505, 172.020; LCMS (ESI, M+1): m/z=698.0. Example 657 ##STR00361## 1-(cyanomethyl)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide ##STR00362## [0587] Step A. tert-butyl N-[[2-[2-(tert-butylamino)-2-oxo-ethyl]-5-(dimethylcarbamoyl) pyrazol-3-yl]methyl]carbamate: To a solution of tert-butyl N-[[5-(dimethylcarbamoyl)-1H-pyrazol-3-yl]methyl]carbamate (650 mg, 1.0 equiv) and 2-bromo-N-tert-butyl-acetamide (940 mg, 2 equiv) in DMF (7 mL) was added Cs.sub.2CO.sub.3 (2.4 g, 3.0 equiv) at 25 C. The mixture was stirred at 80 C. for 12 hours before being poured into ice- water (20 mL) and stirred for 2 mins. The aqueous phase was extracted with ethyl acetate (20 mL3). The combined organic phases were washed with brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC [C18, 0.1% formic acid condition], which was further separated by SFC (column: DAICEL CHIRALPAK AD (250 mm30 mm 10 um); mobile phase: [0.1% NH.sub.3.Math.H.sub.2O IPA]; B %: 35%-35%, 2.3 min) to afford the title compound (369 mg, 39.5% yield) as a yellow solid. .sup.1HNMR (400 MHZ, METHANOL-d.sub.4) 1.35 (s, 9H) 1.44 (s, 9H) 3.07 (s, 3H) 3.30 (br s, 3H) 4.28 (s, 2H) 4.86 (br s, 2H) 6.53 (s, 1H). [0588] Step B. 5-(aminomethyl)-1-[2-(tert-butylamino)-2-oxo-ethyl]-N,N-dimethyl-pyrazole-3-carboxamide: To a solution of tert-butyl N-[[2-[2-(tert-butylamino)-2-oxo-ethyl]-5-(dimethylcarbamoyl) pyrazol-3-yl]methyl]carbamate (341 mg, 1.0 equiv) in dioxane (5 mL) was added HCl/dioxane (4 M, 223 L, 1.0 equiv) at 25 C. The mixture was stirred at 25 C. for 1 hour. The mixture was directly concentrated under vacuum to afford the title compound (270 mg, crude, HCl) as a white solid. [0589] Step C. 1-(2-(tert-butylamino)-2-oxoethyl)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (100 mg, 1.0 equiv) and 5-(aminomethyl)-1-[2-(tert-butylamino)-2-oxo-ethyl]-N,N-dimethyl-pyrazole-3-carboxamide (134 mg, 2.5 equiv, HCl) in DMF (1.5 mL) was added K.sub.3PO.sub.4 (179 mg, 5.0 equiv) at 25 C. The mixture was stirred at 60 C. for 12 hours. The residue was poured into ice-water (20 mL) and stirred for 2 mins. The aqueous phase was extracted with ethyl acetate (20 mL3). The combined organic phases were washed with brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (78 mg, 59% yield) as white solid. LCMS (ESI, M+1): m/z=774.4. [0590] Step D. 1-(cyanomethyl)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: To a solution of 1-(2-(tert-butylamino)-2-oxoethyl)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide (28 mg, 1.0 equiv) in DMF (0.5 mL) was added POCl.sub.3 (6.8 mg, 1.23 equiv) at 25 C. The mixture was stirred at 55 C. for 2 hours. The residue was purified by prep-HPLC [C18, 0.1% NH.sub.4HCO.sub.3 condition] to afford the title compound (4.8 mg, 18.8% yield) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) 0.76 (t, J=7.38 Hz, 3H) 1.84-2.05 (m, 3H) 2.07-2.49 (m, 5H) 2.97-3.07 (m, 1H) 3.10 (s, 3H) 3.36 (s, 3H) 4.28-4.36 (m, 2H) 4.59 (br s, 2H) 4.94-5.10 (m, 3H) 5.22-5.41 (m, 1H) 5.63 (s, 2H) 6.80 (s, 1H) 7.04 (d, J=2.50 Hz, 1H) 7.24 (t, J=9.2 Hz, 1H) 7.30 (d, J=2.4 Hz, 1H) 7.67 (dd, J=9.2, 5.82 Hz, 1H) 9.17 (s, 1H); LCMS (ESI, M+1): m/z=700.3. Example 658 ##STR00363## 1-(cyanomethyl)-3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide ##STR00364## [0591] Step A. tert-butyl N-[[1-(cyanomethyl)-5-(dimethylcarbamoyl) pyrazol-3-yl]methyl]carbamate: To a solution of tert-butyl N-[[5-(dimethylcarbamoyl)-1H-pyrazol-3-yl]methyl]carbamate (150 mg, 1.0 equiv) in DMF (5 mL) was added Cs.sub.2CO.sub.3 (546 mg, 3.0 equiv) and 2-bromoacetonitrile (134 mg, 2.0 equiv). The mixture was stirred at 25 C. for 2 hours. The reaction mixture was filtered, concentrated and purified by reversed phase flash chromatography (C18, 0.1% NH.sub.3.Math.H.sub.2O in water, 10-50% ACN) to afford the title compound (70.0 mg 33% yield) as a brown oil; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =7.39-7.25 (m, 1H), 6.49 (s, 1H), 5.39 (s, 2H), 4.10 (br d, J=5.0 Hz, 2H), 3.08 (s, 3H), 2.99 (s, 3H), 1.40-1.36 (m, 9H) [0592] Step B. 5-(aminomethyl)-2-(cyanomethyl)-N,N-dimethyl-pyrazole-3-carboxamide: To a mixture of tert-butyl N-[[1-(cyanomethyl)-5-(dimethylcarbamoyl) pyrazol-3-yl]methyl]carbamate (45.0 mg, 90.2% purity, 1.0 equiv) in DCM (0.2 mL) was added dropwise TFA (0.1 mL, 10.2 equiv) in DCM (0.1 mL). The mixture was stirred at 0 C. for 1 hour. The reaction mixture was poured into water (2 mL) and pH was adjusted to 8 by NH.sub.3.Math.H.sub.2O. The mixture was concentrated and purified with prep-HPLC [Waters Xbridge 15025 mm5 um; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 1%-20% over 10 min] to afford the title compound (12.0 mg, 44% yield) as a yellow oil; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =6.69 (s, 1H), 5.40-5.37 (m, 2H), 3.92 (s, 2H), 3.23 (s, 3H), 3.13 (br s, 3H) [0593] Step C. 1-(cyanomethyl)-3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide: The title compound was synthesized according to the procedure described for example 622 to produce the desired compound as a yellow gum; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.01-9.83 (m, 1H), 9.61-9.49 (m, 1H), 9.33 (s, 1H), 7.76 (dd, J=6.4, 8.8 Hz, 1H), 7.39-7.31 (m, 2H), 6.99 (s, 1H), 6.75 (s, 1H), 5.45 (s, 2H), 5.36-5.17 (m, 1H), 4.88-4.70 (m, 2H), 4.18-4.01 (m, 2H), 3.10 (s, 3H), 3.00 (s, 3H), 2.97-2.71 (m, 2H), 2.17-1.97 (m, 5H), 1.87-1.73 (m, 3H), 0.71 (br t, J=7.3 Hz, 3H); LCMS (ESI, M+1): m/z=700.5. Example 659 ##STR00365## 3-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-4-yl)hexahydro-2H-pyrrolo[3,4-d]oxazol-2-one ##STR00366## [0594] Step A. tert-butyl 3-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-4-yl)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazole-5 (3H)-carboxylate: A mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (142 mg, 1.0 equiv), tert-butyl N-[[4-methyl-2-oxo-3-(4-piperidyl) oxazolidin-5-yl]methyl]carbamate (92.2 mg, 1.1 equiv, HCl), K.sub.3PO.sub.4 (50.9 mg, 1.0 equiv) in DMF (1 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 25 C. for 12 hours under N.sub.2 atmosphere. The mixture was filtered and concentrated and purified with prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (72 mg, 37% yield). .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.98-8.84 (m, 1H), 7.59-7.52 (m, 1H), 7.24-7.12 (m, 2H), 6.97-6.63 (m, 1H), 5.49-5.24 (m, 1H), 4.98-4.80 (m, 1H), 4.75-4.45 (m, 3H), 4.39-4.31 (m, 1H), 4.19-3.96 (m, 1H), 3.94-3.82 (m, 2H), 3.68-3.35 (m, 5H), 3.33-3.01 (m, 4H), 2.54-1.78 (m, 11H), 1.56-1.39 (m, 9H), 0.87-0.70 (m, 3H). [0595] Step B. 3-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-4-yl)hexahydro-2H-pyrrolo[3,4-d]oxazol-2-one: A mixture of tert-butyl 3-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-4-yl)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazole-5 (3H)-carboxylate (20.1 mg, 1.0 equiv) in HCl/dioxane (0.5 mL) and MeOH (0.5 mL) stirred at 25 C. for 1 hour under N.sub.2 atmosphere. The mixture was concentrated and purified with prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (16 mg, 86% yield, hydrochloride). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.13 (s, 1H), 8.44 (br s, 1H), 7.71 (dd, J=6.0, 9.0 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.28 (t, J=9.6 Hz, 1H), 7.08 (s, 1H), 5.65-5.42 (m, 1H), 5.13 (br dd, J=4.8, 6.9 Hz, 1H), 4.86 (br s, 1H), 4.70-4.51 (m, 3H), 4.02-3.34 (m, 10H), 3.13-2.90 (m, 2H), 2.70-2.02 (m, 12H), 0.82 (t, J=7.2 Hz, 3H); .sup.19F NMR (377 MHz, METHANOL-d4) =121.07 (br s, 1F), 139.19 (br s, 1F), 173.99 (br s, 1F); LCMS (ESI, M+1): m/z=704.3. Example 660 ##STR00367## (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)dimethylphosphine oxide ##STR00368## [0596] Step A. tert-butyl 2-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 2-bromo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (650 mg, 1.0 equiv, HCl) in DCM (8 mL) was added TEA (520 mg, 716 L, 2.0 equiv) and Boc.sub.2O (842 mg, 1.5 equiv). The mixture was stirred at 25 C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue was purified by flash silica gel chromatography (ISCOR; 12 g SepaFlash Silica Flash Column, Eluent of 030% Ethyl acetate/Petroleum ethergradient @ 30 mL/min) to afford the title compound (250 mg, 28.9% yield, 94.0% purity) as a white solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =6.32-6.12 (m, 1H), 4.48-4.35 (m, 4H), 3.78-3.65 (m, 2H), 1.91 (br d, J=4.4 Hz, 2H), 1.51-1.40 (m, 9H); LCMS (ESI, M+1): m/z=318.0. [0597] Step B. tert-butyl 2-(dimethylphosphoryl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: A mixture of tert-butyl 2-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (250 mg, 1.0 equiv), methylphosphonoylmethane (74.1 mg, 1.2 equiv), Pd(OAc).sub.2 (17.7 mg, 0.1 equiv), K.sub.3PO.sub.4 (201 mg, 1.2 equiv) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (45.7 mg, 1.0 equiv) in DMF (4.0 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 140 C. for 12 hours under N.sub.2 atmosphere. The mixture was cooled to 20 C. and filtered through a pad of celite. The filter cake was washed with EtOAc and the filtrate was evaporated and purified with prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (120 mg, 48.4% yield) as a yellow solid. LCMS (ESI, M1): m/z=314.2. [0598] Step C. dimethyl(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)phosphine oxide: To tert-butyl 2-(dimethylphosphoryl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (120 mg, 1.0 equiv) in dioxane (1.0 mL) was added HCl/dioxane (4 M, 2.4 mL, 25.1 equiv). The mixture was stirred at 20 C. for 2 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (90 mg, 94.1% yield, HCl) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =6.94 (s, 1H), 4.69-4.63 (m, 2H), 4.58 (s, 2H), 3.68 (s, 3H), 3.62-3.58 (m, 2H), 2.23-2.15 (m, 2H), 1.82 (dd, J=1.6, 14.0 Hz, 6H). [0599] Step D. (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)dimethylphosphine oxide: A mixture of 2-dimethylphosphoryl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (30 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (75.0 mg, 0.9 equiv), K.sub.3PO.sub.4 (89.6 mg, 3.0 equiv), 4 molecular sieves (10 mg) in DMF (0.2 mL) and MeCN (0.2 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 60 C. for 12 hours under N.sub.2 atmosphere. K.sub.3PO.sub.4, 4 molecular sieves was filtered. The filtrate was concentrated and purified by prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (10 mg, 8.9% yield, 88% purity) as a white solid (0.09 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.17 (s, 1H), 8.57-8.51 (m, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.26 (t, J=9.2 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.91 (s, 1H), 5.46-5.37 (m, 1H), 5.36-5.27 (m, 2H), 4.63 (br d, J=5.6 Hz, 2H), 4.45 (br d, J=4.4 Hz, 2H), 4.40-4.30 (m, 2H), 3.37 (br s, 1H), 3.16-3.06 (m, 1H), 2.54-2.37 (m, 4H), 2.36-2.26 (m, 2H), 2.25-2.03 (m, 5H), 2.00-1.93 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H), 1.38-1.24 (m, 1H), 0.79 (t, J=6.8 Hz, 3H); LCMS (ESI, M+1): m/z=706.2. Example 661 ##STR00369## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-sulfonamide ##STR00370## [0600] Step A. benzyl 2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (500 mg, 1.0 equiv, HCl), TEA (1.07 g, 4.0 equiv) in THF (10 mL) was added CbzCl (452 mg, 1.0 equiv) at 0 C. The reaction was stirred at 20 C. for 2 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (450 mg, 56% yield) as a yellow oil; .sup.1H NMR (400 MHZ, chloroform-d) =7.39-7.29 (m, 5H), 5.67-5.45 (m, 1H), 5.13-5.09 (m, 2H), 4.46-4.39 (m, 2H), 4.23-4.18 (m, 2H), 3.77-3.71 (m, 2H), 1.97-1.85 (m, 2H); LCMS (ESI, M+1): m/z=286.7. [0601] Step B. benzyl 2-(chlorosulfonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of benzyl 2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (500 mg, 1.0 equiv) in ACN (40 mL) at 0 C. was added a solution of HCl (2.55 g, 37% purity, 14.8 equiv) in H.sub.2O (0.9 mL) followed by aqueous solution of NaNO.sub.2 (241 mg, 2.0 equiv) in H.sub.2O (0.8 mL). After stirring at 0 C. for 45 minutes, the mixture was treated with AcOH (945 mg, 9.0 equiv), CuCl (86.4 mg, 0.5 equiv) and CuCl.sub.2 (141 mg, 0.6 equiv) and purged with SO.sub.2 gas at 0 C. for 25 minutes. The reaction was stirred at 0-15 C. for 12 hours. The mixture was poured into ice-water (10 mL) and extracted with EtOAc (315 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated to afford the title compound (600 mg, crude) as a dark green oil. [0602] Step C. benzyl 2-sulfamoyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: A mixture of benzyl 2-(chlorosulfonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (400 mg, 1 equiv) in NH.sub.3.Math.THF (9 mL, 20% purity, 1.0 equiv) was stirred at 20 C. for 2 hours. The mixture was concentrated, diluted with saturated NH.sub.4Cl aqueous solution (5 mL), extracted with EtOAc (310 mL), concentrated, and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (90 mg, 23% yield) as a yellow oil; .sup.1H NMR (400 MHZ, chloroform-d) =7.42-7.29 (m, 5H), 6.72-6.51 (m, 1H), 5.17-5.07 (m, 2H), 4.97-4.88 (m, 2H), 4.60-4.51 (m, 2H), 4.51-4.46 (m, 2H), 3.86-3.77 (m, 2H), 2.04-1.92 (m, 2H); LCMS (ESI, M+1): m/z=350.8. [0603] Step D. 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-sulfonamide; To a solution of benzyl 2-sulfamoyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (80 mg, 1.0 equiv) in MeOH (2 mL) was added NH.sub.3.Math.MeOH (4 M, 0.5 mL, 1.0 equiv) and Pd(OH).sub.2 (30 mg, 10%) under nitrogen. The reaction was degassed and purged with hydrogen 3 times. The reaction was stirred at 20 C. for 1 hours under hydrogen (15 psi) atmosphere. The mixture was filtered and concentrated to afford the title compound (35 mg, crude) as yellow oil. [0604] Step E. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-sulfonamide: To a mixture of 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-sulfonamide (29 mg, 2.0 equiv) and 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (40 mg, 1.0 equiv) in DMF (0.5 mL) and ACN (0.5 mL) were added 4 molecular sieves (20 mg) and K.sub.3PO.sub.4 (43 mg, 3.0 equiv). The reaction mixture was stirred at 40 C. for 36 hours. The mixture was filtered and purified by prep-HPLC [Waters xbridge 15025 mm10 um; mobile phase: A: water (NH.sub.4HCO.sub.3), B: ACN; B %: 20%-50% over 8 min] and followed by prep-HPLC [Waters xbridge 15025 mm10 m; mobile phase: A: water (FA), B: CAN; B %: 8%-38% over 8 min] to afford the title compound (6.89 mg, 13.6% yield, 0.38 FA) as a white solid (0.38 formic acid salt); SFC: >99% ee, Chiralcel OD-3 504.6 mm I.D., 3 m; Isocratic elution: 40% MeOH+ACN (0.05% DEA) in CO.sub.2, 3 mL/min; 220 nm; t.sub.R: 0.604 min; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =9.91-9.85 (m, 1H), 9.07-9.03 (m, 1H), 7.78-7.71 (m, 1H), 7.39-7.23 (m, 2H), 6.99-6.92 (m, 1H), 6.65-6.57 (m, 1H), 5.52-5.32 (m, 1H), 4.44-4.34 (m, 2H), 4.27-4.10 (m, 2H), 4.09-4.00 (m, 2H), 3.82-3.66 (m, 2H), 3.19-3.15 (m, 3H), 3.10-3.04 (m, 2H), 2.31-2.27 (m, 1H), 2.24-2.19 (m, 1H), 2.18-2.06 (m, 2H), 2.03-1.91 (m, 2H), 1.90-1.75 (m, 3H), 0.75-0.63 (m, 3H); .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6+deuterium oxide-d.sub.2) =9.10-9.03 (m, 1H), 7.75-7.68 (m, 1H), 7.37-7.31 (m, 1H), 7.30-7.25 (m, 1H), 6.97-6.92 (m, 1H), 6.65-6.59 (m, 1H), 5.57-5.34 (m, 1H), 4.40-4.35 (m, 2H), 4.35-4.13 (m, 2H), 4.05-3.97 (m, 2H), 3.77-3.65 (m, 2H), 3.61-3.45 (m, 2H), 3.18-3.08 (m, 3H), 2.34-2.30 (m, 1H), 2.29-2.15 (m, 2H), 2.12-1.99 (m, 3H), 1.88-1.74 (m, 3H), 0.71-0.63 (m, 3H); .sup.19F NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =119.825, 141.484, 172.667; LCMS (ESI, M+1): m/z=709.3. Example 662 ##STR00371## 1-(difluoromethyl)-3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide Example 663 ##STR00372## 1-(difluoromethyl)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide ##STR00373## [0605] Step A. 5-cyano-1-(difluoromethyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: A mixture of 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (195 mg, 1.0 equiv), 3-cyano-N,N-dimethyl-1H-pyrazole-5-carboxamide (120 mg, 1.0 equiv), potassium fluoride (84.9 mg, 2.0 equiv) in acetonitrile (5.0 mL) was degassed and purged with nitrogen for 3 times, and stirred at 20 C. for 12 hours under nitrogen atmosphere. The reaction mixture was partitioned between water (5.00 mL) and ethyl acetate (5.00 mL). The organic phase was separated, dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to afford the title compound, a mixture of regioisomers (95.0 mg, 73% yield) as a yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =3.14 (s, 3H) 3.33 (s, 3H) 7.42 (s, 1H) 7.44-7.76 (m, 1H) [0606] Step B. tert-butyl ((1-(difluoromethyl)-3-(dimethylcarbamoyl)-1H-pyrazol-5-yl)methyl)carbamate: A mixture of 5-cyano-1-(difluoromethyl)-N,N-dimethyl-pyrazole-3-carboxamide (95.0 mg, 1.0 equiv), di-tert-butyl dicarbonate (193 mg, 2.0 equiv) and Palladium 10% on carbon (20.0 mg, 10% purity, 1.0 equiv) in methanol (10 mL) was degassed and purged with hydrogen (15.0 psi) for 3 times, and stirred at 20 C. for 14 hours under hydrogen (15.0 psi) atmosphere. The mixture was filtered and concentrated in vacuum to afford the title compound, a mixture of regioisomers (110 mg, 78% yield) as a yellow solid; LCMS (ESI, M+1): m/z=319.1 [0607] Step C. 5-(aminomethyl)-1-(difluoromethyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: To a solution of tert-butyl N-[[2-(difluoromethyl)-5-(dimethylcarbamoyl) pyrazol-3-yl]methyl]carbamate (100 mg, 1.0 equiv) in acetonitrile (1.0 mL) was added HCl/dioxane (4M, 1.0 mL). The mixture was stirred at 20 C. for 0.5 hour. The mixture was concentrated under vacuum. The residue was purified by prep-HPLC (neutral condition; column: Waters Xbridge 15025 mm5 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 1%-30%, 10 min) to afford the title compound, a mixture of regioisomers (10.0 mg, 15% yield) as a white solid. [0608] Step D. 1-(difluoromethyl)-3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide and 1-(difluoromethyl)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: To a solution of 5-(aminomethyl)-1-(difluoromethyl)-N,N-dimethyl-pyrazole-3-carboxamide (70.0 mg, 1.0 equiv) and 5-ethyl-6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (190 mg, 1.0 equiv) in N,N-dimethylformamide (1.0 mL) and acetonitrile (1.0 mL) was added potassium phosphate (68.1 mg, 1.00 equiv). The mixture was stirred at 60 C. for 3 hours. The mixture was concentrated and purified with SFC separation [column: DAICEL CHIRALPAK AS (250 mm30 mm, 10 m); mobile phase: [0.1% NH.sub.3H.sub.2O EtOH]; B %: 30%-30%, 6 minutes] and prep-HPLC [column: Unisil 3-100 C18 Ultra 15050 mm3 m; mobile phase: [water (FA)-ACN]; B %: 13%-43%, 7 minutes] to afford the title compound EXAMPLE 662 (3.96 mg, 1.7% yield, 0.4FA) and EXAMPLE 663 (3.82 mg, 1.6% yield, 0.4FA) as yellow solids. [0609] EXAMPLE 662: .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) ppm 0.78 (br t, J=7.19 Hz, 3H) 1.86-2.04 (m, 2H) 2.04-2.12 (m, 2H) 2.13-2.20 (m, 2H) 2.21-2.37 (m, 2H) 2.37-2.52 (m, 2H) 3.09 (s, 3H) 3.32-3.34 (m, 3H) 3.41 (br d, J=10.8 Hz, 2H) 4.29-4.43 (m, 2H) 5.05-5.18 (m, 2H) 5.27-5.47 (m, 1H) 6.83 (s, 1H) 7.03-7.07 (m, 1H) 7.25 (t, J=9.4 Hz, 1H) 7.31 (d, J=2.4 Hz, 1H) 7.61-8.02 (m, 2H) 8.48-8.56 (m, 1H) 9.22 (s, 1H); LCMS (ESI, M+1): m/z=711.3. [0610] EXAMPLE 663: .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) ppm 0.79 (br t, J=7.2 Hz, 3H) 1.87-2.55 (m, 10H) 3.10 (s, 3H) 3.12 (s, 3H) 3.36-3.44 (m, 2H) 4.26-4.44 (m, 2H) 4.91-4.98 (m, 2H) 5.30 (br s, 1H) 5.26-5.47 (m, 1H) 5.43 (br s, 1H) 6.79 (s, 1H) 7.00-7.09 (m, 1H) 7.25 (br t, J=9.6 Hz, 1H) 7.31 (d, J=2.4 Hz, 1H) 7.61 (br t, J=5.6 Hz, 1H) 7.68 (br dd, J=8.88, 5.88 Hz, 1H) 8.49-8.56 (m, 1H) 9.20 (s, 1H); LCMS (ESI, M+1): m/z=711.3. Example 664 ##STR00374## 2-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-3-yl)-1,2-thiazinane 1,1-dioxide [0611] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a white solid (0.18 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.09 (s, 1H), 8.54 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.06 (dd, J=2.4, 12.4 Hz, 1H), 5.49-5.25 (m, 1H), 4.64-4.47 (m, 2H), 4.40-4.16 (m, 2H), 3.54-3.34 (m, 6H), 3.16-3.02 (m, 3H), 2.63-1.53 (m, 18H), 0.85-0.72 (m, 3H). LCMS (ESI, M+1): m/z=711.3. Example 665 ##STR00375## 1-((1S,3aS,6aR)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)methanesulfonamide ##STR00376## [0612] To a solution of 1-((1S,3aS,6aR)-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)methanesulfonamide, Intermediate 13D (33.7 mg, 2.0 equiv, TFA) in DMF (1 mL) was added K.sub.3PO.sub.4 (53.7 mg, 5.0 equiv) and 4 molecular sieves (30.0 mg). The mixture was stirred at 25 C. for 0.5 hour. Then 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30.0 mg, 1.0 equiv) was added and the mixture was stirred at 25 C. for 1.5 hours. The resulting mixture was filtered and purified by prep-HPLC [Phenomenex Synergi Polar-RP 10025 mm4 um; A: water (TFA), B: ACN, B %: 26%-46% over 7 min] and then further re-purified by prep-HPLC [Waters Xbridge 15025 mm5 um; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 23%-53% over 8 min] and lyophilized to afford the title compound (7.34 mg, 20% yield) as a white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.97 (s, 1H), 9.36 (d, J=3.4 Hz, 1H), 8.09 (br s, 1H), 7.78 (dd, J=6.4, 9.0 Hz, 1H), 7.40-7.34 (m, 2H), 7.08 (s, 2H), 7.02 (d, J=2.8 Hz, 1H), 5.56-5.34 (m, 1H), 4.50-4.32 (m, 3H), 4.21 (br d, J=8.4 Hz, 2H), 3.96 (br d, J=6.8 Hz, 2H), 3.45 (br d, J=7.6 Hz, 4H), 3.28 (br s, 3H), 3.13-3.03 (m, 1H), 2.41-2.29 (m, 3H), 2.21-2.11 (m, 2H), 2.06-1.90 (m, 3H), 0.73 (d, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=712.3. SFC: Rt=2.068 min; Method details: column: Chiralpak IC-3 504.6 mm I.D., 3 um; mobile phase: phase A for CO.sub.2, and phase B for MeOH+ACN (0.05% DEA); gradient elution: 40% MeOH+ACN (0.05% DEA) in CO.sub.2; flow rate: 3 mL/min; detector: PDA; column temp: 35 C.; back pressure: 100 Bar. Example 666 ##STR00377## 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-2-carboxamide ##STR00378## [0613] Step A. tert-butyl 2-(dimethylcarbamoyl)-8,9-dihydro-5H-pyrido[3,2-c]azepine-6(7H)-carboxylate: To a mixture of tert-butyl 2-chloro-8,9-dihydro-5H-pyrido[3,2-c]azepine-6(7H)-carboxylate (1.00 g, 1.0 equiv) and TEA (1.07 g, 3.0 equiv) in EtOH (10 mL) was added (1,1-bis(diphenylphosphino)ferrocene)palladium (II) dichloride (258 mg, 0.1 equiv) and dimethylamine (478 mg, 3.0 equiv). The mixture was degassed and purged with argon for 3 times, and then the mixture was degassed and purged with CO for 3 times. The reaction was stirred at 80 C. for 24 hours under CO at 50 psi. The mixture was concentrated under vacuum to give a residue. The residue was diluted with water (15 mL) and extracted with ethyl acetate (330 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reversed phase flash chromatography [C18, water (FA, 0.1%)/acetonitrile] to afford the title compound (700 mg, 62% yield) as a black oil. LCMS (ESI, M+1): m/z=320.2 [0614] Step B. N,N-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-2-carboxamide: To a mixture of tert-butyl 2-(dimethylcarbamoyl)-8,9-dihydro-5H-pyrido[3,2-c]azepine-6(7H)-carboxylate (130 mg, 1.0 equiv) in MeCN (0.5 mL) was added HCl.Math.dioxane (4 M, 0.6 mL). The reaction was stirred at 25 C. for 2 hours. The mixture was concentrated to afford the title compound (150 mg, crude, HCl) as a colorless oil and used into next step without further purification. [0615] Step C. 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-2-carboxamide: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (100 mg, 1.0 equiv), N,N-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-2-carboxamide (74.0 mg, 1.7 equiv, HCl) in DMF (0.2 mL) and MeCN (0.2 mL) were added K.sub.3PO.sub.4 (179 mg, 5.0 equiv) and 4 molecular sieves (10 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 12%-42% over 10 min) to afford the title compound (52.0 mg, 42% yield, FA 0.26) as an off-white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.15 (s, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.33-7.19 (m, 2H), 7.04 (s, 1H), 5.47-5.29 (m, 1H), 5.29-5.18 (m, 2H), 4.49-4.36 (m, 2H), 4.34-4.16 (m, 2H), 3.50-3.33 (m, 3H), 3.26 (br d, J=7.2 Hz, 2H), 3.12 (s, 4H), 3.02 (s, 3H), 2.55-2.43 (m, 1H), 2.42-2.23 (m, 4H), 2.16 (br d, J=9.2 Hz, 2H), 2.11-2.02 (m, 2H), 2.01-1.88 (m, 1H), 0.78 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=712.6. Example 667 ##STR00379## 11-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-thia-11-azaspiro[5.6]dodecane 3,3-dioxide [0616] The title compound was synthesized according to the procedure described for example 538 to produce the desired compound as a yellow solid (0.89 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d4) =9.20 (s, 1H), 8.46 (br s, 1H), 7.69 (dd, J=5.6, 9.2 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.26 (t, J=9.6 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 5.63-5.36 (m, 1H), 4.72-4.37 (m, 4H), 4.37-4.23 (m, 3H), 4.21 (br d, J=2.8 Hz, 2H), 3.81-3.68 (m, 3H), 3.67-3.56 (m, 2H), 3.50-3.34 (m, 2H), 3.17-3.04 (m, 2H), 2.65-2.43 (m, 3H), 2.40-2.31 (m, 1H), 2.26-2.10 (m, 6H), 2.06-1.95 (m, 2H), 0.80 (t, J=7.6 Hz, 3H). LCMS (ESI, M+1): m/z=712.3 Example 668 ##STR00380## 1-(2-cyanoethyl)-3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide Example 669 ##STR00381## 1-(2-cyanoethyl)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide ##STR00382## [0617] Step A. tert-butyl ((1-(2-cyanoethyl)-5-(dimethylcarbamoyl)-1H-pyrazol-3-yl)methyl)carbamate: To a mixture of tert-butyl ((5-(dimethylcarbamoyl)-1H-pyrazol-3-yl)methyl)carbamate (150 mg, 1.0 equiv) 3-bromopropanenitrile (149 mg, 2.0 equiv) in ACN (3 mL) was added Cs.sub.2CO.sub.3 (364 mg, 2.0 equiv). The reaction was stirred at 80 C. for 12 hours. The mixture was filtered and purified by prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN; B %: 20%-50% over 10 min] to afford the title compound, a mixture of regioisomers (60 mg, 33% yield) as a white oil; .sup.1H NMR (400 MHZ, chloroform-d) =6.39-6.31 (m, 1H), 5.05-4.89 (m, 1H), 4.61-4.53 (m, 2H), 4.35-4.29 (m, 2H), 3.20-3.09 (m, 6H), 2.98-2.93 (m, 2H), 1.47-1.45 (m, 9H); LCMS (ESI, M+1): m/z=322.2. [0618] Step B. 3-(aminomethyl)-1-(2-cyanoethyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide: To a mixture of tert-butyl ((1-(2-cyanoethyl)-5-(dimethylcarbamoyl)-1H-pyrazol-3-yl)methyl)carbamate (25 mg, 1.0 equiv) in DCM (43 L) was added TFA (133 mg, 15 equiv). The reaction was stirred at 20 C. for 1 hour. The mixture was concentrated to afford the title compound, a mixture of regioisomers (26 mg, crude, TFA) as a yellow oil. [0619] Step C. 1-(2-cyanoethyl)-3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide and 1-(2-cyanoethyl)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30 mg, 1.0 equiv) and 3-(aminomethyl)-1-(2-cyanoethyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide (25 mg, 1.5 equiv, TFA) in ACN (0.2 mL) and DMF (0.2 mL) were added K.sub.3PO.sub.4 (32 mg, 3.0 equiv) and 4 molecular sieves (20 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN; B %: 19%-49% over 10 min] followed by prep-HPLC [Phenomenex Luna C18 15025 mm10 m; A: water (NH.sub.4HCO.sub.3), B: ACN; B %: 37%-67% over 8 min] to afford Example 668 (4.82 mg, 13% yield) as an off-white solid; SFC: Chiralpak AS-3 504.6 mm I.D., 3 m; Isocratic elution: 20% MeOH (0.05% DEA) in CO.sub.2, 3 mL/min; t.sub.R: 1.224 min, 1.888 min; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =9.95-9.89 (m, 1H), 9.57-9.49 (m, 1H), 9.35-9.31 (m, 1H), 7.79-7.73 (m, 1H), 7.39-7.31 (m, 2H), 7.00-6.97 (m, 1H), 6.64-6.61 (m, 1H), 5.36-5.17 (m, 1H), 4.87-4.70 (m, 2H), 4.50-4.40 (m, 2H), 4.16-4.10 (m, 1H), 4.08-4.01 (m, 1H), 3.11-3.04 (m, 5H), 3.03 (s, 2H), 3.01-2.95 (m, 4H), 2.87-2.76 (m, 1H), 2.37 (br s, 1H), 2.15-1.97 (m, 4H), 1.88-1.72 (m, 3H), 0.74-0.67 (m, 3H); .sup.19F NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =119.682, 139.503; 172.082; LCMS (ESI, M+1): m/z=714.4. and Example 669 (1.66 mg, 2.8% yield, 0.64FA) as a white solid; SFC: >99% ee, Chiralcel OD-3 504.6 mm I.D., 3 m; Isocratic elution: 50% MeOH+ACN (0.05% DEA) in CO.sub.2, 3 mL/min, 220 nm, t.sub.R: 0.891 min; .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.23-9.16 (m, 1H), 7.72-7.64 (m, 1H), 7.34-7.28 (m, 1H), 7.28-7.20 (m, 1H), 7.07-7.01 (m, 1H), 6.78-6.71 (m, 1H), 5.49-5.31 (m, 1H), 5.07-5.02 (m, 2H), 4.70-4.63 (m, 2H), 4.51-4.38 (m, 2H), 3.61-3.44 (m, 3H), 3.37 (s, 3H), 3.23-3.13 (m, 3H), 3.12-3.06 (m, 3H), 2.53-2.31 (m, 3H), 2.30-2.21 (m, 1H), 2.19-2.05 (m, 3H), 2.04-1.91 (m, 1H), 0.82-0.73 (m, 3H); .sup.19F NMR (400 MHZ, methanol-d.sub.4) =121.153, 139.106, 173.885; LCMS (ESI, M+1): m/z=714.3. Example 670 ##STR00383## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [0620] The title compound was synthesized according to the procedure described for example 541 to produce the desired compound as a pink solid (0.14 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.14-9.08 (m, 1H), 9.10 (s, 1H), 8.55-8.51 (m, 1H), 7.68 (dd, J=5.8, 9.0 Hz, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.28-7.21 (m, 1H), 7.04 (d, J=2.4 Hz, 1H), 5.41 (br s, 1H), 5.26-5.12 (m, 2H), 4.50 (br d, J=9.4 Hz, 2H), 4.42 (br s, 2H), 4.38-4.28 (m, 2H), 3.44-3.32 (m, 4H), 3.30-3.27 (m, 1H), 3.17-3.06 (m, 7H), 2.52-2.27 (m, 5H), 2.23-1.89 (m, 6H), 0.78 (t, J=7.4 Hz, 3H); LCMS (ESI, M+1): m/z=715.3. Example 671 ##STR00384## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide ##STR00385## [0621] Step A tert-butyl 2-(dimethylcarbamoyl)-6,7,8,9-tetrahydropyrazolo[1,5-a][1,4]diazocine-5(4H)-carboxylate: To a solution of 5-(tert-butoxycarbonyl)-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxylic acid (300 mg, 1.0 equiv) in DMF (5.0 mL) were added DIEA (1.3 g, 10 equiv), HATU (1.2 g, 3.0 equiv) and methanamine hydrochloride (172 mg, 1.5 equiv). The reaction was stirred at 25 C. for 1 hour. The mixture was diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with brine (50 mL3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=2/1 to 1/0) to afford the title compound (210 mg, 64.1% yield) as a colorless oil; LCMS (ESI, M+1): m/z=323.2. [0622] Step B N,N-dimethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide: A solution of tert-butyl 2-(dimethylcarbamoyl)-6,7,8,9-tetrahydropyrazolo[1,5-a][1,4]diazocine-5(4H)-carboxylate (190 mg, 1.0 equiv) in MeCN (1.00 mL) and HCl/dioxane (4 M, 1.0 mL) was stirred at 25 C. for 1 hour. The reaction was concentrated to afford the title compound (120 mg, crude), LCMS (ESI, M+1): m/z=223.2. [0623] Step C: 5-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide: To a solution of 2,4-dichloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidine (203 mg, 1.00 equiv) in DCM (2.00 mL) were added N,N-dimethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide (100 mg, 1.00 equiv) and DIPEA (174 mg, 3.00 equiv). The mixture was stirred at 40 C. for 1 hour. The reaction mixture was partitioned between ethyl acetate (20.0 mL) and water (10.0 mL). The organic phase was separated, concentrated under reduced pressure to give a residue and to afford the title compound (120 mg, 42% yield, 60% purity), LCMS (ESI, M+1): m/z=636.1 [0624] Step D: 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1.4]diazocine-2-carboxamide: To a solution of 5-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide (90.0 mg, 1.00 equiv) in THF (3.00 mL) was added t-BuONa (40.8 mg, 3.00 equiv), 4 molecular sieves (20.0 mg, 1.0 equiv) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (22.5 mg, 1.00 equiv). The mixture was stirred at 0 C. for 1 hour. The reaction mixture was partitioned between ethyl acetate (50.0 mL) and water (30.0 mL). The organic phase was separated, concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM/MeOH=10/1) to afford the title compound (60.0 mg, 56% yield), LCMS (ESI, M+1): m/z=759.4 [0625] Step E: 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide: To 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide (50.0 mg, 1.00 equiv) was added HCl/MeOH (4 M, 3.00 mL). The mixture was stirred at 0 C. for 1 hour. The reaction mixture was concentrated and purified with prep-HPLC (column: Phenomenex C18753 um; mobile phase: [water (FA)-ACN]; B %: 12%-42%, 7 min) to afford the title compound (2.51 mg, 4.80% yield, 96.6% purity) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.06 (s, 1H), 7.67 (dd, J=6.0, 8.8 Hz, 1H), 7.33-7.22 (m, 2H), 7.04 (d, J=2.4 Hz, 1H), 6.71 (s, 1H), 5.42-5.23 (m, 3H), 4.48 (br d, J=2.8 Hz, 2H), 4.34-4.21 (m, 2H), 4.15 (br s, 2H), 3.35 (s, 3H), 3.22 (br d, J=18.6 Hz, 2H), 3.09 (s, 3H), 3.06-2.98 (m, 1H), 2.54-2.42 (m, 1H), 2.38-2.10 (m, 4H), 2.09-1.98 (m, 8H), 1.94-1.83 (m, 1H), 1.35-1.27 (m, 1H), 0.79 (br t, J=7.4 Hz, 3H), LCMS (ESI, M+1): m/z=715.2. Example 672 ##STR00386## 7-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)-N,N,1-trimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide ##STR00387## [0626] Step A. 2-ethoxycyclohex-2-enone: To a mixture of cyclohexane-1,2-dione (15.0 g, 1.0 equiv) and EtOH (122 g, 19.9 equiv) in toluene (300 mL) was added TsOH (2.80 g, 0.12 equiv) at 25 C. under nitrogen atmosphere. The reaction was stirred at 90 C. for 12 hours. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (330.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel chromatography (petroleum ether/ethyl acetate 1:0 to 20:1) to afford the title compound (9.0 g, 42% yield) as a yellow liquid; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =5.98 (t, J=4.8 Hz, 1H), 3.71-3.63 (m, 2H), 2.41-2.31 (m, 4H), 1.89-1.81 (m, 2H), 1.22 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=141.2. [0627] Step B. ethyl 2-(3-ethoxy-2-oxocyclohex-3-en-1-yl)-2-oxoacetate: To a solution of 2-ethoxycyclohex-2-en-1-one (2.00 g, 1.0 equiv) in THF (20.0 mL) was added LiHMDS (3.1 g, 1.3 equiv) at 60 C. After stirring at 60 C. for 30 minutes, a solution of diethyl oxalate (2.7 g, 1.3 equiv) in THF (5.0 mL) was added to the solution. The reaction was stirred at 20 C. for 1 hour. The reaction mixture was poured into ice-water (50 mL), extracted with ethyl acetate (330 mL). The combined organic layers were washed with brine (100.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel chromatography (petroleum ether/ethyl acetate 1:0 to 20:1) to afford the title compound (2.30 g, 67% yield) as a yellow oil; LCMS (ESI, M+1): m/z=241.1 [0628] Step C. ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate: To a mixture of ethyl 2-(3-ethoxy-2-oxo-cyclohex-3-en-1-yl)-2-oxo-acetate (1.80 g, 1.0 equiv) in AcOH (10.0 mL) was added methylhydrazine (949 mg, 1.1 equiv) under nitrogen. The reaction was stirred at 25 C. for 1 hour. The solvent was concentrated. The residue was dissolved in water (30 mL), adjusted to pH=8 with 30% NH.sub.4OH and extracted with DCM (340 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography (petroleum ether/ethyl acetate 10:1 to 4:1) to afford the title compound (1.50 g, 90% yield) as a white solid; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =4.35-4.21 (m, 2H), 4.10 (s, 3H), 2.92 (t, J=6.0 Hz, 2H), 2.53 (br d, J=4.8 Hz, 2H), 2.11-1.99 (m, 2H), 1.30 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=222.9. [0629] Step D. 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid: To a mixture of ethyl 1-methyl-7-oxo-5,6-dihydro-4H-indazole-3-carboxylate (1.0 g, 1.0 equiv) in THF (18.0 mL) was added NaOH (2.0 M, 9.0 mL, 4.0 equiv) at 20 C. under nitrogen. The reaction was stirred at 20 C. for 1 hour. The mixture was diluted with water (2 mL) and adjusted to pH=5 with 1N HCl aqueous solution and extracted with ethyl acetate (33.0 mL). The combined organic layers were filtered and concentrated to afford the title compound (0.9 g, 97% yield) as a yellow solid. [0630] Step E. N,N,1-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide: To a mixture of 1-methyl-7-oxo-5,6-dihydro-4H-indazole-3-carboxylic acid (0.90 g, 1.0 equiv) in DMF (8.0 mL) were added DIPEA (2.80 g, 5.0 equiv) and HATU (3.30 g, 2.0 equiv) at 20 C. under nitrogen. After stirring at 20 C. for 5 minutes, N-methylmethanamine (2.0 M, 4.4 mL, 2.0 equiv) was added. The reaction was stirred at 20 C. for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (330.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purification by silica gel chromatography (petroleum ether/ethyl acetate 10:1 to 1:1) to afford the title compound (1.20 g, 99% yield) as yellow oil; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =4.06 (s, 3H), 3.18 (s, 3H), 2.97 (s, 3H), 2.78 (t, J=6.0 Hz, 2H), 2.54-2.51 (m, 2H), 2.05-1.97 (m, 2H); LCMS (ESI, M+1): m/z=222.2. [0631] Step F. (E)-7-(hydroxyimino)-N,N,1-trimethyl-4.5,6,7-tetrahydro-1H-indazole-3-carboxamide: To a mixture of N,N, 1-trimethyl-7-oxo-5,6-dihydro-4H-indazole-3-carboxamide (0.6 g, 1.0 equiv) and hydroxylamine hydrochloride (376.9 mg. 2.0 equiv) in EtOH (8.0 mL) was added Pyridine (643.5 mg, 3.0 equiv) at 20 C. under nitrogen. The reaction was stirred at 80 C. for 1 hour. The mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (330.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by reversed phase chromatography [water (0.1% formic acid)/acetonitrile)] to afford the title compound (385 mg, 58% yield) as a white solid; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =11.33 (s, 1H), 4.00 (s, 3H), 3.18 (s, 3H), 2.95 (s, 3H), 2.68-2.55 (m, 4H), 1.78-1.69 (m, 2H), LCMS (ESI, M+1): m/z=236.8. [0632] Step G. 7-amino-N,N,1-trimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide: To a solution of (7E)-7-hydroxyimino-N,N,1-trimethyl-5,6-dihydro-4H-indazole-3-carboxamide (300 mg, 1.0 equiv) in MeOH (2.0 mL) and THF (1.0 mL) was added Pd(OH).sub.2/C (100 mg, 20% purity, 0.56 equiv) under nitrogen. The reaction was stirred at 60 C. for 60 hours under hydrogen (45 psi). The mixture was filtered, concentrated and purified by reversed phase chromatography [water (0.1% formic acid)/acetonitrile)] to afford the title compound (65.0 mg, 23% yield) as a white solid; LCMS (ESI, M+1): m/z=223.1 [0633] Step H. 7-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)-N,N,1-trimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv) in DMF (0.1 mL) were added DIPEA (218 mg, 20.0 equiv) and 7-amino-N,N,1-trimethyl-4,5,6,7-tetrahydroindazole-3-carboxamide (37.5 mg, 2.0 equiv) under nitrogen. The reaction was stirred at 40 C. for 2 hours. The mixture was purified by prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN; B %: 20%-50% over 10 min] and lyophilized to afford the title compound (15.0 mg, 22% yield, 0.46FA) as a white solid; SFC: Chiralcel OJ-3 504.6 mm I.D., 3 m, Gradient elution: MeOH (0.05% DEA) in CO.sub.2 from 5% to 40%, 3 mL/min, 220 nm, t.sub.R: 1.548 min, 1.617 min; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =9.41 (d, J=2.4 Hz, 1H), 9.34-9.21 (m, 1H), 7.84-7.70 (m, 1H), 7.42-7.28 (m, 2H), 6.98 (d, J=2.4 Hz, 1H), 5.83-5.68 (m, 1H), 5.42-5.16 (m, 1H), 4.25-4.06 (m, 2H), 3.71 (d, J=16.4 Hz, 3H), 3.25 (br s, 3H), 3.13-3.00 (m, 4H), 2.97 (s, 3H), 2.87-2.64 (m, 3H), 2.41-2.35 (m, 1H), 2.23-2.10 (m, 2H), 2.06-1.92 (m, 3H), 1.90-1.74 (m, 5H), 0.78-0.67 (m, 3H); .sup.19F NMR (400 MHZ, dimethylsulfoxide-d.sub.6)=119.679, 139.505, 172.081; LCMS (ESI, M+1): m/z=715.1. Example 673 ##STR00388## N-ethyl-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide [0634] Synthesized according to Example 671. The title compound was obtained as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.08 (s, 1H), 7.68 (dd, J=6.0, 9.1 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.80 (s, 1H), 5.42-5.23 (m, 3H), 4.45 (br d, J=4.4 Hz, 2H), 4.31-4.11 (m, 4H), 3.39 (q, J=7.2 Hz, 2H), 3.28-3.17 (m, 2H), 3.10-2.98 (m, 1H), 2.56-1.76 (m, 13H), 1.21 (t, J=7.2 Hz, 3H), 0.79 (t, J=7.6 Hz, 3H); LCMS (ESI, M+1): m/z=715.5. Example 674 ##STR00389## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-hydroxy-N,N-dimethyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide ##STR00390## [0635] Step A. benzyl 4-((tert-butyldiphenylsilyl)oxy)-5-hydroxyazepane-1-carboxylate: To a solution of benzyl 4,5-dihydroxyazepane-1-carboxylate (1.50 g, 1.0 equiv), imidazole (1.15 g, 3.0 equiv) and DMAP (6.91 mg, 0.01 equiv) in DCM (1 mL) was added TBDPS-Cl (1.09 g, 0.7 equiv) at 0 C. The mixture was stirred at 25 C. for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (420 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 3:1 to 1:1] to afford the title compound (1.20 g, 41% yield) as a yellow liquid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.66-7.17 (m, 15H), 5.12-4.93 (m, 2H), 3.82-3.79 (m, 2H), 3.67-3.43 (m, 1H), 3.38-3.06 (m, 3H), 2.29-2.19 (m, 1H), 2.11-2.01 (m, 1H), 1.97-1.87 (m, 1H), 1.62-1.39 (m, 2H), 1.03 (br d, J=2.0 Hz, 9H); LCMS (ESI, M+1): m/z=504.3. [0636] Step B. benzyl 4-((tert-butyldiphenylsilyl)oxy)-5-oxoazepane-1-carboxylate: To a solution of benzyl 4-((tert-butyldiphenylsilyl)oxy)-5-hydroxyazepane-1-carboxylate (1.20 g, 1.0 equiv) in DCM (12 mL) was added Dess-Martin reagent (3.03 g, 3.0 equiv). The mixture was stirred at 25 C. for 2 hours. The reaction mixture was filtered. The filtrate was diluted with water (15 mL) and extracted with ethyl acetate (415 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 5:1] to afford the title compound (900 mg, 75% yield) as a white liquid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.57-7.44 (m, 15H), 5.05-4.94 (m, 2H), 4.41-4.27 (m, 1H), 3.95-3.57 (m, 3H), 3.46-3.25 (m, 1H), 2.80-2.40 (m, 2H), 1.71-1.41 (m, 2H), 1.05 (s, 9H). [0637] Step C. benzyl 5-((tert-butyldiphenylsilyl)oxy)-3-formyl-4-oxoazepane-1-carboxylate: A solution of 1-tert-butoxy-N,N,N,N-tetramethylmethanediamine and benzyl 4-((tert-butyldiphenylsilyl)oxy)-5-oxoazepane-1-carboxylate (2.0 g, 1.0 equiv) in THF (25 mL) was stirred at 60 C. for 8 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (410 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated to afford the title compound (2.0 g, crude) as a yellow oil. [0638] Step D. benzyl 8-((tert-butyldiphenylsilyl)oxy)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5 (2H)-carboxylate: To a solution of benzyl 5-((tert-butyldiphenylsilyl)oxy)-3-formyl-4-oxoazepane-1-carboxylate (200 mg, 1.0 equiv) in EtOH (3 mL) was added N.sub.2H.sub.4.Math.H.sub.2O (630 mg, 85% purity, 28 equiv). The mixture was stirred at 75 C. for 12 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (45 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (20.0 mg, 10% yield) as a white oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.60-7.20 (m, 16H), 5.08-4.88 (m, 3H), 4.78-4.48 (m, 1H), 4.29-4.08 (m, 1H), 3.86 (br d, J=6.4 Hz, 2H), 1.88-1.61 (m, 2H), 0.97-0.96 (m, 9H). [0639] Step E. benzyl 8-((tert-butyldiphenylsilyl)oxy)-2-(dimethylcarbamoyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5 (2H)-carboxylate: To a solution of benzyl 8-((tert-butyldiphenylsilyl)oxy)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5 (2H)-carboxylate (10.0 mg, 1.0 equiv) in THF (0.5 mL) was added NaH (2.28 mg, 60% purity, 3.0 equiv) at 0 C. The mixture was stirred at 0 C. for 0.5 hour. Then dimethylcarbamic chloride (4.09 mg, 2.0 equiv) was added into the mixture. The mixture was stirred at 0 C. for 0.5 hour. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (45 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (10.0 mg, crude) as a yellow oil; .sup.1H NMR (400 MHz, CHLOROFORM-d) =7.96-7.75 (m, 1H), 7.61-7.60 (m, 2H), 7.40-7.11 (m, 13H), 5.09-4.75 (m, 4H), 4.19-4.07 (m, 1H), 4.03-3.97 (m, 1H), 3.87-3.69 (m, 1H), 2.91 (s, 6H), 1.89-1.79 (m, 1H), 1.77-1.62 (m, 1H), 0.96 (br s, 9H); LCMS (ESI, M+1): m/z=597.4. [0640] Step F. 8-((tert-butyldiphenylsilyl)oxy)-N,N-dimethyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide: To a solution of Pd/C (50.0 mg, 10% purity) in MeOH (2 mL) was added benzyl 8-((tert-butyldiphenylsilyl)oxy)-2-(dimethylcarbamoyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5 (2H)-carboxylate (200 mg, 1.0 equiv) under N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The mixture was stirred under H.sub.2 (15 Psi) at 25 C. for 2 hours. The reaction mixture was filtered and concentrated to afford the title compound (300 mg, crude) as a yellow oil. [0641] Step G. 8-((tert-butyldiphenylsilyl)oxy)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (130 mg, 1.0 equiv) and 8-((tert-butyldiphenylsilyl)oxy)-N,N-dimethyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide (152 mg, 1.5 equiv) in DMF (1.5 mL) were added DIPEA (85.0 mg, 3.0 equiv) and 4 MS (30 mg). The mixture was stirred at 40 C. for 24 hours. The reaction mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (50.0 mg, 21% yield) as a yellow solid; LCMS (ESI, M+1): m/z=955.4. [0642] Step H. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-hydroxy-N,N-dimethyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide: To a solution of 8-((tert-butyldiphenylsilyl)oxy)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide (50.0 mg, 1.0 equiv) in DMF (0.5 mL) was added CsF (80.0 mg, 10 equiv). The mixture was stirred at 40 C. for 12 hours. The reaction mixture was filtered and purified by prep-HPLC [Waters Xbridge 15025 mm5 m; A: water (10 mM NH.sub.4HCO.sub.3), B: ACN, B %: 33%-60% over 9 min] and lyophilized to afford the title compound (7.51 mg, 20% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) 9.18 (d, J=2.4 Hz, 1H), 8.25 (d, J=6.0 Hz, 1H), 7.69-7.65 (m, 1H), 7.34-7.18 (m, 2H), 7.07-7.04 (m, 1H), 5.40-5.22 (m, 2H), 5.11-5.06 (m, 1H), 4.98-4.90 (m, 2H), 4.54-4.44 (m, 1H), 4.34-4.19 (m, 2H), 3.39-3.33 (m, 1H), 3.25 (br s, 1H), 3.20 (br s, 6H), 3.28-3.12 (m, 1H), 3.06-2.98 (m, 1H), 2.52-2.34 (m, 3H), 2.32-2.24 (m, 1H), 2.23-2.12 (m, 3H), 2.04-1.95 (m, 2H), 1.94-1.83 (m, 1H), 0.78 (br t, J=7.1 Hz, 3H); LCMS (ESI, M+1): m/z=717.4. Example 675 ##STR00391## 3-acetamido-4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide ##STR00392## [0643] Step A. 3-(N-acetylacetamido)-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a mixture of 3-amino-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide, Intermediate 15 (500 mg, 1.0 equiv) in Ac.sub.2O (5.00 mL) was added TEA (847 mg, 3.0 equiv) dropwise at 0 C. The reaction was stirred at 60 C. for 4 hours. The mixture was quenched with water (10.0 ml) and extracted with EtOAc (310.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (644 mg, crude) as a yellow solid; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =9.18 (s, 1H), 3.07 (s, 6H), 2.31 (s, 6H). [0644] Step B. 3-acetamido-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a mixture of 3-(N-acetylacetamido)-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide (644 mg, 1.0 equiv) in MeOH (6.50 mL) was added NH.sub.3.Math.H.sub.2O (1.30 mL). The reaction was degassed and stirred at 25 C. for 2 hours. The mixture was concentrated to afford the title compound (570 mg, 99% yield) as a yellow solid. [0645] Step C. tert-butyl ((3-acetamido-1-(dimethylcarbamoyl)-1H-pyrazol-4-yl)methyl)carbamate: To a mixture of 3-acetamido-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide (570 mg, 1.0 equiv) in MeOH (8.00 mL) were added (Boc).sub.2O (1.69 g, 3.0 equiv) and Pd/C (200 mg, 10% purity) under nitrogen atmosphere. The reaction was degassed and purged with hydrogen 3 times. The reaction was stirred under hydrogen (15 psi) at 25 C. for 24 hours. The mixture was filtered and purified by silica gel chromatography (petroleum ether/ethyl acetate 10:1 to dichloromethane/methanol 10:1) followed by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (160 mg, 17% yield) as a yellow solid; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =10.05 (br s, 1H), 7.88 (s, 1H), 7.12 (br s, 1H), 3.88 (br d, J=5.6 Hz, 2H), 3.10 (br s, 6H), 2.03 (s, 3H), 1.38 (s, 9H). [0646] Step D. 3-acetamido-4-(aminomethyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a mixture of tert-butyl ((3-acetamido-1-(dimethylcarbamoyl)-1H-pyrazol-4-yl)methyl)carbamate (140 mg, 1.0 equiv) in DCM (1.50 mL) was added TFA (2.45 g, 50 equiv) dropwise at 0 C. The reaction was stirred at 25 C. for 0.5 hour. The mixture was filtered and concentrated to afford the title compound (169 mg, TFA) as a yellow oil; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =10.51 (br s, 1H), 8.23 (s, 1H), 7.93 (br s, 2H), 3.83 (br d, J=5.6z, 2H), 3.11 (br s, 6H), 2.08 (s, 3H). [0647] Step E. 3-acetamido-4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (100 mg, 1.0 equiv) and 3-acetamido-4-(aminomethyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (114 mg, 3.0 equiv) in DMF (0.50 mL) and ACN (0.50 mL) were added K.sub.3PO.sub.4 (107 mg, 3.0 equiv) and 4 molecular sieves (50.0 mg, 1.0 equiv). The reaction was stirred at 40 C. for 24 hours. The mixture was filtered and purified with prep-HPLC [Phenomenex Luna C18 15025 mm5 m; A: water (FA), B: ACN; B %: 28%-58% over 10 min] to afford the title compound (24.8 mg, 20% yield) as a white solid; SFC: >99% ee, Chiralcel OJ-3 504.6 mm I.D., 3 m; Gradient elution: MeOH (0.05% DEA) in CO.sub.2 from 5% to 40%, 3 mL/min, 220 nm, t.sub.R: 1.535 min; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =10.79-9.37 (m, 1H), 9.33-9.12 (m, 1H), 8.15 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.29 (t, J=9.6 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 5.41-5.11 (m, 1H), 4.58 (br d, J=8.4 Hz, 2H), 4.17-4.11 (m, 1H), 4.09-4.02 (m, 1H), 3.19-2.98 (m, 9H), 2.87-2.75 (m, 1H), 2.40-2.28 (m, 1H), 2.21-1.94 (m, 7H), 1.88-1.69 (m, 3H), 0.70 (t, J=7.2 Hz, 3H); .sup.19F NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =139.519, 171.851; LCMS (ESI, M+1): m/z=718.3. Example 676 ##STR00393## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-sulfonamide ##STR00394## [0648] Step A. benzyl 2-(N-methylsulfamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of methylamine hydrochloride (109 mg, 3.0 equiv) and K.sub.2CO.sub.3 (448 mg, 6.0 equiv) in THF (1.2 mL) and H.sub.2O (3.6 mL) was added a solution of benzyl 2-(chlorosulfonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (200 mg, 1.0 equiv) in THF (2.3 mL) dropwise below 5 C. The reaction was stirred at 5-15 C. for 14 hours. The mixture was diluted with H.sub.2O (10 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with 1N HCl (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (70 mg, 35% yield) as a yellow oil; .sup.1H NMR (400 MHZ, chloroform-d) =7.42-7.28 (m, 5H), 6.71-6.49 (m, 1H), 5.15-5.08 (m, 2H), 4.60-4.52 (m, 2H), 4.52-4.41 (m, 3H), 3.87-3.77 (m, 2H), 2.81-2.73 (m, 3H), 2.04-1.93 (m, 2H); LCMS (ESI, M1): m/z=364.9. [0649] Step B. N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-sulfonamide: To a mixture of benzyl 2-(N-methylsulfamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (80 mg, 1.0 equiv) in MeOH (5 mL) were added NH.sub.3.Math.MeOH (12 M, 0.5 mL) and Pd/C (30 mg, 10% purity) under nitrogen. The reaction was degassed and purged with hydrogen 3 times. The reaction was stirred at 20 C. for 1 hours under hydrogen (15 psi) atmosphere. The mixture was filtered and concentrated to afford the title compound (43 mg, crude) as a yellow oil. [0650] Step C. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-sulfonamide: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (45 mg, 1.0 equiv) and N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-sulfonamide (35 mg, 2.0 equiv) in DMF (0.2 mL) and ACN (0.2 mL) were added 4 molecular sieves (20 mg) and K.sub.3PO.sub.4 (48 mg, 3.0 equiv). The reaction was stirred at 40 C. for 24 hours. The mixture was filtered and purified with HPLC [Phenomenex luna C18 15025 mm10 m; A: water (NH.sub.4HCO.sub.3), B: ACN; B %: 36%-66% over 8 min] to afford the title compound (16.1 mg, 29% yield) as an off-white solid; SFC: >99% ee, Chiralcel OJ-3 504.6 mm I.D., 3 m; Gradient elution: MeOH (0.05% DEA) in CO.sub.2 from 5% to 40%; 3 mL/min; 220 nm; t.sub.R: 1.947 min; .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.19-9.16 (m, 1H), 7.71-7.65 (m, 1H), 7.32-7.29 (m, 1H), 7.28-7.21 (m, 1H), 7.06-7.03 (m, 1H), 6.85-6.82 (m, 1H), 5.41-5.16 (m, 3H), 4.63-4.53 (m, 2H), 4.52-4.38 (m, 2H), 4.30-4.25 (m, 1H), 4.25-4.20 (m, 1H), 3.28 (br d, J=1.6 Hz, 2H), 3.16 (s, 1H), 3.06-2.96 (m, 1H), 2.69-2.62 (m, 3H), 2.54-2.40 (m, 3H), 2.35-2.23 (m, 1H), 2.23-2.09 (m, 3H), 2.05-1.87 (m, 3H), 0.83-0.74 (m, 3H); .sup.19F NMR (400 MHZ, methanol-d.sub.4) =121.145, 138.407, 173.621; LCMS (ESI, M+1): m/z=723.4. Example 677 ##STR00395## 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-(2-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide ##STR00396## [0651] Step A. (2-benzyloxycyclobutyl) methanesulfonate: To a solution of 2-benzyloxycyclobutanol (1 g, 1.0 equiv) and TEA (1.7 g, 2.3 mL, 3.0 equiv) in DCM (10 mL) was added MsCl (964 mg, 1.5 equiv) dropwise at 0 C. under N.sub.2. The reaction mixture was warmed to 25 C. and stirred at 25 C. for 2 hours. The reaction was quenched by iced water slowly and then extracted with DCM (20 mL3). The combined organic phases were washed with brine (25 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the title compound (1.3 g, crude) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) 2.04-2.15 (m, 1H) 2.18-2.29 (m, 2H) 2.30-2.45 (m, 1H) 3.04 (s, 3H) 4.22-4.28 (m, 1H) 4.59 (q, J=11.6 Hz, 2H) 5.11-5.18 (m, 1H) 7.33-7.40 (m, 5H). [0652] Step B. tert-butyl N-[[2-[(1R,2S)-2-benzyloxycyclobutyl]-5-(dimethylcarbamoyl) pyrazol-3-yl]methyl]carbamate: To a solution of tert-butyl N-[[3-(dimethylcarbamoyl)-1H-pyrazol-5-yl]methyl]carbamate (325 mg, 1.0 equiv) and (2-benzyloxycyclobutyl) methanesulfonate (620.9 mg, 2.0 equiv) in DMF (4 mL) was added 4 molecular sieves (250 mg) and Cs.sub.2CO.sub.3 (1.2 g, 3.0 equiv) at 25 C. The mixture was stirred at 80 C. for 12 hours. The residue was purified by prep-HPLC [C18, 0.1% NH.sub.4HCO.sub.3 condition] to afford the title compound (76 mg, 8% yield) as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) 1.43 (s, 9H) 1.68-1.80 (m, 1H) 1.91-2.01 (m, 1H) 2.14-2.27 (m, 2H) 3.07 (s, 3H) 3.26-3.30 (m, 3H) 4.18-4.33 (m, 2H) 4.39-4.47 (m, 2H) 4.47-4.56 (m, 1H) 4.70-4.78 (m, 1H) 6.50 (s, 1H) 7.18-7.31 (m, 5H). [0653] Step C. tert-butyl N-[[5-(dimethylcarbamoyl)-2-(2-hydroxycyclobutyl) pyrazol-3-yl]methyl]carbamate: To a solution of tert-butyl N-[[2-(2-benzyloxycyclobutyl)-5-(dimethylcarbamoyl) pyrazol-3-yl]methyl]carbamate (76.0 mg, 1.0 equiv) in MeOH (2 mL) was added Pd/C (100 mg, 10% purity) under N.sub.2 at 25 C. The suspension was degassed under vacuum and purged with H.sub.2 several times. The mixture was stirred under H.sub.2 (15 Psi) at 40 C. for 2 hours. The reaction mixture was filtered, and the filterate was concentrated to afford the title compound (54 mg, crude) as a white solid. [0654] Step D. 5-(aminomethyl)-1-(2-hydroxycyclobutyl)-N,N-dimethyl-pyrazole-3-carboxamide: To a solution of tert-butyl N-[[5-(dimethylcarbamoyl)-2-(2-hydroxycyclobutyl) pyrazol-3-yl]methyl]carbamate (60.0 mg, 1.0 equiv) in dioxane (2 mL) was added HCl/dioxane (4 M, 44.3 L, 1.0 equiv) at 25 C. The mixture was stirred at 25 C. for 0.5 hour. The reaction mixture was filtered, and the filterate was concentrated to afford the title compound (42 mg, crude, HCl) as a white solid. [0655] Step E. 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-(2-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: To a solution of 5-ethyl-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (20 mg, 1.0 equiv) and 5-(aminomethyl)-1-(2-hydroxycyclobutyl)-N,N-dimethyl-pyrazole-3-carboxamide (38.3 mg, 4.0 equiv, HCl) in DMF (1.5 mL) was added K.sub.3PO.sub.4 (37 mg, 5.0 equiv) at 25 C. The mixture was stirred at 60 C. for 6 hours. The residue was purified by prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (5.2 mg, 20.1% yield) as a white solid (0.33 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) 0.78 (br t, J=6.8 Hz, 3H) 1.74 (br t, J=9.2 Hz, 1H) 1.86-2.29 (m, 9H) 2.29-2.54 (m, 3H) 3.10 (s, 3H) 3.13-3.20 (m, 1H) 3.39 (s, 3H) 3.41 (br s, 2H) 4.35-4.62 (m, 3H) 4.92-5.16 (m, 3H) 5.35 (s, 1H) 6.71 (s, 1H) 7.04 (d, J=2.32 Hz, 1H) 7.22-7.32 (m, 2H) 7.68 (dd, J=9.2, 5.87 Hz, 1H) 8.50-8.53 (m, 1H) 9.19 (s, 1H); LCMS (ESI, M+1): m/z=731.3. Example 678 ##STR00397## 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-(cis-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide ##STR00398## [0656] Step A. ((cis-3-bromocyclobutoxy)methyl)benzene: To a solution of 3-benzyloxycyclobutanol (1.0 g, 1 equiv), CBr.sub.4 (4.5 g, 2.4 equiv) and TEA (1.3 g, 2.3 equiv) in DCM (10 mL) was added PPh.sub.3 (3.4 g, 2.4 equiv) in DCM (5 mL) at 0 C. The mixture was stirred at 50 C. for 5 hours. The residue was poured into ice-NaHCO.sub.3 (sat.) (20 mL) and stirred for 5 mins. The aqueous phase was extracted with DCM (50 mL3). The combined organic phases were washed with brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate 1:0, 20:1) to afford the title compound (1.1 g, 81.3% yield) as a yellow liquid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.41-7.30 (m, 5H), 4.59-4.49 (m, 2H), 4.45 (s, 2H), 2.78-2.64 (m, 4H). [0657] Step B. tert-butyl ((1-(cis-3-(benzyloxy)cyclobutyl)-3-(dimethylcarbamoyl)-1H-pyrazol-5-yl)methyl)carbamate and tert-butyl ((1-(cis-3-(benzyloxy)cyclobutyl)-5-(dimethylcarbamoyl)-1H-pyrazol-3-yl)methyl)carbamate: To a mixture of tert-butyl N-[[3-(dimethylcarbamoyl)-1H-pyrazol-5-yl]methyl]carbamate (500 mg, 1.0 equiv) and (3-bromocyclobutoxy)methylbenzene (674 mg, 1.5 equiv) in DMF (10 mL) was added Cs.sub.2CO.sub.3 (1.8 g, 3.0 equiv) at 25 C. under N.sub.2. The mixture was stirred at 80 C. for 2 hours. The residue was poured into ice-water (20 mL) and stirred for 2 mins. The aqueous phase was extracted with ethyl acetate (30 mL3). The combined organic phases were washed with brine (25 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, concentrated and purified with prep-TLC (SiO.sub.2, Petroleum ether/Ethyl acetate 1:2) and SFC separation (column: DAICEL CHIRALPAK AD (250 mm30 mm, 10 um); mobile phase: [0.1% NH.sub.3H.sub.2O ETOH]; B %: 25%-25%, 3.5 min) to afford the title compound tert-butyl ((1-(cis-3-(benzyloxy)cyclobutyl)-3-(dimethylcarbamoyl)-1H-pyrazol-5-yl)methyl)carbamate (385 mg, 47.2% yield) as yellow solid and tert-butyl ((1-(cis-3-(benzyloxy)cyclobutyl)-5-(dimethylcarbamoyl)-1H-pyrazol-3-yl)methyl)carbamate (193 mg, 23.0% yield) as yellow solid. [0658] Step C. tert-butyl ((3-(dimethylcarbamoyl)-1-(cis-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)methyl)carbamate: To a solution of tert-butyl ((1-(cis-3-(benzyloxy)cyclobutyl)-3-(dimethylcarbamoyl)-1H-pyrazol-5-yl)methyl)carbamate (385 mg, 1.0 equiv) in MeOH (10 mL) was added Pd/C (200 mg, 10% purity, 1.0 equiv) under N.sub.2 at 25 C. The suspension was degassed under vacuum and purged with H.sub.2 several times. The mixture was stirred under H.sub.2 (15 Psi) at 40 C. for 2 hours. The reaction mixture was filtered and the filterate was concentrated to afford the title compound (193 mg, crude) as a white solid. [0659] Step D. 5-(aminomethyl)-1-(cis-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: To a solution of tert-butyl ((3-(dimethylcarbamoyl)-1-(cis-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)methyl)carbamate (152 mg, 1.0 equiv) in dioxane (3.0 mL) was added HCl/dioxane (4 M, 561 L,5.0 equiv) at 25 C. The mixture was stirred at 25 C. for 1 hour. The reaction mixture was concentrated to afford the title compound (100 mg, crude, HCl) as a a white solid. [0660] Step E. 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-(cis-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50 mg, 1.0 equiv) and 5-(aminomethyl)-1-(cis-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide (46.4 mg, 2.0 equiv, HCl) in DMF (2.0 mL) was added K.sub.3PO.sub.4 (89.5 mg, 5.0 equiv) at 25 C. The mixture was stirred at 40 C. for 12 hours. The reaction mixture was diluted with DMF (5 mL), filtered and purified with prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (24.1 mg, 37.2% yield, 95.1% purity) as a white solid (0.33 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.23-9.19 (m, 1H), 8.53 (br s, 1H), 7.70 (dd, J=5.8, 9.0 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.27 (t, J=9.4 Hz, 1H), 7.06 (d, J=2.6 Hz, 1H), 6.72 (s, 1H), 5.50-5.31 (m, 1H), 4.99-4.92 (m, 2H), 4.69 (t, J=7.6 Hz, 1H), 4.49-4.37 (m, 2H), 4.16 (br t, J=7.2 Hz, 1H), 3.50-3.39 (m, 5H), 3.22-3.07 (m, 4H), 2.91-2.81 (m, 2H), 2.69-2.57 (m, 2H), 2.54-1.80 (m, 10H), 0.80 (t, J=7.3 Hz, 3H); LCMS (ESI, M+1): m/z=731.4. Example 679 ##STR00399## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-(2-hydroxyethyl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide ##STR00400## [0661] Step A: Tert-butyl 2-((2-hydroxyethyl)(methyl) carbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (400 mg, 1 equiv) in dimethyl formamide (10 mL) was added dropwise triethylamine (287 mg, 395 L, 2 equiv) and HATU (193 mg, 3.00 equiv) at 0 C. and the mixture was stirred for 0.5 hour. Then 2-(methylamino) ethanol (117 mg, 125 L, 1.1 equiv) in tetramethylurea hexafluorophosphate (540 mg, 1 equiv) was added dropwise at 0 C. The resulting mixture was stirred at 25 C. for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (320 mL). The combined organic layers were washed with brine (315 mL), dried over anhydrous sodium sulfate, concentrated and purified with column choursomatography [SiO.sub.2, petroleum ether/ethyl acetate 3:1 to 0:1] to afford the title compound (350 mg, 73% yield) as a colorless oil. LCMS (ESI, M+1): m/z=339.2 [0662] Step B: N-(2-hydroxyethyl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of tert-butyl 2-((2-hydroxyethyl)(methyl) carbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (350 mg, 1 equiv) in DCM (3 mL) was added TFA (1 mL) at 0 C. and stirred for 0.5 hour. The reaction mixture was concentrated to give a residue. The residue was purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 2%-30%, 9 minutes] to afford the title compound (210 mg, 85% yield) as a white solid. LCMS (ESI, M+1): m/z=239.2 [0663] Step C: 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-(2-hydroxyethyl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (90 mg, 1.0 equiv) and N-(2-hydroxyethyl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (181 mg, 5.0 equiv) in DMF (3 mL) was added K.sub.3PO.sub.4 (96.7 mg, 3.0 equiv). The mixture was stirred at 60 C. for 5 hours. The reaction mixture was concentrated and purified with prep-HPLC [column: Phenomenex Luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 7%-37%, 10 minutes] to afford the title compound (12.8 mg, 11% yield) as a white solid (0.68 formic acid salt). .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.15-8.95 (m, 1H), 8.13 (s, 1H), 7.76 (dd, J=6.0, 9.0 Hz, 1H), 7.38-7.28 (m, 2H), 7.04 (d, J=2.4 Hz, 1H), 6.49 (br s, 1H), 5.44-5.20 (m, 1H), 4.89 (br d, J=4.0 Hz, 2H), 4.43-4.21 (m, 6H), 4.08 (br s, 3H), 2.96-2.87 (m, 3H), 2.68 (br s, 1H), 2.36-2.27 (m, 2H), 2.26-2.14 (m, 3H), 2.13-2.00 (m, 3H), 1.96-1.78 (m, 6H), 0.72 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=731.6. Example 680 ##STR00401## 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide ##STR00402## [0664] Step A. 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide: The title compound was synthesized according to the procedure described for example 622 using 3-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide to produce the desired compound as a white solid (0.22 formic acid salt). .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.19-9.72 (m, 1H), 9.52 (br t, J=5.6 Hz, 1H), 9.34 (s, 1H), 8.17 (s, 1H), 7.76 (dd, J=6.0, 9.1 Hz, 1H), 7.39-7.29 (m, 2H), 6.99 (d, J=2.1 Hz, 1H), 6.50-6.44 (m, 1H), 5.37-5.18 (m, 1H), 5.08-4.95 (m, 1H), 4.88-4.67 (m, 2H), 4.49-4.38 (m, 1H), 4.19-4.12 (m, 1H), 4.06 (dd, J=1.6, 10.3 Hz, 1H), 3.08 (br d, J=5.8 Hz, 2H), 3.00 (br s, 1H), 2.96 (br d, J=5.2 Hz, 6H), 2.86-2.78 (m, 1H), 2.72-2.59 (m, 3H), 2.38-2.23 (m, 4H), 2.20-1.94 (m, 5H), 1.87-1.71 (m, 3H), 0.70 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=731.1. Example 681 ##STR00403## 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-(cis-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide [0665] The title compound was synthesized from t-butyl ((1-(cis-3-(benzyloxy)cyclobutyl)-5-(dimethylcarbamoyl)-1H-pyrazol-3-yl)methyl)carbamate according to the 3-step procedure described in Steps C,D,E for Example 678 to produce the desired compound as a white solid (0.23 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d4) =9.21 (s, 1H), 8.59-8.50 (m, 1H), 7.70 (dd, J=6.0, 9.1 Hz, 1H), 7.32 (d, J=2.6 Hz, 1H), 7.27 (t, J=9.4 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 6.52 (s, 1H), 5.47-5.28 (m, 1H), 4.95 (s, 2H), 4.50-4.35 (m, 3H), 4.10 (t, J=6.8 Hz, 1H), 3.53-3.39 (m, 2H), 3.15-3.03 (m, 7H), 2.87-2.73 (m, 2H), 2.63-2.55 (m, 2H), 2.55-1.88 (m, 10H), 0.81 (t, J=7.3 Hz, 3H); LCMS (ESI, M+1): m/z=731.4. Example 682 ##STR00404## 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide ##STR00405## [0666] Step A. 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (80 mg, 1.0 equiv) and 5-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide (66.8 mg, 1.8 equiv, HCl salt) in DMF (1 mL) were added 4 MS (50 mg, 1.0 equiv) and K.sub.3PO.sub.4 (143 mg, 5.0 equiv) drop-wise at 25 C. under N.sub.2. The reaction was stirred at 40 C. for 12 hours. The reaction mixture was diluted with DMF (1 mL), filtered, and purified by prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (2.5 mg, 3% yield,) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.30 (s, 1H), 8.57-8.52 (m, 1H), 7.72 (dd, J=5.9, 9.0 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.29 (t, J=9.6 Hz, 1H), 7.08 (s, 1H), 6.71 (s, 1H), 6.03-5.93 (m, 1H), 5.44-5.23 (m, 2H), 4.46-4.36 (m, 2H), 4.08 (s, 2H), 3.48 (s, 3H), 3.26-3.18 (m, 3H), 3.16 (s, 3H), 3.13-3.02 (m, 4H), 2.53-1.85 (m, 9H), 0.80 (t, J=7.6 Hz, 3H); LCMS (ESI, M+1): m/z=731.0. Example 683 ##STR00406## 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1-(oxetan-3-ylmethyl)-1H-pyrazole-3-carboxamide Example 684A ##STR00407## 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1-(oxetan-3-ylmethyl)-1H-pyrazole-5-carboxamide ##STR00408## ##STR00409## [0667] Step A. tert-butyl ((3-(dimethylcarbamoyl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-5-yl)methyl)carbamate and tert-butyl ((5-(dimethylcarbamoyl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-3-yl)methyl)carbamate: To a mixture of tert-butyl ((5-(dimethylcarbamoyl)-1H-pyrazol-3-yl)methyl)carbamate (250 mg, 1 equiv) and 3-(bromomethyl) oxetane (281 mg, 2.0 equiv) in ACN (3 mL) was added Cs.sub.2CO.sub.3 (607 mg, 2.0 equiv). The reaction was stirred at 80 C. for 12 hours. The mixture was filtered and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN; B %: 20%-50% over 10 min] to afford the title compound (140 mg, 43% yield) as a yellow solid; LCMS (ESI, M+1): m/z=339.1. [0668] Step B. 5-(aminomethyl)-N,N-dimethyl-1-(oxetan-3-ylmethyl)-1H-pyrazole-3-carboxamide and 3-(aminomethyl)-N,N-dimethyl-1-(oxetan-3-ylmethyl)-1H-pyrazole-5-carboxamide: To a mixture of tert-butyl N-[[5-(dimethylcarbamoyl)-2-(oxetan-3-ylmethyl) pyrazol-3-yl]methyl]carbamate (140 mg, 1.0 equiv) in DCM (229 L) was added TFA (707 mg, 15 equiv). The reaction was stirred at 20 C. for 0.5 hour. The mixture was concentrated to afford the title compound (140 mg, TFA) as a yellow oil. [0669] Step C. 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1-(oxetan-3-ylmethyl)-1H-pyrazole-3-carboxamide and 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1-(oxetan-3-ylmethyl)-1H-pyrazole-5-carboxamide: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (40.0 mg, 1.0 equiv) and 5-(aminomethyl)-N,N-dimethyl-1-(oxetan-3-ylmethyl)-1H-pyrazole-3-carboxamide (47.6 mg, 2.0 equiv, TFA) in DMF (0.3 mL) and ACN (0.3 mL) were added 4 molecular sieves (20 mg, 1.0 equiv) and K.sub.3PO.sub.4 (43.0 mg, 3.0 equiv). The mixture was stirred at 40 C. for 36 hours. The mixture was filtered and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 um; A: water (1.26FA), B: ACN; B %: 9%-39% over 10 min] followed by chiral SFC to afford Example 683 (3.82 mg, 7% yield) as an off-white solid; SFC: >99% ee, Chiralcel AD-3.504.6 mm I.D., 3 m; Isocratic elution: 40% MeOH (0.05% DEA) in CO.sub.2, 3 mL/min, 220 nm, t.sub.R: 0.617 min; .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.21 (s, 1H), 7.72-7.64 (m, 1H), 7.37-7.30 (m, 1H), 7.29-7.20 (m, 2H), 7.08-6.99 (m, 1H), 5.44-5.24 (m, 1H), 5.11-4.99 (m, 2H), 4.97-4.92 (m, 1H), 4.78-4.75 (m, 1H), 4.74-4.70 (m, 1H), 4.60-4.53 (m, 1H), 4.41-4.25 (m, 2H), 3.88-3.75 (m, 2H), 3.65-3.53 (m, 1H), 3.43-3.32 (m, 2H), 3.30-3.28 (m, 1H), 3.27-3.22 (m, 3H), 3.15-3.11 (m, 3H), 3.10-3.04 (m, 1H), 2.50-2.36 (m, 1H), 2.35-2.22 (m, 2H), 2.20-2.10 (m, 2H), 2.09-2.05 (m, 1H), 2.03-1.98 (m, 1H), 1.97-1.86 (m, 1H), 0.82-0.71 (m, 3H); .sup.19F NMR (400 MHZ, methanol-d.sub.4) =121.115, 138.670, 173.966; LCMS (ESI, M+1): m/z=731.4. the and Example 684 (3.2 mg, 5% yield) as an off-white solid; SFC: >99% ee, Chiralcel OJ-3.504.6 mm I.D., 3 m; Isocratic elution: 40% MeOH+ACN (0.05% DEA) in CO.sub.2, 3 mL/min, 254 nm, t.sub.R: 0.481 min; .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.25-9.17 (m, 1H), 7.74-7.65 (m, 1H), 7.36-7.30 (m, 1H), 7.29-7.20 (m, 2H), 7.06-6.99 (m, 1H), 5.55-5.35 (m, 1H), 5.10-5.03 (m, 2H), 4.66-4.43 (m, 6H), 3.87-3.76 (m, 2H), 3.66-3.53 (m, 4H), 3.27-3.22 (m, 4H), 3.16-3.10 (m, 3H), 2.56-2.36 (m, 3H), 2.32-2.24 (m, 1H), 2.23-2.08 (m, 4H), 0.82-0.73 (m, 3H): .sup.19F NMR (400 MHZ, methanol-d.sub.4) =76.918, 121.100, 174.161; LCMS (ESI, M+1): m/z=731.4. Example 685 ##STR00410## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-sulfonamide [0670] The title compound was synthesized according to the 3-step procedure described for example 676 except for dimethylamine was used in Step A, to produce the desired compound as an off-white solid. .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.17 (s, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.90-6.83 (m, 1H), 5.41-5.15 (m, 3H), 4.62-4.52 (m, 2H), 4.51-4.37 (m, 2H), 4.33-4.19 (m, 2H), 3.39-3.32 (m, 1H), 3.28-3.17 (m, 2H), 3.09-2.98 (m, 1H), 2.77 (s, 6H), 2.54-2.40 (m, 3H), 2.36-2.25 (m, 1H), 2.24-2.12 (m, 3H), 2.06-1.91 (m, 3H), 0.83-0.74 (m, 3H); LCMS (ESI, M+1): m/z=737.4. Example 686 ##STR00411## 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-((trans-3-hydroxycyclobutyl)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide Example 687 ##STR00412## 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-((cis-3-hydroxycyclobutyl)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide ##STR00413## ##STR00414## [0671] Step A. tert-butyl N-[[5-(dimethylcarbamoyl)-2-[(3-hydroxycyclobutyl)methyl]pyrazol-3-yl]methyl]carbamate and tert-butyl N-[[5-(dimethylcarbamoyl)-1-[(3-hydroxycyclobutyl)methyl]pyrazol-3-yl]methyl]carbamate: A mixture of tert-butyl N-[[3-(dimethylcarbamoyl)-1H-pyrazol-5-yl]methyl]carbamate (1 g, 1.0 equiv), (3-hydroxycyclobutyl)methyl 4-methylbenzenesulfonate (1.2 g, 1.2 equiv) and Cs.sub.2CO.sub.3 (2.4 g, 2.0 equiv) in DMF (10 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 80 C. for 12 hours under N.sub.2 atmosphere. The reaction mixture was diluted with H.sub.2O (5 mL) and extracted with Ethyl acetate (4 mL5). The combined organic layers were washed with brine (5 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated and purified with prep-HPLC [C18, 0.1% formic acid condition] to afford the title compounds (340 mg, mixture, 23.2% yield) as a white solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.04 (s, 1H), 8.08-7.99 (m, 1H), 6.60-6.26 (m, 1H), 5.08-4.79 (m, 2H), 4.38-4.26 (m, 3H), 4.18-4.10 (m, 2H), 3.37-3.04 (m, 6H), 2.83-2.68 (m, 1H), 2.49-2.35 (m, 1H), 2.32-2.20 (m, 1H), 1.77-1.61 (m, 1H), 1.47 (s, 9H); LCMS (ESI, M+1): m/z=353.2. [0672] Step B. 5-(aminomethyl)-2-[(3-hydroxycyclobutyl)methyl]-N,N-dimethyl-pyrazole-3-carboxamide and 5-(aminomethyl)-1-[(3-hydroxycyclobutyl)methyl]-N,N-dimethyl-pyrazole-3-carboxamide: To the mixture of tert-butyl N-[[5-(dimethylcarbamoyl)-2-[(3-hydroxycyclobutyl)methyl]pyrazol-3-yl]methyl]carbamate and tert-butyl N-[[5-(dimethylcarbamoyl)-1-[(3-hydroxycyclobutyl)methyl]pyrazol-3-yl]methyl]carbamate (340 mg, 1.0 equiv) in dioxane (0.5 mL) was added HCl/dioxane (4 M, 2.4 mL, 20 equiv). The mixture was stirred at 20 C. for 4 hours. The reaction mixture was concentrated under reduced pressure to afford the title compounds (300 mg, crude mixture, HCl). The crude mixture (150 mg) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: [0.1% NH.sub.3H.sub.2O MEOH]; B %: 35%-35%, 4.5 min) to afford 5-(aminomethyl)-1-((3-hydroxycyclobutyl)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide (50 mg, 33.3% yield) and 3-(aminomethyl)-1-((3-hydroxycyclobutyl)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide (100 mg, 66.7% yield). [0673] 5-(aminomethyl)-1-((3-hydroxycyclobutyl)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =6.48-6.47 (m, 1H), 4.34-4.20 (m, 3H), 4.08-3.95 (m, 1H), 3.81 (s, 2H), 3.15-3.11 (m, 7H), 2.67 (qdd, J=4.2, 8.5, 12.7 Hz, 1H), 2.35-2.27 (m, 2H), 2.25-2.07 (m, 2H), 2.05-1.96 (m, 1H), 1.68-1.57 (m, 2H). [0674] 3-(aminomethyl)-1-((3-hydroxycyclobutyl)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =6.64 (s, 1H), 4.20-4.14 (m, 5H), 4.02-3.92 (m, 1H), 3.25 (d, J=3.2 Hz, 3H), 3.00 (s, 3H), 2.70-2.59 (m, 1H), 2.33-2.06 (m, 4H), 2.02-1.90 (m, 1H), 1.66-1.55 (m, 2H) [0675] Step C. 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-((trans-3-hydroxycyclobutyl)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide and 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-((cis-3-hydroxycyclobutyl)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: A mixture of 5-(aminomethyl)-1-((3-hydroxycyclobutyl)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide (50.0 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (111.5 mg, 0.95 equiv), K.sub.3PO.sub.4 (126 mg, 3 equiv) in DMF (1 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 40 C for 4 hours. The reaction mixture was filtered, concentrated and purified with prep-HPLC [C18, 0.1% NH.sub.3.Math.H.sub.2O condition] to afford the two title compounds EXAMPLE 686 (6.8 mg, 4.6% yield) and EXAMPLE 687 (3.6 mg, 2.4% yield) and the as white solids. [0676] EXAMPLE 686 .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.22-9.12 (m, 1H), 8.53 (s, 1H), 7.68 (dd, J=5.9, 9.0 Hz, 1H), 7.31 (d, J=2.6 Hz, 1H), 7.25 (t, J=9.4 Hz, 1H), 7.08-7.02 (m, 1H), 6.69 (s, 1H), 5.46-5.24 (m, 1H), 5.04-4.94 (m, 3H), 4.62 (s, 1H), 4.43-4.30 (m, 4H), 4.22-3.99 (m, 1H), 3.37-3.34 (m, 3H), 3.24-3.20 (m, 1H), 3.10-3.06 (m, 4H), 2.85-2.71 (m, 1H), 2.51-1.86 (m, 12H), 1.86-1.60 (m, 1H), 0.78 (t, J=7.2 Hz, 3H); .sup.19F NMR (376 MHz, methanol-d4) =121, 138, 173; LCMS (ESI, M+1): m/z=745.2. [0677] EXAMPLE 687 .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.23-9.13 (m, 1H), 7.69 (dd, J=5.6, 8.8 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.26 (t, J=9.3 Hz, 1H), 7.04 (d, J=1.6 Hz, 1H), 6.65 (d, J=5.4 Hz, 1H), 5.71 (quin, J=6.4 Hz, 1H), 5.48 (br t, J=7.3 Hz, 1H), 5.41-5.22 (m, 1H), 4.74-4.50 (m, 1H), 4.42-4.31 (m, 4H), 4.06-4.00 (m, 2H), 3.37-3.34 (m, 4H), 3.21 (br s, 1H), 3.10 (d, J=5.6 Hz, 3H), 3.08-3.00 (m, 2H), 2.83-2.72 (m, 1H), 2.66-2.56 (m, 2H), 2.46-2.35 (m, 1H), 2.34-2.20 (m, 3H), 2.17-2.07 (m, 2H), 2.06-1.96 (m, 3H), 1.96-1.86 (m, 1H), 0.76 (t, J=7.3 Hz, 3H); .sup.19F NMR (376 MHz, methanol-d4) =121, 138, 173; LCMS (ESI, M+1): m/z=745.2. Example 688 ##STR00415## 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-((3-hydroxycyclobutyl)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide [0678] The title compound was synthesized using 5-(aminomethyl)-2-[(3-hydroxycyclobutyl)methyl]-N,N-dimethyl-pyrazole-3-carboxamide according to the procedure described for example 622 to produce the desired compound as a yellow oil. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.17 (s, 1H), 8.55 (s, 1H), 7.67 (dd, J=5.6, 9.1 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.04 (d, J=2.8 Hz, 1H), 6.58-6.56 (m, 1H), 5.39-5.21 (m, 1H), 4.90 (s, 2H), 4.32-4.23 (m, 4H), 4.01 (quin, J=7.6 Hz, 1H), 3.29-3.20 (m, 2H), 3.20-3.16 (m, 1H), 3.12-3.09 (m, 6H), 3.04-2.97 (m, 1H), 2.71-2.60 (m, 1H), 2.47 (td, J=7.2, 8.9 Hz, 1H), 2.36-2.08 (m, 8H), 2.04-1.93 (m, 3H), 1.93-1.84 (m, 1H), 1.66 (br d, J=2.8 Hz, 1H), 1.64-1.57 (m, 1H), 0.79 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=745.1. Example 689 ##STR00416## 5-acetyl-3-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-4-yl)hexahydro-2H-pyrrolo[3,4-d]oxazol-2-one ##STR00417## [0679] A mixture of 3-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-4-yl)hexahydro-2H-pyrrolo[3,4-d]oxazol-2-one (15.0 mg, 1.0 equiv), TEA (6.50 mg, 3.0 equiv), acetyl chloride (2.00 mg, 1.2 equiv) in DCM (0.5 mL) was stirred at 0 C. for 2 hours under N.sub.2 atmosphere. The mixture was concentrated and purified by prep-TLC (MeOH (10% NH.sub.3.Math.H.sub.2O)/DCM 1:5) to afford the title compound (3.4 mg, 20.5% yield). 1H NMR (400 MHz, METHANOL-d.sub.4) =9.00 (s, 1H), 7.58 (dd, J=5.9, 9.0 Hz, 1H), 7.21 (d, J=2.8 Hz, 1H), 7.15 (t, J=9.6 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 5.42-5.17 (m, 1H), 5.12-4.93 (m, 1H), 4.54-4.24 (m, 3H), 4.04-3.57 (m, 4H), 3.56-3.23 (m, 6H), 3.18-2.98 (m, 2H), 2.59-1.73 (m, 13H), 1.29-1.08 (m, 4H), 0.81-0.63 (m, 3H); .sup.19F NMR (377 MHZ, METHANOL-d4) =121.09 (br s, 1F), 139.12 (br s, 1F), 173.88 (br s, 1F); LCMS (ESI, M+1): m/z=746.4. Example 690 ##STR00418## (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocin-2-yl)(morpholino)methanone [0680] The title compound was synthesized according to the 3-step procedure described for example 671 to produce the desired compound as a yellow solid; .sup.1H NMR (400 MHZ, CD.sub.3OD) =9.04 (s, 1H), 7.63 (dd, J=6.0, 8.8 Hz, 1H), 7.29-7.16 (m, 2H), 7.02 (d, J=2.4 Hz, 1H), 6.74 (s, 1H), 5.42-5.20 (m, 3H), 4.47 (br s, 2H), 4.31-4.19 (m, 2H), 4.15 (br s, 2H), 4.06 (br s, 2H), 3.79-3.66 (m, 6H), 3.19 (br d, J=19.2 Hz, 2H), 3.06-2.95 (m, 1H), 2.52-2.40 (m, 1H), 2.36-1.86 (m, 12H), 0.79 (t, J=7.2 Hz, 3H); .sup.19F NMR (376 MHz, CD.sub.3OD) =122.10 (br s, 1F), 138.16 (s, 1F), 173.58 (s, 1F). LCMS (ESI, M+1): m/z=757.2 Example 691 ##STR00419## 1-(1,1-dioxidothietan-3-yl)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide Example 692 ##STR00420## 1-(1,1-dioxidothietan-3-yl)-3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide ##STR00421## ##STR00422## [0681] Step A 1,1-dioxidothietan-3-yl 4-methylbenzenesulfonate: To a solution of 1,1-dioxothietan-3-ol (200 mg, 1.64 mmol, 1 eq) in THF (10 mL) was added NaH (130.99 mg, 3.27 mmol, 60% purity, 2 eq) at 0 C. and the resulting was stirred for 0.5 hr. Then TosCl (936.51 mg, 4.91 mol, 3 eq) was added and the mixture was stirred at 40 C. for 2.5 hr. The mixture was quenched with H.sub.2O (1 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 030% Ethyl acetate/Petroleum ethergradient @ 36 mL/min) to afford (1,1-dioxothietan-3-yl) 4-methylbenzenesulfonate (100 mg, 361.89 umol, 22.10% yield) as a white solid. [0682] LCMS (ESI, M+1): m/z=277.0 [0683] Step B. tert-butyl ((3-(dimethylcarbamoyl)-1-(1,1-dioxidothietan-3-yl)-1H-pyrazol-5-yl)methyl)carbamate and tert-butyl ((5-(dimethylcarbamoyl)-1-(1,1-dioxidothietan-3-yl)-1H-pyrazol-3-yl)methyl)carbamate: A mixture of (1,1-dioxothietan-3-yl) 4-methylbenzenesulfonate (61.8 mg, 1 equiv), tert-butyl N-[[3-(dimethylcarbamoyl)-1H-pyrazol-5-yl]methyl]carbamate (60 mg, 1 equiv) and Cs.sub.2CO.sub.3 (219 mg, 3 equiv) in DMF (4.00 mL) was degassed and stirred at 60 C. for 2 hours under N.sub.2 atmosphere. The mixture was extracted with EtOAc 90 mL (30 mL3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO.sub.2, DCM/MeOH 10:1) to afford the title compound (50 mg, 54% yield) as a yellow solid. LCMS (ESI, M+1): m/z=373.1 [0684] Step C. 5-(aminomethyl)-1-(1,1-dioxidothietan-3-yl)-N,N-dimethyl-1H-pyrazole-3-carboxamide and 3-(aminomethyl)-1-(1,1-dioxidothietan-3-yl)-N,N-dimethyl-1H-pyrazole-5-carboxamide: A mixture of tert-butyl N-[[5-(dimethylcarbamoyl)-2-(1,1-dioxothietan-3-yl) pyrazol-3-yl]methyl]carbamate (50 mg, 1 equiv) in DCM (1.5 mL) and TFA (0.5 mL) was stirred at 10 C. for 1 hour under N.sub.2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Waters Atlantis T3 150*30 mm*5 um; mobile phase: [water (FA)-ACN]; B %: 1%-20%, 10 min) to afford the title compound (25 mg, 68% yield) as a yellow solid. LCMS (ESI, M+1): m/z=273.1 [0685] Step D. 1-(1,1-dioxidothietan-3-yl)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide and 1-(1,1-dioxidothietan-3-yl)-3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide: A mixture of regioisomeric 3- and 5-(aminomethyl)-1-(1,1-dioxothietan-3-yl)-N,N-dimethyl-pyrazole-3-carboxamide (18.4 mg, 2 equiv), 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (20.0 mg, 1 equiv), 4 molecular sieves (10 mg) and K.sub.3PO.sub.4 (71.7 mg, 10 equiv) in ACN (1.00 mL) and DMF (1.00 mL) was stirred at 60 C. for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition; column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 32%-62%, 8.5 min) and following that separated by chiral SFC (condition: column: DAICEL CHIRALCEL OJ (250 mm30 mm, 10 um); mobile phase: [0.1% NH.sub.3H.sub.2O ETOH]; B %: 40%-40%, 6.5 min) to afford the title compound EXAMPLE 691 (11.2 mg, 93% yield) as a yellow solid and EXAMPLE 692 (2.45 mg, 20% yield) as a yellow solid. [0686] EXAMPLE 691 .sup.1H NMR (400 MHZ, METHANOL-d4) =9.15 (br s, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.24 (t, J=9.6 Hz, 1H), 7.04 (br s, 1H), 6.77 (s, 1H), 5.83 (br s, 1H), 5.44-5.14 (m, 1H), 4.99-4.93 (m, 2H), 4.80 (br s, 3H), 4.36-4.24 (m, 2H), 3.41 (s, 3H), 3.26 (br d, J=10.3 Hz, 2H), 3.19 (br s, 1H), 3.10 (s, 3H), 3.06-2.98 (m, 1H), 2.49-2.38 (m, 1H), 2.37-2.28 (m, 1H), 2.25-2.20 (m, 1H), 2.18-2.08 (m, 2H), 2.03-1.95 (m, 2H), 1.92-1.82 (m, 1H), 1.34-1.27 (m, 1H), 0.77 (br t, J=7.2 Hz, 3H). LCMS (ESI, M+1): m/z=765.4 [0687] EXAMPLE 692 .sup.1H NMR (400 MHZ, METHANOL-d4) =9.19 (s, 1H), 7.67 (dd, J=2.8, 8.8 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.04 (d, J=2.8 Hz, 1H), 6.67 (s, 1H), 5.50-5.44 (m, 1H), 4.95 (s, 2H), 4.79-4.70 (m, 2H), 4.67-4.58 (m, 4H), 4.49-4.34 (m, 2H), 3.46-3.36 (m, 3H), 3.35 (s, 1H), 3.15 (s, 3H), 3.09 (s, 3H), 2.48-2.43 (m, 1H), 2.36-2.30 (m, 1H), 2.20 (br d, J=8.7 Hz, 1H), 2.12-2.06 (m, 2H), 2.00-1.92 (m, 1H), 1.29 (s, 1H), 0.78 (t, J=7.2 Hz, 3H). LCMS (ESI, M+1): m/z=765.4 Example 693 ##STR00423## 4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-3-(3-hydroxycyclobutanecarboxamido)-N,N-dimethyl-1H-pyrazole-1-carboxamide ##STR00424## [0688] Step A. tert-butyl ((1-(dimethylcarbamoyl)-3-(3-hydroxycyclobutanecarboxamido)-1H-pyrazol-4-yl)methyl)carbamate: To a mixture of tert-butyl ((3-amino-1-(dimethylcarbamoyl)-1H-pyrazol-4-yl)methyl)carbamate (400 mg, 1.0 equiv) and 3-hydroxycyclobutanecarboxylic acid (245 mg, 1.5 equiv) in dichloromethane (4 mL) was added DIPEA (547 mg, 3.0 equiv) and HATU (805 mg, 1.5 equiv). The reaction was stirred at 20 C. for 2 hours. The mixture was diluted with water (20 ml) and extracted with EtOAc (230 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (53 mg, 10% yield) as yellow solid; LCMS (ESI, M+1): m/z=382.0. [0689] Step B. 4-(aminomethyl)-3-(3-hydroxycyclobutanecarboxamido)-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a solution of tert-butyl ((1-(dimethylcarbamoyl)-3-(3-hydroxycyclobutanecarboxamido)-1H-pyrazol-4-yl)methyl)carbamate (43 mg, 1.0 equiv) in dichloromethane (0.5 mL) was added TFA (193 mg, 15 equiv). The reaction was stirred at 20 C. for 0.5 hour. The mixture was concentrated to afford the title compound (45 mg, TFA) as a yellow oil. [0690] Step C. 4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-3-(3-hydroxycyclobutanecarboxamido)-N,N-dimethyl-1H-pyrazole-1-carboxamide: The title compound was synthesized according to the procedure described for example 541 to produce the desired compound as a white solid; SFC: Chiralcel OJ-3 504.6 mm I.D., 3 m, Gradient elution: MeOH (0.05% DEA) in CO.sub.2 from 5% to 40%, 3 mL/min; 220 nm, t.sub.R: 1.593 min; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =10.12-10.02 (m, 1H), 9.92 (br t, J=7.2 Hz, 1H), 9.29 (s, 1H), 9.20 (br d, J=4.4 Hz, 1H), 8.17 (d, J=3.6 Hz, 1H), 7.76 (dd, J=6.0, 9.6 Hz, 1H), 7.38-7.28 (m, 2H), 6.99 (d, J=2.4 Hz, 1H), 5.36-5.17 (m, 1H), 5.16-5.05 (m, 1H), 4.63-4.52 (m, 2H), 4.26-3.91 (m, 3H), 3.11 (br s, 6H), 3.09-2.99 (m, 3H), 2.86-2.78 (m, 1H), 2.35-2.25 (m, 3H), 2.20-2.08 (m, 2H), 2.06-1.97 (m, 4H), 1.96-1.67 (m, 4H), 0.71 (t, J=7.2 Hz, 3H); .sup.19F NMR (377 MHz, dimethylsulfoxide-d.sub.6) =119.689, 139.615, 172.029; LCMS (ESI, M+1): m/z=774.6. Example 694 ##STR00425## 1-(1,1-dioxidotetrahydrothiophen-3-yl)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide ##STR00426## [0691] Step A. (1,1-dioxothiolan-3-yl) methanesulfonate: To a solution of 1,1-dioxothiolan-3-ol (400 mg, 1.0 equiv) and TEA (445.9 mg, 1.5 equiv) in DCM (10 mL) was added methanesulfonyl chloride (403.8 mg, 1.2 equiv) dropwise at 0 C. under N.sub.2. The reaction mixture was warmed up to 25 C. and stirred for 2 hours. The reaction was quenched by iced water slowly and then extracted with DCM (25 Ml3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the title compound (615 mg, crude) as an off-white solid. [0692] Step B. tert-butyl N-[[5-(dimethylcarbamoyl)-1-(1,1-dioxothiolan-3-yl) pyrazol-3-yl]methyl]carbamate: To a solution of tert-butyl N-[[3-(dimethylcarbamoyl)-1H-pyrazol-5-yl]methyl]carbamate (260 mg, 1.0 equiv) and (1,1-dioxothiolan-3-yl) methanesulfonate (415.2 mg, 2.0 equiv) in DMF (3 mL) was added Cs.sub.2CO.sub.3 (947.2 mg. 3.0 equiv). The mixture was stirred at 40 C. for 4 hours. The residue was purified by prep-TLC (SiO.sub.2, DCM/MeOH 10:1) to afford the title compound (350 mg, 85% yield) as a white solid. [0693] Step C. 5-(aminomethyl)-1-(1,1-dioxothiolan-3-yl)-N,N-dimethyl-pyrazole-3-carboxamide: To a solution of tert-butyl N-[[5-(dimethylcarbamoyl)-1-(1,1-dioxothiolan-3-yl) pyrazol-3-yl]methyl]carbamate (380 mg, 1.0 equiv) in DCM (1.5 mL) was added TFA (770 mg, 6.9 equiv). The mixture was stirred at 25 C. for 1 hour. The residue was concentrated and purified by prep-HPLC [C18, 0.1% NH.sub.3.Math.H.sub.2O condition], which was further separated by SFC to afford the title compound (72 mg, 25% yield) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) 2.60-2.75 (m, 2H) 3.09 (s, 3H) 3.19-3.27 (m, 1H) 3.37 (s, 3H) 3.48-3.57 (m, 2H) 3.68 (dd, J=13.6, 8.44 Hz, 1H) 3.92 (s, 2H) 5.34-5.46 (m, 1H) 6.61 (s, 1H). [0694] Step D. 1-(1,1-dioxidotetrahydrothiophen-3-yl)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (12 mg, equiv) and 5-(aminomethyl)-1-(1,1-dioxothiolan-3-yl)-N,N-dimethyl-pyrazole-3-carboxamide (23.2 mg, 4.0 eq) in DMF (0.5 mL) was added K.sub.3PO.sub.4 (21.5 mg, 5.0 equiv) at 25 C. The mixture was stirred at 40 C. for 12 hours before being filtered and concentrated. The residue was purified by prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (7.5 mg, 46.6% yield) as a white solid (0.39 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) 0.71-0.85 (m, 3H) 1.30 (br s, 1H) 1.95-2.34 (m, 6H) 2.36-2.56 (m, 3H) 2.66-2.81 (m, 2H) 3.10 (s, 3H) 3.40 (s, 2H) 3.53-3.80 (m, 6H) 4.48-4.67 (m, 5H) 5.03-5.10 (m, 1H) 5.34-5.54 (m, 1H) 5.63-5.77 (m, 1H) 6.77 (s, 1H) 7.01 (s, 1H) 7.25 (t, J=9.6 Hz, 1H) 7.29-7.36 (m, 1H) 7.64-7.72 (m, 1H) 8.48 (br d, J=6.8 Hz, 1H) 9.17-9.23 (m, 1H); LCMS (ESI, M+1): m/z=779.4. Example 695 ##STR00427## (3R)-1-(2-((3-azabicyclo[3.1.0]hexan-1-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00428## [0695] Step A. tert-butyl 1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate: To a solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 2.2 equiv) and (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (225 mg, 1.0 equiv) in THF (4.00 mL) was added t-BuOK (1.07 mL, 2.50 equiv). The mixture was stirred at 60 C. for 12 hours. The reaction mixture was quenched by addition of water (20.0 mL) at 20 C., and extracted with ethyl acetate (30.0 mL3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by prep-TLC (SiO.sub.2, DCM/MeOH 10:1) to afford the title compound (220 mg, 61% yield) as a yellow solid; LCMS (ESI, M+1): m/z=706.4. [0696] Step B. (3R)-1-(2-((3-azabicyclo[3.1.0]hexan-1-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of tert-butyl 1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (50.0 mg, 1.0 equiv) in HCl/MeOH (2.00 mL). The mixture was stirred at 0 C. for 1 hour. The reaction mixture was concentrated and purified with prep-HPLC (column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 16%-46%, 10 min) to afford the title compound (7.13 mg, 18% yield) as a white solid (0.76 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d4) =9.24 (s, 1H), 8.55 (s, 1H), 7.74-7.64 (m, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.27 (t, J=9.6 Hz, 1H), 7.07 (s, 1H), 4.75-4.53 (m, 4H), 4.39-4.26 (m, 1H), 3.72-3.56 (m, 1H), 3.54-3.39 (m, 4H), 2.58-2.40 (m, 1H), 2.30-2.11 (m, 2H), 1.96-1.73 (m, 4H), 1.31 (d, J=10.0 Hz, 3H), 1.17-1.07 (m, 1H), 0.83 (q, J=7.2 Hz, 4H); .sup.19F NMR (376 MHz, METHANOL-d4) =121.15 (br d, J=11.2 Hz, 1F), 135.57-143.88 (m, 1F); LCMS (ESI, M+1): m/z=562.3. Example 696 ##STR00429## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((methylamino)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00430## [0697] Step A: (R)-tert-butyl ((1-(((7-chloro-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)carbamate: To a solution of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (2 g, 1.0 equiv) and tert-butyl ((1-(hydroxymethyl)cyclopropyl)methyl)(methyl)carbamate (1.82 g, 1.4 equiv) in DMSO (10 mL) was added CsF (4.56 g, 5.0 equiv). The mixture was stirred at 100 C. for 2 hours. The mixture was diluted with H.sub.2O (100 mL), extracted with ethyl acetate (420 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (1.1 g, 23% yield) as a yellow solid; LCMS (ESI, M+1): m/z=510.3. [0698] Step B: (R)-tert-butyl ((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)carbamate: A mixture of (R)-tert-butyl ((1-(((7-chloro-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)carbamate (110 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (88.6 mg, 1.3 equiv), CataCXium A Pd G3 (15.8 mg, 0.1 equiv) and K.sub.3PO.sub.4 (1.5 M, 3.0 equiv) in methoxycyclopentane (1.0 mL) was degassed and stirred at 90 C. for 2 hours under N.sub.2 atmosphere. The mixture was diluted with H.sub.2O (5 mL), extracted with ethyl acetate (35 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, concentrated and purified by reversed phase flash chromatography [C18, 0.1% NH.sub.3.Math.H.sub.2O condition] to afford the title compound (20 mg, 13% yield,) as a yellow oil. LCMS (ESI, M+1): m/z=664.3. [0699] Step C: (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((methylamino)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-tert-butyl ((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)carbamate (100 mg, 1.0 equiv) in DCM (0.5 mL) was added 2,6-dimethylpyridine (161 mg, 175 L, 10.0 equiv) and trimethylsilyl trifluoromethanesulfonate (335 mg, 10 equiv) at 0 C. The reaction solution was stirred at 20 C. for 0.5 hour. The solution was diluted with water (5 mL) and extracted with ethyl acetate (35 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, concentrated and purified by prep HPLC (Phenomenex Synergi, C18 15025 mm10 m, A: water (FA), B: ACN, B %: 15%-45% over 10 min) to afford the title compound (19.6 mg, 0.85 formic acid salt, 21% yield) as an off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.25 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H), 7.26 (t, J=9.2 Hz, 1H), 7.06 (s, 1H), 4.57 (br d, J=12.4 Hz, 1H), 4.47-4.38 (m, 2H), 4.36-4.27 (m, 1H), 3.67-3.55 (m, 1H), 3.47-3.37 (m, 1H), 3.20-3.10 (m, 2H), 2.72 (s, 3H), 2.53-2.40 (m, 1H), 2.27-2.08 (m, 2H), 1.91-1.73 (m, 3H), 1.29 (d, J=8.8 Hz, 3H), 0.93-0.88 (m, 2H), 0.87-0.84 (m, 2H), 0.84-0.76 (m, 3H); LCMS (ESI, M+1): m/z=564.4. Example 697 ##STR00431## (3R)-1-(2-((3-azabicyclo[4.1.0]heptan-1-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol [0700] The title compound was synthesized from tert-butyl 1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate according to the 2-step procedure described for example 695 to produce the desired compound as a white solid (0.66 formic acid salt). .sup.1H NMR (400 MHZ, CD.sub.3OD) =9.22 (s, 1H), 8.55 (s, 1H), 7.68 (dd, J=5.6, 8.8 Hz, 1H), 7.35-7.20 (m, 2H), 7.08-7.02 (m, 1H), 4.55 (br d, J=12.8 Hz, 1H), 4.47-4.39 (m, 1H), 4.35-4.23 (m, 2H), 3.72-3.54 (m, 2H), 3.48-3.39 (m, 1H), 3.24 (br d, J=13.6 Hz, 1H), 3.09-2.98 (m, 1H), 2.77 (m, 1H), 2.47 (m, 1H), 2.32-2.09 (m, 3H), 1.97-1.73 (m, 4H), 1.41-1.33 (m, 1H), 1.29 (d, J=10.0 Hz, 3H), 1.05 (dd, J=5.6, 9.2 Hz, 1H), 0.88-0.74 (m, 4H); .sup.19F NMR (377 MHz, CD.sub.3OD) =121.17 (s, 1F), 139.53 (s, 1F). LCMS (ESI, M+1): m/z=576.2. Example 698 ##STR00432## 6-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol [0701] The title compound was synthesized according to the 3-step procedure described for example 585 to produce the desired compound as a white solid (0.24FA). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.07 (d, J=5.8 Hz, 1H), 7.68-7.66 (m, 1H), 7.31 (d, J=2.6 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.07 (t, J=2.4 Hz, 1H), 4.50-4.38 (m, 2H), 4.33-4.21 (m, 1H), 4.18-4.05 (m, 2H), 4.04-3.90 (m, 2H), 2.94-2.80 (m, 2H), 2.63-2.62 (m, 6H), 2.54-2.44 (m, 1H), 2.34-2.14 (m, 3H), 1.87-1.67 (m, 6H), 0.87-0.78 (m, 5H), 0.70 (s, 2H); LCMS (ESI, M+1): m/z=604.3. Example 699 ##STR00433## (S)-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol Example 700 ##STR00434## (R)-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ##STR00435## [0702] Step A. 6-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane: To a solution of 2,4-dichloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidine (500 mg, 1.0 equiv) and DIEA (717 mg, 5.0 equiv) in DCM (5.0 mL) was added 1-oxa-8-azaspiro[3.5]nonane (241 mg, 1.0 equiv). The reaction mixture was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. The mixture was concentrated under reduced pressure and purified with prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (130 mg, 22% yield) as white solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.36 (s, 1H), 7.70 (dd, J=6.0, 9.2 Hz, 1H), 7.61-7.47 (m, 1H), 7.31-7.27 (m, 1H), 7.22 (s, 1H), 5.60-5.05 (m, 2H), 4.81-4.51 (m, 3H), 4.49-4.31 (m, 1H), 3.78 (dd, J=13.6, 18.4 Hz, 1H), 3.58-3.39 (m, 4H), 2.62-2.43 (m, 3H), 2.39-2.28 (m, 1H), 2.24-2.02 (m, 2H), 1.99-1.75 (m, 2H), 0.85 (q, J=7.2 Hz, 3H). [0703] Step B. 1-(1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine: A mixture of 8-[2-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-1-oxa-8-azaspiro[3.5]nonane (60.0 mg, 1.0 equiv) and [1-[(dimethylamino)methyl]cyclopropyl]methanol (400 mg, 28.0 equiv) was stirred at 110 C. for 1 hour under N.sub.2 atmosphere. The mixture was poured into ice-water (5 mL) and extracted with ethyl acetate (5 mL2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated, and purified with prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (60 mg, 85% yield) as a white solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.25 (d, J=3.0 Hz, 1H), 7.70 (dd, J=6.0, 8.8 Hz, 1H), 7.53 (d, J=2.8 Hz, 1H), 7.29 (s, 1H), 7.25 (s, 1H), 5.40-5.24 (m, 2H), 4.67-4.58 (m, 2H), 4.52-4.37 (m, 3H), 4.25 (br t, J=12.4 Hz, 1H), 3.97-3.68 (m, 1H), 3.53 (d, J=0.8 Hz, 4H), 2.87-2.67 (m, 2H), 2.64-2.41 (m, 8H), 2.38-2.17 (m, 2H), 2.14-2.00 (m, 1H), 1.99-1.75 (m, 2H), 0.93-0.79 (m, 5H), 0.68 (br s, 2H). [0704] Step C. (S)-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol and (R)-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To solution of 1-[1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-(1-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]-N,N-dimethylmethanamine (40.0 mg, 1.0 equiv) in DCM (1.0 mL) was added TFA (108 mg, 15 equiv) at 0 C. The reaction mixture was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. The mixture was poured into sat. NaHCO.sub.3 (5 mL) and extracted with ethyl acetate (5 mL2). The combined organic phases were concentrated and purified with prep-HPLC [C18, 0.1% formic acid condition] to afford the two title compounds: [0705] EXAMPLE 699 (10.6 mg, 27% yield) as white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.31 (d, J=6.8 Hz, 1H), 7.71 (dd, J=6.0, 8.8 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.28 (t, J=9.2 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 4.82-4.35 (m, 7H), 3.90 (s, 1H), 3.57-3.37 (m, 1H), 3.11-2.93 (m, 2H), 2.86-2.67 (m, 6H), 2.60-2.44 (m, 3H), 2.37-2.27 (m, 1H), 2.27-2.13 (m, 1H), 2.12-1.71 (m, 3H), 0.92 (s, 2H), 0.87-0.80 (m, 3H), 0.77 (br s, 2H); .sup.19F NMR (376 MHZ, METHANOL-d.sub.4) =121.06 (br s, 1F), 139.88 (br s, 1F); LCMS (ESI, M+1): m/z=590.5. [0706] EXAMPLE 700 (8.8 mg, 16% yield) as white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.32 (d, J=7.6 Hz, 1H), 7.71 (dd, J=6.0, 9.2 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.28 (t, J=9.2 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 4.84-4.66 (m, 1H), 4.64-4.40 (m, 5H), 3.83 (dd, J=9.6, 13.6 Hz, 1H), 3.58-3.36 (m, 1H), 3.26-3.10 (m, 2H), 2.89 (s, 6H), 2.63-2.44 (m, 3H), 2.43-2.27 (m, 1H), 2.27-2.12 (m, 1H), 2.11-1.89 (m, 2H), 1.88-1.73 (m, 1H), 1.04-0.91 (m, 2H), 0.90-0.74 (m, 5H); .sup.19F NMR (376 MHZ, METHANOL-d.sub.4) =121.05 (br s, 1F), 140.12 (br s, 1F); LCMS (ESI, M+1): m/z=590.5. Example 701 ##STR00436## (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-methyl-3-azabicyclo[4.1.0]heptan-1-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00437## [0707] Step A: (3-methyl-3-azabicyclo[4.1.0]heptan-1-yl)methanol: To a solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (100 mg, 1.0 equiv) in THF (5.00 mL) was slowly added lithium aluminum hydride (25.1 mg, 1.5 equiv) at 0 C. The mixture was stirred at 60 C. for 4 hours. The reaction mixture was quenched by addition of water (25.0 L), 15% NaOH solution (25.0 L) and water (75.0 L) at 0 C., and then diluted with ethyl acetate (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (150 mg, crude) as a colorless oil; MS (ESI, M+1): m/z=142.2. [0708] Step B: (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((3-methyl-3-azabicyclo[4.1.0]heptan-1-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3-methyl-3-azabicyclo[4.1.0]heptan-1-yl)methanol (150 mg, 2.0 equiv) in THF (5.00 mL) was added t-BuOK/THF (1 M, 1.33 mL, 2.5 equiv). The mixture was stirred at 20 C. for 0.5 hour. Then the mixture was added to (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (281 mg, 1.0 equiv) in THF (5.00 mL) The mixture and stirred at 60 C. for 12 hours. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL2). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO.sub.2, dichloromethane/methyl alcohol 10:1) to afford the title compound (55.0 mg, 16% yield) as a yellow solid; LCMS (ESI, M+1): m/z=634.3. [0709] Step C: (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-methyl-3-azabicyclo[4.1.0]heptan-1-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A solution of (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[(3-methyl-3-azabicyclo[4.1.0]heptan-1-yl)methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol (55.0 mg, 1.0 equiv) in HCl/MeOH (2.50 mL) was stirred at 0 C. for 1 hour. The reaction mixture was concentrated and was purified by prep-HPLC (FA condition; column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 18%-48%, 10 min) and lyophilized to afford the title compound (13.5 mg, 25% yield) as a yellow solid (0.74 formic acid salt). .sup.1H NMR (400 MHZ, CD.sub.3OD) =9.25-9.20 (m, 1H), 8.53 (s, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.35-7.20 (m, 2H), 7.05 (s, 1H), 4.59-4.49 (m, 1H), 4.48-4.21 (m, 3H), 3.68-3.54 (m, 1H), 3.53-3.38 (m, 2H), 3.30-3.23 (m, 1H), 3.09 (br d, J=13.2 Hz, 1H), 2.90-2.76 (m, 1H), 2.62 (s, 3H), 2.54-2.41 (m, 1H), 2.36-2.10 (m, 3H), 2.04-1.93 (m, 1H), 1.91-1.73 (m, 3H), 1.46-1.23 (m, 4H), 1.13-0.98 (m, 1H), 0.86-0.74 (m, 4H); .sup.19F NMR (376 MHz, CD.sub.3OD) =121.12 (s, 1F), 139.44 (s, 1F). LCMS (ESI, M+1): m/z=590.3. Example 702 ##STR00438## (3R)-1-(2-((1-((dimethylamino)methyl)-2-methylcyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00439## [0710] Step A. dimethyl 2-methylcyclopropane-1,1-dicarboxylate: To a solution of dimethyl propanedioate (3.70 g, 1.0 equiv) in DME (40.0 mL) was added NaH (2.30 g, 60% purity, 2.0 equiv) slowly at 0 C. under nitrogen atmosphere. The mixture was stirred at 0 C. for 0.5 hour. Then (S)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (3.90 g, 1.0 equiv) in DME (40.0 mL) was added dropwise at 0 C. and the resulting mixture warmed to 25 C. and stirred at 25 C. for 2 hours. The reaction mixture was quenched with ammonium chloride solution (80.0 mL) dropwise at 0 C., and extracted with ethyl acetate (40.0 mL3). The combined organic layer was dried over Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 10:1] to afford the title compound (3.00 g, 62% yield) as a colorless oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =3.76 (s, 3H), 3.71 (s, 3H), 1.98-1.88 (m, 1H), 1.42 (dd, J=4.4, 9.0 Hz, 1H), 1.34 (dd, J=4.4, 7.6 Hz, 1H), 1.09 (d, J=6.4 Hz, 3H). [0711] Step B. 1-(methoxycarbonyl)-2-methylcyclopropane-1-carboxylic acid: To a solution of dimethyl 2-methylcyclopropane-1,1-dicarboxylate (3.00 g, 1.0 equiv) in MeOH (30.0 mL) was added NaOH (1.7 M, 1.20 equiv) and THF (125 mg). The mixture was stirred at 30 C. for 12 hours. The mixture was concentrated and purified by column chromatography [SiO.sub.2, ethyl acetate/MeOH 1:0 to 10/1] to afford the tittle compound (2.50 g, 91% yield) as a colorless oil; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =3.59 (s, 3H), 1.53-1.47 (m, 1H), 1.12-1.05 (m, 2H), 0.94 (d, J=6.4 Hz, 3H). [0712] Step C. methyl 1-(dimethylcarbamoyl)-2-methylcyclopropane-1-carboxylate: To a solution of 1-(methoxycarbonyl)-2-methylcyclopropane-1-carboxylic acid (2.50 g. 1.0 equiv) in DMF (40.0 mL) was added HATU (18.0 g, 3.0 equiv) and DIPEA (20.4 g, 10 equiv) at 20 C. After addition, the mixture was stirred at this temperature for 0.5 hour, and then N-methylmethanamine (1.80 g, 40% purity, 1.0 equiv) was added at 20 C. The resulting mixture was stirred at 20 C. for 11.5 hours. The reaction mixture was diluted with water (80.0 mL) and extracted with ethyl acetate (40.0 mL3). The combined organic layer was dried over Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 3:1] to afford the title compound (1.00 g, 34% yield) as a brown solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =3.74 (s, 3H), 3.01 (s, 3H), 2.97 (s, 3H), 1.91-1.81 (m, 1H), 1.43 (dd, J=4.4, 7.2 Hz, 1H), 1.33 (dd, J=4.4, 9.2 Hz, 1H), 1.25 (d, J=6.4 Hz, 3H) [0713] Step D. (1-((dimethylamino)methyl)-2-methylcyclopropyl)methanol: To a solution of methyl 1-(dimethylcarbamoyl)-2-methylcyclopropane-1-carboxylate (1.00 g, 1.0 equiv) in THF (10.0 mL) was added LiAlH.sub.4 (819 mg, 4.0 equiv) at 0 C. The mixture was stirred at 20 C. for 1 hour. The reaction mixture was quenched by addition of water (0.8 mL), 15% NaOH solution (0.8 mL) and water (2.4 mL) at 0 C., and then diluted with ethyl acetate. The mixture was filtered, the filtrate was concentrated and purified by reversed phase flash chromatography [column: Waters Xbridge 15025 mm5 um; mobile phase: [water (NH.sub.4HCO.sub.3)-ACN]; B %: 1%-30%, 10 minutes] to afford the title compound (240 mg 31% yield) as a colorless oil. [0714] Step E. (3R)-1-(2-((1-((dimethylamino)methyl)-2-methylcyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (1-((dimethylamino)methyl)-2-methylcyclopropyl)methanol (50.0 mg, 1.0 equiv) and (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (184 mg, 1.0 equiv) in dioxane (2.00 mL) was added Cs.sub.2CO.sub.3 (341 mg, 3.0 equiv) at 78 C. The mixture was stirred at 25 C. for 2 hours. The reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (15.0 mL3). The combined organic layer was dried over Na.sub.2SO.sub.4, concentrated and purified with prep-TLC (SiO.sub.2, dichloromethane/methyl alcohol 10:1) to afford the title compound (6.00 mg, 3% yield) as a white solid. [0715] Step F. (3R)-1-(2-((1-((dimethylamino)methyl)-2-methylcyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A solution of (3R)-1-(2-((1-((dimethylamino)methyl)-2-methylcyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (6.00 mg, 1.0 equiv) in HCl/MeOH (0.50 mL) was stirred at 20 C. for 1 hour. The mixture was filtered, concentrated and purified by reversed phase flash chromatography [column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 18%-48%, 10 minutes] and lyophilized to afford the title compound (2.00 mg, 33% yield) as a white solid (0.69 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.24 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 7.68 (dd, J=6.0, 9.0 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.26 (t, J=9.2 Hz, 1H), 7.06 (t, J=2.8 Hz, 1H), 4.69 (d, J=12.0 Hz, 1H), 4.60-4.55 (m, 1H), 4.47 (d, J=12.0 Hz, 1H), 4.31 (br t, J=13.2 Hz, 1H), 3.69-3.58 (m, 1H), 3.52-3.40 (m, 1H), 3.05-2.79 (m, 2H), 2.69 (br s, 6H), 2.54-2.39 (m, 1H), 2.26-2.10 (m, 2H), 1.92-1.73 (m, 3H), 1.33-1.23 (m, 6H), 1.14-1.04 (m, 1H), 0.90-0.76 (m, 4H), 0.61 (t, J=5.2 Hz, 1H); LCMS (ESI, M+1): m/z=592.3. Example 703 ##STR00440## (3R)-1-(2-((1-((dimethylamino)methyl)-2-ethylcyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00441## [0716] Step A. dimethyl 2-ethylcyclopropane-1,1-dicarboxylate: To a mixture of dimethyl propanedioate (1.00 g, 1.0 equiv) and 1,2-dibromobutane (2.1 g, 1.3 equiv) in DMF (20 mL) was added K.sub.2CO.sub.3 (3.10 g, 3.0 equiv) and TBAB (2.40 g, 1.0 equiv) at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 12 hours. The reaction was poured into ice-water (15 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (20 mL3). The combined organic phases were washed with brine (25 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=20/1, 10/1) to afford the tittle compound (1.20 g, 85% yield) as colorless oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =3.76 (s, 3H), 3.72 (s, 3H), 1.88 (quin, J=7.6 Hz, 1H), 1.50-1.35 (m, 3H), 1.30-1.20 (m, 1H), 1.03-0.98 (m, 3H). [0717] Steps B-F. (3R)-1-(2-((1-((dimethylamino)methyl)-2-ethylcyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: The title compound was synthesized from dimethyl 2-ethylcyclopropane-1,1-dicarboxylate according to the 5-step procedure described in Steps B-F for example 702 to produce the desired compound as a white solid (0.38 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.23 (dd, J=2.0, 4.0 Hz, 1H), 8.54 (s, 1H), 7.68 (dd, J=5.6, 8.8 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.06 (s, 1H), 4.66 (d, J=12.0 Hz, 1H), 4.60-4.45 (m, 2H), 4.29 (br t, J=12.0 Hz, 1H), 3.70-3.56 (m, 1H), 3.52-3.39 (m, 1H), 2.94-2.77 (m, 2H), 2.64 (br s, 6H), 2.53-2.40 (m, 1H), 2.28-2.08 (m, 2H), 1.91-1.74 (m, 3H), 1.66 (td, J=7.2, 14.0 Hz, 1H), 1.44 (td, J=7.2, 14.4 Hz, 1H), 1.29 (d, J=9.6 Hz, 3H), 1.12-1.03 (m, 3H), 1.01-0.93 (m, 1H), 0.87-0.76 (m, 4H), 0.59 (br t, J=5.2 Hz, 1H); LCMS (ESI, M+1): m/z=606.5. Example 704 ##STR00442## (3R)-1-(2-((1-((dimethylamino)methyl)-2,2-dimethylcyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00443## [0718] Step A. diethyl 2,2-dimethylcyclopropane-1,1-dicarboxylate: To a solution of trimethylsulfoxonium iodide (4.95 g, 1.5 equiv) in DMSO (15 mL) was added NaH (899 mg, 60% purity, 1.5 equiv). The mixture was stirred at 0 C. for 0.5 hour. Diethyl 2-isopropylidenepropanedioate (3 g, 1.0 equiv) was added. The mixture was stirred at 0 C. for 12 hours. The reaction mixture was quenched by addition NH.sub.4Cl (sat. 10 mL) at 0 C., and then diluted with water (20 mL) and extracted with EtOAc (20 mL3). The combined organic layers were washed with brine (50 mL2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography [ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 025% Ethyl acetate/Petroleum ethergradient @ 50 mL/min] to afford the tittle compound (2.3 g, 72% yield) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =4.13 (ttd, J=3.6, 7.2, 10.8 Hz, 4H), 1.35 (s, 2H), 1.21 (t, J=7.2 Hz, 6H), 1.18 (s, 6H). [0719] Steps B-F. (3R)-1-(2-((1-((dimethylamino)methyl)-2,2-dimethylcyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: The title compound was synthesized from diethyl 2,2-dimethylcyclopropane-1,1-dicarboxylate according to the 5-step procedure described in Steps B-F for example 702 to produce the desired compound as a white solid (0.48 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.24 (dd, J=3.6, 8.0 Hz, 1H), 8.56 (s, 1H), 7.70 (dd, J=6.0, 9.2 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.27 (t, J=9.2 Hz, 1H), 7.08 (s, 1H), 4.83-4.78 (m, 1H), 4.60-4.54 (m, 1H), 4.47-4.38 (m, 1H), 4.31 (br t, J=12.4 Hz, 1H), 3.74-3.58 (m, 1H), 3.56-3.42 (m, 1H), 3.29-3.13 (m, 1H), 2.87-2.73 (m, 1H), 2.60 (br s, 5H), 2.51-2.42 (m, 1H), 2.34-2.11 (m, 2H), 1.96-1.75 (m, 3H), 1.40-1.28 (m, 6H), 1.27-1.15 (m, 3H), 0.93-0.77 (m, 4H), 0.66 (br d, J=4.8 Hz, 1H); .sup.19F NMR (377 MHz, METHANOL-d.sub.4) =121.11 (br s, 1F), 139.72 (br s, 1F); LCMS (ESI, M+1): m/z=606.4. Example 705 ##STR00444## (3R)-1-[2-[[2-[(dimethylamino)methyl]spiro[2.3]hexan-2-yl]methoxy]-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol ##STR00445## [0720] Step A. dimethyl 2-cyclobutylidenepropanedioate: To a solution of cyclobutanone (10 g, 1.0 equiv) and dimethyl propanedioate (18.9 g, 1.0 equiv) in toluene (100 mL) was added TiCl.sub.4 (29.8 g, 1.1 equiv) and pyridine (22.6 g, 2.0 equiv) at 25 C. The mixture was stirred at 25 C. for 12 hours and concentrated. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate 20:1 to 10:1) to afford the title compound (14.3 g, 54% yield) as a yellow oil. [0721] Step B. dimethyl spiro[2.3]hexane-2,2-dicarboxylate: NaH (3.3 g, 60% purity, 1.5 equiv) was suspended in anhydrous DMSO (100 mL) in a flame-dried round-bottom flask under N.sub.2. Trimethylsulfoxonium iodide (17.9 g, 1.5 equiv) was added and the solution stirred at 0 C. for 1 hour. Then dimethyl 2-cyclobutylidenepropanedioate (10.0 g, 1.0 equiv) in anhydrous DMSO (20 mL) was added. The mixture was stirred at 25 C. for 11 hours. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate 20:1 to 10:1) to afford the title compound (5.2 g, 48% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) 1.64 (s, 2H) 1.86-1.97 (m, 1H) 2.02-2.10 (m, 3H) 2.28-2.40 (m, 2H) 3.70 (s, 6H). [0722] Step C. 2-methoxycarbonylspiro[2.3]hexane-2-carboxylic acid: To a solution of dimethyl spiro[2.3]hexane-2,2-dicarboxylate (1.2 g, 1.0 equiv) in EtOH (20 mL) was added a solution of NaOH (1.0 M, 6.7 mL, 1.1 equiv) drop-wise at 0 C. under N.sub.2. The reaction mixture was warmed to 25 C. and stirred at 25 C. for 2 hours. The residue was poured into ice-water (20 mL) and extracted with DCM (20 mL2). Then HCl (1 M, 5 mL) was added and the resulting was stirred for 2 mins. The aqueous phase was extracted with DCM (20 mL3). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (840 mg, crude) as a white solid. [0723] Step D. methyl 2-(dimethylcarbamoyl)spiro[2.3]hexane-2-carboxylate: To a solution of 2-methoxycarbonylspiro[2.3]hexane-2-carboxylic acid (840 mg, 1.0 equiv) and N-methylmethanamine (744 mg, 2.0 equiv, HCl) in DCM (10 mL) were added HATU (3.5 g, 2.0 equiv) and DIPEA (3.0 g, 5.0 equiv) at 25 C. The mixture was stirred at 25 C. for 12 hours. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 1:4) to afford the title compound (765 mg, 79% yield) as a colorless liquid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) 1.54-1.63 (m, 2H) 1.89-2.01 (m, 2H) 2.07-2.18 (m, 1H) 2.21-2.31 (m, 2H) 2.41-2.52 (m, 1H) 2.99 (s, 3H) 3.05 (s, 3H) 3.69 (s, 3H). [0724] Step E. [2-[(dimethylamino)methyl]spiro[2.3]hexan-2-yl]methanol: To a solution of methyl 2-(dimethylcarbamoyl)spiro[2.3]hexane-2-carboxylate (765 mg, 1.0 equiv) in THF (10 mL) was added LiAlH.sub.4 (687 mg, 5.0 equiv) at 0 C. The mixture was stirred at 25 C. for 2 hours. The residue was poured into Na.sub.2SO.sub.4 (sat., 2 mL) at 0 C. and stirred for 5 minutes. The reaction mixture was filtered and the filterate was concentrated to afford the title compound (552 mg, crude) as a colorless liquid. [0725] Step F. (3R)-1-[2-[[2-[(dimethylamino)methyl]spiro[2.3]hexan-2-yl]methoxy]-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol: To a solution of (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 1.0 equiv) and [2-[(dimethylamino)methyl]spiro[2.3]hexan-2-yl]methanol (64.0 mg, 1.0 equiv) in THF (1.5 mL) was added NaHMDS (1 M, 567 L, 1.5 equiv) at 0 C. The mixture was stirred at 25 C. for 12 hours. The residue was concentrated and purified by prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (81 mg, 32% yield) as a yellow solid. [0726] Step G. (3R)-1-[2-[[2-[(dimethylamino)methyl]spiro[2.3]hexan-2-yl]methoxy]-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol: To a solution of (3R)-1-[2-[[2-[(dimethylamino)methyl]spiro[2.3]hexan-2-yl]methoxy]-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol (28 mg, 1.0 equiv) in dioxane (1 mL) was added HCl/dioxane (4 M, 0.5 mL, 47.3 equiv) at 0 C. . . . The mixture was stirred at 25 C. for 1 hour. The mixture was concentrated and purified by prep-HPLC [C18, 0.1% formic acid condition] and lyophilized to afford the title compound (2.7 mg, 9.3% yield) as a yellow solid (0.72 formic acid salt). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) =0.83 (br dd, J=7.2, 3.6 Hz, 3H), 0.95 (br d, J=3.6 Hz, 1H), 1.07 (br d, J=4.8 Hz, 1H), 1.20 (t, J=7.2 Hz, 2H), 1.31 (br d, J=8.4 Hz, 3H), 1.74-1.94 (m, 3H), 1.98-2.13 (m, 3H), 2.13-2.33 (m, 4H), 2.37-2.60 (m, 4H), 3.41-3.52 (m, 1H), 3.53-3.70 (m, 3H), 4.19 (br dd, J=11.2, 6.8 Hz, 1H), 4.28-4.39 (m, 1H), 4.60 (dt, J=7.69, 3.78 Hz, 3H), 7.08 (br s, 1H), 7.28 (br t, J=9.2 Hz, 1H), 7.33 (br d, J=2.0 Hz, 1H), 7.70 (br dd, J=8.8, 5.6 Hz, 1H), 8.47-8.62 (m, 1H), 9.21-9.32 (m, 1H); LCMS (ESI, M+1): m/z=618.4. Example 706 ##STR00446## ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl methylcarbamate ##STR00447## [0727] Step A. ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl methylcarbamate: To a solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (300 mg, 1.0 equiv) in tetrahydrofuran (2 mL) was added NaH (36.1 mg, 60% purity, 2.0 equiv) at 0 C., the mixture was stirred at 0 C. for 0.5 hour. Then N-methylcarbamoyl chloride (84.5 mg, 2.0 equiv) in tetrahydrofuran (2 mL) was added and the mixture was stirred at 0 C. for 2 hours. The reaction mixture was quenched with water (5 mL) and was extracted with ethyl acetate (25 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO.sub.2, dichloromethane:methanol 5:1) to afford the title compound (40.0 g, 11% yield) as a colorless oil; LCMS (ESI, M+1): m/z=721.3. [0728] Step B. ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl methylcarbamate: To a solution of ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl methylcarbamate (40.0 mg, 1.0 equiv) in acetonitrile (0.5 mL) was added HCl.Math.MeOH (4 M, 36 equiv). The mixture was stirred at 0 C. for 0.5 hour. The reaction mixture was concentrated and diluted with acetonitrile (3 mL) and the pH of the mixture was adjusted to 7 using DIEA. The mixture was purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3); B: ACN, B %: 43%-73%, over 9 min] and lyophilized to afford the title compound (6.61 mg, 17% yield) as a white solid; SFC: Chiralcel OJ-3 504.6 mm I.D., 3 m, MeOH (0.05% DEA) in CO.sub.2 from 5% to 40% Flow rate: 3 mL/min, detector: 220 nm, t.sub.R1=1.410 min; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.12 (d, J=13.2 Hz, 1H), 7.58 (dd, J=5.6, 8.8 Hz, 1H), 7.24-7.16 (m, 2H), 7.06 (dd, J=2.4, 6.4 Hz, 1H), 4.48-4.16 (m, 4H), 4.12-3.96 (m, 2H), 3.68-3.52 (m, 1H), 3.48-3.28 (m, 2H), 3.12-2.92 (m, 3H), 2.24-2.12 (m, 2H), 1.92-1.84 (m, 3H), 1.76-1.64 (m, 4H), 1.48-1.24 (m, 13H), 0.85 (td, J=7.2, 10.8 Hz, 3H); LCMS (ESI, M+1): m/z=677.5. Example 707 ##STR00448## ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate ##STR00449## [0729] Step A. 3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 3-azabicyclo[3.2.1]octan-6-ol (1.27 g, 1.5 equiv) and 2,4-dichloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidine (3.00 g, 1.0 equiv) in DCM (40 mL) was added DIPEA (2.58 g, 3.0 equiv). The mixture was stirred at 40 C. for 1.5 hr. The reaction mixture was diluted with water (5 mL) and extracted with DCM (2.0 mL3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=20/1 to 1/1) to afford the title compound (1.90 g, 50% yield) as a white solid; LCMS (ESI, M+1): m/z=541.2. [0730] Step B. 2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(6-(methoxymethoxy)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine: To a solution of 3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (700 mg, 1 equiv) in DCM (10 mL) was added DIPEA (1.00 g, 6.0 equiv) and bromo(methoxy) methane (912 mg, 5.0 eq). The mixture was stirred at 25 C. for 12 hrs. The reaction mixture was filtered. The filtrate was diluted with water (5.0 mL) and extracted with ethyl acetate (5.0 mL3). The combined organic layers were washed with brine (5.0 mL3), dried over anhydrous sodium sulfate, filtered, concentrated and purified by reversed-phase HPLC (0.1% FA condition) to afford the title compound (800 mg, 68% yield) as a white solid; LCMS (ESI, M+1): m/z=585.3. [0731] Step C. ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(6-(methoxymethoxy)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of 2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(6-(methoxymethoxy)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv) in THF (4 mL) was added t-BuONa (98.6 mg, 3.0 equiv) and ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (91.1 mg, 1.1 equiv). The mixture was stirred at 0 C. for 0.5 hrs. The reaction mixture was filtered. The filtrate was diluted with water (5.0 mL) and extracted with ethyl acetate (5.0 mL3). The combined organic layers were washed with brine (5.0 mL3), dried over anhydrous sodium sulfate, filtered, concentrated and purified by reversed-phase HPLC (0.1% FA condition) to afford the title compound (90.0 mg, 30% yield) was as a yellow oil; LCMS (ESI, M+1): m/z=791.5. [0732] Step D. ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(6-(methoxymethoxy)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (90.0 mg, 1.0 equiv) in ACN (0.4 mL) was added HCl/dioxane (4 M, 0.8 mL, 28 equiv). The mixture was stirred at 0 C. for 0.5 hr. The mixture was poured into iced NaHCO.sub.3 (2.0 mL) and filtered. The filtrate was diluted with water (5.0 mL) and extracted with ethyl acetate (5.0 mL3). The combined organic layers were washed with brine (5.0 mL3), dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC (column: YMC Triart C18 15025 mm5 um; A: water [(FA)]; B: ACN, B %: 19%-49%, over 10 min) to afford the title compound (30.0 mg. 35% yield) as a yellow solid (0.47 formic acid salt); SFC: Chiralpak AD-3 504.6 mm I.D, 3 m, ACN (0.05% DEA) in CO.sub.2 from 5% to 40% Flow rate: 3 mL/min, detector: 220 nm, t.sub.R1=0.745, t.sub.R2=0.998, t.sub.R3=1.165, t.sub.R4=1.727; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.08 (s, 1H), 7.66 (dd, J=6.0, 8.8 Hz, 1H), 7.32-7.29 (m, 1H), 7.26-7.19 (m, 1H), 7.10-7.04 (m, 1H), 5.05-5.0 (m, 1H), 4.85-4.74 (m, 1H), 4.56-4.47 (m, 2H), 4.47-4.10 (m, 3H), 3.85-3.32 (m, 3H), 3.29-3.23 (m, 1H), 3.05 (br s, 6H), 2.59-2.36 (m, 3H), 2.15-1.34 (m, 14H), 0.84 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=703.2. Example 708 ##STR00450## ((3S,7aR)-7a-(((4-(4,6-dioxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate ##STR00451## [0733] Step A. 2-(((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of 2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (10.0 g, 1.0 equiv), ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methanol (8.77 g, 1.1 equiv) in dioxane (10 mL) was added Na.sub.2CO.sub.3 (6.19 g, 3.0 equiv). The mixture was stirred at 40 C. for 14 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 5:1 to 2:1] to afford the title compound (7.50 g, 37% yield) as a yellow oil; LCMS (ESI, M+1): m/z=887.5. [0734] Step B. ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methanol: To a solution of 2-(((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (6.50 g, 1.0 equiv) in THF (35 mL) was added HF.Math.Py (2.09 g, 70% purity, 10 equiv) solution at 0 C. The mixture was stirred at 0 C. for 0.5 hour. The mixture was quenched by sat. NaHCO.sub.3 (100 mL) and extracted with ethyl acetate (250 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (3.80 g, 78% yield) as a yellow oil; LCMS (ESI, M+1): m/z=649.4. [0735] Step C. ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methanol (2.60 g, 1.0 equiv) and DIPEA (3.11 g, 6.0 equiv) in ACN (26 mL) was added 4-nitrophenyl carbonochloridate (3.23 g, 4.0 equiv) at 0 C. The mixture was stirred at 50 C. for 4 hours. To the mixture was added N-methylmethanamine (1 M, 4.0 mL, 1.0 equiv) at 0 C. and the resulting was stirred at 0 C. for 0.5 hour. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2100 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 5:1 to 1:1] and prep-HPLC [column: Unisil 3-100 C18 Ultra 15050 mm3 m; A: water (FA), B: ACN, B %: 25%-55% over 7 min] to afford the title compound (700 mg, 22% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.25 (d, J=0.8 Hz, 1H), 7.68 (dd, J=5.6, 9.0 Hz, 1H), 7.53 (d, J=2.8 Hz, 1H), 7.30-7.19 (m, 2H), 5.34-5.24 (m, 2H), 5.11-4.83 (m, 2H), 4.45-4.27 (m, 1H), 4.16-3.96 (m, 1H), 3.90-3.71 (m, 2H), 3.52 (s, 3H), 3.13-2.97 (m, 1H), 2.89 (br s, 6H), 2.78-2.68 (m, 1H), 2.51-2.35 (m, 1H), 2.31-2.14 (m, 2H), 2.02-1.85 (m, 4H), 1.68-1.36 (m, 3H), 0.83 (q, J=7.6 Hz, 3H); LCMS (ESI, M1): m/z=720.4. [0736] Step D. ((3S,7aR)-7a-(((4-(4,6-dioxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a mixture of ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (80.0 mg, 1.0 equiv), tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (31.2 mg, 2.0 equiv) and 4 molecular sieves (20 mg) in DMF (0.1 mL) was added DIPEA (43.1 mg, 3 equiv). The reaction was stirred at 90 C. for 24 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (50.0 mg, 59% yield) as a yellow solid; LCMS (ESI, M+1): m/z=760.4. [0737] Step E. ((3S,7aR)-7a-(((4-(4,6-dioxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-(((4-(4,6-dioxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (50.0 mg, 1.0 equiv) in ACN (0.5 mL) was added HCl.Math.dioxane (4 M, 0.5 mL, 30 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hour. The mixture was concentrated, and the pH was adjusted to 8 by sat. NaHCO.sub.3. The mixture was extracted with ethyl acetate (210 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] and prep-HPLC [column: Unisil 3-100 C18 Ultra 15050 mm3 m; A: water (FA), B: ACN, B %: 15%-45% over 7 min] and [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 40%-70% over 8 min] to afford the title compound (5.37 mg, 11% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =8.99 (d, J=2.8 Hz, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.12-7.01 (m, 1H), 4.45-4.31 (m, 1H), 4.17-4.01 (m, 2H), 3.94 (br t, J=10.4 Hz, 1H), 3.75-3.57 (m, 3H), 3.56-3.44 (m, 3H), 2.93-2.77 (m, 7H), 2.71-2.51 (m, 2H), 2.48-2.33 (m, 1H), 2.28-2.12 (m, 1H), 2.06-1.93 (m, 1H), 1.90-1.49 (m, 6H), 1.38-1.17 (m, 1H), 0.86-0.71 (m, 3H); LCMS (ESI, M+1): m/z=716.4. Example 709 ##STR00452## ((3S,7aR)-7a-(((4-(2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate ##STR00453## [0738] Step A. 7-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (600 mg, 1.0 equiv) and DIPEA (517 mg, 3.0 equiv) in DCM (10 mL) was added 1,3,7-triazaspiro[4.5]decane-2,4-dione (203 mg, 0.9 equiv) at 40 C. The mixture was stirred at 40 C. for 0.5 hour. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 12% yield) as a yellow solid; LCMS (ESI, M+1): m/z=583.0. [0739] Step B. ((3S,7aR)-7a-(((4-(2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (57.4 mg, 1.5 equiv) in THF (2 mL) was added t-BuONa (2 M, 0.24 mL, 3.0 equiv) at 0 C. The mixture was stirred at 0 C. for 0.5 hour. To the mixture was added 7-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (92.0 mg, 1.0 equiv) at 0 C. The mixture was stirred at 0 C. for 0.5 hour. The mixture was quenched by water (5 mL) and extracted with ethyl acetate (10 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (36.0 mg, 29% yield) as a yellow solid; LCMS (ESI, M+1): m/z=789.4. [0740] Step C. ((3S,7aR)-7a-(((4-(2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-(((4-(2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (30.0 mg, 1.0 equiv) in ACN (0.5 mL) was added HCl.Math.dioxane (4 M, 1 mL, 105 equiv) at 0 C. The mixture was stirred at 0 C. for 20 minutes. The mixture was concentrated and pH was adjusted to 9 by sat. NaHCO.sub.3. The mixture was extracted with ethyl acetate (215 mL). The organic layer was dried over Na.sub.2SO.sub.4, concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 36%-66% over 9 min] to afford the title compound (10.9 mg, 38 yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.15-9.05 (m, 1H), 7.68 (dd, J=6.0, 9.0 Hz, 1H), 7.35-7.18 (m, 2H), 7.07 (d, J=1.8 Hz, 1H), 4.72-4.56 (m, 1H), 4.52-4.20 (m, 3H), 4.11 (br d, J=5.2 Hz, 1H), 4.04-3.91 (m, 1H), 3.89-3.64 (m, 2H), 3.13 (br s, 2H), 2.91 (br d, J=12.8 Hz, 7H), 2.55-2.34 (m, 1H), 2.30-2.02 (m, 6H), 1.99-1.68 (m, 7H), 0.80 (q, J=7.6 Hz, 3H); LCMS (ESI, M1): m/z=745.4. Example 710 ##STR00454## ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate [0741] The title compound was synthesized using Intermediate 3A according to the 3-step procedure described for example 709 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.54 (br d, J=5.2 Hz, 1H), 7.72-7.61 (m, 1H), 7.30 (br s, 1H), 7.24 (br t, J=9.4 Hz, 1H), 7.13-7.00 (m, 1H), 4.64-4.41 (m, 2H), 4.34-4.14 (m, 3H), 4.10-3.83 (m, 5H), 3.75-3.61 (m, 2H), 3.10-2.77 (m, 9H), 2.57-2.40 (m, 1H), 2.21 (br dd, J=5.2, 11.2 Hz, 2H), 2.08-1.61 (m, 7H), 1.28 (br s, 3H), 0.81 (q, J=7.6 Hz, 3H); LCMS (ESI, M+1): m/z=707.2. Example 711 ##STR00455## ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-oxo-1,3,7-triazaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate [0742] The title compound was synthesized using Intermediate 3 according to the 3-step procedure described for example 709, except for in Step A 4 MS (200 mg) were added and the mixture was stirred at 0 C. for 10 minutes to produce the desired compound as a white solid (0.65 formic acid salt).column: Chiralpak IC-3 504.6 mm I.D., 3 m, mobile phase: [60% MeOH+ACN (0.05% DEA)] in CO.sub.2, flow rate: 3 mL/min, detector: 220 nm, tR: 0.965 min; .sup.1H NMR (400 MHz, MeOH-d4) 9.22-9.05 (m, 1H), 7.69 (dd, J=5.6, 9.2 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.29-7.22 (m, 1H), 7.10-7.04 (m, 1H), 4.62-4.43 (m, 2H), 4.39-4.12 (m, 4H), 4.06-3.86 (m, 2H), 3.54-3.41 (m, 2H), 3.26-3.17 (m, 1H), 2.99-2.79 (m, 6H), 2.54-2.31 (m, 2H), 2.25-1.83 (m, 14H), 0.89-0.74 (m, 3H); LCMS (ESI, M+1): m/z=731.5. Example 712 ##STR00456## ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((2R,4r)-2-hydroxy-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate Example 713 ##STR00457## ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((2S,4s)-2-hydroxy-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate ##STR00458## ##STR00459## [0743] Step A. 6-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol: To a solution of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (2.20 g, 1.0 equiv) and DIPEA (1.89 g, 3.0 equiv) in DCM (22 mL) was added 6-azaspiro[3.5]nonan-2-ol (1.03 g, 1.5 equiv) at 40 C. The mixture was stirred at 40 C. for 1.5 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (2.0 g, 73% yield) as a yellow solid; LCMS (ESI, M+1): m/z=555.2. [0744] Step B. 2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidine: To a solution of 6-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (1.0 g, 1.0 equiv), TsOH (15.5 mg, 0.05 equiv) in THF (10 mL) was added DHP (455 mg, 3.0 equiv) at 0 C. The mixture was stirred at 20 C. for 2 hours. The mixture was quenched with saturated Na.sub.2HCO.sub.3 aqueous solution (20 mL) and extracted with EtOAc (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (1.0 g, 86% yield) as a yellow solid; LCMS (ESI, M+1): m/z=639.4. [0745] Step C. 2-(((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidine: To a mixture of ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methanol (769 mg, 3.0 equiv), 4 molecular sieves (80 mg) in THF (4 mL) was added t-BuONa (2 M, 3.0 equiv) at 0 C. The mixture was stirred at 20 C. for 0.5 hour. Then 2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidine (400 mg, 1.0 equiv) was added to the mixture at 0 C. The mixture was stirred at 20 C. for 0.5 hour. The mixture was diluted with water (10 mL) and extracted with EtOAc (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (150 mg, 21% yield) as a yellow solid; LCMS (ESI, M+1): m/z=1012.6. [0746] Step D. ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methanol: To a solution of 2-(((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidine (150 mg, 1.0 equiv) in DMF (1 mL) was added CsF (225 mg, 10 equiv). The mixture was stirred at 40 C. for 12 hours. The mixture was filtered and washed with DMF (1 mL) and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 74% yield)) as a yellow solid; LCMS (ESI, M+1): m/z=774.5. [0747] Step E. ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methanol (100 mg, 1.0 equiv) in THF (1 mL) was added NaH (10.3 mg, 60% purity, 2.0 equiv) at 0 C. The mixture was stirred at 0 C. for 0.5 hour. Then dimethylcarbamic chloride (34.7 mg, 2.5 equiv) was added to the mixture. The reaction was stirred at 0 C. for 1 hour. The mixture was diluted with water (10 mL) and extracted with EtOAc (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (40.0 mg, 37% yield) as a yellow solid; LCMS (ESI, M+1): m/z=845.5. [0748] Step F. ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((2R,4r)-2-hydroxy-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate and ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((2S,4s)-2-hydroxy-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (50.0 mg, 1.0 equiv) in MeOH (0.5 mL) was added TsOH (204 mg, 20 equiv). The mixture was stirred at 20 C. for 12 hours. The resulting mixture was filtered, washed with MeOH (1 mL) and the filtrate was purified with prep-HPLC [Waters Xbridge 15025 mm5 m; A: water (10 mM NH.sub.4HCO.sub.3), B: ACN; B %: 48%-78% over 8 min] and lyophilized to afford two peaks. EXAMPLE 712 (5.80 mg, 13% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.13-8.95 (m, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.08 (dd, J=2.4, 5.2 Hz, 1H), 4.45-4.19 (m, 3H), 4.18-4.01 (m, 3H), 4.00-3.85 (m, 3H), 3.15-2.99 (m, 2H), 2.92 (br d, J=17.2 Hz, 6H), 2.88-2.77 (m, 1H), 2.57-2.43 (m, 1H), 2.36-2.13 (m, 4H), 2.07-2.00 (m, 1H), 1.98-1.85 (m, 3H), 1.85-1.75 (m, 6H), 1.74-1.63 (m, 3H), 0.81 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=717.4. EXAMPLE 713 (5.80 mg, 13% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.05 (s, 1H), 7.67 (dd, J=5.6, 8.8 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.07 (br s, 1H), 4.36-4.18 (m, 3H), 4.15-3.89 (m, 6H), 3.11-3.00 (m, 2H), 2.92 (br d, J=18.4 Hz, 6H), 2.84 (br dd, J=5.2, 10.4 Hz, 1H), 2.57-2.42 (m, 1H), 2.29-2.14 (m, 4H), 2.08-2.00 (m, 1H), 1.97-1.88 (m, 3H), 1.87-1.78 (m, 6H), 1.77-1.63 (m, 3H), 0.82 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=717.4. Example 714 ##STR00460## ((3S,7aR)-7a-(((4-(2-(dimethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate [0749] The title compound was synthesized using Intermediate 3 according to the 3-step procedure described for example 709 to produce the desired compound as a white solid (0.16 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.17 (s, 1H), 7.67 (dd, J=6.0, 9.0 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.24 (t, J=9.2 Hz, 1H), 7.05 (t, J=2.4 Hz, 1H), 6.75 (s, 1H), 5.41-5.16 (m, 2H), 4.55 (br d, J=6.0 Hz, 2H), 4.50-4.35 (m, 2H), 4.31 (s, 2H), 4.13 (br dd, J=3.0, 6.4 Hz, 1H), 4.08-3.97 (m, 1H), 3.31 (s, 3H), 3.16 (br d, J=5.6 Hz, 2H), 3.07 (s, 3H), 3.00-2.81 (m, 7H), 2.53-2.35 (m, 3H), 2.29-2.11 (m, 2H), 2.08-1.90 (m, 4H), 1.89-1.70 (m, 3H), 0.78 (t, J=7.4 Hz, 3H); LCMS (ESI, M+1): m/z=784.5. Example 715 ##STR00461## ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-oxo-1,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate [0750] The title compound was synthesized using Intermediate 3 according to the 3-step procedure described for example 709, except that TFA-DCM (1:1) was used in Step C, to produce the desired compound as a white solid (0.25 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.12-9.04 (m, 1H), 7.70-7.66 (m, 1H), 7.33-7.20 (m, 2H), 7.06 (br s, 1H), 4.44-4.31 (m, 4H), 4.18-4.11 (m, 1H), 4.09-3.97 (m, 2H), 3.85-3.72 (m, 1H), 3.19 (br d, J=1.2 Hz, 2H), 2.99-2.84 (m, 8H), 2.79-2.72 (m, 1H), 2.51-2.40 (m, 1H), 2.30-2.22 (m, 1H), 2.18-1.99 (m, 6H), 1.95-1.71 (m, 6H), 0.79 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=716.5. Example 716 ##STR00462## ((3S,7aR)-7a-(((4-(2,2-dioxido-2-thia-1,3,7-triazaspiro[4.5]decan-7-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate [0751] The title compound was synthesized using Intermediate 3 according to the 3-step procedure described for example 709, except that for Step B NaH (3 equiv) in THF and stirring at 25 C. for 12 hours were used, to produce the desired compound as a white solid; .sup.1H NMR (400 MHz, METHANOL-d.sub.4) =9.08 (s, 1H), 7.68-7.65 (m, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.24 (t, J=9.2 Hz, 1H), 7.05 (t, J=2.4 Hz, 1H), 4.52-4.48 (m, 1H), 4.31-4.23 (m, 3H), 4.31 (s, 2H), 4.06-3.99 (m, 1H), 3.81-3.62 (s, 1H), 3.38-3.33 (s, 1H), 3.18-3.16 (m, 1H), 3.10-3.01 (s, 2H), 2.92-2.81 (m, 6H), 2.80-2.72 (m, 1H), 2.52-2.41 (m, 1H), 2.20-2.00 (m, 5H), 1.94-1.69 (m, 7H), 1.67-1.63 (m, 1H), 0.80 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=767.2. Example 717 ##STR00463## ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl ethylcarbamate ##STR00464## [0752] Step A. ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl ethylcarbamate: To a solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (100 mg, 1.0 equiv) and isocyanatoethane (53.5 mg, 5.0 equiv) in MeCN (2 mL) was added DABCO (5.07 mg, 0.3 equiv). The mixture was stirred at 20 C. for 12 hours. The mixture was filtered and washed with MeCN (1 mL). The filtrate was concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (90.0 mg, 81% yield) as a yellow solid; LCMS (ESI, M+1): m/z=735.5. [0753] Step B. ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl ethylcarbamate: To a solution of ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl ethylcarbamate (90.0 mg, 1.0 equiv) in MeOH (0.25 mL) was added HCl.Math.MeOH (4 M, 4.50 mL, 147 equiv). The mixture was stirred at 0 C. for 0.5 hour. The pH of the mixture was adjusted to 8 with with saturated NaHCO.sub.3 aqueous solution (3 mL) and extracted with ethyl acetate (35 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Waters Xbridge 15025 mm5 m; A: water (10 mM NH.sub.4HCO.sub.3), B: ACN; B %: 45%-75% over 9 min] and lyophilized to afford the title compound (22.9 mg, 27% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.20 (s, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 4.53 (br d, J=13.6 Hz, 1H), 4.37-4.21 (m, 3H), 4.10-3.93 (m, 2H), 3.71-3.55 (m, 1H), 3.53-3.41 (m, 1H), 3.12 (q, J=7.2 Hz, 2H), 3.08-2.96 (m, 2H), 2.89-2.79 (m, 1H), 2.56-2.38 (m, 1H), 2.27-2.11 (m, 3H), 2.07-1.99 (m, 1H), 1.97-1.84 (m, 4H), 1.83-1.73 (m, 4H), 1.72-1.62 (m, 1H), 1.29 (d, J=10.4 Hz, 3H), 1.09 (t, J=7.2 Hz, 3H), 0.88-0.76 (m, 3H); LCMS (ESI, M+1): m/z=691.5. Example 718 ##STR00465## ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl isopropylcarbamate [0754] The title compound was synthesized from Intermediate 18 according to the 2-step procedure described for example 717 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.20 (s, 1H), 7.67 (dd, J=5.6, 8.8 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 4.53 (br d, J=13.2 Hz, 1H), 4.36-4.20 (m, 3H), 4.07-3.92 (m, 2H), 3.76-3.56 (m, 2H), 3.53-3.41 (m, 1H), 3.11-2.95 (m, 2H), 2.90-2.78 (m, 1H), 2.55-2.41 (m, 1H), 2.27-2.12 (m, 3H), 2.08-1.99 (m, 1H), 1.98-1.84 (m, 4H), 1.83-1.72 (m, 4H), 1.72-1.62 (m, 1H), 1.29 (d, J=10.6 Hz, 3H), 1.12 (d, J=6.4 Hz, 6H), 0.81 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=705.5. Example 719 ##STR00466## ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl pyrrolidine-1-carboxylate [0755] The title compound was synthesized from Intermediate 18 according to the 2-step procedure described for example 706 to produce the desired compound as a white solid; SFC: Chiralcel OJ-3 504.6 mm I.D., 3 m, MeOH (0.05% DEA) in CO.sub.2 from 5% to 40% Flow rate: 3 mL/min, detector: 220 nm, t.sub.R1=1.461 min; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.20-9.00 (m, 1H), 7.60-7.44 (m, 1H), 7.24-7.12 (m, 2H), 7.04-6.92 (m, 1H), 4.56-4.32 (m, 3H), 4.20 (br d, J=10.4 Hz, 1H), 4.12-3.94 (m, 2H), 3.44-3.24 (m, 6H), 3.24-3.08 (m, 1H), 3.04-2.92 (m, 2H), 2.80-2.68 (m, 1H), 2.64-2.40 (m, 1H), 2.28-1.96 (m, 5H), 1.96-1.84 (m, 3H), 1.80-1.54 (m, 8H), 1.36-1.28 (m, 3H), 0.83 (td, J=7.4, 14.6 Hz, 3H); LCMS (ESI, M+1): m/z=717.5. Example 720 ##STR00467## N,N-dimethyl-(((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl)aminosulfonamide ##STR00468## [0756] Step A. (R)-1-(2-(((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A solution of ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (851.8 mg, 1.1 equiv), 4 MS (100 mg) and t-BuONa (545 mg, 3.0 equiv) in toluene (10 mL) was stirred at 0 C. for 10 mins. Then (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1.00 g, 1.0 equiv) was added into the mixture and the mixture was stirred at 0 C. for 1 hour. The reaction mixture was quenched with H.sub.2O (30 mL) at 0 C. and extracted with ethyl acetate (330 mL). Then the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reversed phase flash chromatography [C8, 0.1% formic acid condition]. The desired fractions were collected and neutralized with solid NaHCO.sub.3 and concentrated under vacuum to remove acetonitrile. The aqueous layer was extracted with ethyl acetate (3100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (1.2 g, 69% yield) as a yellow oil. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.20 (d, J=6.0 Hz, 1H), 7.79 (dd, J=6.0, 9.0 Hz, 1H), 7.74-7.66 (m, 4H), 7.62 (d, J=2.8 Hz, 1H), 7.44-7.34 (m, 6H), 7.31 (t, J=9.6 Hz, 1H), 7.22 (t, J=2.8 Hz, 1H), 5.33 (s, 2H), 4.50 (br d, J=13.2 Hz, 1H), 4.30-4.16 (m, 3H), 3.72-3.52 (m, 3H), 3.50 (s, 3H), 3.43-3.34 (m, 1H), 3.02-2.87 (m, 2H), 2.81-2.68 (m, 1H), 2.56-2.42 (m, 1H), 2.26-2.08 (m, 3H), 1.95-1.59 (m, 10H), 1.28-1.24 (m, 4H), 1.04 (d, J=1.2 Hz, 9H), 0.81 (td, J=7.2, 11.3 Hz, 3H); LCMS (ESI, M+1): m/z=902.4. [0757] Step B. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(hydroxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(2-(((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1.10 g, 1.0 equiv) in DMF (11 mL) was added CsF (2.80 g, 15.0 equiv). The mixture was stirred at 40 C. for 12 hours. The reaction mixture was filtered and the filtrate was collected. The crude product was purified by reversed phase flash chromatography [C8, 0.1% formic acid condition] to afford the title compound (690 mg, 82% yield) as a yellow solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.13 (s, 1H), 8.38 (s, 1H), 7.67 (dd, J=5.6, 8.8 Hz, 1H), 7.6 (d, J=2.8 Hz, 1H), 7.26-7.19 (m, 2H), 5.32-5.27 (m, 2H), 4.77-4.46 (m, 4H), 4.41 (br t, J=12.6 Hz, 1H), 3.95 (d, J=4.0 Hz, 2H), 3.72-3.58 (m, 2H), 3.56-3.41 (m, 4H), 3.33 (dt, J=4.8, 10.1 Hz, 1H), 3.21 (qd, J=5.6, 11.4 Hz, 1H), 2.54 (ddd, J=2.8, 6.8, 13.2 Hz, 2H), 2.25-2.07 (m, 7H), 1.96-1.85 (m, 2H), 1.80-1.62 (m, 2H), 1.38 (s, 3H), 0.85 (dt, J=4.8, 7.3 Hz, 3H); LCMS (ESI, M+1): m/z=664.4. [0758] Step C. tert-butyl (N,N-dimethylsulfamoyl) (((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl)carbamate: To a solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(hydroxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50.0 mg, 1.0 equiv) in THF (1.5 mL) was tert-butyl(N,N-dimethylsulfamoyl)carbamate (33.8 mg, 2.0 equiv), PPh.sub.3 (39.5 mg, 2.0 equiv) and DIAD (30.5 mg, 2.0 equiv) at 0 C. under N.sub.2. The mixture was stirred at 20 C. for 12 hours. The reaction mixture was concentrated and purified with prep-HPLC [C18, 0.1% formic acid condition] and lyophilized to afford the title compound (20 mg, 27.5% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) =9.24 (d, J=5.2 Hz, 1H), 7.90 (dd, J=6.0, 9.1 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.44 (t, J=9.6 Hz, 1H), 7.24 (d, J=2.8 Hz, 1H), 5.35 (s, 2H), 4.80-4.70 (m, 1H), 4.35 (br t, J=13.6 Hz, 1H), 4.19-3.98 (m, 3H), 3.67-3.49 (m, 3H), 3.44 (s, 3H), 2.96-2.84 (m, 2H), 2.81 (d, J=1.6 Hz, 6H), 2.69-2.64 (m, 1H), 2.42-2.31 (m, 1H), 2.24-2.10 (m, 1H), 2.07-1.96 (m, 2H), 1.95-1.86 (m, 1H), 1.84-1.76 (m, 3H), 1.75-1.52 (m, 7H), 1.45 (d, J=3.2 Hz, 9H), 1.20-1.15 (m, 4H), 0.75 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=870.4. [0759] Step D. N,N-dimethyl-(((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl)aminosulfonamide: To a solution of TFA (0.45 mL) in DCM (0.3 mL) was added a mixture of tert-butyl(N,N-dimethylsulfamoyl) (((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl)carbamate (15.0 mg, 1.0 equiv) in DCM (0.3 mL) at 0 C. The mixture was stirred at 25 C. for 2 hours. The pH of the reaction mixture was adjusted to pH=8 with 2 N NaOH aqueous solution, the resulting was extracted with DCM (3 mL3). The combined organic layers were concentrated. The residue was purified with prep-HPLC [C18, 0.1% TFA condition] and lyophilized to afford the title compound (10 mg, 78% yield, TFA salt) as a white solid. .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.25 (d, J=2.4 Hz, 1H), 8.45 (br s, 1H), 7.68 (dd, J=6.0, 8.9 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.07 (dd, J=2.4, 11.4 Hz, 1H), 4.64-4.49 (m, 3H), 4.32 (br t, J=13.6 Hz, 1H), 3.69-3.55 (m, 1H), 3.53-3.38 (m, 3H), 3.36-3.32 (m, 1H), 3.30-3.22 (m, 2H), 2.75 (d, J=1.2 Hz, 6H), 2.51-2.32 (m, 2H), 2.27-2.08 (m, 6H), 2.07-1.93 (m, 3H), 1.91-1.73 (m, 3H), 1.35-1.23 (m, 3H), 0.82 (dt, J=4.0, 7.2 Hz, 3H); .sup.19F NMR (376 MHz, methanol-d.sub.4) =77, 121, 139; LCMS (ESI, M+1): m/z=726.4. Example 721 ##STR00469## ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl piperidine-1-carboxylate [0760] The title compound was synthesized from Intermediate 18 according to the 2-step procedure described for example 706 to produce the desired compound as a white solid; SFC: Chiralpak IC-3 504.6 mm I.D., 3 m, 40% MeOH+ACN (0.05% DEA) in CO.sub.2 Flow rate: 3 mL/min, detector: 220 nm, t.sub.R1=1.409 min; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.25-9.03 (m, 1H), 7.64-7.44 (m, 1H), 7.24-7.08 (m, 2H), 7.08-6.80 (m, 1H), 4.64-4.28 (m, 3H), 4.24-4.12 (m, 1H), 4.12-3.76 (m, 2H), 3.56-3.24 (m, 7H), 3.20-2.92 (m, 2H), 2.88-2.64 (m, 1H), 2.64-2.40 (m, 1H), 2.32-1.96 (m, 5H), 1.94-1.64 (m, 9H), 1.62-1.56 (m, 2H), 1.36-1.16 (m, 5H), 0.88-0.76 (m, 3H); LCMS (ESI, M+1): m/z=731.5 Example 722 ##STR00470## 4-cyclohexyl-7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine ##STR00471## [0761] To a solution of 4-(cyclohex-1-en-1-yl)-7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (synthesized via the same procedure as described for Example 524) (10 mg, 1.0 equiv) in EtOAc (2 mL) was added Pd/C (20 mg) under H.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The mixture was stirred under H.sub.2 atmosphere (15 Psi) at 25 C. for 15 min. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 24%-54%, 10 min) to afford the title compound (5 mg, 49% yield, 99.6% purity) as a yellow solid (0.26 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.42 (s, 1H), 8.53 (br s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.53-7.47 (m, 1H), 7.45 (d, J=6.4 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 4.46 (s, 2H), 3.88-3.75 (m, 1H), 3.24-3.16 (m, 2H), 2.86-2.79 (m, 2H), 2.40-2.25 (m, 2H), 2.14 (dd, J=6.4, 12.4 Hz, 2H), 2.09-2.05 (m, 1H), 2.02-1.78 (m, 12H), 1.70-1.59 (m, 2H), 1.47-1.37 (m, 1H), 0.89 (t, J=7.2 Hz, 3H). LCMS (ESI, M+1): m/z=525.3. Example 723 ##STR00472## rac-(R)-7-(8-ethylnaphthalen-1-yl)-8-fluoro-4-(oxepan-4-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine ##STR00473## [0762] Step A. 2,3,4,7-tetrahydrooxepin-5-yl trifluoromethanesulfonate: To a solution of oxepan-4-one (200 mg, 1.0 equiv) in THF (3 mL) was added LDA (2 M, 1 mL, 1.2 equiv) at 78 C. under nitrogen atmosphere. The mixture was stirred at 78 C. for 0.5 hour. Then a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (626 mg, 1.0 equiv) in THF (1 mL) was added. The resulting reaction mixture was stirred at 20 C. for 16 hours. The mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with EtOAc (10 mL2). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 20:1 to 3:1) to afford the title compound (150 mg, mixture) as a light yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.46-7.38 (m, 2H), 7.36-7.27 (m, 3H), 6.76 (br s, 1H), 5.98 (t, J=6.0 Hz, 1H), 5.83 (t, J=4.4 Hz, 1H), 4.25-4.16 (m, 1H), 3.85 (t, J=5.6 Hz, 1H), 3.79 (t, J=5.2 Hz, 2H), 2.74 (t, J=5.2 Hz, 1H), 2.70-2.62 (m, 1H), 2.37 (q, J=5.4 Hz, 1H), 1.99 (td, J=5.9, 11.8 Hz, 1H) [0763] Step B. trimethyl (2,3,6,7-tetrahydrooxepin-4-yl) stannane: To a solution of 2,3,6,7-tetrahydrooxepin-4-yl trifluoromethanesulfonate (100 mg, 1.0 equiv) and trimethyl(trimethylstannyl) stannane (146 mg, 1.1 equiv) in THF (2 mL) was added Pd(PPh.sub.3).sub.4 (46.9 mg, 0.1 equiv) and LiCl (51.6 mg, 3.0 equiv). The mixture was stirred at 60 C. for 16 hours under nitrogen atmosphere. The mixture was filtered. The filtrate was diluted with EtOAc (30 mL) and quenched by KF aqueous solution (50 mL). The mixture was filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 100:1 to 10:1) to afford the title compound (50.0 mg, 47% yield, mixture) as a light yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.38-7.30 (m, 13H), 6.05-5.85 (m, 1H), 4.20-4.16 (m, 2H), 3.87 (t, J=5.6 Hz, 2H), 3.70-3.60 (m, 2H), 2.54-2.48 (m, 2H), 2.45-2.38 (m, 1H), 1.83 (td, J=5.6, 11.4 Hz, 2H), 0.14-0.09 (m, 8H) [0764] Step C. 7-(8-ethylnaphthalen-1-yl)-8-fluoro-4-(methylthio)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.00 g, 1.0 equiv) in DCM (20 mL) was added NaSMe (233 mg, 1.8 equiv). The mixture was stirred at 20 C. for 16 hours. The mixture was filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 0:1) to afford the title compound (650 mg, 72% yield) as a light yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.23-9.16 (m, 1H), 7.99 (dd, J=1.2, 8.1 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.56-7.50 (m, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.43 (dd, J=1.2, 7.2 Hz, 1H), 7.37 (d, J=7.2 Hz, 1H), 4.36 (s, 2H), 3.19-3.08 (m, 2H), 2.80 (s, 3H), 2.67 (td, J=6.8, 10.2 Hz, 3H), 2.45-2.25 (m, 3H), 2.09 (br dd, J=6.2, 12.5 Hz, 3H), 1.90 (quin, J=6.5 Hz, 5H), 1.70 (td, J=7.5, 12.6 Hz, 3H), 1.01-0.88 (m, 4H) [0765] Step D. 7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydrooxepin-4-yl)pyrido[4,3-d]pyrimidine: To a solution of 7-(8-ethylnaphthalen-1-yl)-8-fluoro-4-(methylthio)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (50.0 mg, 1.0 equiv) and trimethyl (2,3,6,7-tetrahydrooxepin-4-yl) stannane (48.1 mg, 1.8 equiv, mixture) in THF (2 mL) was added tris(2-furyl)phosphane (7.13 mg, 0.3 equiv), thiophene-2-carbonyloxycopper (29.3 mg, 1.5 equiv) and Pd.sub.2(dpa).sub.3 (9.37 mg, 0.1 equiv). The mixture was stirred at 60 C. for 16 hours under nitrogen atmosphere. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 0:1) to afford the title compound (45.0 mg, 80.6% yield, 98.8% purity, mixture) as a light yellow oil; LCMS (ESI, M+1): m/z=539.1. [0766] Step E. rac-(R)-7-(8-ethylnaphthalen-1-yl)-8-fluoro-4-(oxepan-4-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydrooxepin-4-yl)pyrido[4,3-d]pyrimidine (35.0 mg, 1.0 equiv) in EtOAc (1.5 mL) was added Pd/C (30.0 mg, 10% purity, wet). The mixture was stirred at 20 C. for 3 hours under H.sub.2 atmosphere (15 psi). The mixture was diluted with EtOAc (10 mL) and filtered. The filtrate was concentrated. The residue was purified by prep-HPLC [Phenomenex Synergi C18 15025 mm10 um; A: water (FA), B: ACN, B %: 26%-46% over 10 min] and lyophilized to afford the title compound (3.24 mg, 8.8% yield, 95.9% purity) as a white solid (0.45 formic acid salt); .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.32 (s, 1H), 8.36 (br s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.56-7.51 (m, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.41 (dd, J=6.8, 15.3 Hz, 2H), 4.82-4.69 (m, 2H), 4.07-3.88 (m, 4H), 3.82-3.72 (m, 3H), 3.01-2.89 (m, 2H), 2.49-2.31 (m, 5H), 2.23 (br dd, J=6.6, 12.7 Hz, 4H), 2.17-2.05 (m, 3H), 2.04-1.90 (m, 4H), 0.97 (br t, J=7.6 Hz, 3H); LCMS (ESI, M+1): m/z=541.3. Example 724 ##STR00474## (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00475## [0767] Step A. 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and Cs.sub.2CO.sub.3 (1.50 M, 1.37 mL, 3.0 equiv) in methoxycyclopentane (8 mL) were added AdanBuP-Pd-G3 (49.8 mg, 0.1 equiv) and 4,4,5,5-tetramethyl-2-(1-naphthyl)-1,3,2-dioxaborolane (261 mg, 1.5 equiv). The mixture was stirred at 100 C. for 3 hours. The reaction mixture was diluted with water (10 mL). The aqueous was extracted with EtOAc (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (180 mg, 47% yield) as a yellow solid; LCMS (ESI, M+1): m/z=531.2. [0768] Step B. (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) in DMF (0.3 mL) were added DIPEA (73.1 mg, 3.0 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (36.0 mg, 1.5 equiv). The mixture was stirred at 40 C. for 12 hours. The reaction mixture was filtered, concentrated and purified by prep-HPLC [Phenomenex luna C18 Ultra 15025 mm10 m; A: water (10 mM FA), B: ACN, B %: 15%-45% over 10 min] and lyophilized to afford the title compound (58.1 mg, 51% yield, 0.8FA) as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.32 (s, 1H), 8.08-8.02 (m, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.71-7.61 (m, 3H), 7.57-7.51 (m, 1H), 7.50-7.44 (m, 1H), 5.58-5.39 (m, 1H), 4.98-4.91 (m, 1H), 4.84-4.78 (m, 1H), 4.61-4.48 (m, 2H), 4.38-4.29 (m, 1H), 3.86-3.59 (m, 4H), 3.55-3.45 (m, 1H), 3.36-3.26 (m, 1H), 2.67-2.38 (m, 3H), 2.36-2.18 (m, 5H), 2.14-2.03 (m, 1H), 1.98-1.88 (m, 1H), 1.86-1.74 (m, 1H), 1.44-1.31 (m, 1H); LCMS (ESI, M+1): m/z=558.2. Example 725 ##STR00476## 3-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00477## [0769] Step A. 3-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a mixture of 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv), 3-azabicyclo[3.2.1]octan-6-ol (52 mg, 2.5 equiv) in DMF (0.6 mL) was added DIPEA (42.0 mg, 2.0 equiv) and 4 molecular sieves (10 mg). The mixture was stirred at 40 C. for 13 hours. The mixture was filtered, concentrated and purified with reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile=3/1] to afford the tittle compound (97 mg, 90% yield) as a light yellow solid; LCMS (ESI, M+1): m/z=642.5. [0770] Step B. 3-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 3-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (95 mg, 1.0 equiv) in DCM (1 mL) was added TFA (1.5 mL) dropwise at 0 C. The mixture was stirred at 25 C. for 1 hour. The mixture was poured into DCM (10 mL) and saturated NaHCO.sub.3 aqueous (20 mL) at 0 C. The pH of the mixture was adjusted to 9 with solid Na.sub.2CO.sub.3 below 10 C. The mixture was extracted with DCM (45 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified with prep-HPLC [column: Phenomenex Synergi C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 9%-39%, 10 minutes] to afford the tittle compound (38.3 mg, 46% yield, 0.42FA) as a white solid; .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.34 (br d, J=5.5 Hz, 1H), 7.59 (br d, J=9.2 Hz, 1H), 7.51 (s, 1H), 5.00-4.92 (m, 2H), 4.85-4.72 (m, 1H), 4.34 (br dd, J=4.8, 10.4 Hz, 1H), 3.80 (br dd, J=13.6, 16.0 Hz, 1H), 3.64-3.43 (m, 3H), 3.23-3.07 (m, 2H), 2.51 (s, 3H), 2.41 (br s, 1H), 2.36-1.88 (m, 15H), 1.87-1.77 (m, 1H), 1.42-1.32 (m, 1H); LCMS (ESI, M+1): m/z=558.4. Example 726 ##STR00478## 5-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione [0771] The title compound was synthesized from Intermediate 19 according to the 2-step procedure described for example 725 to produce the desired compound as a white solid (0.52 formic acid salt); .sup.1H NMR (400 MHZ, methanol-d4) =9.37 (s, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 4.71-4.61 (m, 2H), 4.44-4.29 (m, 2H), 3.84-3.69 (m, 2H), 3.58-3.47 (m, 2H), 3.18-3.08 (m, 2H), 2.51 (s, 3H), 2.32-1.95 (m, 13H); LCMS (ESI, M+1): m/z=571.4. Example 727 ##STR00479## 6-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol ##STR00480## [0772] Step A. 6-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol: To a mixture of 7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (0.9 g, 1.0 equiv), 6-azaspiro[3.5]nonan-2-ol (604 mg, 1.6 equiv, HCl) in DMF (5 mL) were added DIPEA (1.93 g, 7.0 equiv) and 4 molecular sieves (100 mg). The mixture was stirred at 40 C. for 18 hours under N.sub.2 atmosphere. The mixture was filtered and purified by reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile 4:1 to 3:1] to afford the title compound (380 mg, 38% yield) as a yellow oil. [0773] Step B. 6-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol: To a solution of 6-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (135 mg, 1.0 equiv), 5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (115 mg, 1.1 equiv), K.sub.3PO.sub.4 (1.5 M, 585 L, 3.0 equiv) in CPME (2.5 mL) was added CataCXium A Pd G3 (213 mg, 1.0 equiv) under N.sub.2. The mixture was stirred at 90 C. for 1.5 hours under N.sub.2. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The organic layer was washed with brine (10 mL) and dried over Na.sub.2SO.sub.4. The solvent was concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (30.0 mg, 16% yield) as a yellow oil; LCMS (ESI, M+1): m/z=656.5 [0774] Step C. 6-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol: To a solution of 6-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (95.0 mg, 1.0 equiv) in DCM (1 mL) was added TFA (1.54 g, 93 equiv) at 20 C. The mixture was stirred at 20 C. for 1 hour. The mixture was poured into DCM (10 mL) and saturated NaHCO.sub.3 aqueous (20 mL) at 0 C. The pH of the mixture was adjusted to 9 with solid Na.sub.2CO.sub.3 below 10 C. The mixture was extracted with DCM (210 mL). The organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep-HPLC [column: Unisil 3-100 C18 Ultra 15050 mm3 m; A: water (FA), B: ACN, B %: 8%-38% over 7 minutes] and prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (10 mM NH.sub.4HCO.sub.3), B: ACN, B %: 27%-57% over 8 minutes] to afford the title compound (16.1 mg, 19% yield) as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.19 (d, J=6.4 Hz, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 4.68 (d, J=7.2 Hz, 1H), 4.58 (s, 1H), 4.74-4.55 (m, 1H), 4.31 (br d, J=8.3 Hz, 1H), 4.13 (s, 1H), 4.11-3.98 (m, 3H), 3.76-3.63 (m, 2H), 3.29-3.23 (m, 1H), 2.52 (s, 3H), 2.43-2.28 (m, 3H), 2.26-1.98 (m, 10H), 1.84 (br s, 6H); LCMS (ESI, M+1): m/z=572.4. Example 728 ##STR00481## 7-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione [0775] The title compound was synthesized from Intermediate 19 according to the 2-step procedure described for example 725 to produce the desired compound as a white solid; white solid (0.54 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d4) =9.22 (s, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 4.65 (br d, J=13.2 Hz, 1H), 4.60-4.51 (m, 2H), 4.52-4.44 (m, 1H), 3.91-3.77 (m, 2H), 3.62-3.52 (m, 2H), 3.20-3.12 (m, 2H), 2.51 (s, 3H), 2.32-2.25 (m, 2H), 2.22 (s, 3H), 2.19-2.09 (m, 5H), 2.07-1.94 (m, 5H); LCMS (ESI, M+1): m/z=600.3. Example 729 ##STR00482## 7-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one [0776] The title compound was synthesized from Intermediate 19 according to the 2-step procedure described for example 725 to produce the desired compound as a white solid (0.54 formic acid salt); .sup.1H NMR (400 MHZ, methanol-d4) =9.22-9.18 (m, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 4.63-4.55 (m, 1H), 4.52-4.43 (m, 2H), 4.35-4.09 (m, 1H), 4.06-3.78 (m, 2H), 3.58-3.36 (m, 3H), 3.10-3.06 (m, 2H), 2.51 (s, 3H), 2.39-2.15 (m, 5H), 2.14-1.85 (m, 10H); LCMS (ESI, M+1): m/z=586.4. Example 730 ##STR00483## 5-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [0777] The title compound was synthesized according to the 3-step procedure described for example 727 to produce the desired compound as a yellow solid (0.21 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.31 (s, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 6.78 (s, 1H), 5.28 (s, 2H), 4.61 (s, 2H), 4.55-4.47 (m, 4H), 3.72-3.59 (m, 2H), 3.35 (s, 3H), 3.28-3.21 (m, 2H), 3.09 (s, 3H), 2.51 (s, 3H), 2.47 (br d, J=4.4 Hz, 2H), 2.36-2.28 (m, 2H), 2.22 (s, 4H), 2.20-2.13 (m, 3H), 2.12-2.04 (m, 2H); LCMS (ESI, M+1): m/z=639.5. Example 731 ##STR00484## (5R)-7-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione ##STR00485## [0778] Step A: 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (0.50 g, 1.14 mmol, 1.0 equiv) in CPME (6.0 mL) was added CataCXium A Pd G3 (83.0 mg, 0.1 equiv), 5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (528 mg, 1.3 equiv) and Cs.sub.2CO.sub.3 (1.0 M, 3.0 mL, 2.6 equiv). The mixture was stirred at 80 C. for 4 hours. The mixture was quenched with H.sub.2O (10 mL) and extracted with EtOAc (330 mL). The combined organic layer was washed with brine (350 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (370 mg, 51% yield) as a yellow solid; LCMS (ESI, M+1): 633.4. [0779] Step B. 7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (250 mg, 1.0 equiv) in dichloromethane (1.0 mL) was added TFA (1.54 g, 1.0 mL). The mixture was stirred at 015 C. for 16 hours. The mixture was quenched by addition of H.sub.2O (10 mL) and extracted with ethyl acetate (330 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford the title compound (110 mg, 50%) as a yellow solid; LCMS (ESI, M+1): 549.3. [0780] Step C. (5R)-7-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of 7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (110 mg, 1.0 equiv) in DMF (0.2 mL) was added DIPEA (77.8 mg, 3.0 equiv), 4 MS (20.0 mg) and (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (40.7 mg, 1.2 equiv). The mixture was stirred at 40 C. for 16 hours. The mixture was filtered. The filtrate was concentrated. The residue was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (51.4 mg, 39% yield) as a white solid (0.41 formic acid salt); column: Chiralcel OJ-3 504.6 mm I.D., 3 m, mobile phase: 40% [MeOH+0.05% DEA] in CO.sub.2, flow rate: 3 mL/min, detector: 220 nm, tR: 1.429 min; .sup.1H NMR (400 MHZ, Methanol-d4) 9.20 (d, J=1.6 Hz, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 5.52-5.28 (m, 1H), 4.66 (br d, J=13.6 Hz, 1H), 4.54-4.39 (m, 3H), 3.81 (br d, J=13.6 Hz, 2H), 3.65-3.40 (m, 3H), 3.19 (br dd, J=4.0, 9.2 Hz, 1H), 2.51 (s, 3H), 2.49-2.19 (m, 7H), 2.17-1.92 (m, 6H); LCMS (ESI, M+1): m/z=618.4. Example 732 ##STR00486## (5R)-7-(7-(5,6-dimethyl-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione ##STR00487## [0781] Step A. 1-(1-(((7-chloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine: To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (5.0 g, 1.0 equiv), DIPEA (6.13 g, 3.0 equiv) and 4 molecular sieves (1.00 g) in THF (50 mL) was added (1-((dimethylamino)methyl)cyclopropyl)methanol (1.84 g, 0.9 equiv) at 40 C. The mixture was stirred at 40 C. for 0.5 hour. The mixture was diluted with water (50 mL) and extracted with EtOAc (350 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (2.20 g, 34% yield) as a yellow solid; LCMS (ESI, M+1): m/z=409.1. [0782] Step B. 1-(1-(((7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine: To a mixture of 1-(1-(((7-chloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine (1.0 g, 1.0 equiv), 5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.31 g, 1.5 equiv) and Cs.sub.2CO.sub.3 (1.5 M, 4.89 mL, 3.0 equiv) in methoxycyclopentane (10 mL) was added Ad.sub.2nBuP-Pd G3 (178 mg, 0.1 equiv). The mixture was stirred at 90 C. for 3 hours under N.sub.2. The mixture was diluted with water (10 mL) and extracted with EtOAc (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (950 mg, 63% yield) as a light-yellow solid; LCMS (ESI, M+1): m/z=603.3. [0783] Step C. (5R)-7-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a mixture of 1-(1-(((7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine (150 mg, 1.0 equiv), (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (84.2 mg, 2.0 equiv) and 4 molecular sieves (20 mg) in DMF (1 mL) was added DIPEA (96.5 mg, 3.0 equiv). The mixture was stirred at 50 C. for 12 hours. The residue was filtered and washed with DMF (1 mL) and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 57% yield) as a yellow solid; LCMS (ESI, M/2+1): m/z=672.4. [0784] Step D. (5R)-7-(7-(5,6-dimethyl-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of (5R)-7-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.0 equiv) in DCM (0.5 mL) was added TFA (2.31 g, 272 equiv) at 0 C. The mixture was stirred at 20 C. for 12 hours. The pH of the mixture was adjusted to 8 with saturated NaHCO.sub.3 aqueous solution (5 mL) and the resulting was extracted with EtOAc (35 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex C18 7530 mm3 m; A: water (FA), B: ACN; B %: 8%-38% over 7 min] and lyophilized to afford the title compound (9.28 mg, 21% yield) as a white solid (0.40 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.20 (d, J=1.2 Hz, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 4.63 (br d, J=13.6 Hz, 1H), 4.54-4.34 (m, 3H), 3.88-3.73 (m, 2H), 2.96-2.77 (m, 2H), 2.63 (br s, 6H), 2.51 (s, 3H), 2.32-2.24 (m, 1H), 2.22 (s, 3H), 2.15-2.07 (m, 1H), 2.06-1.90 (m, 2H), 0.86 (s, 2H), 0.69 (br s, 2H); LCMS (ESI, M+1): m/z=588.5. Example 733 ##STR00488## 4-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one ##STR00489## [0785] Step A. 4-bromo-5,6-dimethyl-1H-benzo[d]imidazol-2(3H)-one: To a solution of 3-bromo-4,5-dimethylbenzene-1,2-diamine (500 mg, 1.0 equiv) in tetrahydrofuran (10 mL) was added CDI (301 mg, 0.8 equiv). The mixture was stirred at 25 C. for 12 hours. The mixture was filtered. The filter cake was washed with H.sub.2O (20 ml). The solid was dried under reduced pressure to afford the tittle compound (200 mg, 36% yield) as a a white solid; LCMS (ESI, M+1, M+3): m/z=241.0, 243.0. [0786] Step B. 5,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one: To a solution of 4-bromo-5,6-dimethyl-1H-benzo[d]imidazol-2(3H)-one (200 mg, 1.0 equiv) and 4,4,4,4,5,5,5,5-octamethyl-2,2-bi (1,3,2-dioxaborolane) (527 mg, 2.5 equiv) in dioxane (5 mL) was added KOAc (244 mg, 3.0 equiv) and PCy.sub.3 Pd G2 (49.0 mg, 0.1 equiv). The mixture was stirred at 80 C. for 16 hours. The mixture was quenched by addition of water (2 mL) and then extracted with ethyl acetate (35 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 5:1 to 1:1) to afford the title compound (110 mg, 41% yield) as a white solid; LCMS (ESI, M+1): m/z=289.2 [0787] Step C. 4-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one: To a solution of (R)-1-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50.0 mg, 1.0 equiv) and 5,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (39.6 mg, 1.2 equiv) in tetrahydrofuran (1.6 mL) and H.sub.2O (0.4 mL) was added AdanBup-Pd-G3 (8.35 mg, 0.1 equiv) and K.sub.3PO.sub.4 (73.0 mg 3.0 equiv). The mixture was stirred at 60 C. for 12 hours. The mixture was diluted with water (2 mL) and then extracted with ethyl acetate (35 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA); B: ACN, B %: 10%-40%, over 10 min] and lyophilized to afford the title compound (5.38 mg, 9.0% yield) as a yellow solid (0.81 formic acid salt); SFC: Chiralpak IC-3 504.6 mm I.D., 3 m, 40% 50% MeOH+ACN (0.05% DEA) in CO.sub.2 Flow rate: 3 mL/min, detector: 220 nm, t.sub.R1=0.900 min, t.sub.R2=1.793 min; .sup.1H NMR (400 MHz, METHANOL-d4) =9.29 (br s, 1H), 8.54 (s, 1H), 8.96-8.40 (m, 1H), 7.02 (s, 1H), 4.68-4.52 (m, 3H), 4.40-4.32 (m, 1H), 3.68-3.52 (m, 3H), 3.48-3.36 (m, 1H), 3.28-3.08 (m, 2H), 2.37 (s, 3H), 2.32-2.24 (m, 2H), 2.24-2.12 (m, 4H), 2.12-2.08 (m, 3H), 2.08-1.96 (m, 3H), 1.91 (br s, 3H), 1.30 (s, 3H); LCMS (ESI, M+1): m/z=562.2. Example 734 ##STR00490## (3R)-1-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00491## [0788] Step A. 4-bromo-5,6-dimethyl-1H-benzo[d][1,2,3]triazole: To a mixture of 5,6-dimethyl-1H-benzo[d][1,2,3]triazole (1.00 g, 1.0 equiv) in AcOH (10 mL) was added a solution of Br.sub.2 (1.52 g, 1.4 equiv) in AcOH (10 mL) at 50 C. The mixture was stirred at 50 C. for 1 hour. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated and purified by reversed-phase flash chromatography (C18, 0.1% FA condition) to afford the title compound (500 mg, 32% yield) as a white solid; LCMS (ESI, M+1, M+3): m/z=225.9, 227.9. [0789] Step B. 4-bromo-5,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole: To a solution of 4-bromo-5,6-dimethyl-1H-benzo[d][1,2,3]triazole (300 mg, 1 equiv) in THF (9 mL) was added NaH (106 mg, 60% purity, 2.0 equiv) at 0 C. portionwise. The mixture was stirred at 0 C. for 0.5 hour. Then to the mixture was added SEM-Cl (332 mg, 1.5 equiv) at 0 C. The mixture was stirred at 0 C. for 1 hour and then quenched with water (20 mL) at 0 C. and extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate, concentrated to afford the title compound (245 mg, crude) as a yellow oil. [0790] Step C. 5,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole; A mixture of 4-bromo-5,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (130 mg, 1.0 equiv), BIS(PINACOLATO)DIBORON (232 mg, 2.5 equiv) and KOAc (130 mg, 3.6 equiv) in dioxane (3 mL) was degassed and purged with N.sub.2 for 3 times. PCy.sub.3 Pd G2 (21.5 mg, 0.1 equiv) was added and the mixture was stirred at 80 C. for 12 hours under N.sub.2 atmosphere. The mixture was diluted with sat. aq. NaHCO.sub.3 (12 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, concentrated to afford the title compound (257 mg, crude) as a white solid. [0791] Step F. (3R)-1-(7-(5,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A mixture of (R)-1-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (100 mg, 1.0 equiv), 5,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (278 mg, 3.0 equiv), cataCXium A Pd G3 (16.7 mg, 0.1 equiv) and K.sub.3PO.sub.4 (1.5 M, 459 L, 3.0 equiv) in methoxycyclopentane (10 mL) was degassed under vacuum and stirred at 90 C. for 2 hours. The mixture was diluted with H.sub.2O (15 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, concentrated and purified by reversed-phase flash chromatography (C18, 0.1% FA condition) to afford the title compound (25 mg, 7.2% yield) as a yellow solid; LCMS (ESI, M+1): m/z=677.3. [0792] Step G. (3R)-1-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(7-(5,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (23.0 mg, 1.0 equiv) in DCM (2 mL) was added TFA (1.54 g, 397 equiv) at 25 C. The mixture was stirred at 25 C. for 0.5 hour. The mixture was concentrated under vacuum. The residue was purified by prep-HPLC (Phenomenex Synergi C18 15025 mm10 um; mobile phase: A: water (FA), B: ACN; B %: 4% to 34% over 10 min) to afford the title compound (5.80 mg, 30% yield) as a yellow solid (0.80 formic acid salt); .sup.1H NMR (400 MHz, CHLOROFORM-d) =9.48-9.24 (m, 1H), 7.87 (s, 1H), 4.92-4.74 (m, 1H), 4.66 (br s, 2H), 4.34-4.19 (m, 1H), 3.85-3.68 (m, 2H), 3.12-2.81 (m, 4H), 2.66-2.49 (m, 1H), 2.42-2.31 (m, 4H), 2.30-2.07 (m, 5H), 2.05-1.73 (m, 7H), 1.71-1.58 (m, 1H), 1.30 (s, 3H); LCMS (ESI, M+1): m/z=547.4. Example 735 ##STR00492## (R)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00493## [0793] Step A. (R)-1-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-3-methylpiperidin-3-ol hydrochloride (540 mg, 3.0 equiv) in DMF (3.0 mL) was added DIPEA (768 mg, 5.0 equiv) and 7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1.0 equiv). The mixture was stirred at 40 C. for 16 hours. The mixture was diluted with water (20 mL) and then extracted with DCM (230 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography (C18, 0.1% formic acid condition) to afford the title compound (177 mg, 92% yield) as a white solid. LCMS (ESI, M+1): m/z=436.2. [0794] Step B. (R)-tert-butyl (7-fluoro-4-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate: A mixture of (R)-1-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (177 mg, 1.0 equiv), [2-(tert-butoxycarbonylamino)-7-fluoro-1,3-benzothiazol-4-yl]boronic acid (152 mg, 1.2 equiv), K.sub.3PO.sub.4 (1.5 M, 3.0 equiv) and Xphos Pd G4(34.9 mg, 0.1 equiv) in DMAc (4 mL) was degassed and stirred at 60 C. for 48 hours under N.sub.2 atmosphere. The mixture was diluted with water (20 mL) and then extracted with DCM (230 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography (C18, 0.1% formic acid condition) to afford the title compound (73.0 mg, 26% yield) as a white solid; LCMS (ESI, M+1): m/z=668.4 [0795] Step C. (R)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: The mixture of (R)-tert-butyl (7-fluoro-4-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate (68.0 mg, 1.0 equiv) in HCl.Math.MeOH (4 M, 6 mL) was stirred at 25 C. for 2.5 hours. The reaction mixture was concentrated and purified by prep-HPLC [column: Unisil 3-100 C18 Ultra 15050 mm3 m; A: water (FA), B: ACN, B %: 13%-43% over 7 min] to afford the title compound (13.0 mg, 22% yield) as a yellow solid (0.75 formic acid salt). SFC analysis: Chiralcel OD-3 504.6 mm I.D., 3 m Mobile phase: Phase A for CO.sub.2, and Phase B for MeOH+ACN (0.05% DEA); Gradient elution: 40% MeOH+ACN (0.05% DEA) in CO.sub.2. Flow rate: 3 mL/min; Detector: PDA; Column Temp: 35C; Back Pressure: 100 Bar. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.23 (s, 1H), 7.52-7.44 (m, 1H), 7.09-6.95 (m, 1H), 4.65-4.52 (m, 3H), 4.30 (br d, J=13.2 Hz, 1H), 3.65-3.55 (m, 3H), 3.41 (br t, J=11.2 Hz, 1H), 3.25-3.16 (m, 2H), 2.33-2.24 (m, 2H), 2.23-2.08 (m, 5H), 2.07-1.97 (m, 2H), 1.91-1.82 (m, 1H), 1.82-1.70 (m, 2H), 1.28 (s, 3H); LCMS (ESI, M+1): m/z=568.3. Example 736 ##STR00494## 7-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione [0796] The title compound was synthesized from 7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine according to the 3-step procedure described for example 735 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, methanoL-d4) =9.14 (s, 1H), 7.49 (dd, J=5.6, 8.4 Hz, 1H), 7.03 (t, J=8.8 Hz, 1H), 4.70-4.59 (m, 3H), 4.50-4.39 (m, 1H), 3.98-3.61 (m, 4H), 3.36-3.32 (m, 1H), 3.29-3.21 (m, 1H), 2.32-1.99 (m, 12H); LCMS (ESI, M+1): m/z=622.3. Example 737 ##STR00495## (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00496## [0797] Step A. 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.0 g, 1.0 equiv) and 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (859 mg, 1.2 equiv) in methoxycyclopentane (50 mL) was added Ad.sub.2nBuP-Pd-G3 (166 mg, 0.1 equiv) and Cs.sub.2CO.sub.3 (1.5 M, 3.0 equiv). Then the mixture was stirred at 100 C. for 6 hours under N.sub.2. The reaction mixture was diluted with H.sub.2O (25 mL) and extracted with EtOAc (325 mL). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated and purified by prep-HPLC [C18, 0.1% NH.sub.3.Math.H.sub.2O condition] to afford the title compound (540 mg, 38% yield) as a yellow solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.27 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.60-7.48 (m, 2H), 7.42 (d, J=2.0 Hz, 1H), 7.39-7.32 (m, 1H), 5.52-5.11 (m, 5H), 4.35-4.12 (m, 2H), 3.45 (s, 3H), 3.17-3.00 (m, 3H), 2.92-2.78 (m, 1H), 2.22-2.00 (m, 3H), 1.93-1.74 (m, 3H); LCMS (ESI, M+1): m/z=591.2. [0798] Step B. (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (83.1 mg, 1.5 equiv, HCl) in DMF (0.6 mL) was added DIPEA (219 mg, 5.0 equiv) and 4 molecular sieves (80 mg). Then the mixture was stirred at 60 C. for 12 hours. The mixture was filtered and concentrated under reduced pressure. The crude product was purified with prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (130 mg, 57% yield) as a yellow solid; LCMS (ESI, M+1): m/z=618.3. [0799] Step C. (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: A solution of (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (20.0 mg, 1.0 equiv) in HCl.Math.MeOH (4 M, 1 mL, 123 equiv) was stirred at 0 C. for 2 hours. The mixture was concentrated under reduced pressure. Then the residue was dissolved in MeCN (5 mL). The pH was adjusted to 7 with solid NaHCO.sub.3. The mixture was filtered and concentrated under reduced pressure. The crude product was purified with prep-HPLC [Phenomenex Synergi C18 15025 mm10 m; A: water (FA), B: ACN; B %: 10%-40% over 10 min] to afford the title compound (7.0 mg, 37% yield, 0.33FA) as a white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.39 (s, 1H), 8.18 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.52 (br d, J=8.0 Hz, 1H), 7.44 (t, J=7.2 Hz, 1H), 7.32-7.19 (m, 3H), 5.42-5.17 (m, 1H), 4.87-4.51 (m, 3H), 4.25-4.09 (m, 2H), 4.03 (dd, J=4.0, 10.4 Hz, 1H), 3.72 (br d, J=12.4 Hz, 1H), 3.40-3.35 (m, 1H), 3.35 (br d, J=12.0 Hz, 1H), 3.13-3.05 (m, 2H), 3.02 (s, 1H), 2.90-2.75 (m, 1H), 2.33 (br d, J=1.6 Hz, 1H), 2.19-2.11 (m, 2H), 2.10-1.97 (m, 3H), 1.89-1.81 (m, 1H), 1.77 (br d, J=9.2 Hz, 3H), 1.70-1.60 (m, 1H), 1.26 (br d, J=14.4 Hz, 1H); LCMS (ESI, M+1): m/z=574.3. Example 738 ##STR00497## (1S,5S,6R)-3-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00498## [0800] Step A. 3-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) in DMF (1 mL) and ACN (1 mL) were added 3-azabicyclo[3.2.1]octan-6-ol (25.6 mg, 1.2 equiv) and K.sub.3PO.sub.4 (107 mg, 3.0 equiv). The reaction was stirred at 40 C. for 16 hours under nitrogen atmosphere. The reaction mixture was poured into saturated NH.sub.4Cl aqueous solution (5 mL) and extracted with EtOAc (2 mL3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated to afford the title compound (100 mg, crude) as a yellow oil; LCMS (ESI, M+1): m/z=624.5. [0801] Step B. (1S,5S,6R)-3-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 3-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (80.0 mg, 1.0 equiv) in ACN (1 mL) was added HCl/dioxane (4 M, 3 mL, 93.6 equiv). The mixture was stirred at 25 C. for 0.5 hour. The reaction mixture was filtered, concentrated and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 um; A: water (FA), B: ACN, B %: 13%-43% over 10 min] to afford the title compound (18.5 mg, 22% yield, (0.7 formic acid salt)) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.19 (s, 1H), 8.47 (s, 1H), 6.91 (d, J=2.8 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 4.73 (d, J=12.4 Hz, 1H), 4.49 (s, 2H), 4.29-4.21 (m, 1H), 3.71 (d, J=12.0 Hz, 1H), 3.56-3.48 (m, 2H), 3.43 (d, J=12.8 Hz, 1H), 3.15-3.07 (m, 2H), 2.37-2.32 (m, 1H), 2.28-2.16 (m, 4H), 2.16-2.00 (m, 5H), 2.00-1.92 (m, 2H), 1.90-1.85 (m, 1H), 1.80-1.73 (m, 2H), 1.33-1.25 (m, 1H), 0.55 (s, 2H), 0.00 (s, 2H); LCMS (ESI, M+1): m/z=580.3. Example 739 ##STR00499## 7-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione [0802] The title compound was synthesized according to the 2-step procedure described for example 738 to produce the desired compound as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.15 (s, 1H), 6.98 (d, J=2.6 Hz, 1H), 6.82-6.80 (m, 1H), 4.61-4.57 (m, 3H), 4.48-4.41 (m, 1H), 3.89-3.81 (m, 2H), 3.68-3.62 (m, 2H), 3.27-3.20 (m, 2H), 2.34-2.26 (m, 3H), 2.18 (dt, J=6.1, 12.8 Hz, 5H), 2.10-2.06 (m, 2H), 2.02-1.92 (m, 2H), 1.88-1.81 (m, 1H), 0.67-0.56 (m, 2H), 0.07 (br s, 2H); LCMS (ESI, M+1): m/z=622.3. Example 740 ##STR00500## rac-(R)-4-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol ##STR00501## [0803] To a solution of 4-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (30.0 mg, 1.0 equiv) and 3-chloro-4-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (29.3 mg, 1.5 equiv) in CPME (0.8 mL) were added Ad.sub.2nBuP-Pd-G.sub.3 (9.67 mg, 0.2 equiv) and K.sub.3PO.sub.4 (1.5 M, 0.13 mL, 3.0 equiv). The mixture was stirred at 80 C. for 2 hours under nitrogen atmosphere. The reaction mixture was poured into saturated aqueous NH.sub.4Cl solution (5 mL) and extracted with EtOAc (2 mL3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex Luna C18 15025 mm10 um; A: water (FA), B: ACN, B %: 12%-42% over 10 min]. The product was dissolved in saturated aqueous NaHCO.sub.3 solution (2 mL) and extracted with DCM (2 mL3). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate and concentrated to afford the title compound (8.56 mg, 21% yield) as a yellow solid; .sup.1H NMR (400 MHz, METHANOL-d.sub.4) =9.52-9.49 (m, 1H), 6.90 (d, J=2.6 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 4.53-4.46 (m, 4H), 4.15-4.09 (m, 1H), 3.98-3.93 (m, 1H), 3.90-3.79 (m, 2H), 3.67-3.58 (m, 2H), 3.52-3.46 (m, 2H), 3.15-3.07 (m, 2H), 2.23-2.17 (m, 2H), 2.12-2.02 (m, 4H), 1.98-1.93 (m, 2H), 1.82-1.75 (m, 1H), 1.21 (s, 3H), 0.55 (br s, 2H), 0.01 (br dd, J=7.1, 10.6 Hz, 2H); LCMS (ESI, M+1): m/z=584.4. Example 741 ##STR00502## 7-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one [0804] The title compound was synthesized according to the 2-step procedure described for example 738 to produce the desired compound as a as yellow solid (0.85 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.14 (s, 1H), 8.54 (s, 1H), 6.98 (d, J=2.6 Hz, 1H), 6.81 (d, J=2.5 Hz, 1H), 4.65-4.56 (m, 2H), 4.55-4.48 (m, 1H), 4.35 (br d, J=12.8 Hz, 1H), 4.21 (br dd, J=4.1, 14.3 Hz, 1H), 4.03-3.94 (m, 1H), 3.89 (d, J=13.0 Hz, 1H), 3.63-3.51 (m, 2H), 3.42 (d, J=9.4 Hz, 1H), 3.23-3.11 (m, 2H), 2.33-2.22 (m, 2H), 2.14 (qd, J=6.9, 13.6 Hz, 4H), 2.07-1.94 (m, 5H), 1.93-1.80 (m, 2H), 0.76-0.52 (m, 2H), 0.07 (br d, J=1.5 Hz, 2H); LCMS (ESI, M+1): m/z=608.1. Example 742 ##STR00503## (2s,4r)-6-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol Example 743 ##STR00504## (2r,4s)-6-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol ##STR00505## [0805] Step A. (2s,4r)-6-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol and (2r,4s)-6-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol: To a solution of 6-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (40.0 mg, 1.0 equiv) and 3-chloro-4-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (33.2 mg, 1.3 equiv) in CMPE (0.8 mL) were added Catacium Pd G3 (12.6 mg, 0.2 equiv) and K.sub.3PO.sub.4 (1.5 M, 0.17 mL, 3.0 equiv). The reaction was stirred at 80 C. for 2 hours under nitrogen atmosphere. The reaction mixture was poured into saturated NH.sub.4Cl aqueous solution (5 mL) and extracted with EtOAc (2 mL3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [Phenomenex Luna C18 15025 mm10 um; A: water (FA), B: ACN, B %: 13%-43% over 10 min] to afford the title compound EXAMPLE 742 (3.22 mg, 5.5% yield, 0.4FA) as a yellow solid and EXAMPLE 743 (7.44 mg, 13% yield, 0.4FA) as a yellow solid; [0806] EXAMPLE 742: .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.10 (s, 1H), 8.52 (s, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.81 (d, J=2.6 Hz, 1H), 4.63 (s, 2H), 4.32-4.24 (m, 1H), 4.04 (s, 4H), 3.65 (dd, J=6.8, 11.6 Hz, 2H), 3.26-3.23 (m, 2H), 2.31 (br dd, J=6.7, 12.0 Hz, 4H), 2.24 (br s, 4H), 2.12-2.05 (m, 3H), 1.82 (s, 4H), 1.73-1.69 (m, 2H), 0.63 (d, J=6.4 Hz, 2H), 0.07 (br s, 2H); LCMS (ESI, M+1): m/z=594.5. [0807] EXAMPLE 743: .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.05-9.00 (m, 1H), 8.46-8.43 (m, 1H), 6.91 (d, J=2.4 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 4.60-4.57 (m, 2H), 4.24-4.19 (m, 1H), 4.05-3.92 (m, 4H), 3.63-3.56 (m, 2H), 3.21-3.15 (m, 2H), 2.25 (dd, J=6.4, 12.4 Hz, 2H), 2.17-2.08 (m, 6H), 2.06-1.96 (m, 3H), 1.77-1.74 (m, 4H), 1.73-1.59 (m, 2H), 0.56 (d, J=6.4 Hz, 2H), 0.05-0.05 (m, 2H); LCMS (ESI, M+1): m/z=594.3. Example 744 ##STR00506## 5-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [0808] The title compound was synthesized from Intermediate 23 according to the procedure described for example 740 to produce the desired compound as white solid (0.64FA); .sup.1H NMR (400 MHZ, methanol-d4) =9.21 (s, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 6.76 (s, 1H), 5.26 (s, 2H), 4.55-4.52 (m, 4H), 4.47 (br t, J=5.2 Hz, 2H), 3.54-3.51 (m, 2H), 3.34 (s, 3H), 3.14-3.11 (m, 2H), 3.10-3.03 (m, 3H), 2.44 (br d, J=3.2 Hz, 2H), 2.24 (dd, J=6.4, 12.4 Hz, 2H), 2.19-2.06 (m, 4H), 2.05-1.95 (m, 2H), 1.84 (dt, J=2.0, 5.6 Hz, 1H), 0.61 (br d, J=6.4 Hz, 2H), 0.06 (br d, J=1.6 Hz, 2H); LCMS (ESI, M+1): m/z=661.3. Example 745 ##STR00507## 7-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide [0809] The title compound was synthesized according to the 2-step procedure described for example 738 to produce the desired compound as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.08 (s, 1H), 6.95 (d, J=2.6 Hz, 1H), 6.79 (d, J=2.6 Hz, 1H), 4.56 (br d, J=13.5 Hz, 1H), 4.40 (br d, J=13.5 Hz, 1H), 4.37-4.26 (m, 2H), 3.81 (d, J=13.3 Hz, 1H), 3.72-3.62 (m, 1H), 3.41 (d, J=11.9 Hz, 1H), 3.22-3.17 (m, 1H), 3.17-3.09 (m, 2H), 2.80-2.70 (m, 2H), 2.16-2.01 (m, 4H), 2.00-1.83 (m, 7H), 1.82-1.72 (m, 2H), 0.64 (br s, 2H), 0.08 (br s, 2H); LCMS (ESI, M+1): m/z=644.3. Example 746 ##STR00508## (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxy-6-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00509## [0810] Step A. 2,2-dimethyl-5-(2-(m-tolyl)acetyl)-1,3-dioxane-4,6-dione: To a solution of 2-(m-tolyl) acetic acid (8.60 g, 1.0 equiv) and 2,2-dimethyl-1,3-dioxane-4,6-dione (9.90 g, 1.2 equiv) in DCM (90.0 mL) was added DMAP (8.40 g, 1.2 equiv) and EDCI (13.2 g, 1.2 equiv) at 0 C. The mixture was stirred at 25 C. for 12 hours. The reaction mixture was washed with water (100 mL) and the organic layer was dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 10:1 to 3:1] to afford the title compound (12.0 g, 72% yield) as a brown oil; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =7.24-7.18 (m, 1H), 7.14-7.04 (m, 3H), 4.29-4.27 (m, 2H), 2.28 (s, 3H), 1.72-1.68 (s, 6H). [0811] Step B. 1,3-dihydroxy-6-methyl-2-naphthoic acid: 2,2-dimethyl-5-[2-(m-tolyl) acetyl]-1,3-dioxane-4,6-dione (10.0 g, 1.0 equiv) was added into CF.sub.3SO.sub.3H (80.0 mL), then the mixture was stirred at 0 C. for 2 hours. (200 mL) ice water was added to the reaction mixture at 0 C., and then filtered. The filter cake was washed with water (150 mL) and dried to afford the title compound (12.0 g, crude) as a yellow solid; LCMS (ESI, M+1): m/z=219.1. [0812] Step C. 6-methylnaphthalene-1,3-diol: 1,3-dihydroxy-6-methyl-naphthalene-2-carboxylic acid (10.0 g, 1.0 equiv) was dissolved in ACN (60.0 mL) and H.sub.2O (60.0 mL), then stirred at 85 C. for 12 hours. The reaction mixture was extracted with ethyl acetate (3100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (3.30 g, 39% yield) as a yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) =9.95 (s, 1H), 9.37 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.31 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.48 (s, 1H), 6.42 (s, 1H), 2.37 (s, 3H); LCMS (ESI, M+1): m/z=175.1. [0813] Step D. 6-methyl-3-((triisopropylsilyl)oxy)naphthalen-1-ol: To a solution of 6-methylnaphthalene-1,3-diol (3.00 g, 1.0 equiv) in DCM (30.0 mL) was added DIPEA (4.45 g, 2.0 equiv) and TIPSCl (2.99 g. 0.9 equiv). The mixture was stirred at 0 C. for 0.5 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (350 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 50:1 to 10:1] to afford the title compound (1.40 g, crude) as a brown oil; LCMS (ESI, M+1): m/z=331.3. [0814] Step E. 6-methyl-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate: To a solution of 6-methyl-3-triisopropylsilyloxy-naphthalen-1-ol (1.30 g, 1.0 equiv) in DCM (15.0 mL) was added DIPEA (1.52 g, 3.0 equiv) and Tf.sub.2O (1.66 g, 1.5 equiv). The mixture was stirred at 40 C. for 0.5 hour. The reaction mixture was filtered, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether] to afford the title compound (1.40 g, 75% yield) as a colorless oil; LCMS (ESI, M+1): m/z=463.3. [0815] Step F triisopropyl((7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy) silane: To a solution of (6-methyl-3-triisopropylsilyloxy-1-naphthyl)trifluoromethanesulfonate (1.39 g, 1.0 equiv), Bis(pinacolato)diboron (1.14 g, 1.5 equiv) in dioxane (20.0 mL) was added Pd(dppf)Cl.sub.2 (220 mg, 0.1 equiv) and KOAc (885 mg, 3.0 equiv). The mixture was stirred at 100 C. for 6 hours. The reaction mixture was filtered, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 100:1 to 50:1] to afford the title compound (1.15 g, 83% yield) as a yellow oil; LCMS (ESI, M+1): m/z=441.4. [0816] Step G. 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(6-methyl-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (900 mg, 1.0 equiv), triisopropyl-[[7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]oxy]silane (1.08 g, 1.2 equiv) in methoxycyclopentane (20.0 mL) was added AdanBup-Pd-G3 (149 mg, 0.1 equiv) and Cs.sub.2CO.sub.3 (1.5 M, 3.00 equiv). The mixture was stirred at 100 C. for 6 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (350 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=10:1 to 1:1] to afford the title compound (500 mg, crude) as a yellow solid; LCMS (ESI, M+1): m/z=717.6. [0817] Step H. (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxy-6-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(6-methyl-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (10.0 mg, 1.0 equiv) in DMF (0.5 mL) was added DIPEA (14.4 mg, 8.0 equiv), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (1 equiv) and 4 molecular sieves (10.0 mg). The mixture was stirred at 60 C. for 12 hours. The reaction mixture was filtered, and concentrated purified by prep-HPLC [Phenomenex Synergi C18 15025 mm10 m; A: water (FA), B: ACN; B %: 13%-43% over 10 min] to afford the title compound (5.00 mg, 59% yield) as a yellow solid (0.30 formic acid salt); .sup.1H NMR (400 MHZ, DMSO-d6) =9.94-9.89 (m, 1H), 9.38 (s, 1H), 7.57 (s, 1H), 7.42 (br d, J=6.4 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 7.09 (dd, J=1.6, 8.8 Hz, 1H), 5.38-5.17 (m, 1H), 4.78-4.57 (m, 2H), 4.12 (dd, J=7.2, 10.5 Hz, 1H), 4.06-3.98 (m, 1H), 3.77-3.68 (m, 1H), 3.13-3.05 (m, 2H), 3.01 (s, 1H), 2.88-2.78 (m, 1H), 2.70-2.63 (m, 3H), 2.42 (s, 3H), 2.37-2.29 (m, 3H), 2.19-2.10 (m, 2H), 2.06-1.98 (m, 2H), 1.87-1.80 (m, 1H), 1.77 (br d, J=9.6 Hz, 2H), 1.71-1.60 (m, 1H), 1.31-1.21 (m, 1H); LCMS (ESI, M+1): m/z=588.4. Example 747 ##STR00510## (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-hydroxy-5-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00511## [0818] Steps A-F. triisopropyl((8-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy) silane: The title compound was synthesized from 2-(o-tolyl) acetic acid according to the 6-step procedure described for example 746 Steps A-F to produce the desired compound (3.5 g) as a light yellow oil; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =8.40 (d, J=7.6 Hz, 1H), 7.57 (d, J=2.8 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.34-7.28 (m, 2H), 2.56 (s, 3H), 1.36 (s, 12H), 1.34-1.28 (m, 3H), 1.11 (d, J=7.6 Hz, 18H). [0819] Step G. 8-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol: To a solution of triisopropyl((8-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy) silane (2.0 g, 1.0 equiv) in DMF (10 mL) was added CsF (6.90 g, 10 equiv) and the resulting was stirred for 15 mins. The mixture was poured into H.sub.2O (100 mL) and ethyl acetate (30 mL) maintaining the temperature below 5 C. The mixture was extracted with ethyl acetate (310 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 5:1] to afford the tittle compound (0.95 g, 63% yield, 86% purity) as a brown solid; LCMS (ESI, M+1): m/z=285.1. [0820] Step H. 4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-8-methylnaphthalen-2-ol: To a mixture of 8-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (500 mg, 1.5 equiv), 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1 equiv) and Cs.sub.2CO.sub.3 (1 M in H.sub.2O, 3.42 mL, 3.0 equiv) in methoxycyclopentane (10 mL) was added CataCXium A Pd G3 (83 mg, 0.1 equiv). The mixture was stirred at 80 C. for 5 hours under N.sub.2 atmosphere. The mixture was diluted with H.sub.2O (5 mL) and extracted with ethyl acetate (410 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified with reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile=3/1 to 2/1] to afford the tittle compound (0.38 g, 53% yield) as a light-yellow solid; LCMS (ESI, M+1): m/z=561.3. [0821] Step I. (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-hydroxy-5-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a mixture of 4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-8-methylnaphthalen-2-ol (150 mg, 1.0 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (55 mg, 1.6 equiv) in DMF (0.7 mL) was added DIPEA (69.2 mg, 2.0 equiv) and 4 molecular sieves (20 mg). The mixture was stirred at 40 C. for 40 hours under N.sub.2 atmosphere. The mixture was filtered and purified with prep-HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 17%-37%, 7 minutes] to afford the tittle compound (66.0 mg, 40% yield, 0.33FA) as a yellow solid; .sup.1H NMR (400 MHZ, methanol-d4) =9.27 (s, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.35 (br d, J=8.4 Hz, 1H), 7.29 (br d, J=6.8 Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.12 (dd, J=7.2, 8.0 Hz, 1H), 5.39 (d, J=53.2 Hz, 1H), 4.78 (br d, J=12.4 Hz, 1H), 4.45-4.42 (m, 1H), 4.36-4.32 (m, 2H), 3.77 (br d, J=12.4 Hz, 1H), 3.64-3.33 (m, 5H), 3.16 (dt, J=5.2, 9.6 Hz, 1H), 2.65 (s, 3H), 2.53-2.32 (m, 3H), 2.30-2.05 (m, 5H), 2.03-1.75 (m, 3H), 1.42-1.34 (m, 1H); LCMS (ESI, M+1): m/z=588.2. Example 748 ##STR00512## (1R,5R,6R)-3-(8-fluoro-7-(5-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00513## [0822] Step A. 1H-naphtho[1,8-de][1,2,3]triazine: To a solution of naphthalene-1,8-diamine (8.50 g, 1.0 equiv) in MeCN (100 mL) was added AcOH (40 mL) and a solution of NaNO.sub.2 (7.41 g, 2.0 equiv) in H.sub.2O (40 mL) at 0 C. Then the mixture was stirred at 0 C. for 1 hour. The reaction mixture was diluted with H.sub.2O (50 mL) and extracted with EtOAc (350 mL). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford the title compound (9.50 g. 97% yield) as a brown solid; LCMS (ESI, M+1): m/z=170.1. [0823] Step B. 8-fluoronaphthalen-1-amine: A solution of 1H-naphtho[1,8-de][1,2,3]triazine (8.50 g, 1.0 equiv) in pyridine hydrofluoride (62.3 g, 12.5 equiv) was stirred at 90 C. for 2 hours. The mixture was poured into aqueous sodium bicarbonate solution (500 mL) and extracted with EtOAc (3300 mL). The combined organic layer was washed with brine (300 mL), dried over Na.sub.2SO.sub.4, then the mixture was filtered, concentrated and purified by column chromatagraphy [SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 30:1] to afford the title compound 8-fluoronaphthalen-1-amine (5.90 g, 73% yield) as a brown solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =7.52 (d, J=8.4 Hz, 1H), 7.34-7.28 (m, 1H), 7.27-7.21 (m, 1H), 7.12-7.06 (m, 1H), 7.06-6.99 (m, 1H), 6.74 (br d, J=7.6 Hz, 1H), 5.74 (br s, 2H). [0824] Step C. 2,4-dibromo-8-fluoronaphthalen-1-amine: To a solution of Br.sub.2 (12.2 g, 2.2 equiv) in AcOH (44.1 g, 21 equiv) was added a solution of 8-fluoronaphthalen-1-amine (5.60 g, 1.0 equiv) in AcOH (14.7 g, 7.0 equiv) at 25 C. The reaction mixture was stirred at 25 C. for 2 hours. The reaction mixture was filtered. The filter cake was washed with AcOH (60 mL), then added into 20% aqueous of NaOH (50 mL). The mixture was stirred for 20 minutes and filtered. The solid was washed with water (50 mL) and dried to afford the title compound 2,4-dibromo-8-fluoro-naphthalen-1-amine (7.2 g, crude) as a brown solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =7.85 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.57 (dt, J=5.6, 8.0 Hz, 1H), 7.32 (dd, J=7.6, 14.8 Hz, 1H), 5.92 (br d, J=2.8 Hz, 2H). [0825] Step D. 4-bromo-1-diazonio-8-fluoro-naphthalen-2-olate: To a solution of 2,4-dibromo-8-fluoro-naphthalen-1-amine (7.10 g, 1.0 equiv) in AcOH (100 mL) and propionic acid (17.6 g, 10.7 equiv) was added NaNO.sub.2 (1.84 g. 1.2 equiv) portionwise at 5-8 C. The reaction mixture was stirred at 5-8 C. for 1 hour. The reaction mixture was poured into ice-water (500 mL), the generated solid was filtered, washed with water (2200 mL) and dried to afford the title compound 4-bromo-1-diazonio-8-fluoro-naphthalen-2-olate (6.0 g, 72% yield) as a brown solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =7.77 (d, J=8.0 Hz, 1H), 7.51 (br dd, J=8.0, 11.2 Hz, 1H), 7.43-7.37 (m, 1H), 7.21 (s, 1H). [0826] Step E. 4-bromo-8-fluoronaphthalen-2-ol: To a solution of 4-bromo-1-diazonio-8-fluoro-naphthalen-2-olate (5.50 g, 1.0 equiv) in EtOH (50 mL) was added NaBH.sub.4(2.22 g, 2.8 equiv) at 0 C. The mixture was stirred at 20 C. for 2 hours. The mixture was quenched with saturated NH.sub.4Cl aqueous solution (50 mL), then extracted with EtOAc (380 mL). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (1.35 g, 5.42 mmol, 26% yield, 96% purity) as a brown solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.44 (br s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.41-7.30 (m, 2H), 7.28 (d, J=1.6 Hz, 1H). [0827] Step F. 8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol: To a solution of 4-bromo-8-fluoro-naphthalen-2-ol (0.50 g, 1.0 equiv), Bis(pinacolato)diboron (1.05 g, 2.0 equiv) in DMSO (20 mL) were added KOAc (610 mg, 3.0 equiv) and Pd(dppf)Cl.sub.2 (152 mg, 0.1 equiv). The reaction mixture was stirred at 75 C. for 3 hours under N.sub.2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (330 mL). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 50:1 to 20:1] to afford the title compound (410 mg, 58% yield) as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.01 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 7.63 (br s, 1H), 7.35 (br s, 1H), 7.31-7.19 (m, 2H), 1.36 (s, 12H). [0828] Step G. 8-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of 8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (300 mg, 1.2 equiv) and 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (381 mg, 1.0 equiv) in Cyclopentyl Methyl Ether (12 mL) were added Cs.sub.2CO.sub.3 (1.5 M, 3.0 equiv) and AdanBuP Pd G3 (63.2 mg, 0.1 equiv). The mixture was stirred at 100 C. for 3 hours under N.sub.2. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (330 mL). The combined organic layers were washed with brine (40 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 3:1 to 1:2] to afford the title compound (188 mg, 30% yield) as a brown solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.35 (s, 1H), 9.26 (s, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.35-7.31 (m, 2H), 7.31-7.20 (m, 2H), 5.41-5.35 (m, 2H), 4.30-4.17 (m, 2H), 3.31 (s, 2H), 3.14-3.06 (m, 2H), 2.89-2.80 (m, 1H), 2.10-2.01 (m, 2H), 1.92-1.75 (m, 4H). [0829] Step G. (1R,5R,6R)-3-(8-fluoro-7-(5-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 8-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (90.0 mg, 1.0 equiv) and (1S,5S,6R)-3-azabicyclo[3.2.1]octan-6-ol (30.4 mg, 1.2 equiv, HCl) in DMF (1.0 mL) was added DIPEA (103 mg, 5.0 equiv) and 4 molecular sieves (90 mg). The mixture was stirred at 60 C. for 5 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine (15 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by prep-HPLC [Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN; B %: 38%-68% over 9 min] and further re-purified by prep-HPLC [Phenomenex Synergi C18 15025 mm10 m; A: water (FA), B: ACN; B %: 11%-41% over 10 min] to afford the title compound (40.0 mg, 42% yield) as a white solid (0.50 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.29 (d, J=0.8 Hz, 1H), 8.51 (s, 1H), 7.47 (d, J=2.4 Hz, 1H), 7.34 (br d, J=8.0 Hz, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.23-7.12 (m, 2H), 5.57-5.30 (m, 1H), 4.98-4.92 (m, 1H), 4.85-4.74 (m, 1H), 4.54-4.38 (m, 2H), 4.33 (td, J=4.8, 10.0 Hz, 1H), 3.78 (br dd, J=4.4, 12.4 Hz, 1H), 3.70-3.46 (m, 4H), 3.27-3.15 (m, 1H), 2.57-2.33 (m, 3H), 2.30-2.11 (m, 5H), 2.07-1.97 (m, 1H), 1.91 (s, 1H), 1.86-1.77 (m, 1H), 1.38 (br d, J=13.6 Hz, 1H). LCMS (ESI, M+1): m/z=592.4. Example 749 ##STR00514## (1R,5R,6R)-3-(8-fluoro-7-(6-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol [0830] The title compound was synthesized from 2-(3-fluorophenyl) acetic acid according to the 8-step procedure described for example 746 to produce the desired compound as a yellow solid (0.41 formic acid salt); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.21 (br s, 1H), 9.39 (s, 1H), 8.21 (s, 1H), 7.69-7.52 (m, 2H), 7.28 (d, J=2.4 Hz, 1H), 7.24-7.08 (m, 2H), 5.43-5.17 (m, 1H), 4.75 (br d, J=13.2 Hz, 2H), 4.66-4.51 (m, 1H), 4.21-4.08 (m, 2H), 4.01 (dd, J=3.2, 10.4 Hz, 1H), 3.77-3.67 (m, 1H), 3.37-3.36 (m, 1H), 3.15-3.06 (m, 2H), 3.01 (s, 1H), 2.90-2.77 (m, 1H), 2.21-1.95 (m, 6H), 1.87-1.74 (m, 4H), 1.70-1.62 (m, 1H), 1.30-1.19 (m, 1H); LCMS (ESI, M+1): m/z=592.3. Example 750 ##STR00515## (1R,5R,6R)-3-(8-fluoro-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00516## [0831] Step A. 1-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol: To a mixture of 4-bromo-1-fluoronaphthalen-2-ol (500 mg, 1.0 equiv), Bis(pinacolato)diboron (1.05 g, 2.0 equiv) and KOAc (407 mg, 2.0 equiv) in dioxane (10 mL) was added Pd(dppf)Cl.sub.2 (152 mg, 0.1 equiv). The reaction was degassed and stirred at 90 C. for 2 hours under N.sub.2 atmosphere. The reaction mixture was diluted with H.sub.2O (50 mL) and EtOAc (50 mL), and the aqueous layer was extracted with EtOAc (30 mL3). The combined organic layers were washed with brine (30 mL2), dried over Na.sub.2SO.sub.4, filtered, concentrated and purified with column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate 20:1 to 5:1) to afford the title compound (420 mg, 63% yield) as a white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.05 (s, 1H), 8.57 (br d, J=8.4 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.77 (d, J=9.6 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.49-7.38 (m, 1H), 1.36 (s, 12H). [0832] Step B. 1-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a mixture of 1-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (49.2 mg, 1.5 equiv), 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (50.0 mg, 1.0 equiv) and Cs.sub.2CO.sub.3 (1.5 M, 228 L,3.0 equiv) in CPME (1 mL) was added AdanBuP Pd G3 (16.6 mg, 0.2 equiv). The reaction was degassed and stirred at 100 C. for 2 hours under N.sub.2 atmosphere (15 psi). The reaction mixture was diluted with H.sub.2O (10 mL) and EtOAc (10 mL), then filtered and extracted with EtOAc (10 mL3). The combined organic layers were washed with brine (10 mL2), dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by prep-TLC (SiO.sub.2, MeCN) to afford the title compound (55.0 mg, 85% yield) as a yellow solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.40 (s, 1H), 9.27 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.63-7.55 (m, 2H), 7.48-7.42 (m, 1H), 7.40-7.33 (m, 1H), 5.40 (br d, J=8.8 Hz, 2H), 4.32-4.16 (m, 2H), 3.13-3.04 (m, 2H), 2.96-2.79 (m, 2H), 2.19-2.09 (m, 2H), 1.93-1.81 (m, 3H), 1.73-1.62 (m, 1H), 1.23 (br s, 1H). [0833] Step C. (1R,5R,6R)-3-(8-fluoro-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a mixture of 1-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (29.0 mg, 2.0 equiv, HCl) in DMF (0.25 mL) were added DIPEA (57.2 mg, 5.0 equiv) and 4 MS (20.0 mg). The mixture was stirred at 60 C. for 6 hours. The reaction mixture was filtered and purified with prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 15%-45%, 10 min) to afford the title compound (4.83 mg, 9% yield) as a yellow solid (0.18 formic acid salt); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =11.06-9.84 (m, 1H), 9.39 (s, 1H), 8.20 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.72-7.51 (m, 2H), 7.50-7.29 (m, 2H), 5.43-5.13 (m, 1H), 4.95-4.68 (m, 2H), 4.60 (br d, J=12.0 Hz, 1H), 4.24-4.09 (m, 2H), 4.02 (dd, J=4.0, 10.4 Hz, 1H), 3.72 (br d, J=12.0 Hz, 1H), 3.13-3.00 (m, 3H), 2.86-2.79 (m, 1H), 2.33 (br d, J=0.8 Hz, 1H), 2.21-1.98 (m, 5H), 1.92-1.74 (m, 4H), 1.72-1.61 (m, 1H), 1.25 (br d, J=12.8 Hz, 1H); LCMS (ESI, M+1): m/z=592.4. Example 751 ##STR00517## (1R,5R,6R)-3-(8-fluoro-7-(2-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00518## [0834] Step A. 2-fluoro-3-methoxy-1-(methoxymethoxy)naphthalene; To a solution of 3-methoxy-1-(methoxymethoxy)naphthalene (7.50 g, 1.0 equiv) in THF (75 mL) was slowly added n-BuLi (2.5 M, 2.0 equiv) and tetramethylethylenediamine (3.99 g, 1.0 equiv) under N.sub.2 and the mixture was stirred at 0 C. for 2 hours. Then a solution of NFSI (21.7 g, 2.0 equiv) in THF (10 mL) was added to the above reaction solution and the mixture was stirred at 20 C. for 0.5 hour. The mixture was slowly quenched with water (200 mL) at 0 C., and extracted with ethyl acetate (3100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 30:1 to 10:1) to afford the title compound (3.1 g, 39% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.13-8.07 (m, 1H), 7.74-7.69 (m, 1H), 7.48-7.38 (m, 2H), 7.01 (d, J=8.0 Hz, 1H), 5.36 (d, J=0.8 Hz, 2H), 4.01 (s, 3H), 3.66 (s, 3H). [0835] Step B. 2-fluoro-3-methoxynaphthalen-1-ol: To a solution of 2-fluoro-3-methoxy-1-(methoxymethoxy)naphthalene (3.10 g, 1.0 equiv) in DCM (20 mL) was added TFA (30.8 g, 21 equiv) at 0 C. The reaction mixture was stirred at 0 C. for 0.5 hour. The reaction mixture was diluted with water (30 mL), extracted with EtOAc (10 mL), the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 30:1 to 10:1) to afford the title compound (1.50 g, 59% yield) as a red oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.12-8.08 (m, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.49-7.34 (m, 2H), 6.83 (d, J=7.6 Hz, 1H), 5.63 (d, J=4.8 Hz, 1H), 4.00 (s, 3H). [0836] Step C. 2-fluoro-3-methoxynaphthalen-1-yl trifluoromethanesulfonate: To a solution of 2-fluoro-3-methoxy-naphthalen-1-ol (1.00 g, 1.0 equiv) in DCM (10 mL) at 0 C. was added TEA (1.05 g, 2.0 equiv) and Tf.sub.2O (2.20 g, 1.5 equiv). The mixture was stirred at 0 C. for 0.5 hour. The reaction mixture was diluted with water (40 mL), extracted with EtOAc (20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 30:1 to 10:1) to afford the title compound (1.56 mg, 92% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.99-7.92 (m, 1H), 7.81-7.74 (m, 1H), 7.59-7.51 (m, 2H), 7.27-7.24 (m, 1H), 4.04 (s, 3H). [0837] Step D. 2-(2-fluoro-3-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: A mixture of (2-fluoro-3-methoxy-1-naphthyl)trifluoromethanesulfonate (500 mg, 1.0 equiv), bis(pinacolato)diboron (1.57 g, 4.0 equiv), KOAc (454 mg, 3.0 equiv), and Pd(dppf)Cl.sub.2 (113 mg, 0.1 equiv) in dioxane (5 mL) was degassed and stirred at 100 C. for 16 hours under N.sub.2 atmosphere. The reaction mixture was diluted with water (40 mL), extracted with EtOAc (230 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (270 mg, 44% yield) as a black oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.23-8.18 (m, 1H), 7.74-7.68 (m, 1H), 7.43-7.37 (m, 2H), 3.98 (s, 3H), 1.47 (s, 12H); LCMS (ESI, M+1): m/z=303.1. [0838] Step E. 8-fluoro-7-(2-fluoro-3-methoxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: A mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv), 2-(2-fluoro-3-methoxy-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (207 mg, 1.5 equiv), CataCXium A Pd G3 (33.2 mg, 0.1 equiv) and Cs.sub.2CO.sub.3 (1.5 M, 3.0 equiv) in methoxycyclopentane (4 mL) was degassed and stirred at 85 C. for 3 hour under N.sub.2 atmosphere. The reaction mixture was diluted with water (40 mL), extracted with EtOAc (230 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated to give a residue and purified by pre-TLC (Dichloromethane/Methanol 10:1) to afford the title compound (140 mg, 50% yield) as a white solid; LCMS (ESI, M+1): m/z=579.3. [0839] Step F. (1R,5R,6R)-3-(8-fluoro-7-(2-fluoro-3-methoxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 8-fluoro-7-(2-fluoro-3-methoxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (160 mg, 1.0 equiv) in DMF (1.0 mL) was added (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (70.4 mg, 2.0 equiv), DIPEA (107 mg, 3.0 equiv) and 4 molecular sieves (20 mg). The reaction mixture was stirred at 40 C. for 4 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid] to afford the title compound (160 mg, 96% yield) as a white solid; LCMS (ESI, M+1): m/z=606.3. [0840] Step G. (1R,5R,6R)-3-(8-fluoro-7-(2-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(8-fluoro-7-(2-fluoro-3-methoxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 equiv) in DCM (1 mL) was added dropwise BBr.sub.3 (207 mg, 5.0 equiv) in DCM (0.5 mL) at 0 C. The resulting mixture was stirred at 0 C. for 5 hours. The mixture was poured into ice-cooled saturated NaHCO.sub.3 solution (10 mL) extracted with EtOAc (25 mL), the combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 32%-62% over 8 min] to afford the title compound (20.9 mg, 21% yield) as a white solid; Column: Chiralpak IC-3 504.6 mm I.D., 3 um Mobile phase: Phase A for CO.sub.2, and Phase B for MeOH+CAN (0.05% DEA); Gradient elution: 40% MeOH+ACN (0.05% DEA) in CO.sub.2; Flow rate: 3 mL/min; Detector: PDA; Column Temp: 35C; Back Pressure: 100Bar. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.32 (d, J=2.4 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.47-7.34 (m, 3H), 7.30-7.23 (m, 1H), 5.43-5.21 (m, 1H), 5.01-4.90 (m, 1H), 4.79-4.74 (m, 1H), 4.39-4.27 (m, 2H), 4.26-4.20 (m, 1H), 3.79-3.76 (m, 1H), 3.48 (br d, J=12.6 Hz, 1H), 3.29-3.12 (m, 3H), 3.07-2.95 (m, 1H), 2.45-2.37 (m, 1H), 2.35-2.10 (m, 5H), 2.05-1.86 (m, 4H), 1.85-1.76 (m, 1H), 1.46-1.36 (m, 1H); LCMS (ESI, M+1): m/z=592.4; Example 752 ##STR00519## (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00520## [0841] Step A (R)-1-(7-chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1.10 g, 1.0 equiv) in MeCN (10 mL) were added (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol (567 mg, 1.1 equiv) 4 molecular sieves (100 mg) and Cs.sub.2CO.sub.3 (3.25 g, 3.0 equiv). The mixture was stirred at 60 C. for 1 hour. The reaction mixture was partitioned between ethyl acetate (20.0 mL) and water (10.0 mL). The organic phase was separated, concentrated under reduced pressure to afford the title compound (850 mg, 28% yield); LCMS (ESI, M+1): m/z=450.1 [0842] Step B (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (850 mg, 1.00 equiv) in dioxane (10.0 mL) and H.sub.2O (2.00 mL) were added K.sub.3PO.sub.4 (802 mg, 2.0 equiv), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (968 mg, 1.0 equiv) and CataCXium A Pd G3 (138 mg, 0.1 equiv). The mixture was stirred at 90 C. for 2 hours. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic phase was separated, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO.sub.2, dichloromethane/methyl alcohol 10:1) to afford the title compound (310 mg. 20% yield) as a yellow solid; LCMS (ESI, M+1): m/z=800.4 [0843] Step C (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (300 mg, 1.0 equiv) in DMF (8.0 mL) was added CsF (570 mg, 10 equiv). The mixture was stirred at 20 C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO.sub.2, dichloromethane/methyl alcohol 10:1) to afford the title compound (110 mg, 46% yield) as a yellow solid; LCMS (ESI, M+1): m/z=644.4 [0844] Step D (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (100 mg, 1.0 equiv) in EtOAc (3.0 mL) was added HCl/EA (4 M, 3.0 mL). The mixture was stirred at 25 C. for 1 hour. The reaction mixture was concentrated and purified by prep-HPLC (column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 15%-45%, 10 min) and lyophilized to afford the title compound (13.1 mg, 13% yield) as a yellow solid (0.60 formic acid salt); .sup.1H NMR (400 MHZ, CD.sub.3OD) =9.30-9.04 (m, 1H), 8.56 (s, 1H), 7.94-7.85 (m, 1H), 7.42-7.21 (m, 3H), 4.73-4.53 (m, 3H), 4.41-4.26 (m, 2H), 3.72-3.37 (m, 3H), 3.22-2.98 (m, 5H), 2.32-2.11 (m, 1H), 1.99 (br s, 4H), 1.92-1.64 (m, 3H), 1.33-1.21 (m, 3H), 0.88 (br s, 2H), 0.82 (s, 2H); LCMS (ESI, M1): m/z=600.4 Example 753 ##STR00521## ((3S,7aR)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate ##STR00522## [0845] Step A. (R)-1-(7-chloro-8-fluoro-2-(((3S,7aR)-3-(hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (R)-1-(2-(((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (5.00 g, 1.0 equiv) in DMF (50 mL) was added CsF (16.2 g, 15 equiv) at 0 C. under N.sub.2. The mixture was stirred at 25 C. for 1 hour. The residue was poured into ice-water (100 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (100 mL3). The combined organic phases were washed with brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography [DCM/MeOH 10:1 to 5:1] to afford the title compound (3.00 g, 91% yield) as a colorless oil. [0846] Step B. ((3S,7aR)-7a-(((7-chloro-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a mixture of (R)-1-(7-chloro-8-fluoro-2-(((3S,7aR)-3-(hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1.00 g, 1.0 equiv), TEA (568 mg, 3.0 equiv) in DCM (10 mL) at 0 C. under N.sub.2 was added (4-nitrophenyl) carbonochloridate (565 mg, 1.5 equiv). The mixture was stirred at 25 C. for 2 hours. Then N-methylmethanamine (213 mg, 1.5 equiv, HCl) was added dropwise at 0 C. under N.sub.2. The reaction mixture was stirred at 25 C. for 2 hours. The residue was poured into ice-water (15 mL) and stirred for 1 min. The aqueous phase was extracted with DCM (25 mL3). The combined organic phases were washed with brine (35 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate 3:1 to 1:1) to afford the title compound (3.00 g, 91% yield) as a yellow oil; .sup.1H NMR (400 MHZ, DMSO-d6) =9.04-8.96 (m, 1H), 5.74 (s, 1H), 4.75-4.63 (m, 1H), 4.34 (br d, J=13.2 Hz, 1H), 4.03-3.95 (m, 3H), 3.90 (dd, J=5.2, 10.6 Hz, 1H), 3.79 (dd, J=6.4, 10.5 Hz, 1H), 2.97-2.87 (m, 2H), 2.82 (br d, J=13.6 Hz, 6H), 2.70-2.62 (m, 1H), 1.97-1.88 (m, 2H), 1.85-1.73 (m, 4H), 1.71-1.49 (m, 7H), 1.14 (s, 3H). [0847] Step C.: ((3S,7aR)-7a-(((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: ((3S,7aR)-7a-(((7-chloro-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (400 mg, 1.0 equiv), [6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)-2-naphthyl]oxy-triisopropyl-silane (698 mg, 1.5 equiv), K.sub.3PO.sub.4(474 mg, 3.0 equiv), and Pd(dppf)Cl.sub.2 (48.5 mg, 74.5 mol, 0.1 equiv) in dioxane (10 mL) and H.sub.2O (2.5 mL) was degassed and then heated to 80 C. for 2 hours under N.sub.2. The residue was poured into ice-water (5 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (10 mL3). The combined organic phases were washed with brine (10 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The mixture was filtered and purified by prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (180 mg, 24% yield) as a yellow solid. [0848] Step D. ((3S,7aR)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a mixture of ((3S,7aR)-7a-(((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (80.0 mg, 1.0 equiv) in DMF (1 mL) was added CsF (182 mg, 15 equiv) at 25 C. under N.sub.2. The mixture was stirred at 40 C. for 12 hours. The residue was poured into ice-water (10 mL) and stirred for 2 minutes. The aqueous phase was extracted with ethyl acetate (15 mL3). The combined organic phases were filtered and concentrated and purified by prep-HPLC [C18, 0.1% formic acid condition] and lyophilized to afford the title compound (50.6 mg, 85% yield) as a yellow solid (0.25 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d4) =9.24-9.08 (m, 1H), 8.54 (s, 1H), 7.92-7.85 (m, 1H), 7.39-7.31 (m, 2H), 7.30-7.23 (m, 1H), 4.72-4.55 (m, 1H), 4.46-4.28 (m, 3H), 4.25-4.17 (m, 1H), 4.11-4.02 (m, 1H), 3.70-3.60 (m, 2H), 3.51-3.38 (m, 1H), 3.28-3.19 (m, 1H), 3.12-3.01 (m, 1H), 2.97-2.84 (m, 6H), 2.36-1.71 (m, 12H), 1.35-1.24 (m, 3H); LCMS (ESI, M+1): m/z=687.5. Example 754 ##STR00523## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00524## [0849] Step A. 7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: A mixture of 2-(8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150 mg, 1.3 equiv), 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (175 mg, 1.0 equiv), Ad.sub.2n-BuP Pd G.sub.3 (43.7 mg, 0.15 equiv), Cs.sub.2CO.sub.3 (391 mg, 3.0 equiv) in methoxycyclopentane (5.0 mL) was degassed and stirred at 100 C. for 3 hours under N.sub.2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, dichloromethane/methanol 10:1] to afford the title compound (50.0 mg, 22% yield) as a yellow oil. LCMS [M+1]=577.2. [0850] Step B. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (50.0 mg, 1.0 equiv) in DMF (0.5 mL) and acetonitrile (0.5 mL) was added (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (13.2 mg, 1.2 equiv), DIPEA (33.6 mg, 3 equiv) and 4 molecular sieves (10.0 mg). The mixture was stirred at 25 C. for 5 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (230 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 18%-48%, 10 minutes] to afford the title compound (4.30 mg, 8.13% yield) as a white solid (0.18 formic acid salt). .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.43-9.20 (m, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.03 (dd, J=6.4, 8.8 Hz, 1H), 7.59 (s, 1H), 7.54-7.44 (m, 2H), 5.43-5.15 (m, 1H), 4.91-4.69 (m, 2H), 4.64-4.51 (m, 1H), 4.24-4.07 (m, 2H), 4.01 (d, J=10.0 Hz, 1H), 3.75 (br s, 1H), 3.09 (br d, J=7.6 Hz, 2H), 3.02 (s, 1H), 2.83 (br d, J=6.0 Hz, 1H), 2.69-2.65 (m, 1H), 2.34 (br d, J=1.6 Hz, 3H), 2.26-1.95 (m, 6H), 1.93-1.59 (m, 5H), 1.34-1.17 (m, 2H), 0.75 (dt, J=4.0, 7.2 Hz, 3H); LCMS [M+1]=604.4. Example 755 ##STR00525## 7-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione ##STR00526## [0851] Step A. 7-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a mixture of 4-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole (50.0 mg, 1.0 equiv), DIPEA (101 mg, 10 equiv) and 4 molecular sieves (5 mg) in DMF (0.5 mL) was added 1,3,9-triazaspiro[4.5]decane-2,4-dione (19.9 mg, 1.5 equiv). The reaction was stirred at 40 C. for 12 hrs. The mixture was filtered, concentrated and purified by reversed phase flash chromatography [water (FA 0.1%)/acetonitrile] to afford the title compound (26.9 mg, 46% yield) as a yellow solid; LCMS (ESI, M+1): m/z=706.3. [0852] Step B. 7-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: A mixture of 7-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (25.0 mg, 1.0 equiv) in TFA (962 mg, 238 equiv) was stirred at 20 C. for 0.5 hour. The mixture was concentrated and purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (TFA)-ACN]; B %: 12%-42%, 8 min) and then further repurified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (TFA)-ACN]; B %: 10%-40%, 10 min) to afford the title compound (4.01 mg, 14% yield, TFA) as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.35 (s, 1H), 8.25 (s, 1H), 8.15-8.05 (m, 2H), 7.83 (br d, J=8.8 Hz, 1H), 7.56-7.49 (m, 1H), 7.42-7.36 (m, 1H), 4.93-4.90 (m, 1H), 4.86 (br s, 1H), 4.75-4.64 (m, 3H), 4.59-4.51 (m, 1H), 4.04-3.89 (m, 2H), 3.80-3.66 (m, 2H), 2.41-2.00 (m, 12H), LCMS (ESI, M+1): m/z=622.3. Example 756 ##STR00527## 7-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one [0853] The title compound was synthesized from Intermediate 21 according to the 2-step procedure described for example 755 to produce the desired compound as a yellow solid (TFA salt). .sup.1H NMR (400 MHZ, METHANOL-d4) =9.33 (s, 1H), 8.22 (s, 1H), 8.09 (d, J=8.8 Hz, 1H), 8.05-8.02 (m, 1H), 7.80 (br d, J=9.2 Hz, 1H), 7.52-7.47 (m, 1H), 7.39-7.34 (m, 1H), 4.71-4.61 (m, 2H), 4.49-4.28 (m, 2H), 4.10-3.98 (m, 1H), 3.96-3.88 (m, 1H), 3.77-3.68 (m, 2H), 3.50-3.43 (m, 1H), 3.34 (br s, 2H), 3.29 (br s, 1H), 2.40-2.29 (m, 2H), 2.28-2.17 (m, 4H), 2.16-2.08 (m, 2H), 2.07-1.87 (m, 4H); LCMS (ESI, M+1): m/z=608.3. Example 757 ##STR00528## 5-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [0854] The title compound was synthesized from Intermediate 21 according to the 2-step procedure described for example 755 to produce the desired compound as a as yellow solid (0.74 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.36 (s, 1H), 8.21 (s, 1H), 8.10-8.03 (m, 2H), 7.79 (br d, J=8.0 Hz, 1H), 7.52-7.46 (m, 1H), 7.38-7.32 (m, 1H), 6.81 (s, 1H), 5.30 (s, 2H), 4.58-4.46 (m, 6H), 3.49-3.33 (m, 5H), 3.12-2.98 (m, 5H), 2.48 (br s, 2H), 2.25-2.17 (m, 2H), 2.07 (qd, J=6.4, 17.6 Hz, 4H), 1.99-1.90 (m, 2H); LCMS (ESI, M+1): m/z=661.4. Example 758 ##STR00529## 7-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide [0855] The title compound was synthesized from Intermediate 21 according to the 2-step procedure described for example 755 to produce the desired compound as a yellow solid (0.6 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.31 (s, 1H), 8.21 (s, 1H), 8.12-7.98 (m, 2H), 7.85-7.76 (m, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.41-7.29 (m, 1H), 4.68 (br d, J=12.8 Hz, 2H), 4.65-4.49 (m, 2H), 3.92-3.81 (m, 1H), 3.81-3.65 (m, 3H), 3.51-3.38 (m, 1H), 3.23 (br d, J=11.6 Hz, 3H), 2.44-2.30 (m, 2H), 2.29-2.16 (m, 4H), 2.16-2.04 (m, 4H), 2.03 (br s, 1H), 1.93-1.85 (m, 1H); LCMS (ESI, M+1): m/z=644.2. Example 759 ##STR00530## 7-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione [0856] The title compound was synthesized from Intermediate 20 according to the 2-step procedure described for example 755 to produce the desired compound as a yellow solid (0.993 FA). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.31 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 8.13-8.01 (m, 2H), 7.80 (br d, J=9.6 Hz, 1H), 7.54-7.46 (m, 1H), 7.40-7.31 (m, 1H), 5.59-5.38 (m, 1H), 4.73-4.58 (m, 2H), 4.56-4.47 (m, 2H), 3.95-3.81 (m, 2H), 3.80-3.67 (m, 1H), 3.67-3.55 (m, 2H), 3.26 (br s, 1H), 2.64-2.41 (m, 2H), 2.38-2.25 (m, 2H), 2.25 (br s, 2H), 2.17-2.03 (m, 3H), 2.02-1.93 (m, 1H); LCMS (ESI, M+1): m/z=640.4. Example 760 ##STR00531## 7-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one [0857] The title compound was synthesized from Intermediate 20 according to the 2-step procedure described for example 755 to produce the desired compound as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.27 (s, 1H), 8.20 (s, 1H), 8.14-7.97 (m, 2H), 7.79 (br d, J=9.2 Hz, 1H), 7.53-7.45 (m, 1H), 7.40-7.32 (m, 1H), 5.46-5.17 (m, 1H), 4.39-4.24 (m, 2H), 4.18-3.98 (m, 4H), 3.52-3.36 (m, 2H), 3.25-3.18 (m, 3H), 3.04-2.97 (m, 1H), 2.35 (br t, J=4.8 Hz, 3H), 2.08-1.87 (m, 7H) LCMS (ESI, M+1): m/z=626.3 Example 761 ##STR00532## 5-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [0858] The title compound was synthesized from Intermediate 20 according to the 2-step 31 procedure described for example 755 to produce the desired compound as a yellow solid (0. formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.34 (s, 1H), 8.20 (s, 1H), 8.10-8.03 (m, 2H), 7.79 (br d, J=8.8 Hz, 1H), 7.51-7.46 (m, 1H), 7.38-7.32 (m, 1H), 6.80 (s, 1H), 5.47-5.31 (m, 1H), 5.29 (s, 2H), 4.58-4.52 (m, 2H), 4.49 (br t, J=5.2 Hz, 2H), 4.39 (q, J=11.2 Hz, 2H), 3.55-3.37 (m, 3H), 3.35 (s, 3H), 3.14 (dt, J=5.8, 9.6 Hz, 1H), 3.08 (s, 3H), 2.50-2.28 (m, 4H), 2.23-1.95 (m, 4H); LCMS (ESI, M+1): m/z=679.4; Example 762 ##STR00533## 7-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide [0859] The title compound was synthesized from Intermediate 20 according to the 2-step procedure described for example 755 to produce the desired compound as a white solid (0.64 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.29-9.23 (m, 1H), 8.20 (s, 1H), 8.09-8.02 (m, 2H), 7.84-7.77 (m, 1H), 7.51-7.45 (m, 1H), 7.39-7.30 (m, 1H), 5.50-5.25 (m, 1H), 4.67-4.62 (m, 1H), 4.56-4.49 (m, 2H), 4.42 (br d, J=10.8 Hz, 1H), 3.90-3.79 (m, 1H), 3.76-3.64 (m, 1H), 3.62-3.51 (m, 1H), 3.46 (br s, 1H), 3.41 (br d, J=11.6 Hz, 2H), 3.23-3.17 (m, 2H), 2.54-2.40 (m, 1H), 2.40-2.32 (m, 1H), 2.30-2.21 (m, 1H), 2.17-2.07 (m, 3H), 2.06-1.95 (m, 3H), 1.91-1.82 (m, 1H); LCMS (ESI, M+1): m/z=662.3 Example 763 ##STR00534## (1R,5R,6R)-3-(7-(6-chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol [0860] The title compound was synthesized from 2-(3-chlorophenyl) acetic acid according to the 8-step procedure described for example 746 to produce the desired compound as a white solid (0.40 formic acid salt); .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.39 (s, 1H), 8.22 (s, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.56 (br d, J=8.4 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.28-7.22 (m, 2H), 5.42-5.15 (m, 1H), 4.88-4.51 (m, 3H), 4.22-4.08 (m, 2H), 4.03 (dd, J=4.0, 10.4 Hz, 1H), 3.71 (br d, J=12.0 Hz, 1H), 3.35 (br d, J=12.8 Hz, 1H), 3.12-2.99 (m, 3H), 2.86-2.79 (m, 1H), 2.33 (br d, J=2.0 Hz, 1H), 2.23-1.93 (m, 5H), 1.93-1.58 (m, 5H), 1.25 (br d, J=13.2 Hz, 1H); LCMS (ESI, M+1): m/z=608.2. Example 764 ##STR00535## (1R,5R,6R)-3-(7-(4-chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00536## [0861] Step A. (1R,5R,6R)-3-(7-(4-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: A mixture of (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.00 eq.) and NCS (28.1 mg, 1.30 eq.) in ACN (1.50 mL) and DMF (0.20 mL) was stirred at 70 C. for 12 hours. The reaction mixture was filtered, concentrated and purified with prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [water (TFA)-ACN]; B %: 34%-54%, 9 min) to afford title compound (40.0 mg, 36% yield) as a yellow solid; .sup.1H NMR (400 MHZ, DMSO-d6) =10.83-10.67 (m, 1H), 9.48 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.79-7.65 (m, 3H), 7.57-7.48 (m, 1H), 5.65-5.50 (m, 1H), 5.46 (s, 2H), 4.84-4.80 (m, 1H), 4.63 (br d, J=12.4 Hz, 1H), 4.59 (br d, J=2.4 Hz, 2H), 4.18 (td, J=5.2, 10.4 Hz, 1H), 3.92-3.69 (m, 5H), 3.48 (s, 3H), 3.39 (br d, J=13.2 Hz, 1H), 3.35-3.28 (m, 1H), 2.57 (br d, J=5.6 Hz, 1H), 2.35-2.31 (m, 2H), 2.21-2.05 (m, 5H), 1.80 (br d, J=12.0 Hz, 1H), 1.68 (br dd, J=4.4, 7.2 Hz, 1H), 1.27-1.20 (m, 1H). LCMS (ESI, M+1): m/z=652.4. [0862] Step B. (1R,5R,6R)-3-(7-(4-chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: A solution of (1R,5R,6R)-3-(7-(4-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (30.0 mg, 46.0 mol, 1.00 eq.) in HCl/MeOH (4 M, 3.00 mL, 261 eq.) was stirred at 0 C. for 1 hour. The reaction mixture was concentrated and purified with prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 14%-44%, 10 min) to afford title compound (7.81 mg, 28% yield) as a white solid; .sup.1H NMR (400 MHZ, DMSO-d6) =10.74 (s, 1H), 9.41 (s, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.71-7.57 (m, 2H), 7.44 (s, 1H), 7.42-7.35 (m, 1H), 5.44-5.17 (m, 1H), 4.80-4.71 (m, 2H), 4.61 (br d, J=12.4 Hz, 1H), 4.15 (br dd, J=5.4, 8.8 Hz, 2H), 4.10-4.00 (m, 1H), 3.72 (br d, J=11.2 Hz, 1H), 3.38 (br s, 1H), 3.21-2.97 (m, 3H), 2.90-2.80 (m, 1H), 2.22-1.94 (m, 6H), 1.89-1.73 (m, 4H), 1.71-1.61 (m, 1H), 1.25 (br d, J=13.6 Hz, 1H). LCMS (ESI, M+1): m/z=608.3. Example 765 ##STR00537## (1R,5R,6R)-3-(7-(2-chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00538## ##STR00539## [0863] Step A. 3-methoxy-1-(methoxymethoxy)naphthalene: To a solution of 3-methoxynaphthalen-1-ol (10.0 g, 1.0 equiv) in THF (100 mL) was added DIPEA (22.3 g, 3.0 equiv) and bromo(methoxy) methane (8.61 g, 1.2 equiv), the mixture was stirred at 25 C. for 0.5 hour. The reaction mixture was diluted with EtOAc (100 mL) and water (200 mL), extracted with EtOAc (100 mL), the combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 15:1 to 10:1) to afford the title compound (10.5 g, 82% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.08 (d, J=8.4 Hz, 1H), 7.63-7.58 (m, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.28-7.21 (m, 1H), 6.72 (s, 2H), 5.28 (s, 2H), 3.82 (s, 3H), 3.46 (s, 3H); LCMS (ESI, M+1): m/z=219.2. [0864] Step B. 2-chloro-3-methoxy-1-(methoxymethoxy)naphthalene: To a solution of 3-methoxy-1-(methoxymethoxy)naphthalene (7.50 g, 1.0 equiv) in THF (75 mL) was slowly added n-BuLi (2.5 M, 27.5 mL, 2.0 equiv) and tetramethylethylenediamine (4.04 g, 1.0 equiv) under nitrogen at 0 C. and the mixture was stirred at 0 C. for 2 hours. Then a solution of 1,1,1,2,2,2-hexachloroethane (16.3 g, 2.0 equiv) in THF (10 mL) was added to the above reaction and the mixture was stirred at 20 C. for 0.5 hour. The mixture was slowly quenched with water (300 mL) and extracted with ethyl acetate (3200 mL). The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 30:1 to 10:1) to afford the title compound (8.00 g, 92% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.10 (dd, J=0.6, 8.0 Hz, 1H), 7.76-7.71 (m, 1H), 7.51-7.39 (m, 2H), 7.04 (s, 1H), 5.31 (s, 2H), 4.05-3.98 (m, 3H), 3.76-3.68 (m, 3H). [0865] Step C. 2-chloro-3-methoxynaphthalen-1-ol: To a solution of 2-chloro-3-methoxy-1-(methoxymethoxy)naphthalene (4.00 g, 1.0 equiv) in DCM (20 mL) was added TFA (30.8 g, 17 equiv). The reaction mixture was stirred at 0 C. for 0.5 hour. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (250 mL), the combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by reversed phase flash chromatography [C18, 0.1% formic acid] to afford the title compound (1.80 g, 54% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.17-8.10 (m, 1H), 7.71-7.66 (m, 1H), 7.47 (t, J=7.2 Hz, 1H), 7.41-7.35 (m, 1H), 6.82 (s, 1H), 6.16 (br s, 1H), 4.00 (s, 3H). [0866] Step D. 2-chloro-3-methoxynaphthalen-1-yl trifluoromethanesulfonate: To a solution of 2-chloro-3-methoxynaphthalen-1-ol (1.00 g, 1.0 equiv) in DCM (10 mL) at 0 C. was added TEA (970 mg, 2.0 equiv) and Tf.sub.2O (2.03 g, 1.5 equiv). The mixture was stirred at 0 C. for 0.5 hour. The reaction mixture was diluted with water (40 mL), extracted with EtOAc (220 mL), the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 50:1 to 30:1) to afford the title compound (1.33 mg, 81% yield) as a yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.00 (d, J=8.4 Hz, 1H), 7.83-7.77 (m, 1H), 7.61-7.50 (m, 2H), 7.25 (s, 1H), 4.05 (s, 3H). [0867] Step E. 2-(2-chloro-3-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: A mixture of (2-chloro-3-methoxy-1-naphthyl)trifluoromethanesulfonate (1.33 g, 1.0 equiv), bis(pinacolato)diboron (3.97 g, 4.0 equiv), KOAc (1.15 g, 3.0 equiv), and Pd(dppf)Cl.sub.2 (286 mg, 0.1 equiv) in dioxane (13 mL) was degassed and stirred at 100 C. for 16 hours under N.sub.2 atmosphere. The reaction mixture was diluted with water (40 mL), extracted with EtOAc (230 mL), the combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 20:1 to 5:1) to afford the title compound (590 mg, 47% yield) as a white solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.79 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.44-7.36 (m, 1H), 7.39-7.33 (m, 1H), 7.19 (s, 1H), 3.99 (s, 3H), 1.52 (s, 12H). [0868] Step F. 7-(2-chloro-3-methoxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: A mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (400 mg, 1.0 equiv), 2-(2-chloro-3-methoxy-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (377 mg, 1.3 equiv), CataCXium A Pd G3 (66.4 mg, 0.1 equiv), and Cs.sub.2CO.sub.3 (1.5 M, 3.0 equiv) in methoxycyclopentane (10 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 80 C. for 6 hours under N.sub.2 atmosphere. The reaction mixture was diluted with water (40 mL), extracted with EtOAc (230 mL), the combined organic phase was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (289 mg, 53% yield) as a yellow solid; LCMS (ESI, M+1): m/z=595.2. [0869] Step G. (1R,5R,6R)-3-(7-(2-chloro-3-methoxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a mixture of 7-(2-chloro-3-methoxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (280 mg, 1.0 equiv) in DMF (3 mL) was added (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (120 mg, 2.0 equiv), DIPEA (182 mg, 3.0 equiv) and 4 molecular sieves (20 mg). The reaction mixture was stirred at 40 C. for 16 hours. The mixture was filtered and the filtrate was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (240 mg, 82% yield) as a yellow solid; LCMS (ESI, M+1): m/z=622.3. [0870] Step H. (1R,5R,6R)-3-(7-(2-chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(2-chloro-3-methoxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (40.0 mg, 1.0 equiv) in DCM (1 mL) was added a solution of BBr.sub.3 (80.5 mg, 5.0 equiv) in DCM (0.5 mL) dropwise at 0 C. The resulting mixture was stirred at 0 C. for 5 hours. The mixture was poured into ice-cooled saturated NaHCO.sub.3 solution (10 mL), and extracted with EtOAc (25 mL), the combined organic phase was washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; Phase A: water (10 mM NH.sub.4HCO.sub.3), phase B: ACN, B %: 28%-58% over 8 min] to afford the title compound (7.10 mg, 17% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.33 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.47-7.39 (m, 1H), 7.27-7.20 (m, 1H), 7.19-7.14 (m, 1H), 5.41-5.22 (m, 1H), 5.00-4.92 (m, 2H), 4.39-4.28 (m, 2H), 4.28-4.19 (m, 1H), 3.83-3.75 (m, 1H), 3.49 (br d, J=12.4 Hz, 1H), 3.28-3.19 (m, 3H), 3.07-2.97 (m, 1H), 2.43-2.40 (m, 1H), 2.36-2.11 (m, 5H), 2.07-1.88 (m, 4H), 1.86-1.79 (m, 1H), 1.46-1.37 (m, 1H); LCMS (ESI, M+1): m/z=608.4. Example 766 ##STR00540## (5R)-7-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione ##STR00541## ##STR00542## [0871] Step A. 4-bromo-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole: To a solution of 4-bromo-6-chloro-1H-indazole (15.0 g, 1.0 equiv) in THF (200 mL) was added NaH (3.89 g, 60% purity, 1.5 equiv) at 0 C. The mixture was stirred at 20 C. for 0.5 hour. To the mixture was added SEM-Cl (13.0 g, 1.2 equiv) at 0 C. The mixture was stirred at 20 C. for 2 hours. The mixture was quenched with H.sub.2O (100 mL) and extracted with EtOAc (3100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 50:1 to 10:1] to afford the tittle compound (15.0 g, 64% yield) as a yellow solid; .sup.1H NMR (400 MHz, CHLOROFORM-d) =7.99 (d J=0.8 Hz, 1H), 7.55 (d, J=0.8 Hz, 1H), 7.36 (d, J=1.6 Hz, 1H), 5.69 (s, 2H), 3.57-3.50 (m, 2H), 0.93-0.86 (m, 2H), 0.05 (s, 9H). [0872] Step B. 4-bromo-6-chloro-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole: To a solution of 2-[(4-bromo-6-chloro-indazol-1-yl)methoxy]ethyl-trimethyl-silane (2.0 g, 1.0 equiv) in THF (20 mL) was added LDA (2.0 M, 4.15 mL, 1.5 equiv) at 65 C. under N.sub.2. The mixture was stirred at 65 C. for 1 hour. To the solution was slowly added MeI (3.92 g, 5 equiv) at 65 C. The mixture was stirred at 25 C. for 0.5 hour under N.sub.2. The mixture was quenched with H.sub.2O (20 mL) at 0 C. The mixture was extracted with EtOAc (320 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (1.10 g, 52% yield) as a yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.99 (s, 1H), 7.43 (s, 1H), 5.88 (s, 2H), 3.65-3.53 (m, 2H), 2.81 (s, 3H), 0.99-0.88 (m, 2H), 0.00 (s, 9H). [0873] Step C. 6-chloro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole: To a solution of 4-bromo-6-chloro-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (5.0 g, 1.0 equiv) and Pin.sub.2B.sub.2 (5.07 g, 1.5 equiv) in toluene (100 mL) were added Pd(dppf)Cl.sub.2 (974 mg, 0.1 equiv) and KOAc (3.92 mg, 3.0 equiv) under N.sub.2. The mixture was stirred at 110 C. for 12 hours. The reaction mixture was diluted with H.sub.2O (100 mL) and extracted with EtOAc (350 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (3.0 g, 52% yield) as a yellow liquid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.32 (s, 1H), 7.68 (s, 1H), 5.85 (s, 2H), 3.56-3.51 (m, 2H), 2.85 (s, 3H), 1.40 (s, 12H), 0.90-0.86 (m, 2H), 0.05 (s, 9H); LCMS (ESI, M1): m/z=423.1. [0874] Step D. 7-(6-chloro-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (800 mg, 1.0 equiv) and K.sub.3PO.sub.4 (1.50 M, 3.80 mL, 3.0 equiv) in toluene (8.0 mL) were added Ad.sub.2nBup-Pd-G3 (138 mg, 0.1 equiv) and 6-chloro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.21 g, 1.5 equiv). The mixture was stirred at 60 C. for 12 hours under N.sub.2. The reaction mixture was diluted with H.sub.2O (10 mL) and extracted with EtOAc (320 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (300 mg, 22% yield) as a yellow solid; LCMS (ESI, M+1): m/z=681.1. [0875] Step E. (5R)-7-(7-(6-chloro-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of 7-(6-chloro-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) in DMF (1 mL) were added DIPEA (171 mg, 3.0 equiv) and (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (223 mg, 3.0 equiv). The mixture was stirred at 40 C. for 6 hours. The reaction mixture was concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (200 mg, 58% yield) as an off-white solid; LCMS (ESI, M+1): m/z=750.2. [0876] Step F. (5R)-7-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of (5R)-7-(7-(6-chloro-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 equiv) in DCM (2 mL) was added TFA (3.08 g, 203 equiv). The mixture was stirred at 20 C. for 0.5 hour. The reaction mixture was concentrated and purified with prep-HPLC [Phenomenex C18 7530 mm3 m; A: water (10 mM FA), B: ACN, B %: 10%-40% over 7 min] and lyophilized to afford the title compound (135 mg, 75% yield, 0.61 FA) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.24-9.19 (m, 1H), 8.52 (s, 1H), 8.37 (d, J=1.2 Hz, 1H), 7.71 (s, 1H), 4.67-4.61 (m, 1H), 4.60-4.53 (m, 2H), 4.50-4.41 (m, 1H), 3.88-3.74 (m, 2H), 3.67-3.58 (m, 2H), 3.26-3.15 (m, 2H), 2.68 (s, 3H), 2.35-2.24 (m, 3H), 2.23-2.10 (m, 5H), 2.09-2.01 (m, 3H), 1.99-1.94 (m, 1H); LCMS (ESI, M+1): m/z=620.2. Example 767 ##STR00543## (1R,5R,6R)-3-(7-(5-ethyl-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00544## [0877] Step A. (1R,5R,6R)-3-(7-(5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a mixture of 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole (51.0 mg, 1.0 equiv), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (14.2 mg, 1.5 equiv) and 4 molecular sieves (10 mg) in DMF (1 mL) was added DIPEA (29.0 mg, 3.0 equiv). The mixture was stirred at 40 C. for 10 hours. The mixture was filtered, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (43.0 mg, 77% yield) as a yellow solid; LCMS (ESI, M+1): m/z=710.5. [0878] Step B. (1R,5R,6R)-3-(7-(5-ethyl-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To the solution of (1R,5R,6R)-3-(7-(5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (40.0 mg, 1.0 equiv) in DCM (0.5 mL) was added TFA (1.54 g, 240 equiv) at 0 C. The mixture was stirred at 15 C. for 0.5 hour. The pH of the mixture was adjusted 8 by sat. aq. NaHCO.sub.3. The mixture was extracted with DCM (210 mL). The organic layer was dried over Na.sub.2SO.sub.4, concentrated and purified by prep-HPLC [column: YMC Triart C18 15025 mm5 m; A: water (FA), B: ACN, B %: 20%-50% over 10 min] to afford the title compound (6.53 mg, 0.15 FA, 18% yield) as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.34 (d, J=11.6 Hz, 1H), 8.20 (s, 1H), 7.94 (br d, J=8.4 Hz, 1H), 7.77-7.70 (m, 1H), 7.41 (br t, J=7.2 Hz, 1H), 7.27 (br d, J=7.2 Hz, 1H), 5.49-5.29 (m, 1H), 4.49-4.31 (m, 3H), 3.82 (br t, J=11.2 Hz, 1H), 3.56-3.36 (m, 4H), 3.21-3.09 (m, 1H), 2.52-2.17 (m, 8H), 2.14-2.06 (m, 2H), 2.00-1.76 (m, 4H), 1.48-1.17 (m, 2H), 1.03-0.91 (m, 3H); LCMS (ESI, M+1): m/z=626.4. Example 768 ##STR00545## 7-(7-(5-ethyl-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione [0879] The title compound was synthesized from Intermediate 22 according to the 2-step procedure described for example 767 to produce the desired compound as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.22 (s, 1H), 8.20 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.76-7.67 (m, 1H), 7.45-7.38 (m, 1H), 7.30-7.24 (m, 1H), 5.38-5.23 (m, 1H), 4.71-4.45 (m, 2H), 4.43 (br s, 2H), 3.87-3.67 (m, 2H), 3.30-3.15 (m, 3H), 3.07-2.96 (m, 1H), 2.54-2.35 (m, 2H), 2.34-2.11 (m, 4H), 2.06-1.88 (m, 6H), 1.04-0.89 (m, 3H); LCMS (ESI, M+1): m/z=668.3. Example 769 ##STR00546## 7-(7-(5-ethyl-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one [0880] The title compound was synthesized from Intermediate 22 according to the 2-step procedure described for example 767 to produce the desired compound as a yellow solid (0.29 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.23 (s, 1H), 8.20 (s, 1H), 7.95 (br d, J=8.6 Hz, 1H), 7.71 (br d, J=4.8 Hz, 1H), 7.41 (br t, J=7.6 Hz, 1H), 7.28 (br d, J=2.4 Hz, 1H), 5.49-5.26 (m, 1H), 4.53-4.10 (m, 4H), 4.05-3.85 (m, 2H), 3.62-3.34 (m, 5H), 3.14 (br d, J=5.4 Hz, 1H), 2.60-2.34 (m, 3H), 2.33-2.17 (m, 2H), 2.08 (br d, J=7.6 Hz, 2H), 2.03-1.81 (m, 5H), 1.04-0.87 (m, 3H); LCMS (ESI, M+1): m/z=654.4. Example 770 ##STR00547## 5-(7-(5-ethyl-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide ##STR00548## [0881] Step A. 5-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (171 mg, 1.2 equiv) in DMF (2 mL) was added DIPEA (265 mg, 3.0 equiv). The mixture was stirred at 40 C. for 10 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (180 mg, 45% yield) as a white solid; LCMS (ESI, M+1): m/z=547.3. [0882] Step B. 5-(7-(5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a mixture of 5-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (160 mg, 1.3 equiv), 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole (90.0 mg, 0.98 equiv) and K.sub.3PO.sub.4 (1.5 M, 0.45 mL, 3.0 equiv) in methoxycyclopentane (1.5 mL) was added CataCXium A Pd G3 (16.4 mg, 0.1 equiv) under N.sub.2. The mixture was stirred at 90 C. for 2 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 54% yield) as a yellow solid; LCMS (ESI, M+1): m/z=791.5. [0883] Step C. 5-(7-(5-ethyl-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 5-(7-(5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (95.0 mg, 1.0 equiv) in DCM (0.5 mL) was added TFA (1.54 g, 112 equiv) at 0 C. The mixture was stirred at 15 C. for 1 hour. The mixture was quenched by sat. NaHCO.sub.3 (50 mL) and extracted with ethyl acetate (210 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give a residue. The residue was purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 12%-42% over 10 min] and lyophilized to afford the title compound (12.2 mg, 14% yield) as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.29 (s, 1H), 8.20 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.72 (s, 1H), 7.44-7.37 (m, 1H), 7.27 (d, J=6.8 Hz, 1H), 6.77 (s, 1H), 5.53-5.16 (m, 3H), 4.60-4.37 (m, 6H), 3.65-3.43 (m, 3H), 3.33 (s, 3H), 3.25-3.13 (m, 1H), 3.08 (s, 3H), 2.59-2.33 (m, 6H), 2.32-2.22 (m, 1H), 2.19-1.96 (m, 3H), 0.96 (t, J=7.4 Hz, 3H); LCMS (ESI, M+1): m/z=707.5. Example 771 ##STR00549## 6-(7-(5-ethyl-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one [0884] The title compound was synthesized according to the 3-step procedure described for example 770 to produce the desired compound as a yellow solid (0.28 FA); .sup.1H NMR (400 MHz, METHANOL-d.sub.4) =9.22 (s, 1H), 8.23 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.47-7.40 (m, 1H), 7.30 (br d, J=6.8 Hz, 1H), 5.51-5.35 (m, 1H), 4.55-4.32 (m, 4H), 4.05 (dd, J=8.8, 13.2 Hz, 1H), 3.98-3.79 (m, 1H), 3.65-3.45 (m, 3H), 3.25-3.16 (m, 1H), 3.00-2.88 (m, 1H), 2.79 (br d, J=14.8 Hz, 1H), 2.57-2.36 (m, 4H), 2.27-2.12 (m, 4H), 2.07-1.98 (m, 4H), 0.99 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=639.4. Example 772 ##STR00550## 7-(7-(5-ethyl-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide [0885] The title compound was synthesized from Intermediate 22 according to the 2-step procedure described for example 767 to produce the desired compound as a yellow solid (0.60 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.20 (d, J=8.0 Hz, 1H), 8.20 (d, J=3.6 Hz, 1H), 7.95 (br d, J=8.4 Hz, 1H), 7.85-7.68 (m, 1H), 7.45-7.38 (m, 1H), 7.28 (br d, J=6.4 Hz, 1H), 5.52-5.34 (m, 1H), 4.81-4.66 (m, 1H), 4.63-4.42 (m, 3H), 3.86-3.73 (m, 1H), 3.72-3.58 (m, 2H), 3.58-3.48 (m, 2H), 3.42-3.36 (m, 1H), 3.19 (br dd, J=12.0, 18.2 Hz, 2H), 2.57-2.41 (m, 3H), 2.40-2.24 (m, 2H), 2.22-2.05 (m, 4H), 2.02-1.80 (m, 3H), 0.99 (m, 3H); LCMS (ESI, M+1): m/z=690.1. Example 773 ##STR00551## 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00552## [0886] A mixture of 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30 mg, 1.0 equiv), 1-oxa-8-azaspiro[3.5]nonane (11.6 mg, 2.0 equiv), DIPEA (17.5 mg, 4.0 equiv) and 4 molecular sieves (30 mg) in DMF (0.2 mL) was stirred at 40 C. for 12 hours under N.sub.2 atmosphere. The mixture was filtered and the filtrate was concentrated and purified by prep-HPLC [C18, 0.1% formic acid condition] to afford the title compound (10.3 mg, 15.5% yield) as a yellow solid (0.40 formic acid salt). .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.28 (br d, J=11.0 Hz, 1H), 8.60-8.44 (m, 1H), 7.82 (dd, J=5.6, 9.2 Hz, 1H), 7.49-7.32 (m, 2H), 7.25 (s, 1H), 5.57-5.28 (m, 1H), 4.77-4.58 (m, 2H), 4.57-4.36 (m, 4H), 3.81 (br d, J=13.2 Hz, 1H), 3.73-3.38 (m, 4H), 3.22 (br s, 1H), 2.61-2.33 (m, 4H), 2.28 (br s, 2H), 2.15 (br d, J=2.2 Hz, 2H), 2.08-1.87 (m, 3H), 1.82 (br d, J=8.4 Hz, 1H); LCMS (ESI, M+1): m/z=626.4. Example 774 ##STR00553## 7-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane-1,3-dione [0887] The title compound was synthesized from Intermediate 24 according to the procedure described for example 773 to produce the desired compound as a white solid .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.08-9.01 (m, 1H), 7.86-7.76 (m, 1H), 7.41-7.34 (m, 2H), 7.24-7.17 (m, 1H), 5.42-5.21 (m, 1H), 4.71-4.54 (m, 3H), 4.45-4.36 (m, 1H), 4.33-4.21 (m, 2H), 3.97-3.75 (m, 2H), 3.20-2.90 (m, 3H), 2.71-2.63 (m, 1H), 2.40-2.06 (m, 5H), 2.03-1.83 (m, 5H); LCMS (ESI, M+1): m/z=667.2. Example 775 ##STR00554## 4-(((7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-3-((1r,3S)-3-hydroxycyclobutanecarboxamido)-N,N-dimethyl-1H-pyrazole-1-carboxamide ##STR00555## [0888] Step A. tert-butyl((1-(dimethylcarbamoyl)-3-((1r,3r)-3-hydroxycyclobutanecarboxamido)-1H-pyrazol-4-yl)methyl)carbamate: To a mixture of tert-butyl ((3-amino-1-(dimethylcarbamoyl)-1H-pyrazol-4-yl)methyl)carbamate (300 mg, 1.0 equiv) and (1r,3r)-3-hydroxycyclobutanecarboxylic acid (184 mg, 1.5 equiv) in DMF (9 mL) were added TEA (321 mg, 3.0 equiv) and T3P (1.01 g, 50% purity in EtOAc, 1.5 equiv). The reaction was stirred at 20 C. for 3 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (130 mg, 32% yield) as a yellow oil; .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6) =7.94-7.83 (m, 1H), 7.20-7.05 (m, 1H), 5.26-5.10 (m, 1H), 5.10-5.01 (m, 1H), 4.32-4.21 (m, 1H), 3.91-3.86 (m, 2H), 3.84 (br d, J=6.0 Hz, 1H), 3.11 (br s, 6H), 2.40-2.36 (m, 2H), 2.12-2.02 (m, 2H), 1.38-1.37 (m, 9H). [0889] Step B. 4-(aminomethyl)-3-((1r,3r)-3-hydroxycyclobutanecarboxamido)-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a mixture of tert-butyl((1-(dimethylcarbamoyl)-3-((1r,3r)-3-hydroxycyclobutanecarboxamido)-1H-pyrazol-4-yl)methyl)carbamate (130 mg, 1.0 equiv) in ACN (0.6 mL) was added HCl.Math.dioxane (4 M, 1.28 mL, 15 equiv). The reaction was stirred at 20 C. for 0.5 hour. The mixture was concentrated to afford the title compound (108 mg, crude, HCl) as a yellow oil. [0890] Step C. 4-(((7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-3-((1r,3S)-3-hydroxycyclobutanecarboxamido)-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a mixture of 7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (64 mg, 1.0 equiv) and 4-(aminomethyl)-3-((1r,3r)-3-hydroxycyclobutanecarboxamido)-N,N-dimethyl-1H-pyrazole-1-carboxamide (108 mg, 4.0 equiv, HCl) in ACN (0.5 mL) and DMF (0.5 mL) were added K.sub.3PO.sub.4 (144 mg, 8.0 equiv) and 4 molecular sieves (40 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was concentrated and purified by prep-HPLC [Phenomenex luna C 18 15025 mm10 m; A: water (FA), B: ACN; B %: 15%-45% over 10 min] to afford the title compound (30 mg, 43% yield) as a white solid; SFC: >99% ee, Column: Chiralcel OJ-3 504.6 mm I.D., 3 m; Gradient elution: MeOH (0.05% DEA) in CO.sub.2 from 5% to 40%; 3 mL/min; 220 nm; t.sub.R: 1.579 min; .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6 =10.29-10.20 (m, 1H), 10.09-9.99 (m, 1H), 9.31-9.26 (m, 1H), 9.25-9.18 (m, 1H), 8.18-8.15 (m, 1H), 7.97-7.90 (m, 1H), 7.59-7.52 (m, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.20-7.15 (m, 1H), 5.42-5.23 (m, 1H), 4.62-4.55 (m, 2H), 4.28-4.19 (m, 2H), 4.18-4.09 (m, 1H), 3.12 (br s, 6H), 2.95-2.87 (m, 1H), 2.38-2.28 (m, 4H), 2.24-2.11 (m, 2H), 2.10-1.97 (m, 4H), 1.96-1.75 (m, 4H); .sup.1H NMR (400 MHZ, dimethylsulfoxide-d.sub.6+deuterium oxide-d.sub.2) =9.26-9.21 (m, 1H), 8.19-8.11 (m, 1H), 7.94-7.87 (m, 1H), 7.58-7.50 (m, 1H), 7.45-7.40 (m, 1H), 7.19-7.15 (m, 1H), 5.42-5.24 (m, 1H), 4.63-4.53 (m, 2H), 4.15 (s, 3H), 3.31-3.20 (m, 2H), 3.20-3.15 (m, 1H), 3.09 (br s, 6H), 2.97-2.89 (m, 1H), 2.36-2.27 (m, 3H), 2.25-2.19 (m, 1H), 2.16-2.12 (m, 1H), 2.09-1.97 (m, 3H), 1.96-1.75 (m, 3H); 19F NMR (376 MHz, dimethylsulfoxide-d.sub.6+deuterium oxide-d.sub.2) =114.879, 140.224, 172.016; LCMS (ESI, M+1): m/z=780.1. Example 776 ##STR00556## (3R)-1-(7-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00557## ##STR00558## ##STR00559## [0891] Step A: ethyl 1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate: To a solution of ethyl 1H-pyrazole-4-carboxylate (150 g, 1.0 equiv) and DABCO (132 g, 1.1 equiv) in MeCN (1500 mL) was added N,N-dimethylsulfamoyl chloride (169 g, 1.1 eq) at 20 C. portionwise. The reaction was stirred at 20 C. for 2 hours. The mixture was concentrated under vacuum at 40 C. The mixture was diluted with water (800 mL) and extracted with EtOAc (3500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, concentrated, and purified with column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 10:1-3:1) to afford the title compound (550 g, 99% yield) as a white solid; LCMS (ESI, M+1): m/z=248.0. [0892] Step B: (2-amino-5-bromo-4-fluorophenyl)methanol: To a solution of 2-amino-5-bromo-4-fluorobenzoic acid (90.0 g, 1.0 equiv) in THF (1000 mL) was added BH.sub.3.Math.Me.sub.2S (115 mL, 10 M, 3.0 equiv) at 0 C. The reaction was stirred at 20 C. for 12 hours. The mixture was quenched by slow addition of MeOH (700 mL) at 0 C. The mixture was concentrated and diluted with EtOAc (300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 10:1-3:1) to afford the title compound (92.0 g, crude) as a yellow solid. [0893] Step C. (2-amino-4-fluoro-5-vinylphenyl)methanol: To a mixture of (2-amino-5-bromo-4-fluorophenyl)methanol (170 g, 1.0 equiv), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (259 g, 2.5 equiv) and Cs.sub.2CO.sub.3 (755 g, 3.0 equiv) in dioxane (1500 mL), H.sub.2O (500 mL) was added bis-triphenylphosphine-palladium(II) chloride (28.3 g, 0.050 equiv). The reaction was degassed and stirred at 90 C. for 12 hours under nitrogen atmosphere. The mixture was diluted with H.sub.2O (900 mL) and extracted with EtOAc (21000 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 1:3) to afford the title compound (124 g, 96% yield) as a yellow solid; LCMS (ESI, M17): m/z=150.0. [0894] Step D. (2-amino-5-ethyl-4-fluorophenyl)methanol: To a mixture of (2-amino-4-fluoro-5-vinylphenyl)methanol (93.0 g, 1.0 equiv) in MeOH (900 mL) was added Pd/C (4.5 g, 5% purity) under nitrogen atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The reaction was stirred under H.sub.2 (15 Psi) at 20 C. for 24 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (52.8 g, 49% yield) as a yellow solid; LCMS (ESI, M17): m/z=152.0. [0895] Step E. (2-chloro-5-ethyl-4-fluorophenyl)methanol: To a cooled solution of (2-amino-5-ethyl-4-fluorophenyl)methanol (75.0 g, 1.0 equiv) in MeCN (1000 mL), H.sub.2O (500 mL) and HCl (258 mL, 12 M, 7.0 equiv) was added dropwise a solution of NaNO.sub.2 (36.7 g, 1.2 equiv) in H.sub.2O (250 mL). The reaction was stirred at 0 C. for 1 hour. CuCl (263 g, 6.0 equiv) was added to the cooled mixture. The reaction was stirred at 70 C. for another 1 hour. The mixture was diluted with H.sub.2O (100 mL). The mixture was concentrated under reduced pressure to remove MeCN. The mixture was filtered to remove residue. The mixture was diluted with H.sub.2O (50 mL) and extracted with EtOAc (21000 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 5:1) to afford the title compound (28.9 g, 32% yield) as yellow solid; LCMS (ESI, M17): m/z=171.0. [0896] Step F. 1-(bromomethyl)-2-chloro-5-ethyl-4-fluorobenzene: A mixture of (2-chloro-5-ethyl-4-fluorophenyl)methanol (15.0 g, 1.0 equiv) in DCM (100 mL) and PBr.sub.3 (43.1 g, 2.0 equiv) was stirred at 0 C. for 1 hour. The mixture was quenched with water (250 mL) and extracted with EtOAc (2100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 50:1 to 10:1) to afford the title compound (10.8 g, 51% yield) as a white oil; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =7.41 (d, J=8.0 Hz, 1H), 7.15 (d, J=9.6 Hz, 1H), 4.60 (s, 2H), 2.69-2.58 (m, 2H), 1.23-1.18 (m, 3H). [0897] Step G. ethyl 5-(2-chloro-5-ethyl-4-fluorobenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate: To a solution of 1-(bromomethyl)-2-chloro-5-ethyl-4-fluorobenzene (6.89 g, 1.0 equiv) in THF (50 mL) were added LDA (18.1 mL, 2 M, 1.3 equiv) and HMPA (6.49 g, 1.3 equiv) at 78 C. for 0.5 hour. Then 4-(1-ethoxyvinyl)-N,N-dimethyl-1H-pyrazole-1-sulfonamide (5.61 g, 0.80 equiv) was added into the mixture. The reaction was stirred at 78 C. for 0.5 hour. The reaction was warmed to 20 C. and stirred at 20 C. for 0.5 hour. The mixture was quenched with water (50 mL) at 0 C. and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC (column: YMC Triart C18 25050 mm7 m; mobile phase: [water (FA)-ACN]; B %: 55%-75% over 20 min) to afford the title compound (5.28 g, 43% yield) as a yellow solid; LCMS (ESI, M+1): m/z=418.0. [0898] Step H. 5-(2-chloro-5-ethyl-4-fluorobenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid: To a mixture of ethyl 5-(2-chloro-5-ethyl-4-fluorobenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate (5.70 g, 1.0 equiv) in dioxane (50 mL) and H.sub.2O (50 mL) was added NaOH (10.9 g, 20 equiv). The reaction was stirred at 100 C. for 2 hours. The mixture was diluted with ethyl acetate (350 mL) and separated. The organic layer was dried over anhydrous sodium sulfate and concentrated to afford the title compound (7.5 g, crude) as a yellow solid and used for the next step without further purification; LCMS (ESI, M+1): m/z=389.9. [0899] Step I. 8-chloro-5-ethyl-6-fluoro-1H-benzo[f]indazol-4-ol: The mixture of 5-(2-chloro-5-ethyl-4-fluorobenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid (4.40 g, 1.0 equiv) in CF.sub.3SO.sub.3H (44 mL) was stirred at 90 C. for 2 hours. The mixture was diluted with NaHCO.sub.3 aqueous solution and extracted with ethyl acetate (330 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC (column: Phenomenex Luna C18 10030 mm5 m; mobile phase: [water (FA)-ACN]; B %: 19%-49% over 8 min) to afford the title compound (1.17 g, 39% yield) as a yellow solid; LCMS (ESI, M+1): m/z=264.8. [0900] Step J: 8-chloro-5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol: To a solution of 8-chloro-5-ethyl-6-fluoro-1H-benzo[f]indazol-4-ol (1.80 g, 1.0 equiv) and DHP (1.14 g, 2.0 equiv) in THF (20 mL) was added TsOH.Math.H.sub.2O (12.9 mg, 0.010 equiv). The reaction was stirred at 20 C. for 2 hours. The mixture was diluted with water (35 mL) and extracted with EtOAc (315 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reversed phase flash chromatography (C18, 0.1% formic acid condition) to afford the title compound (1.0 g, 42% yield) as a yellow solid. LCMS (ESI, M83): m/z=265.0. [0901] Step K: 5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol: To a solution of 8-chloro-5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol (2.90 g, 1.0 equiv) and NaHCO.sub.3 (2.10 g, 3.0 equiv) in MeOH (50 mL) was added Pd/C (1.0 g, 10% purity) under N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The reaction was stirred under H.sub.2 (15 Psi) at 20 C. for 12 hours. The mixture was diluted with H.sub.2O (40 mL). The mixture was concentrated at 25 C. The mixture was extracted with dichloromethane (340 mL) and dried over anhydrous sodium sulfate, concentrated at 25 C. under reduced pressure and purified with reversed phase flash chromatography (C18, 0.1% formic acid condition) to afford the title compound (2.2 g, 84% yield) as a yellow solid. LCMS (ESI, M83): m/z=231.0. [0902] Step L: 5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate: To a solution of 5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol (1.10 g, 1.0 equiv), DIPEA (1.81 g, 4.0 equiv) and 4 molecular sieves (50.0 mg) in DCM (20 mL) was added Tf.sub.2O (1.97 g, 2.0 equiv) at 40 C. The reaction was stirred at 40 C. for 0.5 hour. The mixture was diluted with water (330 mL) and extracted with EtOAc dichloromethane (3 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated at 25 C. under reduced pressure, and purified with column (Al.sub.2O.sub.3, petroleum ether/ethyl acetate 20:1-5:1) to afford the title compound (1.0 g, crude) as a yellow solid. LCMS (ESI, M83): m/z=362.7. [0903] Step M: 5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole: To a solution of 5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (800 mg, 1.0 equiv), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.29 g, 10 equiv) and TEA (544 mg, 3.0 equiv) in MeCN (10 mL) was added bis(triphenylphosphine)palladium(II) chloride (131 mg, 0.10 equiv). The reaction was stirred at 80 C. for 3 hours. The mixture was diluted with water (315 mL) and extracted with dichloromethane (315 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography (C18, 0.1% formic acid condition) to afford the title compound (120 mg, 16% yield) as a yellow solid. LCMS (ESI, M+1): m/z=425.2. [0904] Step N: (3R)-1-(7-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (100 mg, 1.0 equiv), 5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole (112 mg, 1.2 equiv) and K.sub.3PO.sub.4 (1.5 M, 3.0 equiv) in methoxycyclopentane (2 mL) was added CataCXium A Pd G3 (16.1 mg, 0.10 equiv). The reaction was stirred at 90 C. for 4 hours. The mixture was diluted with water (35 mL) and extracted with dichloromethane (35 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography (C18, 0.1% formic acid condition) to afford the title compound (68 mg, 42% yield) as a yellow oil. LCMS (ESI, M+1): m/z=716.5. [0905] Step O: (3R)-1-(7-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(7-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (35.0 mg, 1.0 equiv) in DCM (0.6 mL) was added TFA (924 mg, 166 equiv). The mixture was stirred at 20 C. for 10 minutes. The mixture was concentrated at 20 C. The residue was adjusted with saturated NaHCO.sub.3 aqueous solution to pH7, extracted with dichloromethane (23 mL). The combined organic layer was concentrated and purified with prep-HPLC (column: Welch Xtimate C18 15025 mm5 m; mobile phase: [water (TFA)-ACN]; B %: 18%-48% over 10 min) to afford the title compound (9.78 mg, 31% yield, TFA) as an off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.41 (d, J=3.6 Hz, 1H), 8.26 (s, 1H), 8.02 (dd, J=6.0, 9.2 Hz, 1H), 7.71 (d, J=16.4 Hz, 1H), 7.34 (t, J=9.2 Hz, 1H), 5.66-5.48 (m, 1H), 4.78-4.70 (m, 2H), 4.69 (s, 1H), 4.42 (br t, J=14.8 Hz, 1H), 4.11-3.95 (m, 1H), 3.94-3.80 (m, 2H), 3.74-3.57 (m, 1H), 3.54-3.40 (m, 2H), 2.80-2.56 (m, 3H), 2.49-2.28 (m, 4H), 2.25-2.09 (m, 2H), 1.95-1.76 (m, 3H), 1.32 (d, J=6.8 Hz, 3H), 0.92-0.81 (m, 3H); LCMS (ESI, M+1): m/z=632.3. Example 777 ##STR00560## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-methoxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00561## [0906] Step A. 2-(8-ethyl-7-fluoro-3-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (5.0 g, 1.0 equiv) in MeOH (50 mL) was added slowly diazomethyl(trimethyl) silane (2 M, 23.7 mL, 3.0 equiv) during period of 30 minutes. The mixture was stirred at 15 C. for 24 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (4 20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 100:1 to 50:1] to afford the title compound (4.50 g, 85% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =7.72-7.54 (m, 1H), 7.40-6.99 (m, 3H), 3.88 (s, 3H), 3.11-3.01 (m, 2H), 1.42 (br s, 12H), 1.25-1.26 (m, 3H); LCMS (ESI, M+1): m/z=331.3 [0907] Step B. 7-(8-ethyl-7-fluoro-3-methoxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: A mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (4.50 g, 1.0 equiv), Cs.sub.2CO.sub.3 (1.5 M, 20.5 mL, 3.0 equiv), 2-(8-ethyl-7-fluoro-3-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.06 g, 1.2 equiv) in methoxycyclopentane (100 mL) was degassed and then AdanBuP-Pd-G3 (747 mg, 0.1 equiv) was added. The mixture was stirred at 100 C. for 12 hours under N.sub.2 atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (410 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (3.0 g, 46% yield) as a yellow oil; LCMS (ESI, M+1): m/z=607.1 [0908] Step C. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-methoxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 7-(8-ethyl-7-fluoro-3-methoxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.50 g, 1.0 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (472 mg, 1.5 equiv) in DMF (5 mL) was added DIPEA (959 mg, 3.0 equiv). The mixture was stirred at 40 C. for 12 hours. The reaction mixture was filtered and purified with prep-HPLC [column: Kromasil Eternity XT 25080 mm10 m; A: water (10 mM NH.sub.4HCO.sub.3), B: ACN, B %: 50%-80% over 20 min] and lyophilized to afford the title compound (1.50 g, 95% yield) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.23 (d, J=19.2 Hz, 1H), 7.83-7.79 (m, 1H), 7.45 (d, J=2.8 Hz, 1H), 7.32-7.27 (m, 1H), 7.14-7.10 (m, 1H), 5.37-5.23 (m, 1H), 5.03-4.97 (m, 1H), 4.78-4.75 (m, 1H), 4.35-4.29 (m, 2H), 4.23-4.19 (m, 1H), 3.95 (s, 3H), 3.83-3.76 (m, 1H), 3.50-3.43 (m, 1H), 3.28-3.17 (m, 3H), 3.03-3.00 (m, 1H), 2.55-2.47 (m, 1H), 2.40-2.30 (m, 2H), 2.26-2.10 (m, 5H), 2.02-1.86 (m, 4H), 1.82-1.80 (m, 1H), 1.42-1.38 (m, 1H), 0.83-0.77 (m, 3H); LCMS (ESI, M+1): m/z=634.2. Example 778 ##STR00562## (1R,5R,6R)-3-(7-(8-ethyl-4,7-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00563## [0909] Step A. 5-ethyl-1,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol: To a solution of 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (1.50 g, 1.0 equiv) in MeCN (15 mL) was added Select F (1.68 g, 1.0 equiv) at 0 C. The reaction was stirred at 0-20 C. for 12 hours. The mixture was filtered and purified with reversed-phase HPLC (0.1% FA condition) to afford the title compound (650 mg, 40% yield) as a brown solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.06 (s, 1H), 7.85 (dd, J=6.0, 9.2 Hz, 1H), 7.45-7.35 (m, 2H), 3.03 (dq, J=2.0, 7.6 Hz, 2H), 1.42-1.30 (m, 12H), 1.21-1.15 (m, 3H); LCMS (ESI, M+1): m/z=334.9. [0910] Step B. 5-ethyl-1,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: A mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv), 5-ethyl-1,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (343 mg, 1.5 equiv), CataCXium A Pd G3 (49.8 mg, 0.10 equiv) and Cs.sub.2CO.sub.3 (668 mg, 3.0 equiv) in methoxycyclopentane (3 mL) and H.sub.2O (0.75 mL) was degassed and stirred at 90 C. for 2 hours under nitrogen atmosphere. The mixture was diluted with H.sub.2O (3 mL) and extracted with EtOAc (35 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed-phase HPLC (0.1% FA condition) to afford the title compound (80.0 mg, 12% yield) as a yellow solid; LCMS (ESI, M+1): m/z=611.3. [0911] Step C. (1R,5R,6R)-3-(7-(8-ethyl-4,7-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 5-ethyl-1,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (80.0 mg, 1.0 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (25.0 mg, 1.5 equiv) in DMF (0.5 mL) were added DIPEA (371 mg, 22 equiv) and 4 molecular sieves (10.0 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by reversed-phase HPLC (0.1% FA condition) and purified by prep-HPLC (column: Welch Xtimate C18 15025 mm5 m; mobile phase: [water (NH.sub.3.Math.H.sub.2O)-ACN]; B %: 22%-52%, 8 min) to afford the title compound (23.8 mg, 28% yield) as a yellow solid; .sup.1H NMR (400 MHz, METHANOL-d.sub.4) =9.22 (d, J=19.6 Hz, 1H), 7.99 (dd, J=6.0, 9.2 Hz, 1H), 7.35 (t, J=9.2 Hz, 1H), 7.18 (dd, J=8.8, 14.4 Hz, 1H), 5.39-5.22 (m, 1H), 4.68-4.53 (m, 2H), 4.37-4.28 (m, 2H), 4.25-4.17 (m, 1H), 3.85-3.74 (m, 1H), 3.46 (br dd, J=13.2, 16.8 Hz, 1H), 3.30-3.16 (m, 3H), 3.06-2.95 (m, 1H), 2.55-2.11 (m, 8H), 2.04-1.75 (m, 5H), 1.40 (br d, J=13.6 Hz, 1H), 0.91-0.69 (m, 3H); LCMS (ESI, M+1): m/z=638.4. Example 779 ##STR00564## (5R)-7-(7-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione ##STR00565## [0912] Step A. (5R)-7-(7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of 7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (60.0 mg, 1.0 equiv) and (5R)-1,3,9-triazaspiro[4.5]decane-2,4-dione (43.1 mg, 3.0 equiv) in DMF (0.5 mL) was added DIPEA (32.9 mg, 3.0 equiv). The mixture was stirred at 40 C. for 12 hours. The mixture was filtered, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] followed by prep-HPLC [Phenomenex C18 7530 mm3 m; A: water (10 mM FA), B: ACN, 2%-32% over 7 min] and lyophilized to afford the title compound (50.0 mg, 76% yield) as an off-white solid; LCMS (ESI, M+1): m/z=776.3. [0913] Step B. (5R)-7-(7-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4.3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of (5R)-7-(7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.0 equiv) in DCM (0.25 mL) was added TFA (1.93 g, 1.25 mL, 262 equiv). The mixture was stirred at 20 C. for 10 minutes. The reaction mixture was concentrated and purified with prep-HPLC [Unisil 3-100 C18 Ultra 15050 mm3 m; A: water (10 mM FA), B: ACN, B %: 12%-42% over 7 min] and lyophilized to afford the title compound (11.4 mg, 26% yield) as an off-white solid (0.61 formic acid salt); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.26 (d, J=1.6 Hz, 1H), 7.81 (d, J=6.8 Hz, 2H), 4.72-4.63 (m, 1H), 4.57-4.46 (m, 3H), 3.95-3.76 (m, 2H), 3.51-3.42 (m, 2H), 3.13-2.99 (m, 2H), 2.33-2.20 (m, 3H), 2.17-1.93 (m, 10H), 0.97-0.86 (m, 1H), 0.70-0.53 (m, 1H), 0.35-0.24 (m, 1H), 0.17-0.02 (m, 1H); LCMS (ESI, M+1): m/z=646.2. Example 780 ##STR00566## (5R)-7-(7-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione [0914] The title compound was synthesized from Intermediate 25 according to the 2-step procedure described for example 779 to produce the desired compound as yellow solid (0.38FA); .sup.1H NMR (400 MHz, methanol-d4) =9.24 (d, J=2.4 Hz, 1H), 7.80 (d, J=9.6 Hz, 2H), 5.47 (d, J=36.0 Hz, 1H), 4.69-4.62 (m, 1H), 4.49-4.36 (m, 3H), 3.85-3.72 (m, 2H), 3.48-3.35 (m, 4H), 3.25-3.11 (m, 1H), 2.53-2.33 (m, 2H), 2.30-2.20 (m, 2H), 2.17-2.07 (m, 3H), 2.05-1.92 (m, 3H), 1.03-0.80 (m, 1H), 0.69-0.50 (m, 1H), 0.34-0.19 (m, 1H), 0.10-0.06 (m, 1H); LCMS (ESI, M+1, M+3): m/z=664.2. Example 781 ##STR00567## (1R,5R,6R)-3-(7-(4-bromo-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00568## [0915] Step A. 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.00 g, 2.28 mmol, 1.0 equiv) and 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (859 mg, 2.73 mmol, 1.2 equiv) in methoxycyclopentane (50 mL) under N.sub.2 were added CataCxium A Pd G3 (166 mg, 228 mol, 0.1 equiv) and Cs.sub.2CO.sub.3 (1.5 M, 4.56 mL, 3.0 equiv). The reaction was stirred at 100 C. for 6 hours under N.sub.2. The reaction mixture was diluted with H.sub.2O (25 mL) and extracted with EtOAc (25 mL3). The combined organic layers were washed with brine (20 mL1), dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by reversed-phase HPLC [0.1% NH.sub.3.Math.H.sub.2O] to afford the title compound (640 mg, 1.02 mmol, 44% yield, 94% purity) as a yellow solid; LCMS (ESI, M+1): m/z=591.4. [0916] Step B. (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (640 mg, 1.0 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (266 mg, 1.5 equiv, HCl) in DMF (1.92 mL) were added DIPEA (700 mg, 5.0 equiv) and 4 MS (256 mg). The reaction was stirred at 60 C. for 12 hours. The mixture was filtered, concentrated and purified by reversed-phase HPLC [0.1% FA condition] to afford the title compound (480 mg, 71% yield) as a yellow solid. LCMS (ESI, M+1): m/z=618.5. [0917] Step C. (1R,5R,6R)-3-(7-(4-bromo-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 equiv) in THF (2 mL) was added 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (55.5 mg, 1.2 equiv). The reaction was stirred at 20 C. for 2 hours. The reaction mixture was diluted with H.sub.2O (15 mL) and extracted with EtOAc (15 mL3). The combined organic layers were washed with brine (20 mL1), dried over Na.sub.2SO.sub.4, filtered, concentrated and purified with prep-HPLC [column: Phenomenex luna C18 150*25 mm*10 m; mobile phase: [water (FA)-ACN]; B %: 24%-54%, 10 min] to afford the title compound (22 mg, 30.6 mol, 18% yield, 97% purity) as a white solid; LCMS (ESI, M+1): m/z=696.2. [0918] Step D. (1R,5R,6R)-3-(7-(4-bromo-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: A solution of (1R,5R,6R)-3-(7-(4-bromo-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (22 mg, 31.6 mol, 1.0 equiv) in HCl/MeOH (2 mL) was stirred at 0 C. for 0.5 hour. The mixture was concentrated and dissolved in MeCN (5 mL). The pH was adjusted to 7 with solid NaHCO.sub.3. The mixture was filtered, concentrated and purified with prep-HPLC [column: Phenomenex Synergi C18 150*25 mm*10 m; mobile phase: [water (FA)-ACN]; B %: 13%-43%, 10 min] to afford the title compound (8 mg, 11.3 mol, 35% yield, 99% purity, 0.15 FA) as a yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) =10.86 (br s, 1H), 9.43 (s, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.72-7.53 (m, 2H), 7.45 (s, 1H), 7.41-7.33 (m, 1H), 5.57-5.30 (m, 1H), 4.87-4.70 (m, 2H), 4.63 (br d, J=11.6 Hz, 1H), 4.46-4.22 (m, 2H), 4.17 (br dd, J=5.2, 10.0 Hz, 1H), 3.74 (br d, J=12.0 Hz, 1H), 3.38 (br d, J=12.8 Hz, 1H), 3.16 (br s, 2H), 3.13-2.96 (m, 1H), 2.89-2.72 (m, 1H), 2.39-2.21 (m, 3H), 2.20-1.87 (m, 6H), 1.78 (br d, J=10.4 Hz, 1H), 1.72-1.60 (m, 1H), 1.25 (br d, J=14.0 Hz, 1H); LCMS (ESI, M+3): m/z=652.0, 654.0. Example 782 ##STR00569## (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-hydroxy-4-(trifluoromethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00570## [0919] Step A. 4-bromo-1-iodonaphthalen-2-ol: To a solution of 4-bromonaphthalen-2-ol (100 mg, 448.30 mol, 1 eq) in acetic acid (1.0 mL) was added NIS (151 mg, 1.5 equiv). The mixture was stirred at 25 C. for 3 hours under N.sub.2 atmosphere. The mixture was poured into ice water (10 mL) and extracted with ethyl acetate (330 mL). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by reversed phase flash chromatography [water (0.1% formic acid)/acetonitrile) 0%-100%] to afford 4-bromo-1-iodonaphthalen-2-ol (50.0 mg, 32% yield) as a brown solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.80 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.23 (dt, J=1.2, 7.6 Hz, 1H), 7.16-7.10 (m, 1H), 5.43 (s, 1H). [0920] Step B. 4-bromo-1-iodo-2-(methoxymethoxy)naphthalene: To a solution of 4-bromo-1-iodo-naphthalen-2-ol (100 mg, 1.0 equiv) and N-ethyl-N-isopropylpropan-2-amine (111 mg, 3.0 equiv) in dichloromethane (2.0 mL) was added bromo(methoxy) methane (71.6 mg, 2.0 equiv). The mixture was stirred at 25 C. for 1 hour. The mixture was poured into ice water (10 mL) and extracted with ethyl acetate (330 mL). The organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate 50:1 to 5:1) to afford the title compound (100 mg, 89% yield) as a yellow solid; .sup.1H NMR (400 MHz, CHLOROFORM-d) =8.28-8.13 (m, 2H), 7.74 (s, 1H), 7.64-7.46 (m, 2H), 5.36 (s, 2H), 3.59 (s, 3H). [0921] Step C. 4-bromo-2-(methoxymethoxy)-1-(trifluoromethyl)naphthalene: To a solution of 4-bromo-1-iodo-2-(methoxymethoxy)naphthalene (100 mg, 1.0 equiv) and methyl 2,2-difluoro-2-fluorosulfonyl-acetate (978 mg, 20 equiv) in N,N-dimethylacetamide (2.0 mL) was added CuI (485 mg, 10 equiv). The reaction mixture was stirred at 90 C. for 18 hours. The mixture was poured into ice water (10 mL) and extracted with ethyl acetate (330 mL). The organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with prep-TLC (SiO.sub.2, Petroleum ether/Ethyl acetate 10:1) to afford the title compound (50.0 mg, 59% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.27 (d, J=8.4 Hz, 1H), 8.23 (br d, J=8.8 Hz, 1H), 7.85 (s, 1H), 7.64-7.59 (m, 1H), 7.57-7.50 (m, 1H), 5.32 (s, 2H), 3.57 (s, 3H). [0922] Step D. (3-(methoxymethoxy)-4-(trifluoromethyl)naphthalen-1-yl)trimethylstannane: To a mixture of 4-bromo-2-(methoxymethoxy)-1-(trifluoromethyl)naphthalene (50 mg, 1.0 equiv) and Pd(PPh.sub.3).sub.4 (17.2 mg, 0.10 equiv) in toluene (2.0 mL) was added trimethyl(trimethylstannyl) stannane (0.990 g. 20 equiv) at 25 C. under N.sub.2. The reaction mixture was stirred at 90 C. for 2.5 hours under N.sub.2 atmosphere. The mixture was poured into ice water (5 mL) and extracted with ethyl acetate (310 mL). The organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with column chromatography by prep-TLC (SiO.sub.2, DCM:PE 0:1) to afford the title compound (2.00 mg, 3.2% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.41-8.21 (m, 1H), 7.78 (br d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.60-7.53 (m, 1H), 7.51-7.43 (m, 1H), 5.58-5.21 (m, 2H), 3.59 (s, 3H), 0.73-0.32 (m, 9H) [0923] Step E. 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-(methoxymethoxy)-4-(trifluoromethyl)naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of [3-(methoxymethoxy)-4-(trifluoromethyl)-1-naphthyl]-trimethyl-stannane (477 mg, 1.0 equiv), 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1.0 equiv), CuI (86.8 mg, 0.40 equiv) in toluene (20 mL) were added Pd(dppf)Cl.sub.2 (83.4 mg, 0.10 equiv) and (+)-2,2-bis(diphenylposphino)-1,1-binaphthalene (142 mg, 228 mol, 0.20 equiv). The reaction mixture was stirred at 90 C. for 12 hours under N.sub.2 atmosphere. The mixture was poured into ice water (10 mL) and extracted with ethyl acetate (320 mL). The organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with reversed phase flash chromatography [water (0.1% formic acid)/acetonitrile) 0% to 100%] to afford the title compound (170 mg, 20% yield) as a yellow solid. LCMS (ESI, M+1): m/z=659.2 [0924] Step F. (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-(methoxymethoxy)-4-(trifluoromethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-4-(trifluoromethyl)naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (150 mg, 1.0 equiv), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (57.9 mg, 2.0 equiv) in N,N-dimethylformamide (1.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (147 mg, 5.0 equiv) and 4 molecular sieves (100 mg). The reaction mixture was stirred at 40 C. for 36 hours under N.sub.2 atmosphere. The reaction mixture was poured into ice water (10 mL) and extracted with ethyl acetate (320 mL). The organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with reversed phase flash chromatography [water (0.1% formic acid)/acetonitrile) 0% to 100%] to afford the title compound (140 mg, 90% yield) as a yellow solid. LCMS (ESI, M+1): m/z=686.1 [0925] Step G. (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-hydroxy-4-(trifluoromethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: A mixture of (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-4-(trifluoromethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (110 mg, 160.42 mol, 1 eq) and HCl.Math.MeOH (4 M, 1.10 mL, 27.43 eq) in MeOH (1 mL) was stirred at 25 C. for 10 min under N.sub.2 atmosphere. The mixture was poured into ice water (10 mL) and extracted with ethyl acetate (320 mL). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with prep-HPLC [column: Unisil 3-100 C18 Ultra 15050 mm3 m; A: water (FA); B: ACN, B %: 20%-50% over 7 min] to afford the title compound (36.4 mg, 35% yield, 0.74 HCOOH salt) as a white solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.09 (s, 1H), 8.16 (br d, J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.35-7.28 (m, 1H), 5.50-5.30 (m, 1H), 5.12 (br d, J=12.0 Hz, 1H), 4.85 (br d, J=10.8 Hz, 1H), 4.39 (br d, J=11.2 Hz, 1H), 4.36-4.26 (m, 2H), 3.89 (br dd, J=1.6, 14.0 Hz, 1H), 3.83-3.60 (m, 3H), 3.42-3.28 (m, 2H), 3.20-3.08 (m, 1H), 2.70-2.45 (m, 1H), 2.44-2.35 (m, 1H), 2.33-2.25 (m, 2H), 2.25-2.06 (m, 4H), 1.83-1.69 (m, 2H), 1.21 (br d, J=14.8 Hz, 1H). LCMS (ESI, M+1): m/z=642.2. Example 783 ##STR00571## (3R)-1-(2-((1-((dimethylamino)methyl)spiro[2.2]pentan-1-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00572## [0926] Step A. diethyl 2-(1-hydroxycyclopropyl) malonate: To a mixture of triethyl methanetricarboxylate (25.0 g, 1.0 equiv) and Ti(Oi-Pr).sub.4 (12.2 g, 0.4 equiv) in THF (200 mL) was added EtMgBr (3 M, 7.0 equiv). The reaction mixture was stirred at 20 C. for 1 hour under N.sub.2 atmosphere. The reaction mixture was quenched with aqueous HCl solution (4 M, 500 mL), extracted with EtOAc (500 mL), washed with brine (500 mL2), dried over Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 3:1] to afford the title compound (6.1 g, 26% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =4.26-4.17 (m, 4H), 3.86-3.69 (m, 1H), 2.94 (s, 1H), 1.24 (t, J=7.2 Hz, 6H), 0.92-0.83 (m, 2H), 0.65-0.58 (m, 2H). [0927] Step B. diethyl 2-cyclopropylidenemalonate: To a mixture of diethyl 2-(1-hydroxycyclopropyl) malonate (6.0 g, 1.0 equiv) and TEA (15.7 g, 7.0 equiv) in DCM (60.0 mL) was added methylsulfonyl methanesulfonate (7.7 g, 2.0 equiv). The reaction mixture was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. The mixture was poured into ice-water (50 mL), extracted with DCM (20 mL2), washed with brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 4:1] to afford the title compound (1.9 g, 43% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =4.31-4.28 (m, 4H), 1.55 (s, 4H), 1.35-1.31 (m, 6H). [0928] Step C. diethyl spiro[2.2]pentane-1,1-dicarboxylate: To a solution of trimethylsulfoxonium iodide (3.2 g, 1.5 equiv) in DMSO (20 mL) was added NaH (575 mg, 60% purity, 1.5 equiv). The mixture was stirred at 0 C. for 0.5 hour. Then diethyl 2-cyclopropylidenemalonate (1.9 g, 1.0 equiv) was added. The mixture was stirred at 25 C. for 12 hours. The reaction mixture was quenched with aqueous NH.sub.4Cl solution (30 mL) at 0 C., diluted with water (30 mL) and extracted with EtOAc (30 mL3). The combined organic layers were washed with brine (50 mL2), dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 4:1] to afford the title compound (680 mg, 33% yield) as a yellow oil. .sup.1H NMR (400 MHZ, xCHLOROFORM-d) =4.29-4.18 (m, 4H), 1.91 (s, 2H), 1.31-1.26 (m, 6H), 1.10-1.01 (m, 4H). [0929] Step D. 1-(ethoxycarbonyl)spiro[2.2]pentane-1-carboxylic acid: To a mixture of diethyl spiro[2.2]pentane-1,1-dicarboxylate (630 mg, 1.0 equiv) in EtOH (6 mL) was added aqueous NaOH solution (1 M, 1.1 equiv). The reaction mixture was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. The reaction mixture was adjusted to pH=2 with 1M HCl and extracted with EtOAc (10 mL). The combined layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated to afford the title compound (480 mg, 88% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =4.40-4.20 (m, 2H), 2.35 (d, J=3.2 Hz, 1H), 2.26 (d, J=3.2 Hz, 1H), 1.35-1.29 (m, 3H), 1.22-1.01 (m, 4H). [0930] Step E. ethyl 1-(dimethylcarbamoyl)spiro[2.2]pentane-1-carboxylate: To a mixture of 1-(ethoxycarbonyl)spiro[2.2]pentane-1-carboxylic acid (200 mg, 1.0 equiv), N-methylmethanamine (177 mg, 2.0 equiv, HCl salt) and HATU (826 mg, 2.0 equiv) in DCM (3 mL) was added DIEA (702 mg, 5.0 equiv). The mixture was stirred at 25 C. for 12 hours. The mixture was poured into ice-water (3 mL), extracted with EtOAc (6 mL), washed with brine (3 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 10:1 to 1:1] to afford the title compound (200 mg, 87% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =4.19 (q, J=7.2 Hz, 2H), 2.98 (s, 3H), 2.83 (s, 3H), 1.89-1.80 (m, 2H), 1.28-1.22 (m, 3H), 1.15-0.88 (m, 4H). [0931] Step F. (1-((dimethylamino)methyl)spiro[2.2]pentan-1-yl)methanol: To a mixture of ethyl 1-(dimethylcarbamoyl)spiro[2.2]pentane-1-carboxylate (150 mg, 1.0 equiv) in THF (1 mL) was added LiAlH.sub.4 (135 mg, 5.0 equiv) at 0 C. The reaction mixture was stirred at 25 C. for 1 hour. The mixture was added sat. Na.sub.2SO.sub.4 (3 mL) at 0 C., dried over anhydrous Na.sub.2SO.sub.4 and concentrated to afford the title compound (100 mg, 91% yield) as a yellow oil. [0932] Step G. (3R)-1-(2-((1-((dimethylamino)methyl)spiro[2.2]pentan-1-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (395 mg, 1.0 equiv) and (1-((dimethylamino)methyl)spiro[2.2]pentan-1-yl)methanol (180 mg, 1.0 equiv) in THF (2 mL) was added NaHMDS (1 M, 897 L, 1.5 equiv). The reaction mixture stirred at 10 C. for 1 hour under N.sub.2 atmosphere. The reaction mixture was quenched by addition of sat. aqueous NH.sub.4Cl solution (10 mL) at 0 C., extracted with EtOAc (20 mL), washed with brine (10 mL2), dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified with prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; mobile phase: [water (FA)-ACN]; B %: 23%-53%, 10 minutes] to afford the title compound (38 mg, 10% yield, HCOOH salt) as a white solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.23 (s, 1H), 7.90 (dd, J=6.0, 9.2 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.44 (t, J=9.6 Hz, 1H), 7.24 (s, 1H), 5.35 (s, 2H), 4.92-4.65 (m, 1H), 4.49 (br d, J=9.6 Hz, 1H), 4.42-4.16 (m, 2H), 4.12-3.92 (m, 1H), 2.67 (d, J=1.6 Hz, 1H), 2.33 (br s, 2H), 2.28-2.09 (m, 9H), 2.07-1.92 (m, 2H), 1.82-1.42 (m, 4H), 1.27-1.06 (m, 4H), 0.93-0.41 (m, 9H); LCMS (ESI, M+1): m/z=648.1. [0933] Step H. (3R)-1-(2-((1-((dimethylamino)methyl)spiro[2.2]pentan-1-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A solution of (3R)-1-(2-((1-((dimethylamino)methyl)spiro[2.2]pentan-1-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (38.0 mg, 1.0 equiv) in HCl.Math.MeOH (4 M, 1 mL, 68.2 equiv) was stirred at 0 C. for 1 hour. The mixture was poured into sat. aqueous NaHCO.sub.3 solution (5 mL), extracted with EtOAc (5 mL2), washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified with prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; mobile phase: [water (FA)-ACN]; B %: 18%-48%, 10 minutes] to afford the title compound (10.7 mg, 29% yield, 0.78 HCOOH salt) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.26 (dd, J=4.2, 6.9 Hz, 1H), 8.37 (s, 1H), 7.70 (dd, J=6.0, 8.8 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.27 (t, J=9.2 Hz, 1H), 7.08 (s, 1H), 4.78-4.52 (m, 3H), 4.46-4.26 (m, 2H), 3.74-3.54 (m, 1H), 3.52-3.35 (m, 2H), 2.88-2.63 (m, 7H), 2.62-2.38 (m, 1H), 2.35-2.06 (m, 2H), 1.98-1.69 (m, 3H), 1.42-1.19 (m, 5H), 1.14-0.71 (m, 7H); LCMS (ESI, M+1): m/z=604.4. Example 784 ##STR00573## 4-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5,6-dimethylindolin-2-one ##STR00574## [0934] Step A. (E)-N-(3-bromo-4,5-dimethylphenyl)-2-(hydroxyimino)acetamide: A mixture of 3-bromo-4,5-dimethyl-aniline (10.0 g, 1.0 equiv), 2,2,2-trichloroethane-1,1-diol (9.92 g, 1.2 equiv), Na.sub.2SO.sub.4 (28.4 g, 20.3 mL, 4.0 equiv) and NH.sub.2OH.Math.HCl (5.21 g, 1.5 equiv) in ethyl alcohol (200 mL) and H.sub.2O (200 mL) was degassed and stirred at 80 C. for 12 hours under N.sub.2 atmosphere. The reaction was extracted with ethyl acetate (3 500 mL). The combined organic layers were washed with brine (500 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with reversed phase flash chromatography [C 18, FA condition] to afford the title compound (7.50 g, crude) as a yellow solid. [0935] Step B. 4-bromo-5,6-dimethylindoline-2,3-dione: A mixture of (E)-N-(3-bromo-4,5-dimethylphenyl)-2-(hydroxyimino)acetamide (8.00 g, 1.0 equiv) and H.sub.2SO.sub.4 (18.1 M, 20 equiv) in H.sub.2O (32 mL) was stirred at 80 C. for 12 hours under N.sub.2 atmosphere. The mixture was cooled to room temperature. The pH was adjusted to 7 with ammonium hydroxide. The mixture was extracted with ethyl acetate (3 500 mL). The combined organic layers were washed with brine (500 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with reversed phase flash chromatography [C 18, 0.1% FA] to afford the title compound (2.00 g, 27% yield) as a yellow solid; LCMS (ESI, M+1): m/z=254.0. [0936] Step C. 4-bromo-5,6-dimethyl-2-oxoindolin-3-yl diethyl phosphate: To a solution of 4-bromo-5,6-dimethyl-indoline-2,3-dione (270 mg, 1.0 equiv), 1-ethoxyphosphonoyloxyethane (176 mg, 1.2 equiv) in acetonitrile (2.0 mL) was added Na.sub.2CO.sub.3 (11.3 mg, 0.10 equiv). The reaction mixture was stirred at 60 C. for 6 hours under N.sub.2 atmosphere. The mixture was diluted with water (20 mL) and extracted with dichloromethane (330 mL). The organic layers were washed with brine (500 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by trituration to afford the title compound (290 mg, 70% yield) as a yellow solid; LCMS (ESI, M+1): m/z=392.0. [0937] Step D. 4-bromo-5,6-dimethylindolin-2-one: To a solution of (4-bromo-5,6-dimethyl-2-oxo-indolin-3-yl) diethyl phosphate (200 mg, 1.0 equiv) in acetonitrile (1.0 mL) and H.sub.2O (0.2 mL) was added hydroiodic acid (572 mg, 57% purity, 5.0 equiv). The reaction mixture was stirred at 50 C. for 1 hour under N.sub.2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (320 mL). The organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by trituration to afford the title compound (100 mg, 82% yield) as a yellow solid; LCMS (ESI, M+1): m/z=240.0 [0938] Step E. 5,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indolin-2-one: To a solution of 4-bromo-5,6-dimethyl-indolin-2-one (500 mg, 1.0 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.06 g, 2.0 equiv), KOAc (613 mg, 3.0 equiv) in dioxane (10 mL) was added PCy3 Pd G2 (123 mg, 0.1 equiv). The reaction mixture was stirred at 80 C. for 12 hours under N.sub.2 atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (320 mL). The organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by reversed phase flash chromatography [C 18, water (FA); B: ACN, B %: 0%-75%, 25 min] to afford the title compound (100 mg, 82% yield) as a yellow solid; LCMS (ESI, M+1): m/z=288.1 [0939] Step F. 4-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5,6-dimethylindolin-2-one: To a solution of 5,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indolin-2-one (160 mg, 1.5 equiv), (R)-1-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (162 mg, 1.0 equiv) in toluene (3 mL) were added CataCXium A Pd G3 (27.1 mg, 0.10 equiv) and K.sub.3PO.sub.4 (1.5 M in H.sub.2O, 3.0 equiv). The reaction mixture was stirred at 100 C. for 12 hours under N.sub.2 atmosphere. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (330 mL). The organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with prep-HPLC [column: Welch Ultimate XB-SiOH 2505010 m; A: Hexane; B: EtOH, B %: 5%-45% over 15 min] and prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA); B: ACN, B %: 10%-40% over 10 min] to afford the title compound (22.5 mg, 11% yield, 0.84 HCOOH salt) as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.29 (d, J=8.8 Hz, 1H), 6.89 (s, 1H), 4.60 (s, 3H), 4.33 (br d, J=13.2 Hz, 1H), 3.74-3.52 (m, 3H), 3.51-3.32 (m, 2H), 3.27-3.10 (m, 2H), 2.58-2.33 (m, 4H), 2.32-2.25 (m, 2H), 2.24-2.08 (m, 6H), 2.08-2.00 (m, 4H), 1.94-1.69 (m, 3H), 1.30 (d, J=1.6 Hz, 3H). LCMS (ESI, M+1): m/z=561.4 Example 785 ##STR00575## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-(hydroxymethyl) pyrrolo[3,4-c]pyrazol-5 (2H,4H,6H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00576## [0940] Step A: 5-(tert-butoxycarbonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid: To a solution of 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid (40.0 mg, 1.0 equiv) and TEA (79.3 mg, 3.0 equiv) in DCM (2.00 mL) was added Boc.sub.2O (85.5 mg, 1.5 equiv). The mixture was stirred at 20 C. for 1 hour. The reaction mixture was concentrated and purified with prep-HPLC [FA condition; column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 21%-51%, 10 minutes] to afford the title compound (35.0 mg, 53% yield) as a white solid. LCMS (ESI, M+1): m/z=198.0. [0941] Step B: tert-butyl 3-(hydroxymethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5 (2H)-carboxylate: To a solution of 5-(tert-butoxycarbonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid (100 mg, 1.0 equiv) in THF (20.0 mL) was slowly added BH.sub.3.Math.Me.sub.2S (10 M, 197 L, 5.0 equiv). The mixture was stirred at 20 C. for 12 hours. The reaction mixture was quenched with methanol (1.0 mL) at 0 C., diluted with water (20.0 mL), extracted with ethyl acetate (20.0 mL2), washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and purified with prep-HPLC [TFA condition; column: 3_Phenomenex Luna C18 7530 mm3 um; mobile phase: [water (TFA)-ACN]; B %: 19%-39%, 9 minutes] to afford the title compound (60.0 mg, 64% yield) as a white solid. LCMS (ESI, M+1): m/z=240.1. [0942] Step C: (2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanol: To a solution of tert-butyl 3-(hydroxymethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5 (2H)-carboxylate (50.0 mg, 1.0 equiv) in DCM (0.75 mL) was added TFA (0.25 mL). The reaction mixture was stirred at 20 C. for 0.5 hour. The mixture was concentrated to afford the title compound (50.0 mg, crude) as a yellow oil. LCMS (ESI, M+1): m/z=140.1. [0943] Step D: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-(hydroxymethyl) pyrrolo[3,4-c]pyrazol-5 (2H,4H,6H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of (2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanol (50.0 mg, 3.0 equiv), K.sub.3PO.sub.4 (254 mg, 10.0 equiv) and 4 molecular sieves (100 mg) in DMF (5.0 mL) was added 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (71.0 mg, 1.0 equiv). The mixture was stirred at 60 C. for 2 hours. The reaction mixture was diluted with water (50.0 mL), extracted with ethyl acetate (50.0 mL2), washed with brine (50.0 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [basic condition; column: Waters Xbridge 15025 mm5 m; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 27%-57%, 9 minutes] to afford the title compound (12.5 mg, 16% yield) as a white solid. .sup.1H NMR (400 MHZ, CD.sub.3OD) =9.43 (s, 1H), 7.67 (dd, J=6.0, 8.8 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.07 (s, 1H), 5.41-5.07 (m, 5H), 4.71 (s, 2H), 4.66-4.51 (m, 1H), 4.47-4.25 (m, 2H), 3.26-3.18 (m, 2H), 3.08-2.98 (m, 1H), 2.53-1.90 (m, 8H), 0.80 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=632.3. Example 786 ##STR00577## (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-hydroxy-2-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00578## [0944] Step A. 3-methoxynaphthalen-1-ol: To a solution of naphthalene-1,3-diol (50.0 g, 1.0 equiv) in methanol (750 mL) was added HCl.Math.MeOH (4 M, 750 mL) dropwise at 0 C. The mixture was stirred at 15 C. for 36 hours. The pH of the mixture was adjusted to 7 with 3M NaOH aqueous at 0 C. The mixture was concentrated, diluted with water (1 L) and extracted with ethyl acetate (3 500 mL). The combined organic layer dried over Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 50:1 to 10:1] to afford the title compound (38.0 g, 70% yield) as a red solid; .sup.1H NMR (400 MHz, DMSO-d6) =10.20 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.45-7.36 (m, 1H), 7.30-7.19 (m, 1H), 6.77 (d, J=2.0 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 3.81 (s, 3H). [0945] Step B. 3-methoxy-1-(methoxymethoxy)naphthalene: To a solution of 3-methoxynaphthalen-1-ol (12.5 g, 1.0 equiv) and N-ethyl-N,N-diisopropylamine (21.7 g, 2.3 equiv) in tetrahydrofuran (100 mL) was added bromo(methoxy) methane (10.5 g, 1.2 equiv) dropwise at 0 C. The reaction mixture was stirred at 0 C. for 1 hour. The mixture was quenched with saturated NaHCO.sub.3 aqueous (50 mL) at 0 C. and extracted with ethyl acetate (3 40 mL). The organic phase was dried over Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 100:1 to 20:1] to afford the title compound (44.2 g, 92% yield) as a colorless oil; .sup.1H NMR (400 MHZ, DMSO-d6) =8.06 (d, J=8.4 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.47 (dt, J=1.2, 7.6 Hz, 1H), 7.33 (ddd, J=1.2, 7.2, 8.4 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 5.40 (s, 2H), 3.85 (s, 3H), 3.45 (s, 3H). [0946] Step C. 3-methoxy-1-(methoxymethoxy)-2-methylnaphthalene: To a solution of 3-methoxy-1-(methoxymethoxy)naphthalene (3.00 g, 1.0 equiv) and N,N,N,N-tetramethylethane-1,2-diamine (1.61 g, 1.0 equiv) in tetrahydrofuran (30 mL) was added n-BuLi (2.5 M, 11 mL, 2.0 equiv) over the period of 5 minutes at 0 C. The mixture was stirred at 0 C. for 2 hours. CH.sub.3I (3.90 g, 2.0 equiv) was added slowly over 2 minutes at 0 C. and the mixture was stirred at 0 C. for 0.5 hour. The mixture was quenched with saturated aqueous NH.sub.4Cl (10 mL) at 0 C. and extracted with ethyl acetate (210 mL). The organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate 0:1 to 20:1] to afford the title compound (2.80 g, crude) as a yellow oil; .sup.1H NMR (400 MHz, METHANOL-d.sub.4) =7.95 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.39-7.33 (m, 1H), 7.33-7.27 (m, 1H), 7.01 (s, 1H), 5.09 (d, J=1.2 Hz, 2H), 3.90 (d, J=1.2 Hz, 3H), 3.61 (d, J=1.2 Hz, 3H), 2.29 (d, J=0.8 Hz, 3H). [0947] Step D. 3-methoxy-2-methylnaphthalen-1-ol: To a solution of 3-methoxy-1-(methoxymethoxy)-2-methylnaphthalene (1.40 g, 1.0 equiv) in ACN (7 mL) was added HCl.Math.dioxane (4 M, 14 mL, 9.3 equiv) at 0 C. The mixture was stirred at 0 C. for 0.5 hours. The mixture was poured into saturated aqueous NaHCO.sub.3 (15 mL) and extracted with ethyl acetate (2 10 mL). The organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 0:1 to 10:1] to afford the title compound (500 mg, 44% yield) as a yellow oil; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =8.05 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.32 (dt, J=1.2, 7.6 Hz, 1H), 7.27-7.21 (m, 1H), 6.81 (s, 1H), 3.91 (s, 3H), 2.24 (s, 3H); LCMS (ESI, M+1): m/z=189.2. [0948] Step E. 3-methoxy-2-methylnaphthalen-1-yl trifluoromethanesulfonate: To a solution of 3-methoxy-2-methylnaphthalen-1-ol (1.00 g, 1.0 equiv) and N-ethyl-N,N-diisopropylamine (2.06 g, 3.0 equiv) in dichloromethane (8 mL) was added trifluoromethylsulfonic anhydride (2.25 g, 1.5 equiv) at 40 C. The mixture was stirred at 40 C. for 30 minutes. The mixture was diluted with water (10 mL) and extracted with dichloromethane (210 mL). The organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 20:1] to afford the title compound (1.50 g crude) as a yellow oil. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =7.89 (dd, J=8.0, 14.0 Hz, 2H), 7.55-7.49 (m, 1H), 7.47 (dd, J=1.2, 8.4 Hz, 1H), 7.37 (s, 1H), 4.01 (s, 3H), 2.39 (s, 3H). [0949] Step F. 2-(3-methoxy-2-methylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of 3-methoxy-2-methylnaphthalen-1-yl trifluoromethanesulfonate (700 mg, 1.0 equiv) and 4,4,4,4,5,5,5,5-octamethyl-2,2-bi (1,3,2-dioxaborolane) (2.22 g, 4.0 equiv) in dioxane (8 mL) were added potassium acetate (643 mg, 3.0 equiv) and Pd(dppf) C12 (160 mg, 0.1 equiv). The mixture was stirred at 100 C. for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate 1:0 to 20:1] to afford the title compound (350 mg, 54% yield) as a yellow oil; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =7.87 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.37-7.30 (m, 1H), 7.29-7.22 (m, 1H), 7.21 (s, 1H), 3.93 (s, 3H), 2.41 (s, 3H), 1.48 (s, 12H). [0950] Step G. 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-methoxy-2-methylnaphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and 2-(3-methoxy-2-methylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (285 mg, 1.4 equiv) in methoxycyclopentane (0.6 mL) were added CataCXium A Pd G3 (50 mg, 0.1 equiv) and Cs.sub.2CO.sub.3 (1.5 M in H.sub.2O, 1.37 mL, 3.0 equiv). The mixture was stirred at 80 C. for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (50 mg, 12% yield) as a yellow solid; LCMS (ESI, M+1): m/z=575.2. [0951] Step H. (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-methoxy-2-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-methoxy-2-methylnaphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (44.3 mg, 2.0 equiv) in N,N-dimethylformamide (0.5 mL) were added N-ethyl-N,N-diisopropylamine (45.0 mg, 2.0 equiv) and 4 molecular sieves (20.0 mg). The mixture was stirred at 40 C. for 12 hours. The mixture was filtered and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] and prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (10 mM NH.sub.4HCO.sub.3), B: ACN, B %: 45%-75% over 8 minutes] to afford the title compound (30.0 mg, 23% yield) as a yellow solid; LCMS (ESI, M+1): m/z=602.2. [0952] Step I. (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-hydroxy-2-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-methoxy-2-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (30.0 mg, 1.0 equiv) in dichloromethane (3 mL) was added BBr.sub.3 (100 mg, 8.0 equiv) dropwise at 0 C. for 5 minutes. The mixture was stirred at 0 C. for 1 hour. The mixture was added into saturated aqueous NaHCO.sub.3 (15 mL) at 0 C. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (10 mM NH.sub.4HCO.sub.3), B: ACN, B %: 37%-67% over 8 minutes] to afford the title compound (5.21 mg, 17% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.32 (d, J=3.1 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.34 (br t, J=7.4 Hz, 1H), 7.26 (s, 1H), 7.18-7.08 (m, 2H), 5.37 (br s, 1H), 5.00-4.93 (m, 2H), 4.33 (br d, J=10.5 Hz, 2H), 4.27-4.19 (m, 1H), 3.79 (br d, J=2.0 Hz, 1H), 3.49 (br dd, J=5.1, 12.7 Hz, 1H), 3.27-3.17 (m, 3H), 3.05-2.97 (m, 1H), 2.44-2.36 (m, 1H), 2.30-2.15 (m, 4H), 2.12 (s, 3H), 2.05-1.73 (m, 6H), 1.42 (br d, J=12.6 Hz, 1H); LCMS (ESI, M+1): m/z=588.2. Example 787 ##STR00579## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aR)-3-(((dimethylsulfamoyl)amino)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol [0953] The title compound was synthesized from according to the 4-step procedure described for example 720 to produce the desired compound as a white solid (0.27 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.29 (d, J=8.0 Hz, 1H), 8.47-8.40 (m, 1H), 7.73-7.64 (m, 1H), 7.34-7.22 (m, 2H), 7.13-7.03 (m, 1H), 4.75-4.53 (m, 4H), 4.35 (br t, J=11.2 Hz, 1H), 4.12-3.92 (m, 1H), 3.73-3.55 (m, 2H), 3.51-3.34 (m, 3H), 2.78 (d, J=10.0 Hz, 6H), 2.54-2.29 (m, 3H), 2.28-2.13 (m, 4H), 2.13-1.96 (m, 4H), 1.93-1.74 (m, 3H), 1.30 (d, J=9.0 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=726.3. Example 788 ##STR00580## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(((dimethylsulfamoyl)amino)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol [0954] The title compound was synthesized from according to the 4-step procedure described for example 720 to produce the desired compound as an off-white solid (0.5340 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.24 (d, J=2.8 Hz, 1H), 8.52 (br s, 1H), 7.69 (dd, J=6.0, 9.0 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.27 (t, J=9.2 Hz, 1H), 7.11-7.05 (m, 1H), 4.64-4.53 (m, 1H), 4.52-4.39 (m, 2H), 4.37-4.26 (m, 1H), 3.71-3.57 (m, 1H), 3.54-3.43 (m, 1H), 3.30-3.12 (m, 4H), 3.11-3.00 (m, 1H), 2.77 (d, J=1.2 Hz, 6H), 2.58-2.40 (m, 1H), 2.38-2.11 (m, 4H), 2.10-1.99 (m, 3H), 1.97-1.73 (m, 6H), 1.32 (d, J=9.0 Hz, 3H), 0.83 (q, J=7.4 Hz, 3H); LCMS (ESI, M+1): m/z=726.5. Example 789 ##STR00581## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(((dimethylsulfamoyl)amino)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol [0955] The title compound was synthesized from according to the 4-step procedure described for example 720 to produce the desired compound as a white solid (0.54 formic acid salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.24 (s, 1H), 8.60-8.49 (m, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.07 (dd, J=2.4, 8.4 Hz, 1H), 4.64-4.41 (m, 3H), 4.40-4.27 (m, 1H), 3.81-3.69 (m, 1H), 3.68-3.57 (m, 1H), 3.53-3.33 (m, 4H), 3.15-2.99 (m, 1H), 2.78 (d, J=4.0 Hz, 6H), 2.55-2.40 (m, 1H), 2.36-2.27 (m, 1H), 2.26-2.04 (m, 5H), 2.02-1.74 (m, 7H), 1.30 (d, J=8.4 Hz, 3H), 0.87-0.74 (m, 3H); LCMS (ESI, M+1): m/z=726.5. Example 790 ##STR00582## (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-hydroxy-4-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00583## [0956] Step A. 2,2-dimethyl-5-(2-phenylpropanoyl)-1,3-dioxane-4,6-dione: To a mixture of 2-phenylpropanoic acid (10.0 g, 1.0 equiv), 2,2-dimethyl-1,3-dioxane-4,6-dione (10.5 g, 1.1 equiv), DMAP (732 mg, 0.10 equiv) and DIEA (18.5 g, 2.1 equiv) in ACN (100 mL) was added pivaloyl chloride (8.83 g, 1.1 equiv) at 20 C. The reaction was stirred at 45 C. for 2 hours. The mixture was extracted with EtOAc (350 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to afford the title compound (35.0 g, crude) as a yellow oil. [0957] Step B. 1,3-dihydroxy-4-methyl-2-naphthoic acid: A mixture of 2,2-dimethyl-5-(2-phenylpropanoyl)-1,3-dioxane-4,6-dione (35.0 g, 1.0 equiv) in CF.sub.3SO.sub.3H (595 g, 31 equiv) was stirred at 10 C. for 2 hours. The mixture was quenched with H.sub.2O (50 mL) and filtered to afford the title compound (25.0 g, crude) as a yellow solid. LCMS (ESI, M44): m/z=174.8. [0958] Step C. 4-methylnaphthalene-1,3-diol: A mixture of 1,3-dihydroxy-4-methyl-2-naphthoic acid (25.0 g, 1.0 equiv) in ACN (125 mL) and H.sub.2O (125 mL) was stirred at 90 C. for 12 hours. The mixture was concentrated, diluted with water (100 mL) and extracted with EtOAc (2200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 24%-54%, 10 min] to afford the title compound (3.00 g, 13% yield) as a yellow solid. LCMS (ESI, M+1): m/z=175.1. [0959] Step D. 4-methyl-3-((triisopropylsilyl)oxy)naphthalen-1-ol: To a mixture of 4-methylnaphthalene-1,3-diol (2.50 g, 1.0 equiv) and DIEA (14.8 g, 8.0 equiv) in DCM (25 mL) was added TIPSCl (2.49 g, 0.90 equiv). The reaction was stirred at 0 C. for 20 min. The mixture was quenched with H.sub.2O (50 mL) and extracted with EtOAc (330 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [column: Phenomenex Luna C18 20040 mm10 um; mobile phase: [water (TFA)-ACN]; B %: 70%-100%, 10 min] to afford the title compound (1.20 g, 25% yield) as a yellow oil. LCMS (ESI, M+1): m/z=331.3. [0960] Step E. 4-methyl-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate: To a mixture of 4-methyl-3-((triisopropylsilyl)oxy)naphthalen-1-ol (500 mg, 1.0 equiv), DIEA (1.56 g, 8.0 equiv) and 4 molecular sieves (100 mg) in DCM (5 mL) was added Tf.sub.2O (85.0 mg, 2.0 equiv) at 40 C. The reaction was stirred at 40 C. for 0.5 hour. The mixture was quenched with H.sub.2O (5 mL) and extracted with DCM (310 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO.sub.2, Petroleum ether) to afford the title compound (450 mg, 51% yield) as a yellow oil. LCMS (ESI, M+1): m/z=463.1. [0961] Step F. triisopropyl((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy) silane: To a mixture of 4-methyl-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate (400 mg, 1.0 equiv), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.11 g, 10 equiv) and TEA (262 mg, 3.0 equiv) in ACN (5 mL) was added cis-dichloro-1,1-bis(diphenylphosphino)ferrocene palladium(II) (63.2 mg, 0.10 equiv). The reaction was degassed and stirred at 80 C. for 3 hours under nitrogen atmosphere. The mixture was concentrated and purified by column chromatography (SiO.sub.2, Petroleum ether) to afford the title compound (500 mg, 90% yield) as a yellow solid. LCMS (ESI, M+1): m/z=441.3. [0962] Step G. 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(4-methyl-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (451 mg, 1.2 equiv) and Cs.sub.2CO.sub.3 (835 mg, 3.0 equiv) in methoxycyclopentane (6 mL) and H.sub.2O (2 mL) was added [2-(2-aminophenyl)phenyl]palladium bis(1-adamantyl)butylphosphane methanesulfonate (62.2 mg, 0.10 equiv). The reaction was degassed and stirred at 90 C. for 2 hours under nitrogen atmosphere. The mixture was filter and purified by reversed-phase HPLC (0.1% FA condition) to afford the title compound (270 mg, 39% yield) as a yellow solid. LCMS (ESI, M+1): m/z=717.3. [0963] Step H. (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(3-hydroxy-4-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(4-methyl-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv), (1S,5S,6R)-3-azabicyclo[3.2.1]octan-6-ol (35.4 mg, 2.0 equiv) and 4 molecular sieves (50 mg) in DMF (1 mL) was added DIEA (108 mg, 6.0 equiv). The reaction was stirred at 60 C. for 12 hours. The mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18 15025 mm10 m; mobile phase: [water (FA)-ACN]; B %: 15%-45%, 9 min) to afford the title compound (62.4 mg, 75% yield, 0.5 HCOOH salt) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.28 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.62-7.43 (m, 2H), 7.34-7.17 (m, 2H), 5.52-5.33 (m, 1H), 4.94 (br d, J=12.4 Hz, 1H), 4.80 (br d, J=12.8 Hz, 1H), 4.57-4.37 (m, 2H), 4.33 (td, J=5.2, 10.4 Hz, 1H), 3.86-3.61 (m, 2H), 3.58-3.47 (m, 3H), 3.27-3.15 (m, 1H), 2.59 (s, 3H), 2.56-2.44 (m, 1H), 2.43-2.35 (m, 2H), 2.31-2.20 (m, 3H), 2.19-2.09 (m, 2H), 2.07-1.96 (m, 1H), 1.96-1.88 (m, 1H), 1.86-1.76 (m, 1H), 1.37 (d, J=6.4 Hz, 1H); LCMS (ESI, M+1): m/z=588.2. Example 791 ##STR00584## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00585## [0964] Step A: ethyl(S)-2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate. Racemic ethyl 2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (12.0 g) was separated by SFC (Column: Chiralpak AD-3 504.6 mm I.D., 3 um; Mobile phase: Phase A for CO.sub.2, and Phase B for EtOH (0.05% DEA); Gradient elution: B in A from 5% to 40%; Flow rate: 3 mL/min; Detector: DAD; Column Temp: 35C; Back Pressure: 100 Bar) to afford the tile compound (5.00 g, the first peak) as a yellow oil and the other enantiomer (6.0 g, the second peak) as a yellow oil. [0965] Step B: ethyl (S,Z)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate. To a solution of 2-((fluoromethyl) sulfonyl)pyridine (18.0 g, 102 mmol, 1.07 eq) in THF (800 mL) was added KHMDS (1 M, 122 mL, 1.27 eq) at 78 C., and the mixture was stirred at 78 C. for 30 min. Ethyl(S)-2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (20.0 g, 96.0 mmol, 1.0 eq) in THF (100 mL) was added dropwise at 78 C., and then the reaction stirred for another 3 hour under N.sub.2. The reaction was quenched with NH.sub.4Cl saturated solution, acidified with HCl (3M, 102 mL) and stirred for 30 mins. The mixture was then diluted with H.sub.2O (1.00 L), extracted with ethyl acetate (300 mL3), dried over with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 3/1), and then reversed-phase HPLC. [0966] Step C: (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. To a solution of ethyl (S,Z)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (2.00 g) in THF (10.0 mL) was added dropwise DIBAL-H (1 M, 96.8 mL, 10.0 eq) at 0 C. Then the reaction was stirred at this temperature for 2 hrs. The reaction was quenched with Na.sub.2SO.sub.4.Math.10.Math.H.sub.2O (5.0 g) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to dichloromethane:Methanol=5/1) to give the title compound (1.20 g, 7.01 mmol, 79.6% yield) as yellow solid. [0967] Step D: (R)-1-(7-chloro-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. To a solution of (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (108 mg, 634 mol, 1.05 eq) in dioxane (2.00 mL) were added 4A MS (200 mg), DIEA (351 mg, 2.72 mmol, 473 L, 4.50 eq), and then (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 603.92 mol, 1.00 eq). The reaction was stirred at 95 C. for 2 hrs. The reaction mixture was extracted with Ethyl acetate 10.0 mL (5.00 mL2). The combined organic layers were washed with brine (5.00 mL2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/Ethyl acetate=1/1, R.sub.f=0.50) to give the title compound (80.0 mg, 142 mol, 83.0% purity) as a white solid. LCMS: Rt=0.396 min, m/z=466.3, M+H.sup.+. [0968] Step E: (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. A mixture of (R)-1-(7-chloro-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (60.0 mg, 128 mol, 1.00 eq), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (69.6 mg, 193 mol, 1.50 eq), Ad.sub.2nBup-Pd-G3 (28.1 mg, 38.6 mol, 0.30 eq) and K.sub.3PO.sub.4 (1.50 M, 258 L, 3.00 eq) in THF (1.00 mL) was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 60 C. under N.sub.2 atmosphere for 2 hours. The residue was diluted with H.sub.2O (2.00 mL) and extracted with Ethyl acetate 5.00 mL (2.50 mL2). The combined organic layers were washed with brine 5.00 mL (2.50 mL2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/Ethyl acetate=1/1, R.sub.f=0.70) to give the tile compound (63.0 mg, 88.5 mol, 93.2% purity) as a white solid. [0969] Step F: (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. A mixture of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol and HCl/dioxane (4 M, 218 L, 10.0 eq) in MeCN (0.70 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 0 C. under N.sub.2 atmosphere for 1 hour. The residue was diluted with saturated NaHCO.sub.3 solution (1.00 mL) and extracted with ethyl acetate 2.00 mL (1.00 mL2). The combined organic layers were washed with brine 2.00 mL (1.00 mL2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; gradient: 15%-45% B over 10 min). Then the fractions were freeze-dried to give the title compound (17.5 mg, 25.6 mol, FA salt, 97.4% purity) as a white solid. LCMS: Rt=0.460 min, m/z=620.3, M+H.sup.+. Example 792 ##STR00586## (3R)-1-(2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00587## [0970] Step A: (3R)-1-(7-chloro-2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. A mixture of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 604 mol, 1.00 eq), (2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (114 mg, 6042 mol, 1.00 eq) in THF (4.00 mL) was degassed and purged with N.sub.2 for 3 times. To the mixture was added dropwise NaHMDS (1 M, 755 L, 1.25 eq) at 10 C. The reaction was stirred at 20 C. for 3 hrs. The residue was poured into NH.sub.4Cl (5.00 mL) and stirred for 30 min. The aqueous phase was extracted with ethyl acetate (5.00 mL2). The combined organic phase was washed with brine (5.00 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by prep-TLC (SiO.sub.2, petroleum ether:ethyl acetate=0:1) to give compound the title compound (130 mg, 268 mol, 44.5% yield) as yellow solid. LCMS: RT=0.413 min, M/Z=484.3 [M+H].sup.. [0971] Step B: (3R)-1-(2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (3R)-1-(7-chloro-2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (130 mg, 268 mol, 1.00 eq), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (116 mg, 322 mol, 1.20 eq), and K.sub.3PO.sub.4 (171 mg, 806 mol, 3.00 eq) in dioxane (2.00 mL) H.sub.2O (50.0 uL) was added Pd(dtbpf)Cl.sub.2 (17.5 mg, 26.9 mol, 0.10 eq) in one portion at 20 C. under N.sub.2. Then the reaction was heated to 100 C. and stirred for 2 hrs. The residue was poured into ice-water (5.00 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (5.00 mL2). The combined organic phase was washed with brine (3.00 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by prep-TLC (SiO.sub.2, petroleum ether:ethyl acetate=0:1) to give the title compound (120 mg, 176 mol, 66% yield) as yellow solid. LCMS: RT=0.501 min, M/Z=682.6 [M+H].sup.+. [0972] Step C: (3R)-1-(2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (3R)-1-(2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (110 mg, 161 mol, 1.00 eq) in MeCN (1.00 mL) was added HCl/dioxane (4 M, 0.5 mL, 12.4 eq) in one portion at 20 C. under N.sub.2. The mixture was stirred at 20 C. for 1 hour. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (HCl)-ACN]; gradient: 22%-52% B over 8 min) to give compound the title compound (45.6 mg, 59.3 mol, 44.3% yield, HCl) as yellow solid. .sup.1H NMR: 400 MHZ CD.sub.3OD, 9.63 (s, 1H), 7.77-7.74 (m, 1H), 7.42-7.41 (d, J=2.40 Hz, 1H), 7.36-7.31 (t, J=9.20 Hz, 1H), 7.21-7.20 (d, J=2.40 Hz, 1H), 5.00-4.94 (m, 2H), 4.63-4.57 (m, 1H), 4.49-4.45 (m, 1H), 4.17-4.14 (d, J=14.0 Hz, 1H), 3.74-3.70 (m, 1H), 3.51-3.50 (m, 1H), 3.41-3.35 (m, 1H), 3.17-3.14 (d, J=12.0 Hz, 1H), 2.99-2.95 (d, J=16.0 Hz, 1H), 2.51-2.19 (m, 8H), 1.92-1.90 (m, 3H), 1.40 (s, 3H), 0.93-0.88 (m, 3H). LCMS: RT=0.464 min, M/Z=638.3 [M+H].sup.+. Example 793 ##STR00588## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00589## [0973] Step A. 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,2,2-trifluoroethan-1-ol (872 mg, 1.1 equiv) in THF (10 mL) was added t-BuONa (2 M, 4.36 mL, 1.1 equiv). The reaction was stirred at 25 C. for 1 hour. A solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.00 g, 1.0 equiv) in THF (15 mL) was added into the reaction mixture at 40 C. The reaction was stirred at 0 C. for 1 hour. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (320 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified with column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=1/0 to 100/1) to afford the title compound (1.60 g, 57% yield) as white solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.18 (s, 1H), 5.19-5.02 (m, 2H). [0974] Step B. (Z)-7-chloro-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (250 mg, 1.0 equiv), (Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (203 mg, 1.5 equiv) and 4 molecular sieve (30.0 mg) in THF (5.0 mL) was added DIEA (307 mg, 3.0 equiv). The reaction was stirred at 40 C. for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (320 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (175 mg, 47% yield) as yellow solid; LCMS (ESI, M+1): m/z=451.0. [0975] Step C. (Z)-5-ethyl-6-fluoro-4-(8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of (Z)-7-chloro-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (175 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (307 mg, 2.5 equiv) and K.sub.3PO.sub.4 (1.5 M, 0.776 mL, 3.0 equiv) in 1,4-dioxane (3.0 mL) was added cataCXium Pd G4 (28.3 mg, 0.1 equiv). The reaction was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 90 C. for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (320 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (60.0 mg, 23% yield) as yellow solid; LCMS (ESI, M+1): m/z=605.2. [0976] Step D. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (Z)-5-ethyl-6-fluoro-4-(8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (60.0 mg, 1.0 equiv), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (48.7 mg, 3.0 equiv, HCl) and 4 molecular sieve (30 mg) in DMF (1.0 mL) was added DIEA (64.1 mg, 5.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified with prep-HPLC [Welch Xtimate C18 15025 mm5 um; A: water (FA), B: ACN, B %: 11%-41% over 10 min] to afford the title compound (22.0 mg 34% yield, 0.33 HCOOH) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.29-9.16 (m, 1H), 7.72-7.61 (m, 1H), 7.34-7.19 (m, 2H), 7.06 (br d, J=16.0 Hz, 1H), 6.86-6.56 (m, 1H), 5.07-4.91 (m, 1H), 4.85-4.71 (m, 2H), 4.49-4.25 (m, 3H), 4.01 (br d, J=14.4 Hz, 1H), 3.88-3.72 (m, 1H), 3.64 (br d, J=14.4 Hz, 1H), 3.54-3.38 (m, 1H), 2.93-2.75 (m, 2H), 2.61-2.33 (m, 3H), 2.31-2.12 (m, 4H), 2.10-1.89 (m, 4H), 1.87-1.73 (m, 1H), 1.40 (br d, J=13.2 Hz, 1H), 0.87-0.71 (m, 3H); LCMS (ESI, M+1): m/z=632.3. Example 794 ##STR00590## (5R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione ##STR00591## [0977] To a mixture of (Z)-5-ethyl-6-fluoro-4-(8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (45.0 mg, 1.0 equiv) and (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (25.2 mg, 2.0 equiv) in DMF (0.5 mL) were added DIEA (48.1 mg, 5.0 equiv) and 4 molecular sieve (10.0 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA); B: ACN; B %: 16%-46% over 10 min] to afford the title compound (7.91 mg, 20% yield, 0.28 HCOOH) as white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.96-10.80 (m, 1H), 9.88 (s, 1H), 9.16-9.04 (m, 1H), 8.70 (d, J=5.2 Hz, 1H), 7.73 (s, 1H), 7.42-7.29 (m, 2H), 7.06 (s, 1H), 6.89-6.58 (m, 1H), 4.56-4.31 (m, 2H), 4.21-4.10 (m, 1H), 4.09-4.01 (m, 1H), 3.77-3.65 (m, 1H), 3.63-3.37 (m, 4H), 3.05-2.97 (m, 1H), 2.63-2.56 (m, 2H), 2.38-2.28 (m, 2H), 2.19-2.00 (m, 3H), 2.00-1.89 (m, 2H), 1.85 (br s, 2H), 1.75 (br s, 1H), 0.80-0.67 (m, 3H); LCMS (ESI, M+1): m/z=674.3. Example 795 ##STR00592## (Z)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide ##STR00593## [0978] Step A. 5-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and DIEA (768 mg, 5.0 equiv) in DCM (10 mL) was added N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (291 mg, 1.0 equiv, HCl) at 40 C. The reaction was stirred at 40 C. for 0.5 hours. The mixture was quenched with water (20.0 mL) and extracted with ethyl acetate (320.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (450 mg, 88% yield) as yellow solid; LCMS (ESI, M+1): m/z=423.9. [0979] Step B. (Z)-5-(7-chloro-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: A solution of 5-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (180 mg, 1.0 equiv) and (Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (145 mg, 2.0 equiv) in DMSO (0.5 mL) was stirred at 80 C. for 5 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (320.0 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC (SiO.sub.2, dichloromethane/methanol=10/1) to afford the title compound (55.0 mg, 20% yield) as yellow solid; LCMS (ESI, M+1): m/z=559.3. [0980] Step C. (Z)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of (Z)-5-(7-chloro-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (50.0 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (42.4 mg, 1.5 equiv) and K.sub.3PO.sub.4 (1.5 M, 3.0 equiv) in 1,4-dioxane (1.0 mL) was added cataCXium Pd G4 (6.51 mg, 0.10 equiv). The reaction was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 90 C. for 1 hour. The mixture was filtered, concentrated and purified by prep-HPLC [Welch Xtimate C18 15025 mm5 um; A: water (FA), B: ACN; B %: 13%-43% over 10 min] to afford the title compound (19.3 mg, 29% yield, 0.34 HCOOH) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.19 (s, 1H), 7.72-7.62 (m, 1H), 7.35-7.20 (m, 2H), 7.05 (d, J=2.4 Hz, 1H), 6.81-6.55 (m, 2H), 5.37-5.29 (m, 1H), 5.27-5.18 (m, 1H), 4.56 (br d, J=5.4 Hz, 2H), 4.48-4.35 (m, 3H), 4.35-4.29 (m, 1H), 3.94 (br d, J=14.8 Hz, 1H), 3.57 (br d, J=14.8 Hz, 1H), 3.32 (br s, 3H), 3.28-3.22 (m, 1H), 3.08 (s, 3H), 2.85-2.68 (m, 2H), 2.56-2.36 (m, 4H), 2.21-2.09 (m, 2H), 2.06-1.86 (m, 3H), 0.79 (t, J=7.4 Hz, 3H); LCMS (ESI, M+1): m/z=713.6. Example 796 ##STR00594## (1R,5R,6R)-3-(2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00595## [0981] Step A. 1-(tert-butyl) 2-methyl 2-(2-(chloromethyl) allyl)-4-methylenepyrrolidine-1,2-dicarboxylate: To a solution of 1-(tert-butyl) 2-methyl(S)-4-methylenepyrrolidine-1,2-dicarboxylate (5.00 g, 1.00 equiv) in THF (50 mL) was added dropwise LiHMDS (1 M, 41.4 mL, 2.00 equiv) at 78 C. The mixture was stirred at this temperature for 1 hour, and then 3-chloro-2-(chloromethyl) prop-1-ene (6.48 g, 2.50 equiv) was added dropwise at 78 C. The reaction was stirred at 25 C. for 12 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (350 mL). The combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified with column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=0/1 to 10/1) to afford the title compound (3.00 g, 44% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CDCl.sub.3) =5.34 (d, J=7.6 Hz, 1H), 5.07-4.94 (m, 3H), 4.28-3.96 (m, 4H), 3.75 (s, 3H), 3.38-3.21 (m, 1H), 2.91-2.68 (m, 3H), 1.47 (s, 9H); LCMS (ESI, M1): m/z=230.1. [0982] Step B. methyl 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate: To a solution of 1-(tert-butyl) 2-methyl 2-(2-(chloromethyl) allyl)-4-methylenepyrrolidine-1,2-dicarboxylate (12.5 g, 1.00 equiv) in DCM (100 mL) was added TFA (64.8 g, 15.0 equiv). The reaction was stirred at 25 C. for 12 hrs. The mixture was concentrated under reduced pressure. The residue was diluted with H.sub.2O (100 mL) and washed with MTBE (2100 mL). The aqueous phase was adjusted to pH=9 with saturated Na.sub.2CO.sub.3 aqueous at 20 C. for 1 hour and extracted with ethyl acetate (3100 mL). The combined organic phase was washed with brine (2100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford the title compound (6.00 g, 61% yield, 74% purity) as a yellow oil; .sup.1H NMR (400 MHZ, CDCl.sub.3) =4.89 (d, J=19.2 Hz, 4H), 4.06-3.65 (m, 5H), 3.18 (d, J=16.4 Hz, 2H), 2.93-2.88 (m, 2H), 2.50 (d, J=16.8 Hz, 1H); LCMS (ESI, M1): m/z=194.2. [0983] Step C. (2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol: To a solution of LAH (2.5 M, 6.99 mL, 0.75 equiv) in THF (50.0 mL) was added dropwise a solution of methyl 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (4.50 g, 1.00 equiv) in THF (10 mL) at 0 C.10 C. The reaction was stirred at 10 C. for 2 hours. The mixture was quenched with water (0.81 mL), 15% NaOH (0.81 mL) and water (2.43 mL) in turn at 0 C.5 C. and stirred at 25 C. for 30 mins. The mixture was filtered and concentrated in vacuum to afford the title compound (3.00 g, 72% yield) as a colorless oil; .sup.1H NMR (400 MHZ, CDCl.sub.3) =4.96-4.84 (m, 4H), 3.67 (d, J=14.8 Hz, 2H), 3.29-3.23 (m, 4H), 3.11-2.98 (m, 1H), 2.55-2.51 (m, 2H), 2.42-2.37 (m, 2H); LCMS (ESI, M+1): m/z=166.1. [0984] Step D. 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of CF.sub.3CH.sub.2OH (2.28 g, 1.15 equiv) in THF (40 mL) was added t-BuONa (2.09 g, 1.10 equiv) at 0 C. The reaction was stirred for 0.5 hours. A solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (5.00 g, 1.00 equiv) in THF (25.0 mL) was added dropwise at 50 C. under N.sub.2 atmosphere. The reaction was stirred at this temperature for 1.5 hours. The mixture was diluted with H.sub.2O (50 mL) and extracted with ethyl acetate (330 mL). The combined organic layers were washed with brine (50.0 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was triturated with MTBE (50.0 mL) at 25 C. for 5 hours to afford the title compound (4.00 g, 64% yield) as a white solid; LCMS (ESI, M+1): m/z=315.9. [0985] Step E. 7-chloro-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.05 g, 1.10 equiv) and (2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (500 mg, 1.00 eq) in dioxane (5.00 mL) was added DIEA (1.56 g, 4.00 equiv). The reaction was stirred at 60 C. for 6 hours. The mixture was quenched with saturated NH.sub.4Cl (1 mL) aqueous at 0 C. and extracted with DCM (32 mL). The combined organic layers were washed with brine (5 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified with column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 1/1) to afford the title compound (500 mg, 35% yield) as a yellow solid; .sup.1H NMR (400 MHZ, CDCl.sub.3) =8.92 (s, 1H), 4.98-4.94 (m, 3H), 4.91-4.28 (m, 6H), 4.30 (s, 2H), 3.74 (d, J=14.4 Hz, 2H), 3.24 (d, J=14.4 Hz, 2H), 2.69 (d, J=16.4 Hz, 2H), 2.47 (d, J=16.0 Hz, 2H); LCMS (ESI, M+1): m/z=445.0. [0986] Step F. 2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (340 mg, 1.00 equiv) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (330 mg, 1.20 equiv) in methoxy cyclopentane (6.8 mL) were added Cs.sub.2CO.sub.3 aqueous (1 M, 2.29 mL, 3.00 equiv) and AdanBuP-Pd-G.sub.3 (83.5 mg, 0.15 equiv). The reaction was stirred at 90 C. for 3 hours. The mixture was diluted with H.sub.2O (5 mL) and extracted with MTBE (5 mL). The organic phase was washed with brine (5.00 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified with prep-TLC (Petroleum ether:Ethyl acetate=1:1.5) to afford the title compound (160 mg, 30% yield) was obtained as a brown solid; LCMS (ESI, M+1): m/z=643.3. [0987] Step G. (1R,5R,6R)-3-(2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (140 mg, 1.00 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (53.4 mg, 1.50 equiv, HCl salt) in DMF (0.70 mL) and MeCN (0.70 mL) was added K.sub.2CO.sub.3 (90.3 mg, 3.00 equiv). The reaction was stirred at 40 C. for 3 hours. The mixture was diluted with H.sub.2O (10 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with brine (310 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified with prep-TLC (DCM:MeOH=10:1) to afford the title compound (125 mg, 82% yield) as a yellow solid; LCMS (ESI, M+1): m/z=670.4. [0988] Step H. (1R,5R,6R)-3-(2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (125 mg, 1.00 equiv) in MeCN (1.25 mL) was added HCl.Math.dioxane (4 M, 699 L, 15.0 equiv). The reaction was stirred at 0 C. for 0.5 hours. The mixture was quenched with saturated NaHCO.sub.3 aqueous (10 mL) at 0 C. and extracted with ethyl acetate (25 mL). The combined organic layers were washed with brine (210 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified with prep-TLC (SiO.sub.2, Petroleum ether:Ethyl acetate=0:1) to afford the title compound (40.0 mg, 31% yield) as a yellow solid; .sup.1H NMR (400 MHZ, MeOD) =9.29-9.16 (m, 1H), 7.67 (m, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 5.02 (m, 4H), 4.82-4.71 (m, 2H), 4.37-4.28 (m, 3H), 3.84-3.73 (m, 3H), 3.52-3.34 (m, 3H), 2.81 (d, J=16.4 Hz, 2H), 2.59 (d, J=16.8 Hz, 2H), 2.54-2.44 (m, 1H), 2.40 (s, 1H), 2.28-2.09 (m, 3H), 1.92 (m, 1H), 1.84-1.75 (m, 1H), 1.45-1.33 (m, 1H), 0.80 (m, 3H); LCMS (ESI, M+1): m/z=626.2. Example 797 ##STR00596## (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00597## [0989] Step A. (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv) and DIEA (307.16 mg, 3.0 equiv) in DCM (2.0 mL) was added (R)-3-methylpiperidin-3-ol (96.1 mg, 0.8 equiv, HCl) at 40 C. The reaction was stirred at 40 C. for 1 hour. The mixture was quenched with water (5.0 mL) and extracted with ethyl acetate (310.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=30/1 to 1/1) to afford the title compound (95.0 mg, 36% yield) as yellow solid; LCMS (ESI, M+1): m/z=331.0. [0990] Step B. (3R)-1-(7-chloro-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (65.0 mg, 1.0 equiv), (2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (45.0 mg, 1.5 equiv) and 4 molecular sieve (10.0 mg) in THF (1.0 mL) was added DIEA (76.1 mg, 3.0 equiv). The reaction was stirred at 60 C. for 24 hours. The mixture was quenched with water (5.0 mL) and extracted with ethyl acetate (310.0 mL). The combined organic layers were washed with brine (15.0 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (50.0 mg, 57% yield) as white solid; LCMS (ESI, M+1): m/z=448.1. [0991] Step C. (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(7-chloro-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50.0 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (42.3 mg, 1.2 equiv) and K.sub.3PO.sub.4 (1.5 M, 3.0 equiv) in dioxane (1.0 mL) was added cataCXium Pd G4 (8.13 mg, 0.10 equiv). The reaction was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 90 C. for 1 hour. The mixture was concentrated and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 18%-48% over 10 min] to afford the title compound (4.29 mg, 5.9% yield, 0.51 HCOOH) as white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.73 (s, 1H), 9.34-9.08 (m, 1H), 7.76 (dd, J=6.0, 8.8 Hz, 1H), 7.42-7.27 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 4.94-4.85 (m, 2H), 4.82-4.66 (m, 1H), 4.40-4.26 (m, 1H), 4.11-3.99 (m, 3H), 3.65-3.54 (m, 2H), 3.21 (br s, 1H), 3.02-2.97 (m, 1H), 2.62-2.54 (m, 2H), 2.40-2.23 (m, 3H), 2.18-2.08 (m, 1H), 2.04-1.93 (m, 2H), 1.90-1.75 (m, 2H), 1.72-1.62 (m, 4H), 1.16 (br d, J=8.8 Hz, 3H), 0.73 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=602.3. Example 798 ##STR00598## (1R,5R,6R)-3-(2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00599## [0992] Step A. (1R,5R,6R)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.00 g, 1.0 equiv) and DIEA (3.07 g, 3.0 equiv) in DCM (40 mL) was slowly added (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (1.01 g, 1.0 equiv) at 40 C. The reaction was stirred at 40 C. for 1 hour. The mixture was quenched with water (10 mL) and extracted with dichloromethane (2 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to afford the title compound (3.50 g, crude) as yellow solid; LCMS (ESI, M+1): m/z=343.1. [0993] Step B. 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine: To a solution of (1R,5R,6R)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (2.60 g, 1.0 equiv), tert-butylchlorodimethylsilane (2.28 g, 2.0 equiv) and DMAP (463 mg, 0.5 equiv) in DMF (30 mL) was added 1H-imidazole (1.6 g, 3.0 equiv). The reaction was stirred at 40 C. for 2 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with silica gel chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=20/1 to 10/1) to afford the title compound (1.00 g, 28% yield) as white solid; LCMS (ESI, M+1): m/z=457.2. [0994] Step C. 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-7-chloro-2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidine: To a mixture of 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (500 mg, 1.0 equiv), (2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (310 mg, 1.5 equiv) and DABCO (123 mg, 1.0 equiv) in THF (5 mL) and DMF (5 mL) was added Cs.sub.2CO.sub.3 (1.07 g, 3.0 equiv). The reaction was stirred at 30 C. for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The organic layers were dried over Na.sub.2SO.sub.4, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (130 mg, 17% yield) as yellow solid; LCMS (ESI, M+1): m/z=610.3. [0995] Step D. 4-(4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a solution of 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-7-chloro-2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidine (110 mg, 1.0 equiv), K.sub.3PO.sub.4 (1.5 M, 318 mg, 8.3 equiv) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (171 mg, 3.0 equiv) in methoxycyclopentane (1 mL) was added cataCXium-A-Pd-G3 (39.0 mg, 0.3 equiv). The reaction was stirred at 90 C. for 1 hour under N.sub.2 atmosphere. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (210 mL). The organic layers were dried over Na.sub.2SO.sub.4, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 59% yield) as yellow solid; LCMS (ESI, M+1): m/z=764.4. [0996] Step E. (1R,5R,6R)-3-(2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: A solution of 4-(4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (45 mg, 1.0 equiv) in HCl.Math.MeOH (2 mL) was stirred at 25 C. for 0.5 hours. [0997] The mixture was diluted with water (20 mL), adjusted to pH=7 with saturated NaHCO.sub.3 (10 mL) and extracted with ethyl acetate (210 mL). The organic layers were dried over Na.sub.2SO.sub.4, concentrated and purified with prep-HPLC [Welch Xtimate 15025 mm5 m; A: water (0.1% FA); B: ACN; B %: 15%-45% over 10 min] to afford the title compound (22.1 mg, 53% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.32-9.17 (d, J=10.8 Hz, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.28-7.21 (m, 1H), 7.06 (dd, J=2.4, 15.6 Hz, 1H), 5.01 (br d, J=12.4 Hz, 1H), 4.79 (br t, J=11.2 Hz, 1H), 4.54-4.44 (m, 1H), 4.42-4.28 (m, 2H), 4.01 (br d, J=14.8 Hz, 1H), 3.88-3.72 (m, 1H), 3.64 (br d, J=14 Hz, 1H), 3.48 (br dd, J=14, 18.8 Hz, 1H), 3.40-3.33 (m, 1H), 3.01-2.83 (m, 2H), 2.63 (br d, J=16.4 Hz, 1H), 2.56-2.36 (m, 2H), 2.31-1.88 (m, 8H), 1.86-1.73 (m, 1H), 1.46-1.33 (m, 1H), 0.80 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=650.3. Example 799 ##STR00600## (R)-1-(2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00601## [0998] Step A. (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.00 g, 1.0 equiv) and DIEA (1.54 g, 3.0 equiv) in DCM (30 mL) was added (R)-3-methylpiperidin-3-ol (456 mg, 1.0 equiv) at 40 C. The reaction was stirred at 40 C. for 2 hours. The mixture was quenched with water (1.0 mL) at 0 C. and extracted with DCM (350 mL). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (1.02 g, 77% yield) as yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.07 (s, 1H), 4.61-4.40 (m, 2H), 3.43-3.31 (m, 2H), 2.18-2.03 (m, 1H), 1.94-1.87 (m, 1H), 1.82-1.68 (m, 2H), 1.36 (s, 3H); LCMS (ESI, M+1, M+2): m/z=331.2, 333.2. [0999] Step B. (R)-1-(7-chloro-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A mixture of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (120 mg, 1.0 equiv), (2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (89.8 mg, 1.5 equiv) and DIEA (140 mg, 3 equiv) in DMF (0.05 mL) was stirred at 80 C. for 17 hours. The mixture was concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 49% yield) as yellow solid; LCMS (ESI, M+1): m/z=460.2. [1000] Step C. (R)-1-(2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (R)-1-(7-chloro-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50.0 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (48.1 mg, 1.4 equiv) and Cs.sub.2CO.sub.3 (1.5 M, 3.0 equiv) in methoxycyclopentane (2.2 mL) was added cataCXium Pd G4 (7.92 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen for 3 times. The reaction was stirred at 90 C. for 2.5 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (35.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 19%-49% over 10 min] to afford the title compound (22.2 mg, 30% yield, 0.74 HCOOH) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.24 (d, J=2.0 Hz, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.06 (t, J=2.4 Hz, 1H), 5.18-5.10 (m, 4H), 4.57 (br d, J=12.4 Hz, 1H), 4.53 (s, 2H), 4.32 (br t, J=12.8 Hz, 1H), 4.07 (br d, J=14.8 Hz, 2H), 3.67-3.56 (m, 3H), 3.49-3.40 (m, 1H), 2.93 (br d, J=17.2 Hz, 2H), 2.71 (br d, J=16.4 Hz, 2H), 2.46 (m, 1H), 2.25-2.11 (m, 2H), 1.87-1.75 (m, 3H), 1.29 (d, J=9.2 Hz, 3H), 0.81 (q, J=7.6 Hz, 3H); LCMS (ESI, M+1): m/z=614.4. Example 800 ##STR00602## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00603## [1001] Step A. (1R,5R,6R)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv) and DIEA (307 mg, 3.0 equiv) in DCM (2.0 mL) was added (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (104 mg, 0.8 equiv) at 40 C. The reaction was stirred at 40 C. for 1 hour. The mixture was quenched with water (5.0 mL) and extracted with DCM (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and triturated with acetonitrile at 25 C. to afford the title compound (170 mg, 63% yield) as brown oil; LCMS (ESI, M+1, M+3): m/z=343.0, 345.0. [1002] Step B. 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine: To a solution of (1R,5R,6R)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (170 mg, 1.0 equiv), DMAP (30.3 mg, 0.5 equiv) and imidazole (101 mg, 3.0 equiv) in DMF (2.0 mL) was added TBSCl (224 mg, 3.0 equiv). The reaction was stirred at 25 C. for 16 hours. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (315 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC (SiO.sub.2, petroleum ether/ethyl acetate=5/1) to afford the title compound (196 mg, 86% yield) as off-white solid; LCMS (ESI, M+1): m/z=457.1. [1003] Step C. 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-7-chloro-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine: To a mixture of 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (170 mg, 1.0 equiv), (2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (85.4 mg, 1.5 equiv) and 4 molecular sieve (10 mg) in THF (1.0 mL) was added DIEA (192 mg, 4.0 equiv). The reaction was stirred at 60 C. for 16 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (310 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (117 mg, 55% yield) as off-white oil; LCMS (ESI, M+1): m/z=574.3. [1004] Step D. 4-(4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a mixture of 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-7-chloro-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (112 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (92.5 mg, 1.5 equiv) and K.sub.3PO.sub.4 (1.5 M, 3.0 equiv) in dioxane (1.0 mL) was added cataCXium Pd G4 (14.2 mg, 0.1 equiv). The reaction was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 90 C. for 1 hour. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (310 mL). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (45.0 mg, 36% yield) as yellow solid; LCMS (ESI, M+1): m/z=728.6. [1005] Step E. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 4-(4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (40.0 mg, 1.0 equiv) in MeOH (1.0 mL) was added HCl.Math.MeOH (4 M, 1.0 mL). The reaction was stirred at 25 C. for 1 hour. The mixture was concentrated and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 20%-50% over 8 min] to afford the title compound (14.4 mg, 41% yield, 0.40 HCOOH) as white solid: .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.31-9.59 (m, 1H), 9.39-9.21 (m, 1H), 7.76 (br dd, J=6.4, 8.4 Hz, 1H), 7.39-7.29 (m, 2H), 7.03 (dd, J=2.0, 14.8 Hz, 1H), 4.91 (br s, 2H), 4.86-4.77 (m, 1H), 4.75-4.66 (m, 1H), 4.58 (br t, J=10.4 Hz, 1H), 4.20-4.12 (m, 1H), 4.09-3.97 (m, 2H), 3.78-3.68 (m, 1H), 3.57 (br d, J=14.0 Hz, 1H), 3.21 (br d, J=14.4 Hz, 2H), 3.04-2.99 (m, 1H), 2.63-2.56 (m, 2H), 2.37 (br d, J=16.0 Hz, 3H), 2.17-2.05 (m, 3H), 2.01-1.95 (m, 1H), 1.89-1.75 (m, 3H), 1.71-1.62 (m, 2H), 1.25 (br d, J=11.6 Hz, 1H), 0.77-0.67 (m, 3H); LCMS (ESI, M+1): m/z=614.3. Example 801 ##STR00604## (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00605## [1006] Step A. 8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidine-2,4-diol: To a mixture of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (517 mg, 1.0 equiv), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (1.50 g, 1.0 equiv) and K.sub.3PO.sub.4 (1.5 M in water, 4.80 mL, 3.0 equiv) in EtOH (15 mL) was added CataCXium A Pd G3 (175 mg, 0.1 equiv). The reaction was degassed and purged with N.sub.2 for 3 times and stirred at 80 C. for 4 hours under N.sub.2 atmosphere. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (350 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 8/1) to afford the title compound (1.46 g, 42% yield) as yellow solid; LCMS (ESI, M+1): m/z=678.3. [1007] Step B. 2,4-dichloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidine: To a solution of 8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidine-2,4-diol (1.36 g, 1.0 equiv) and DIEA (778 mg, 3.0 equiv) in toluene (15 mL) was added POCl.sub.3 (1.54 g, 5.0 equiv) dropwise at 0 C. The reaction was stirred at 100 C. for 1 hour. The mixture was concentrated, diluted with ethyl acetate (10 mL), slowly poured into saturated NaHCO.sub.3 solution (20 mL) at 0 C., and extracted with ethyl acetate (210 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated and purified with column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 3/1) to afford the title compound (430 mg, 30% yield) as yellow solid. [1008] Step C. (R)-1-(2-chloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of 2,4-dichloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidine (430 mg, 1.0 equiv) and (R)-3-methylpiperidin-3-ol hydrochloride (95.8 mg, 1.0 equiv) in DCM (15 mL) was added DIEA (233 mg, 3.0 equiv) slowly. The reaction was stirred at 40 C. for 1 hour. The mixture was diluted with water (10 mL) and extracted with DCM (210 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated and purified with silica gel column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 3/1) to afford the title compound (443 mg, 93% yield) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.41-9.23 (m, 1H), 7.74 (dd, J=5.6, 9.0 Hz, 1H), 7.35-7.28 (m, 2H), 7.21 (dd, J=2.5, 7.0 Hz, 1H), 4.69-4.33 (m, 2H), 3.58-3.25 (m, 2H), 2.27-2.08 (m, 1H), 1.98-1.88 (m, 1H), 1.86-1.62 (m, 2H), 1.38 (d, J=1.6 Hz, 3H), 1.35-1.29 (m, 3H), 1.15 (br s, 36H), 0.69-0.45 (m, 3H). [1009] Step D (3R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (47.5 mg, 1.1 equiv) in THF (2 mL) was added NaH (18.1 mg, 60% purity, 1.8 equiv) at 0 C. The reaction was stirred at 25 C. for 0.5 hours. (R)-1-(2-chloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 1.0 equiv) was added. The reaction was stirred at 25 C. for 0.5 hours. The mixture was quenched by addition of water (10 mL), extracted with ethyl acetate (310 mL), dried over Na.sub.2SO.sub.4 and concentrated to afford the title compound (207 mg, crude) as yellow oil. [1010] Step E. (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (207 mg, 1.0 equiv) in DMF (2 mL) was added CsF (339 mg, 10 equiv). The reaction was stirred at 40 C. for 1 hour. The mixture was diluted with water (10 mL), extracted with ethyl acetate (210 mL), concentrated and purified with prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 18%-48% B over 9 min] to afford the title compound (31.3 mg, 22% yield) as yellow solid; .sup.1H NMR (400 MHZ, DMSO-d6) =9.26-9.03 (m, 1H), 7.98 (dd, J=6.0, 9.2 Hz, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.39 (s, 1H), 7.21 (dd, J=2.4, 18.0 Hz, 1H), 6.91-6.61 (m, 1H), 4.93-4.62 (m, 1H), 4.43-4.27 (m, 1H), 4.16-3.98 (m, 3H), 3.95 (s, 1H), 3.71 (br d, J=14.6 Hz, 1H), 3.64-3.51 (m, 2H), 3.31 (br s, 1H), 3.01 (ddd, J=4.4, 6.0, 9.6 Hz, 1H), 2.61-2.52 (m, 2H), 2.33 (br d, J=14.8 Hz, 1H), 2.14-1.92 (m, 2H), 1.91-1.75 (m, 2H), 1.74-1.57 (m, 4H), 1.16 (d, J=16.4 Hz, 3H); LCMS (ESI, M+1): m/z=616.3. Example 802 ##STR00606## 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one ##STR00607## [1011] Step A: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol: To a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.00 g, 1.57 mmol, 1.00 eq) in H.sub.2O (10.00 mL) and THF (10.0 mL) was added LiOH.Math.H.sub.2O (197 mg, 4.71 mmol, 3.00 eq). The reaction was stirred at 25 C. for 16 hrs and then quenched by 10% citric acid. The pH of the mixture was adjusted to 7 at 25 C., and extracted with ethyl acetate (10.0 mL). The organic layer was washed with brine (20.0 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give the title compound (820 mg, 1.28 mmol, 81.2% yield, 86.3% purity) as a yellow solid. LCMS: Rt=0.468 min, m/z=555.2, M+H.sup.+ [1012] Step B: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate. To a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (50.0 mg, 90.1 umol, 1.00 eq) in dichloromethane (1.00 mL) were added TEA (54.7 mg, 541 umol, 75.3 uL, 6.00 eq) and Tf.sub.2O (61.0 mg, 216 umol, 35.7 uL, 2.40 eq). The mixture was stirred at 0 C. for 15 min. The reaction was quenched by 2 mL aq. NaHCO.sub.3 at 25 C., and extracted with 2 mL dichloromethane twice. [1013] The combined organic layers were washed with brine 2.00 mL, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (72 mg, crude) as a yellow oil. [1014] Step C: 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one. A mixture of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (120 mg, 175 umol, 1.00 eq) and cis-8-oxa-3-azabicyclo[4.2.0]octan-7-one (44.4 mg, 349 umol, 2.00 eq), TEA (53.0 mg, 524 umol, 73.0 uL, 3.00 eq) in DMF (1.00 mL) was degassed and purged with N.sub.2 for 3 times. The mixture was stirred under N.sub.2 atmosphere at 25 C. for 1 hour. The reaction mixture was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (34.0 mg, 51.2 umol, 14.7% yield) as a yellow oil. LCMS: Rt=0.712 min, m/z=664.5, M+H.sup.+ [1015] Step D: 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one. A mixture of 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one (20.0 mg, 30.1 umol, 1.00 eq), HCl/EtOAc (4 M, 22.6 uL, 3.00 eq) in dichloromethane (0.20 mL) was degassed and purged with N.sub.2 for 3 times. The reaction was stirred under N.sub.2 atmosphere at 0 C. for 1 hour. The mixture was concentrated and the residue was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (8.6 mg, 12.28 umol, 40.75% yield, 89.0% purity) as a white solid; .sup.1H NMR: EW39947-1-PIE (400 MHZ, CDCl.sub.3): : 9.03-9.00 (m, 1H), 7.54-7.51 (m, 1H), 7.24-7.16 (m, 2H), 7.09-7.01 (m, 1H), 5.49-5.26 (m, 1H), 4.93-4.88 (m, 1H), 4.67-4.58 (m, 2H), 4.44-4.35 (m, 2H), 4.09-3.80 (m, 4H). 3.59-3.56 (m, 2H), 3.45-3.28 (m, 2H), 3.15-3.08 (m, 2H), 2.58-2.28 (m, 6H), 1.32-1.26 (m, 4H). LCMS: Rt=0.440 min, m/z=620.3, M+H.sup.+ Example 803 ##STR00608## 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol ##STR00609## ##STR00610## [1016] Step A. 2-((tert-butyldimethylsilyl)oxy)-N-(2,4-dimethoxybenzyl) ethan-1-amine: To a solution of 2-((tert-butyldimethylsilyl)oxy) ethan-1-amine (5.00 g, 1.0 equiv) and 2,4-dimethoxybenzaldehyde (2.37 g, 0.50 equiv) in DCE (30 mL) was added NaBH(OAc).sub.3 (7.25 g, 1.2 equiv) at 0 C. The reaction was stirred at 20 C. for 2 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (330 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, concentrated, and purified with column chromatography [SiO.sub.2, Dichloromethane/Methanol=100/1 to 50/1] to afford the title compound (3.00 g, 31% yield) as white solid: LCMS (ESI, M+1): m/z=326.3. [1017] Step B. methyl (4-bromo-2,6-dichloro-5-fluoronicotinoyl) carbamimidothioate: A solution of 4-bromo-2,6-dichloro-5-fluoronicotinic acid (20.0 g, 1.0 equiv) in SOCl.sub.2 (200 mL) and DMF (1 mL) was stirred at 100 C. for 1 hour. The mixture was concentrated. The residue was dissolved in THF (200 mL). DIEA (25.2 g, 3.0 equiv) and methyl carbamimidothioate (36.2 g, 2.0 equiv) were added at 0 C. The reaction was stirred at 20 C. for 12 hours. The mixture was filtered, diluted with water (200 mL) and extracted with EtOAc (3200 mL). The combined organic layers were washed with brine (600 mL), dried over anhydrous sodium sulfate, concentrated, and purified with column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=20/1 to 5/1] to afford the title compound (8.00 g, 32% yield) as yellow solid; LCMS (ESI, M+1, M+3): m/z=359.8, 361.8. [1018] Step C. 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol: To a solution of methyl (4-bromo-2,6-dichloro-5-fluoronicotinoyl) carbamimidothioate (6.00 g, 1.0 equiv) in dioxane (40 mL) was added DIEA (6.44 g, 3.0 equiv). The reaction was stirred at 100 C. for 12 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (350 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 3/1] to afford the title compound (5.00 g, 93% yield) as yellow solid; LCMS (ESI, M+1): m/z=280.0. [1019] Step D. 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine: To a mixture of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.00 g, 1.0 equiv) and DIEA (1.38 g, 3.0 equiv) in MeCN (10 mL) was added POCl.sub.3 (2.74 g, 5.0 equiv) at 0 C. The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 C. for 2 hours. The mixture was concentrated to afford the title compound (1.00 g, crude) as yellow solid. [1020] Step E. N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5,7-dichloro-N-(2,4-dimethoxybenzyl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-amine: To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (250 mg, 1.0 equiv) and DIEA (325 mg, 3.0 equiv) in DCM (5.0 mL) was added 2-((tert-butyldimethylsilyl)oxy)-N-(2,4-dimethoxybenzyl) ethan-1-amine (409 mg, 1.5 equiv) at 40 C. The reaction was stirred at 40 C. for 0.5 hours. The mixture was diluted with water (10 mL) and extracted with DCM (310 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (380 mg, 72% yield) as yellow oil; LCMS (ESI, M+1): m/z=587.2. [1021] Step F. 5-chloro-10-(2,4-dimethoxybenzyl)-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene: To a solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5,7-dichloro-N-(2,4-dimethoxybenzyl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-amine (370 mg, 1.0 equiv) in DMF (8 mL) was added CsF (478 mg, 5.0 equiv). The reaction was stirred at 40 C. for 4 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (200 mg, 72% yield) as yellow solid; LCMS (ESI, M+1): m/z=437.2. [1022] Step G. 5-chloro-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene: A solution of 5-chloro-10-(2,4-dimethoxybenzyl)-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (190 mg, 1.0 equiv) in TFA (2 mL) was stirred at 80 C. for 4 hours. The pH of the mixture was adjusted to >8 with saturated NaHCO.sub.3 aqueous (10 mL) at 0 C. and the mixture was extracted with DCM (310 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound (200 mg, crude) as yellow oil; LCMS (ESI, M+1): m/z=286.9. [1023] Step H. 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene: To a mixture of 5-chloro-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (170 mg, 1.0 equiv), K.sub.3PO.sub.4 (1.5 M in H.sub.2O, 1.19 mL, 3.0 equiv) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (214 mg, 1.0 equiv) in DMF (3 mL) was added CataCXium A Pd G3 (43.2 mg, 0.10 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 C. for 2 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (120 mg, 41% yield) as yellow solid; LCMS (ESI, M+1): m/z=485.2. [1024] Step I. 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene: To a solution of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (110 mg, 1.0 equiv) in MeOH (0.3 mL), THF (1 mL) and H.sub.2O (0.3 mL) was added oxone (126 mg, 0.9 equiv) at 0 C. The reaction was stirred at 20 C. for 2 hours. The mixture was diluted with water (3 mL) and extracted with EtOAc (33 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (110 mg, crude) as yellow solid; LCMS (ESI, M+1): m/z=501.2. [1025] Step J. 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene: A mixture of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (110 mg, 1.0 equiv) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (175 mg, 5.0 equiv) was stirred at 60 C. for 2 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (35 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (110 mg, 83% yield) as yellow solid; LCMS (ESI, M+1): m/z=596.3 [1026] Step K. 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol: To a solution of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (50.0 mg, 1.0 equiv) in MeOH (0.5 mL) was added HCl.Math.MeOH (4 M, 0.5 mL). The reaction was stirred at 0 C. for 0.5 hours. The pH of the mixture was adjusted to pH>8 with saturated NaHCO.sub.3 aqueous (5 mL) at 0 C. and the mixture was extracted with DCM (35 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN; B %: 24%-44% over 10 min] to afford the title compound (20.1 mg, 43% yield, 0.41 HCOOH) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =7.68-7.64 (m, 1H), 7.33-7.19 (m, 2H), 7.15-7.05 (m, 1H), 5.50-5.28 (m, 1H), 4.65-4.58 (m, 2H), 4.49-4.30 (m, 2H), 3.85-3.82 (m, 2H), 3.64-3.41 (m, 3H), 3.24-3.11 (m, 1H), 2.60-2.49 (m, 1H), 2.49-2.26 (m, 3H), 2.25-2.06 (m, 3H), 1.98-1.96 (m, 1H), 0.87 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=552.3. Example 804 ##STR00611## 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,8,9,10-tetrahydro-1,3,6,7,10-pentaazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol Example 805 ##STR00612## (R)-1-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00613## [1027] Step A. (R)-1-(7-(3-chloro-5-(methoxymethoxy)-2-((1R,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 1.0 equiv), 2-(3-chloro-5-(methoxymethoxy)-2-((1R,2R)-2-methylcyclopropyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (186 mg, 1.2 equiv) and K.sub.3PO.sub.4 (1.5 M in water, 3.0 equiv) in CPME (3.0 mL) was added CataCXium A Pd G3 (32.1 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 C. for 3 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 33% yield) as white solid; LCMS (ESI, M+1): m/z=644.3. [1028] Step B. (R)-1-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol To a solution of (R)-1-(7-(3-chloro-5-(methoxymethoxy)-2-((1R,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (100 mg, 1.0 equiv) in MeCN (1.5 mL) was added HCl.Math.dioxane (4 M, 100 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hours. The mixture was concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 51%-81% over 10 min] to afford the title compound (29.0 mg, 31% yield) as off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.19 (d, J=13.2 Hz, 1H), 7.00 (d, J=2.8 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 5.41-5.18 (m, 1H), 4.62-4.46 (m, 2H), 4.37-4.18 (m, 3H), 3.61 (br d, J=13.2 Hz, 1H), 3.50-3.39 (m, 1H), 3.30-3.12 (m, 3H), 3.01 (dt, J=5.6, 9.2 Hz, 1H), 2.40-2.06 (m, 4H), 2.05-1.69 (m, 7H), 1.28 (d, J=2.0 Hz, 3H), 1.18-1.02 (m, 1H), 0.74-0.52 (m, 4H); LCMS (ESI, M+1): m/z=600.4. Example 806 ##STR00614## 3-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(cis-2-methylcyclopropyl)phenol ##STR00615## [1029] Step A. (S,Z)-7-chloro-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv) and (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (130 mg, 1.2 equiv) in THF (5 mL) were added DIEA (327 mg, 4.0 equiv) and 4 molecular sieves (30.0 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (220 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=1/0 to 5/1] to afford the title compound (250 mg, 72% yield) as yellow solid; LCMS (ESI, M+1): m/z=450.9. [1030] Step B. 7-(3-chloro-5-(methoxymethoxy)-2-(cis-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of (S,Z)-7-chloro-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv) and 2-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (156 mg, 1.0 equiv) in methoxycyclopentane (4 mL) and water (1 mL) were added Cs.sub.2CO.sub.3 (434 mg, 3.0 equiv) and CataCXium A Pd G3 (64.6 mg, 0.2 equiv). The reaction was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 100 C. for 2 hours under N.sub.2 atmosphere. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, Petroleum ether/Ethyl acetate=1/1] to afford the title compound (55.0 mg, 16% yield) as yellow solid; LCMS (ESI, M+1): m/z=641.2. [1031] Step C. tert-butyl(1R,5S)-3-(7-(3-chloro-5-(methoxymethoxy)-2-(cis-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of 7-(3-chloro-5-(methoxymethoxy)-2-(cis-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (50.0 mg, 1.0 equiv) and tert-butyl(1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (24.8 mg, 1.5 equiv) in DMF (1 mL) were added DIEA (30.2 mg, 3.0 equiv) and 4 molecular sieves (20.0 mg). The reaction was stirred at 40 C. for 10 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, petroleum ether/ethyl acetate=0/1] to afford the title compound (30.0 mg, 43% yield) as yellow solid; LCMS (ESI, M+1): m/z=753.4. [1032] Step D. 3-(4-(cis-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(cis-2-methylcyclopropyl)phenol: To a solution of tert-butyl(1R,5S)-3-(7-(3-chloro-5-(methoxymethoxy)-2-(cis-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (27.0 mg, 1.0 equiv) in MeCN (2 mL) was added HCl.Math.dioxane (2 mL). The reaction was stirred at 0 C. for 0.5 hours. The mixture was concentrated, dissolved in MeOH (2 mL), adjusted to pH=7 with solid NaHCO.sub.3 and filtered. The filtrate was concentrated and purified with prep-HPLC [column: Phenomenex C18 7530 mm3 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; gradient: 40%-70% B over 10 minutes] to afford the title compound (9.06 mg, 41% yield) as white solid, .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.04 (s, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.77-6.50 (m, 1H), 4.67-4.53 (m, 2H), 4.36-4.21 (m, 2H), 3.84 (br d, J=14.8 Hz, 1H), 3.75-3.63 (m, 4H), 3.46 (br d, J=15.2 Hz, 1H), 3.22-3.06 (m, 1H), 2.80-2.64 (m, 2H), 2.44 (br d, J=15.6 Hz, 1H), 2.19-1.67 (m, 10H), 1.23-1.01 (m, 1H), 0.65 (br d, J=6.0 Hz, 4H); LCMS (ESI, M+1): m/z=609.3. Example 807 ##STR00616## ##STR00617## [1033] Step A. 7-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide: To a mixture of 7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (50.0 mg, 66.2 umol, 1.00 eq.), 2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide (37.8 mg, 3.00 equiv), 4 molecular sieve (50 mg) in DMF (0.5 mL) was added K.sub.3PO.sub.4 (70.3 mg, 5.00 equiv) The reaction was stirred at 60 C. for 12 hours. The mixture was filtered, concentrated and purified by prep-HPLC [Waters Xbridge 15025 mm5 m; A: water (NH.sub.3.Math.H.sub.2O); B: ACN, B %: 30%-60% over 9 min] followed by prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA); B: ACN, B %: 13%-43% over 10 min] to give title compound (15.1 mg, 15% yield) as a yellow solid; .sup.1H NMR (400 MHz, DMSO-d6) =9.10 (d, J=7.6 Hz, 1H), 8.17 (d, J=2.8 Hz, 1H), 7.99-7.89 (m, 1H), 7.56 (dt, J=3.6, 8.8 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.42-7.33 (m, 1H), 7.24-7.15 (m, 1H), 5.40-5.16 (m, 1H), 4.23-3.97 (m, 4H), 3.83-3.70 (m, 1H), 3.69-3.49 (m, 2H), 3.25-3.17 (m, 2H), 3.15-3.06 (m, 2H), 3.06-2.98 (m, 1H), 2.91-2.77 (m, 1H), 2.31-2.21 (m, 1H), 2.20-2.10 (m, 2H), 2.03-1.89 (m, 3H), 1.88-1.68 (m, 5H); LCMS (ESI, M+1): m/z=689.3. Example 808 ##STR00618## 7-(8-fluoro-7-(5-methyl-1H-benzo[f]indazol-4-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide ##STR00619## ##STR00620## [1034] Step A. (2-chloro-5-methylphenyl)methanol: To a mixture of 2-chloro-5-methylbenzoic acid (45.0 g, 1.0 equiv) in THF (500 mL) was added BH.sub.3.Math.Me.sub.2S (10 M, 158 mL, 6.0 equiv) at 0 C. The reaction was stirred at 20 C. for 12 hours. The mixture was quenched with MeOH (500 ml) and concentrated to afford the title compound (40 g, crude) as yellow solid. [1035] Step B. 2-(bromomethyl)-1-chloro-4-methylbenzene: To a mixture of (2-chloro-5-methylphenyl)methanol (40.0 g, 1.0 equiv) in DCM (400 mL) was added PBr.sub.3 (138 g, 2.0 equiv) at 0 C. The reaction was stirred at 0 C. for 1 hour. The mixture was concentrated under vacuum. The mixture was diluted with water (100 mL) at 0 C. The pH value of the mixture was adjusted to 7 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (2300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified with column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=10/1) to afford the title compound (47.1 g, 83% yield) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =7.30 (d, J=1.2 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.10 (dd, J=1.6, 8.0 Hz, 1H), 4.59 (s, 2H), 2.30 (s, 3H). [1036] Step C. ethyl 5-(2-chloro-5-methylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate: To a solution of ethyl 1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate (74.6 g, 1.0 equiv) in THF (500 mL) were added LDA (2 M, 196 mL, 1.3 equiv) and HMPA (70.3 g, 1.3 equiv) at 78 C. in 0.5 hour. The reaction was stirred at 78 C. for 0.5 hour. 2-(bromomethyl)-1-chloro-4-methylbenzene (53.0 g, 0.8 equiv) was added into above mixture. The reaction was stirred at 78 C. for 0.5 hour and 20 C. for 3 hours. The mixture was quenched with water (500 mL) at 0 C. and extracted with ethyl acetate (1000 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified with reversed phase flash chromatography [water (FA 0.1%)/acetonitrile] to afford the title compound (17.0 g, 14% yield) as yellow solid; LCMS (ESI, M+1): m/z=386.1. [1037] Step D. 5-(2-chloro-5-methylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid: To a mixture of ethyl 5-(2-chloro-5-methylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate (23.0 g, 1.0 equiv) in dioxane (160 mL) was added a solution of NaOH (47.7 g, 20.0 equiv) in H.sub.2O (160 mL). The reaction was stirred at 90 C. for 2 hours. The mixture was extracted with ethyl acetate (2200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated to afford the title compound (27.0 g, crude) as yellow solid. [1038] Step E. 8-chloro-5-methyl-1H-benzo[f]indazol-4 (9H)-one: A mixture of 5-(2-chloro-5-methylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid (36.6 g, 1.0 equiv) in CF.sub.3SO.sub.3H (300 mL) was stirred at 90 C. for 2 hours. The mixture was poured into ice water (600 mL) and adjusted to pH8 with NaHCO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate (31000 ml). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified with reversed phase flash chromatography [water (FA 0.1%)/acetonitrile] to afford the title compound (20.1 g, 83% yield) as yellow solid; LCMS (ESI, M+1): m/z=233.1. [1039] Step F. 8-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4 (9H)-one: To a mixture of 8-chloro-5-methyl-1H-benzo[f]indazol-4 (9H)-one (5.40 g, 1.0 equiv) and TsOH.Math.H.sub.2O (44.1 mg, 0.01 equiv) in THF (50 mL) was added DHP (3.90 g 2.0 equiv). The reaction was stirred at 20 C. for 2 hours. The mixture was quenched with water (40 mL) and extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified with reversed phase flash chromatography [water (FA 0.1%)/acetonitrile] to afford the title compound (3.62 g, 49% yield) as yellow solid. [1040] Step G. 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol: To a mixture of 8-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4 (9H)-one (3.60 g, 1.0 equiv) and NaHCO.sub.3 (2.86 g, 3.0 equiv) in MeOH (50 mL) was added Pd/C (360 mg, 5% purity) under N.sub.2 atmosphere. The reaction was degassed and purged with H.sub.2 3 times. The reaction was stirred under H.sub.2 (15 Psi) at 20 C. for 5 hours. The mixture was diluted with water (50 mL) and concentrated under vacuum to remove MeOH. The mixture was extracted with EtOAc (3 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (2.29 g, 60% yield) as yellow solid; LCMS (ESI, M+1): m/z=282.8. [1041] Step H. 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate: To a mixture of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol (2.7 g, 1.0 equiv), DIEA (4.9 g, 4.0 equiv) and 4 molecular sieve (100 mg) in DCM (20 mL) was added Tf.sub.2O (5.40 g, 2.0 equiv) at 40 C. The reaction was stirred at 40 C. for 0.5 hour. The mixture was quenched with water (20 mL) and extracted with dichloromethane (2 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified with column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=10/1) to afford the title compound (1.08 g, 27% yield) as yellow solid; LCMS (ESI, M+1): m/z=415.0. [1042] Step I. 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole: To a solution of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (550 mg, 1.0 equiv), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.70 g, 10.0 equiv) and TEA (403 mg, 3.0 equiv) in MeCN (5 mL) was added Pd(dppf)Cl.sub.2 (97.1 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 80 C. for 12 hours. The mixture was concentrated and purified with prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 54%-84%, 8 min) to afford the title compound (229 mg, 36% yield) as yellow solid; LCMS (ESI, M+1): m/z=393.1. [1043] Step J. 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine; To a mixture of POCl.sub.3 (17.8 g, 5.0 equiv) in toluene (50 mL) were added 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (5.00 g, 1.0 equiv) and DIEA (6.00 g, 2.0 equiv). The reaction was stirred at 110 C. for 24 hours. The mixture was concentrated under vacuum. The residue was diluted with iced saturated NaHCO.sub.3 solution (50 ml) and brought the pH to 8. The mixture was filtered and filter cake was dissolved in ethyl acetate (100 ml). The mixture washed with saturated NaHCO.sub.3 aqueous solution (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, concentrated under vacuum to afford the title compound (4.9 g, crude) as yellow solid. [1044] Step K. 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,2,2-trifluoroethanol (991 mg, 1.0 equiv) in THF (8 mL) was added t-BuONa (2 M, 4.95 mL, 1.0 equiv) at 25 C. The reaction was stirred at 25 C. for 1 hour. The above mixture was added to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.5 g, 1.0 equiv) in THF (20 mL) at 40 C. The reaction was stirred at 40 C. for 1 hour. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated to afford the title compound (3.28 g, crude) as yellow solid; LCMS (ESI, M+1): m/z=315.7. [1045] Step L. 7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (4.00 g, 1.0 equiv) and Na.sub.2CO.sub.3 (4.02 g, 3.0 equiv) in THF (40 mL) was added (hexahydro-1H-pyrrolizin-7a-yl)methanol (3.57 g, 2.0 equiv). The reaction was stirred at 60 C. for 3 hours. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified with reversed phase flash chromatography [water (FA 0.1%)/acetonitrile] to afford the title compound (800 mg, 15% yield) as yellow solid; LCMS (ESI, M+1): m/z=421.2. [1046] Step M. 7-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: To a mixture of 7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv), DIEA (614 mg, 10 equiv) and 4 molecular sieve (20 mg) in DMF (2 mL) was added 2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (227 mg, 2.5 equiv). The reaction was stirred at 60 C. for 2 hours. The mixture was filtered and concentrated and purified with reversed phase flash chromatography [water (FA 0.1%)/acetonitrile] to afford the title compound (200 mg, 81% yield) as yellow solid; LCMS (ESI, M+1): m/z=512.1. [1047] Step N. 7-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: To a mixture of 7-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (50.0 mg, 1.0 equiv), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole (38.3 mg, 1.0 equiv) and K.sub.3PO.sub.4 (62.2 mg, 3.0 equiv) in Methoxycyclopentane (1 mL) and H.sub.2O (0.3 mL) was added cataCXium A Pd G3 (7.11 mg 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 C. for 3 hours. The mixture was quenched with water (3 mL) and extracted with ethyl acetate (25 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified with column chromatography (SiO.sub.2, Dichloromethane:Methanol=0/1) to afford the title compound (17.8 mg, 23% yield) as yellow solid. LCMS (ESI, M+1): m/z=742.8. [1048] Step O. 7-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(5-methyl-1H-benzo[f]indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: A mixture of 7-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (25.0 mg 1.0 equiv) in TFA (770 mg, 0.5 mL) was stirred at 25 C. for 0.5 hour. The mixture was concentrated under vacuum. The residue was diluted with water (1 mL). The mixture was adjusted to pH=8 with saturated NaHCO.sub.3 (10 mL) and extracted with ethyl acetate (32 ml). The combined organic layers were washed with brine (4 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified with prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 12%-42%, 10 min) to afford the title compound (3.40 mg 15% yield, HCOOH salt) as yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.26-9.15 (m, 1H), 8.54 (br s, 1H), 8.19 (d, J=4.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.88-7.66 (m, 1H), 7.39-7.33 (m, 1H), 7.19 (br d, J=6.4 Hz, 1H), 4.66-4.49 (m, 4H), 3.84 (d, J=13.6 Hz, 1H), 3.67-3.36 (m, 4H), 3.22-3.15 (m, 1H), 3.14-3.01 (m, 2H), 2.32-2.20 (m, 2H), 2.15 (s, 3H), 2.13-2.04 (m, 5H), 2.03-1.76 (m, 5H). LCMS (ESI, M+1): m/z=658.3. Example 809 ##STR00621## (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(hydroxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00622## [1049] Step A. (R)-1-(2-(((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of ((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (618 mg, 1.0 equiv), t-BuONa (2 M, 1.5 mL, 2.0 equiv) and 4 molecular sieve (100 mg) in toluene (5.0 mL) was added (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (500 mg, 1.0 equiv). The reaction was stirred at 0 C. for 1 hour under N.sub.2 atmosphere. The mixture was diluted with water (30 mL), extracted with ethyl acetate (330 mL), washed with brine (2 30 mL), dried, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=2/1 to methylene chloride/methanol=10/1] to afford the title compound (860 mg, 54% yield,) as yellow solid; LCMS (ESI, M+1): m/z=704.5. [1050] Step B. (R)-1-(2-(((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (R)-1-(2-(((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50.0 mg, 1.0 equiv), Ad.sub.2nBu Pd G.sub.3 (5.17 mg, 0.1 equiv) and Cs.sub.2CO.sub.3 (69.4 mg, 3.0 equiv) in H.sub.2O (0.2 mL) and CPME (1.0 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (43.7 mg, 1.2 equiv). The reaction was stirred at 80 C. for 2 hours under N.sub.2 atmosphere. The mixture was diluted with water (20 mL), extracted with DCM (320 mL), washed with brine (10 mL), dried, concentrated and purified with prep-TLC (SiO.sub.2, methylene chloride/methanol=10:1) to afford the title compound (50.0 mg, 67% yield) as white solid; LCMS (ESI, M+1): m/z=1054.5. [1051] Step C. (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(hydroxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(2-(((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50.0 mg, 1.0 equiv) in DMF (1.0 mL) was added CsF (259 mg, 30 equiv). The reaction was stirred at 20 C. for 2 hours. The mixture was diluted with water (20 mL), extracted with DCM (320 mL), washed with brine (20 mL), dried and concentrated to afford the title compound (30.0 mg, crude) as white solid; LCMS (ESI, M+1): m/z=660.3. [1052] Step D. (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(hydroxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(hydroxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (30.0 mg, 1.0 equiv) in ACN (1.0 mL) was added HCl.Math.dioxane (4 M, 1.0 mL). The reaction was stirred at 0 C. for 1 hour. The mixture was quenched with NaHCO.sub.3 at 0 cand adjusted pH to 7, filtered and purified with prep-HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 10%-40%, 10 min] to afford the title compound (10.0 mg, 36% yield,) as orange solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.26-9.03 (m, 1H), 8.54 (s, 1H), 7.94-7.79 (m, 1H), 7.40-7.17 (m, 3H), 4.70-4.58 (m, 1H), 4.55-4.44 (m, 2H), 4.40-4.25 (m, 1H), 3.76-3.49 (m, 4H), 3.46-3.33 (m, 2H), 3.28-3.13 (m, 2H), 2.39-2.27 (m, 1H), 2.25-2.15 (m, 1H), 2.14-2.02 (m, 4H), 2.00-1.88 (m, 3H), 1.88-1.70 (m, 3H), 1.38-1.19 (m, 3H); LCMS (ESI, M+1): m/z=616.3. Example 810 ##STR00623## 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1-(oxetan-3-yl)-1H-pyrazole-3-carboxamide ##STR00624## [1053] Step A. tert-butyl((3-(dimethylcarbamoyl)-1-(oxetan-3-yl)-1H-pyrazol-5-yl)methyl)carbamate: To a mixture of tert-butyl N-[[3-(dimethylcarbamoyl)-1H-pyrazol-5-yl]methyl]carbamate (686 mg, 2.0 equiv) in ACN (5 mL) was added Cs.sub.2CO.sub.3 (1.21 g, 2.0 equiv). The reaction was stirred at 80 C. for 12 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (500 mg, 82% yield) as yellow solid; LCMS (ESI, M+1): m/z=324.9. [1054] Step B. 5-(aminomethyl)-N,N-dimethyl-1-(oxetan-3-yl)-1H-pyrazole-3-carboxamide: To a solution of tert-butyl((3-(dimethylcarbamoyl)-1-(oxetan-3-yl)-1H-pyrazol-5-yl)methyl)carbamate (70 mg, 1.0 equiv) in DCM (120 L) was added TFA (369 mg, 15 equiv). The reaction was stirred at 20 C. for 0.5 hours. The mixture was concentrated to afford the title compound (73 mg, CF.sub.3COOH) as yellow oil. [1055] Step C. 5-(((2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1-(oxetan-3-yl)-1H-pyrazole-3-carboxamide: To a mixture of 5-(aminomethyl)-N,N-dimethyl-1-(oxetan-3-yl)-1H-pyrazole-3-carboxamide (73.0 mg, 0.9 equiv, CF.sub.3COOH) and DIEA (651 mg, 21 equiv) in DCM (1 mL) were added 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (108 mg, 1.0 equiv) and 4 molecular sieve (50.0 mg, 1.0 equiv) at 40 C. The reaction was stirred at 40 C. for 15 minutes. The mixture was diluted with water (5 mL) and extracted with DCM (35 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [Welch Xtimate C18 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN; B %: 35%-65% over 2 min] to afford the title compound (30.0 mg, 19% yield) as white solid; LCMS (ESI, M+1): m/z=638.6. [1056] Step D. 5-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1-(oxetan-3-yl)-1H-pyrazole-3-carboxamide: To a mixture of 5-(((2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1-(oxetan-3-yl)-1H-pyrazole-3-carboxamide (200 mg, 1.0 equiv) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (100 mg, 2.0 equiv) in dioxane (2 mL) was added DIEA (406 mg, 10 equiv). The reaction was stirred at 90 C. for 12 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (35 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] followed by purified by prep-HPLC [Waters xbridge 15025 mm10 m; A: water (NH.sub.4HCO.sub.3), B: ACN; B %: 39%-69% over 9 min] to afford the title compound (30 mg, 12% yield) as yellow solid; LCMS (ESI, M+1): m/z=761.4. [1057] Step E. 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1-(oxetan-3-yl)-1H-pyrazole-3-carboxamide: To a mixture of 5-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-N,N-dimethyl-1-(oxetan-3-yl)-1H-pyrazole-3-carboxamide (25.0 mg, 1.0 equiv) in DCM (2.5 mL) was added TFA (770 mg, 205 equiv). The reaction was stirred at 0 C. for 1 hour. The mixture was concentrated by blowing of nitrogen, dissolved in methanol (1 mL), neutralized with solid NaHCO.sub.3, filtered and purified by prep-HPLC [Phenomenex luna C 1815025 mm10 m; A: water (FA), B: ACN; B %: 15%-45% over 60 min] to afford the title compound (6.25 mg, 24% yield, HCOOH) as off-white solid; .sup.1H NMR (400 MHZ, methanol-d.sub.4) =9.19-9.13 (m, 1H), 8.501 (s, 1H), 7.71-7.64 (m, 1H), 7.35-7.29 (m, 1H), 7.28-7.21 (m, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.78-6.72 (m, 1H), 6.04-5.95 (m, 1H), 5.49-5.30 (m, 1H), 5.20-5.12 (m, 2H), 5.09-5.01 (m, 2H), 4.93 (s, 2H), 4.50-4.36 (m, 2H), 3.58-3.39 (m, 6H), 3.23-3.15 (m, 1H), 3.14-3.08 (m, 3H), 2.53-2.31 (m, 3H), 2.29-2.19 (m, 1H), 2.18-2.06 (m, 3H), 2.05-1.92 (m, 1H), 0.77 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=717.5. Example 811 ##STR00625## (1R,5R,6R)-3-(7-(8-ethyl-2,7-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00626## [1058] Step A. 5-(2-(4-fluorophenyl) acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione: To a mixture of 2-(4-fluorophenyl) acetic acid (250 g, 1.0 equiv) and 2,2-dimethyl-1,3-dioxane-4,6-dione (257 g, 1.1 equiv) in acetonitrile (1.25 L) were added DMAP (16.9 g, 0.09 equiv) and DIPEA (451 g, 2.1 equiv) below 30 C. for 1 hour. Pivaloyl chloride (215 g, 1.1 equiv) was added into above mixture dropwise below 40 C. for 1 hour. The reaction was stirred at 45 C. for 3 hours. The mixture was cooled to 0 C. and adjusted pH to 5 with 4 N HCl (5.00 L). The mixture was stirred at 0 C. for 1 hour. The mixture was diluted with H.sub.2O (15 L) and the pH of the mixture was adjusted to 2 with 4N HCl. The mixture was filtered. The filter cake was washed with H.sub.2O until the pH of filtrate was 56. The solid was dried under reduced pressure to afford the tittle compound (500 g, crude) as white solid; .sup.1H NMR (400 MHZ, chloroform-d) =7.36 (dd, J=5.6, 8.4 Hz, 2H), 7.01 (t, J=8.4 Hz, 2H), 4.38 (s, 2H), 1.72 (s, 6H). [1059] Step B. 7-fluoro-1,3-dihydroxy-2-naphthoic acid: To CF.sub.3SO.sub.3H (2.04 kg, 7.8 equiv) in reaction bottle was added 5-(2-(4-fluorophenyl) acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (490 g, 1.0 equiv) in portions below 30 C. The reaction was stirred at 20 C. for 2 hours. The mixture was poured into ice water (30 L) and filtered. The filter cake was washed with H.sub.2O until the pH of the filtrate was 34 to afford the tittle compound (500 g, crude) as brown solid. [1060] Step C. 7-fluoronaphthalene-1,3-diol: A mixture of 7-fluoro-1,3-dihydroxy-2-naphthoic acid (375 g, crude) in H.sub.2O (1.8 L) and acetonitrile (1.8 L) was stirred at 78 C. for 13 hours. The mixture was concentrated to remove acetonitrile. The residue was diluted with H.sub.2O (1 L) and saturated NaHCO.sub.3 aqueous (0.3 L) and extracted with ethyl acetate (4 0.5 L). The combined organic layers were washed with saturated NaHCO.sub.3 aqueous (0.5 L), H.sub.2O (0.5 L) and brine (0.5 L), dried over anhydrous sodium sulfate and concentrated to give a residue. The solid was dispersed in n-heptane (0.8 L) and the mixture was stirred for 1 hour. The mixture was filtered and the solid was dried under reduced pressure to afford the tittle compound (145 g, 60% yield over three steps) as light red solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) =10.18 (s, 1H), 9.48 (s, 1H), 7.65-7.56 (m, 2H), 7.23 (dt, J=2.8, 8.8 Hz, 1H), 6.64 (d, J=1.6 Hz, 1H), 6.56 (d, J=1.6 Hz, 1H). [1061] Step D. 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol: To a mixture of 7-fluoronaphthalene-1,3-diol (173 g, 1.0 equiv) and (bromoethynyl)triisopropylsilane (266 g, 1.05 equiv) in dioxane (1.5 L) were added KOAc (191 g, 2.0 equiv) and [Ru(p-cymene)Cl.sub.2].sub.2 (17.8 g, 0.03 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 100 C. for 3.5 hours. The mixture was filtered through a pad of Celite. The filter cake was washed with ethyl acetate (4500 mL). The filtrate was concentrated and dissolved in ethyl acetate (3 L). The solution was washed with saturated NaHCO.sub.3 aqueous (0.5 L) and brine (0.2 L), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=15/1 to 10/1] to give a residue. The residue was dispersed in n-heptane (0.5 L) and stirred for 1 hour. The mixture was filtered, and the filter cake was washed with n-heptane (0.5 L). The solid was dried under reduced pressure to afford the tittle compound (204 g, 56% yield) as light yellow solid; .sup.1H NMR (400 MHZ, DMSO-d6) =10.04 (s, 1H), 9.58 (s, 1H), 7.63 (dd, J=5.6, 9.2 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 6.58 (d, J=2.0 Hz, 1H), 1.13 (s, 21H). [1062] Step E. ((2-fluoro-6,8-bis(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane: To a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (50.0 g, 1.0 equiv) and DIEA (90.1 g, 5.0 equiv) in dichloromethane (500 mL) was added bromo(methoxy) methane (69.7 g, 4.0 equiv) at 0 C. The reaction was stirred at 15 C. for 10 hours. The mixture was diluted with water (200 mL). The organic layer was concentrated and purified with column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 20/1] to afford the title compound (58.0 g, 93% yield) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.61 (dd, J=5.6, 9.0 Hz, 1H), 7.21 (t, J=8.8 Hz, 1H), 7.04 (s, 2H), 5.33 (s, 2H), 5.26 (s, 2H), 3.55 (s, 3H), 3.52 (s, 3H), 1.20 (s, 21H); LCMS (ESI, M+1): m/z=447.3. [1063] Step F. ((2,7-difluoro-6,8-bis(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane: To a solution of ((2-fluoro-6,8-bis(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (6.70 g, 1.0 equiv) and TMEDA (1.92 g, 1.1 equiv) in THF (100 mL) was added n-BuLi (2.5 M in THF, 2.0 equiv) at 0 C. The reaction was stirred at 0 C. for 1 hour. To the mixture was added a mixture of NFSI (5.20 g, 1.1 equiv) in THF (30 mL) at 60 C. The reaction was stirred at 15 C. for 2 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (2100 mL). The combined organic layers were concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 15/1] to afford the title compound (1.90 g, 27% yield) as yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) 8-7.64 (dd, J=5.6, 8.8 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.20 (t, J=8.8 Hz, 1H), 5.33 (s, 2H), 5.24 (s, 2H), 3.67 (s, 3H), 3.56 (s, 3H), 1.21-1.18 (m, 21H); LCMS (ESI, M+1): m/z=465.3. [1064] Step G. 2,7-difluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol: To a solution of ((2,7-difluoro-6,8-bis(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (3.00 g, 1.0 equiv) in MeOH (8 mL) was added HCl.Math.MeOH (4 M, 10 equiv) at 0 C. The reaction was stirred at 0 C. for 1 hour. The mixture was concentrated. The residue was diluted with water (10 mL). The mixture was adjusted to pH=7 with saturated sat. NaHCO.sub.3 (10 mL). The mixture was extracted with ethyl acetate (2 30 mL), concentrated, and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 4/1] to afford the title compound (2.10 g, 82% yield) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.11 (s, 1H), 7.60 (dd, J=5.6, 9.2 Hz, 1H), 7.15 (t, J=8.8 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.87 (br d, J=3.2 Hz, 1H), 1.24-1.16 (m, 21H); LCMS (ESI, M1): m/z=377.1. [1065] Step H. 2,7-difluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-ol: To a solution of 2,7-difluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (2.10 g, 1.0 equiv) and DIEA (1.44 g, 2.0 equiv) in dichloromethane (10 mL) was added chlorotriisopropylsilane (1.18 g, 1.1 equiv) at 0 C. The reaction was stirred at 20 C. for 1 hour. The mixture was concentrated and purified with column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 15/1] to afford the title compound (2.20 g, 74% yield) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.97 (s, 1H), 7.58 (dd, J=5.6, 9.2 Hz, 1H), 7.13 (t, J=8.8 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 1.22-1.11 (m, 42H); LCMS (ESI, M+1): m/z=533.3. [1066] Step I. 2,7-difluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate: To a solution of 2,7-difluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-ol (2.20 g, 1.0 equiv) and DIEA (1.60 g, 3.0 equiv) in dichloromethane (20 mL) was added Tf.sub.2O (1.63 g, 1.4 equiv) at 40 C. The reaction was stirred at 40 C. for 0.5 hours. The mixture was concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 20/1] to afford the title compound (2.20 g, 80% yield) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.62 (dd, J=5.2, 9.0 Hz, 1H), 7.31-7.28 (m, 1H), 7.28-7.25 (m, 1H), 1.22-1.10 (m, 42H). [1067] Step J. ((3,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane: To a solution of 2,7-difluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate (1.20 g, 1.0 equiv), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (924 mg, 4.0 equiv) and TEA (730 mg, 4.0 equiv) in acetonitrile (20 mL) was added Pd(dppf)Cl.sub.2 (132 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 80 C. for 2 hours. The mixture was quenched with methanol (0.5 mL), concentrated, and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 15/1] to afford the title compound (700 mg, 54% yield) as yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.57 (dd, J=5.6, 9.2 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.16 (t, J=8.8 Hz, 1H), 1.48 (s, 12H), 1.19-1.16 (m, 21H), 1.15-1.11 (m, 21H). [1068] Step K. 7-(2,7-difluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (246 mg, 1.2 equiv), ((3,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (300 mg, 1.0 equiv) and Cs.sub.2CO.sub.3 (1.5 M in water, 3.0 equiv) in methoxycyclopentane (2.5 mL) was added CataCXium A Pd G3 (34.0 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 C. for 3 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (215 mL). The combined organic layers were concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 1/1] to afford the title compound (120 mg, 21 yield) as yellow solid; LCMS (ESI, M+1): m/z=919.5. [1069] Step L. (1R,5R,6R)-3-(7-(2,7-difluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a mixture of 7-(2,7-difluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (120 mg, 1.0 equiv), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (24.9 mg, 1.5 equiv) and 4 molecular sieve (30 mg) in DMF (0.8 mL) was added DIEA (50.6 mg, 3.0 equiv). The mixture was stirred at 40 C. for 36 hours. The mixture was filtered. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (215 mL). The combined organic layers were concentrated to afford the title compound (200 mg, crude) as yellow oil; LCMS (ESI, M+1): m/z=790.4. [1070] Step M. (1R,5R,6R)-3-(7-(8-ethynyl-2,7-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(2,7-difluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (200 mg, 1.0 equiv) in DMF (1 mL) was added CsF (384 mg, 10 equiv). The reaction was stirred at 40 C. for 0.5 hours. The mixture was filtered and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (45.0 mg, 56% yield over two steps) as yellow solid; LCMS (ESI, M+1): m/z=634.3. [1071] Step N. (1R,5R,6R)-3-(7-(8-ethyl-2,7-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(8-ethynyl-2,7-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (45.0 mg, 1.0 equiv) in MeOH (5 mL) was added Pd/C (20 mg, 10% purity) under N.sub.2. The reaction was degassed and purged with H.sub.2 3 times. The reaction was stirred under H.sub.2 (15 psi) at 20 C. for 0.5 hours. The mixture was filtered and concentrated and purified by prep-HPLC [column: Unisil 3-100 C18 Ultra 15050 mm3 m; A: water (FA), B: ACN, B %: 17%-47% over 7 min] to afford the title compound (8.76 mg, 19% yield, HCOOH salt) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.35-9.22 (m, 1H), 7.68 (dd, J=5.6, 8.8 Hz, 1H), 7.47 (d, J=9.2 Hz, 1H), 7.23 (t, J=9.2 Hz, 1H), 5.50-5.29 (m, 1H), 5.07-4.97 (m, 1H), 4.83-4.70 (m, 1H), 4.46-4.41 (m, 1H), 4.37-4.28 (m, 2H), 3.91-3.73 (m, 1H), 3.60-3.36 (m, 4H), 3.21-3.07 (m, 1H), 2.52-2.17 (m, 7H), 2.14-1.88 (m, 5H), 1.82 (br s, 1H), 1.39 (br d, J=13.6 Hz, 1H), 0.78 (td, J=7.2, 10.8 Hz, 3H); LCMS (ESI, M+1): m/z=638.3. Example 812 ##STR00627## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-(hydroxymethyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00628## [1072] Step A. 3-azabicyclo[3.2.1]octan-1-ylmethanol: To a solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (100 mg, 1.0 equiv) in MeCN (1 mL) was added HCl.Math.dioxane (4 M, 2.00 mL, 19 equiv). The reaction was stirred at 25 C. for 1 hour. The mixture was concentrated to afford the title compound (50.0 mg, 85.45% yield, hydrochloride). [1073] Step B. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(1-(hydroxymethyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (140 mg, 1.0 equiv) in DMF (2 mL) was added 3-azabicyclo[3.2.1]octan-1-ylmethanol hydrochloride (50.0 mg, 1.5 equiv), DIEA (152 mg, 5.0 equiv) and 4 molecular sieve (50.0 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (35 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, concentrated and purified by prep-HPLC [column: Phenomenex luna 15025 mm10 m; A: water (FA), B: ACN; B %: 15%-45% over 10 min] to afford the title compound (43.0 mg, 27% yield, HCOOH); .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.96-8.84 (m, 1H), 7.45 (br s, 1H), 7.17-6.78 (m, 3H), 5.40-5.16 (m, 1H), 4.62-4.20 (m, 4H), 3.56-2.96 (m, 10H), 2.53-2.09 (m, 6H), 2.06-1.89 (m, 3H), 1.57-1.16 (m, 5H), 0.78 (br d, J=5.6 Hz, 3H); LCMS (ESI, M+1): m/z=634.3. Example 813 ##STR00629## (3R)-1-(2-((1-((dimethylamino)methyl)-2-(hydroxymethyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00630## [1074] Step A. diethyl 2-(oxiran-2-ylmethyl) malonate: To a mixture of diethyl 2-allylpropanedioate (10.0 g, 1.0 equiv) in DCM (100 mL) was added m-CPBA (12.9 g, 80% purity, 1.2 equiv). The mixture was stirred at 25 C. for 15 hours under N.sub.2 atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was re-crystallized from petroleum ether (100 mL) at 25 C. and the solid was triturated with saturated NaHCO.sub.3 aqueous solution (100 mL) to afford the title compound (10.4 g, 85% yield) as a yellow oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) =4.23-4.09 (m, 4H), 3.47 (dd, J=6.0, 8.8 Hz, 1H), 3.01-2.89 (m, 1H), 2.71 (t, J=4.4 Hz, 1H), 2.46 (dd, J=2.4, 4.8 Hz, 1H), 2.28-2.13 (m, 1H), 2.02-1.86 (m, 1H), 1.21 (dt, J=4.0, 7.2 Hz, 6H). [1075] Step B. diethyl 2-(hydroxymethyl)cyclopropane-1,1-dicarboxylate: To a mixture of diethyl 2-(oxiran-2-ylmethyl) malonate (5.00 g, 1.0 equiv) in THF (50 mL) was added Mg(ClO.sub.4).sub.2 (5.16 g, 1.0 equiv). The mixture was stirred at 60 C. for 2 hours under N.sub.2 atmosphere. The mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (350 mL). The combined organic phases were washed with brine (250 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, concentrated under vacuum and purified with flash silica gel chromatography (ISCO; 80 g SepaFlash Silica Flash Column, Eluent of 050% Ethyl acetate/Petroleum ethergradient@75 mL/min) to afford the title compound (1.10 g, 22% yield) as a white solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =4.32-4.17 (m, 4H), 3.96 (dd, J=5.2, 12.4 Hz, 1H), 3.27 (dd, J=9.6, 12.4 Hz, 1H), 2.15 (ddt, J=5.2, 7.2, 9.2 Hz, 1H), 1.55 (dd, J=5.2, 9.2 Hz, 1H), 1.36-1.21 (m, 9H). [1076] Step C. diethyl 2-((benzyloxy)methyl)cyclopropane-1,1-dicarboxylate: To a mixture of diethyl 2-(hydroxymethyl)cyclopropane-1,1-dicarboxylate (500 mg, 1.0 equiv) and DIEA (598 mg, 2.0 equiv) in DMF (5 mL) was added BnBr (791 mg, 2.0 equiv). The mixture was stirred at 110 C. for 12 hours under N.sub.2 atmosphere. The mixture was poured into ice-water (5 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated under vacuum and purified with flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 010% Ethyl acetate/Petroleum ethergradient@20 mL/min) to afford the title compound (490 mg, 69% yield) as a white solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.36-7.28 (m, 5H), 4.45 (br d, J=8.8 Hz, 2H), 4.28-4.08 (m, 4H), 3.53 (dq, J=6.4, 10.8 Hz, 2H), 2.34-2.19 (m, 1H), 1.55 (dd, J=4.8, 7.6 Hz, 1H), 1.44 (dd, J=4.8, 9.2 Hz, 1H), 1.26 (q, J=7.2 Hz, 6H). [1077] Step D. 2-((benzyloxy)methyl)-1-(ethoxycarbonyl)cyclopropanecarboxylic acid: To a mixture of diethyl 2-((benzyloxy)methyl)cyclopropane-1,1-dicarboxylate (420 mg, 1.0 equiv) in EtOH (6 mL) was added NaOH aqueous solution (1 M, 1.51 mL, 1.1 equiv). The mixture was stirred at 25 C. for 1 hour. The reaction mixture was adjusted to pH=2 with 1M HCl, diluted with H.sub.2O (10 mL) and extracted with EtOAc (10 mL). The organic phase was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford the crude title compound (350 mg, 92% yield) as a white solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.38-7.29 (m, 5H), 4.54-4.49 (m, 1H), 4.45-4.39 (m, 1H), 4.23 (qd, J=7.2, 10.8 Hz, 1H), 4.16-4.02 (m, 1H), 3.86 (dd, J=5.6, 10.8 Hz, 1H), 3.49 (dd, J=9.6, 10.8 Hz, 1H), 2.47 (dq, J=5.6, 9.2 Hz, 1H), 2.02 (dd, J=4.4, 9.2 Hz, 1H), 1.81 (dd, J=4.4, 8.4 Hz, 1H), 1.21 (t, J=7.2 Hz, 3H). [1078] Step E. ethyl 2-((benzyloxy)methyl)-1-(dimethylcarbamoyl)cyclopropanecarboxylate: To a mixture of 2-(benzyloxymethyl)-1-ethoxycarbonyl-cyclopropanecarboxylic acid (240 mg, 1.0 equiv) and N-methylmethanamine (141 mg, 2.0 equiv, HCl salt) in DCM (3 mL) were added HATU (656 mg, 2.0 equiv) and DIEA (557 mg, 5.0 equiv). The mixture was stirred at 25 C. for 12 hours under N.sub.2 atmosphere. The mixture was poured into ice-water (3 mL) and extracted with ethyl acetate (6 mL). The organic phase was washed with brine (3 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated under vacuum and purified with flash silica gel chromatography (ISCOR; 4 g SepaFlash Silica Flash Column, Eluent of 050% Ethyl acetate/Petroleum ethergradient@36 mL/min) to afford the title compound (180 mg, 68% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.38-7.29 (m, 5H), 4.52 (d, J=3.6 Hz, 2H), 4.28-4.09 (m, 2H), 3.86 (dd, J=5.6, 10.4 Hz, 1H), 3.74-3.56 (m, 1H), 3.13 (s, 3H), 2.99 (s, 3H), 2.19-2.07 (m, 1H), 1.60-1.47 (m, 2H), 1.24 (t, J=7.2 Hz, 3H). [1079] Step F. (2-((benzyloxy)methyl)-1-((dimethylamino)methyl)cyclopropyl)methanol: To a mixture of ethyl 2-(benzyloxymethyl)-1-(dimethylcarbamoyl)cyclopropanecarboxylate (3.00 g, 1.0 equiv) in THF (30 mL) was added LAH (1.86 g, 5.0 equiv) at 0 C. The mixture was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. The mixture was cooled to 0 C. and sat. Na.sub.2SO.sub.4 aqueous solution (6 mL) was added to the mixture dropwise carefully. After stirring for 15 mins, the mixture was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum to afford the crude title compound (1.70 g, 69% yield) as a yellow oil. [1080] Step G. (3R)-1-(2-((2-((benzyloxy)methyl)-1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (683 mg, 1.0 equiv) and (2-((benzyloxy)methyl)-1-((dimethylamino)methyl)cyclopropyl)methanol (500 mg, 0.97 equiv) in THF (5 mL) was added NaHMDS (1 M THF solution, 1.55 mL, 1.5 equiv) at 10 C. The mixture was stirred at 10 C. for 1 hour under N.sub.2 atmosphere. The reaction mixture was quenched with NH.sub.4Cl aqueous solution (sat. 10 mL) at 0 C., diluted with water (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (210 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified with prep-HPLC (column: YMC Triart C18 150*25 mm*5 um; mobile phase: [water (FA)-ACN]; B %: 13%-43%, 10 min) to afford the title compound (320 mg, 42% yield) as a white solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.25-9.07 (m, 1H), 8.29 (s, 1H), 7.68 (br dd, J=6.0, 8.8 Hz, 1H), 7.52 (br d, J=2.4 Hz, 1H), 7.35-7.26 (m, 5H), 6.71-6.41 (m, 2H), 5.37-5.23 (m, 2H), 4.89-4.65 (m, 1H), 4.62-4.40 (m, 5H), 3.86-3.68 (m, 1H), 3.52 (s, 4H), 3.46-3.37 (m, 1H), 3.35-3.07 (m, 2H), 2.73-2.61 (m, 6H), 2.60-2.45 (m, 2H), 2.33-2.04 (m, 2H), 1.88 (br d, J=11.6 Hz, 1H), 1.78-1.57 (m, 2H), 1.46 (br d, J=6.8 Hz, 1H), 1.32 (s, 3H), 0.87 (br dd, J=6.8, 14.0 Hz, 5H); LCMS (ESI, M+1): m/z=742.4. [1081] Step H. (3R)-1-(2-((1-((dimethylamino)methyl)-2-(hydroxymethyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(2-((2-((benzyloxy)methyl)-1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50.0 mg, 1.0 equiv) in EtOAc (1 mL) were added Pd/C (10.0 mg, 10% purity) and Pd(OH).sub.2/C (10.0 mg, 20% purity) under N.sub.2 atmosphere. The suspension was degassed under vacuum and purged with H.sub.2 several times. The mixture was stirred at 25 C. for 2 hours under H.sub.2 (15 Psi) atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure and purified with prep-HPLC (column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water (NH.sub.4HCO.sub.3)-ACN]; B %: 47%-77%, 8 min) to afford the title compound (20.0 mg, 46% yield) as a white solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.16 (d, J=4.4 Hz, 1H), 7.75-7.65 (m, 1H), 7.57-7.51 (m, 1H), 7.32-7.28 (m, 1H), 7.24 (td, J=2.4, 5.2 Hz, 1H), 5.43-5.24 (m, 2H), 5.14-4.99 (m, 1H), 4.64-4.35 (m, 2H), 4.30-4.14 (m, 1H), 4.08-3.92 (m, 1H), 3.60-3.39 (m, 5H), 3.38-3.20 (m, 1H), 2.98-2.84 (m, 1H), 2.62-2.45 (m, 1H), 2.29 (s, 6H), 2.16-2.08 (m, 1H), 1.98-1.60 (m, 9H), 1.36 (s, 3H), 1.25 (br d, J=7.2 Hz, 1H), 0.96-0.76 (m, 4H), 0.75-0.60 (m, 1H); LCMS (ESI, M+1): m/z=652.3. [1082] Step I. (3R)-1-(2-((1-((dimethylamino)methyl)-2-(hydroxymethyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(2-((1-((dimethylamino)methyl)-2-(hydroxymethyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (43.9 mg, 1.0 equiv) in MeOH (1 mL) was added HCl/MeOH (4 M, 0.3 mL) at 0 C. The mixture was stirred at 0 C. for 0.5 hour. The mixture was poured into NaHCO.sub.3 aqueous solution (5 mL, sat.) and extracted with ethyl acetate (25 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated under vacuum and purified with prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 17%-37%, 10 min) to afford the title compound (6.50 mg, 15% yield) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.26 (d, J=3.2 Hz, 1H), 8.55 (br s, 1H), 7.70 (dd, J=5.6, 9.2 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.32-7.23 (m, 1H), 7.08 (s, 1H), 4.77-4.63 (m, 2H), 4.63-4.52 (m, 1H), 4.34 (br t, J=12.0 Hz, 1H), 3.90 (br dd, J=5.6, 11.6 Hz, 1H), 3.72-3.55 (m, 2H), 3.54-3.41 (m, 1H), 3.23 (br s, 1H), 2.80 (br s, 7H), 2.49 (br dd, J=7.6, 14.4 Hz, 1H), 2.33-2.07 (m, 2H), 1.95-1.69 (m, 3H), 1.43 (br d, J=5.2 Hz, 1H), 1.31 (d, J=8.8 Hz, 3H), 1.01-0.75 (m, 5H); LCMS (ESI, M+1): m/z=608.2. Example 814 ##STR00631## (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(hydroxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol [1083] Synthesized according to Example 809. The title compound was obtained as yellow solid (FA salt). .sup.1H NMR (400 MHZ, METHANOL-d4) =9.27-9.01 (m, 1H), 8.54 (s, 1H), 7.91-7.82 (m, 1H), 7.38-7.29 (m, 2H), 7.28-7.19 (m, 1H), 4.51 (br s, 3H), 4.48-4.40 (m, 1H), 4.39-4.26 (m, 1H), 3.73-3.60 (m, 3H), 3.50-3.35 (m, 2H), 3.28-3.10 (m, 2H), 2.39-2.27 (m, 1H), 2.25-2.15 (m, 1H), 2.14-2.00 (m, 4H), 2.00-1.88 (m, 3H), 1.87-1.68 (m, 3H), 1.28 (d, J=19.6 Hz, 3H); LCMS [ESI, M+1]: m/z=616.3. Example 815 ##STR00632## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((6R,8aS)-6-fluorohexahydroindolizin-8a (1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00633## [1084] Step A. ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl benzoate: To a solution of ((3R,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (2.6 g, 1 equiv) in DCM (26 mL) was added TEA (1.28 g, 1.77 mL, 2 equiv) and B.sub.2Cl (1.34 g, 1.5 eq) at 0 C. The reaction was stirred at 25 C. for 12 hours. The mixture was washed with saturated NaHCO.sub.3 (80 mL), extracted with DCM (3 50 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 1/1) to afford the tittle compound (2.9 g, 88.94% yield) s a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.12-8.03 (m, 2H), 8.02-7.95 (m, 2H), 7.70-7.60 (m, 4H), 7.58-7.49 (m, 1H), 7.44-7.31 (m, 10H), 4.53-4.33 (m, 2H), 3.99 (br s, 2H), 3.76-3.64 (m, 1H), 3.47-3.33 (m, 1H), 3.20-2.98 (m, 1H), 2.20 (br dd, J=3.9, 6.2 Hz, 1H), 2.01-1.82 (m, 5H), 1.80-1.59 (m, 1H), 1.06 (s, 9H). [1085] Step B. ((3S,7aS)-3-(hydroxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl benzoate: To a solution of ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl benzoate (2.9 g, 1 equiv) in DMF (30 mL) was added CsF (8.57 g, 10 eq). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the tittle compound (1.5 g, 94% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.42 (s, 1H), 8.06 (dd, J=1.2, 8.4 Hz, 2H), 7.61-7.54 (m, 1H), 7.51-7.42 (m, 2H), 4.61-4.50 (m, 2H), 4.16-4.04 (m, 1H), 3.98 (dd, J=3.6, 13.2 Hz, 1H), 3.93-3.85 (m, 1H), 3.77-3.70 (m, 1H), 3.04 (dt, J=7.2, 10.7 Hz, 1H), 2.36-2.26 (m, 1H), 2.26-2.16 (m, 1H), 2.16-2.03 (m, 3H), 1.98 (dd, J=8.0, 13.2 Hz, 1H), 1.92-1.83 (m, 1H), 1.82-1.68 (m, 1H). [1086] Step C. ((6R,8aS)-6-fluorohexahydroindolizin-8a (1H)-yl)methyl benzoate: To a solution of ((3S,7aS)-3-(hydroxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl benzoate (300 mg, 1 eq) in DCM (20 mL) was added DAST (526 mg, 3 equiv) at 0 C. The reaction was stirred at 20 C. for 12 hours. The reaction was set up in four batches. The reaction mixture was quenched by saturated NaHCO.sub.3 (10 mL), extracted with DCM (2 20 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 1/1) to afford the tittle compound (330 mg, 35.20% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.04 (br d, J=8.0 Hz, 2H), 7.63-7.54 (m, 1H), 7.51-7.42 (m, 2H), 4.83-4.60 (m, 1H), 4.47 (d, J=11.2 Hz, 1H), 4.14 (d, J=10.8 Hz, 1H), 3.32-3.18 (m, 2H), 3.13-2.95 (m, 2H), 2.11-1.97 (m, 2H), 1.95-1.77 (m, 4H), 1.76-1.63 (m, 2H) [1087] Step D. ((6R,8aS)-6-fluorohexahydroindolizin-8a (1H)-yl)methanol: To a solution of [(6R,8aS)-6-fluoro-2,3,5,6,7,8-hexahydro-1H-indolizin-8a-yl]methyl benzoate (200 mg, 1 equiv) in MeOH (2 mL) was added NaOMe (5 M, 144 L, 1.0 equiv) The reaction was stirred at 20 C. for 1 hour. The mixture was quenched by water (0.5 mL), washed with petroleum ether (31 mL), concentrated, diluted with DCM (5 mL), dried over anhydrous sodium sulfate and concentrated to afford the tittle compound (107 mg, crude) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =4.77-4.50 (m, 1H), 3.58 (d, J=10.0 Hz, 1H), 3.32 (q, J=8.4 Hz, 1H), 3.22-3.08 (m, 3H), 2.91-2.75 (m, 1H), 2.05-1.55 (m, 9H). [1088] Step E. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((6R,8aS)-6-fluorohexahydroindolizin-8a (1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of [(6R,8aS)-6-fluoro-2,3,5,6,7,8-hexahydro-1H-indolizin-8a-yl]methanol (50.00 mg, 1.0 equiv) and (3R)-1-[2-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol (153 mg, 1.0 equiv) in THF (2 mL) was added NaHMDS (1 M, 433 L, 1.5 eq) at 0 C. The reaction was stirred at 20 C. for 1 hour. The mixture was concentrated and purified by prep-HPLC [Phenomenex C18 7530 mm3 m; A: water (FA), B: ACN, B %: 18%-48% over 7 min] to afford the tittle compound (80 mg, 39% yield) as a yellow solid. LCMS (ESI, M+1): m/z=666.3 [1089] Step F. (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((6R,8aS)-6-fluorohexahydroindolizin-8a (1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-[2-[[(6R,8aS)-6-fluoro-2,3,5,6,7,8-hexahydro-1H-indolizin-8a-yl]methoxy]-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol (40 mg, 1.0 equiv) in MeOH (0.5 mL) was added HCl/MeOH (2 M, 0.5 mL, 16.6 equiv). The reaction was stirred at 0 C. for 0.5 hours. The mixture was concentrated and purified by rep-HPLC [Phenomenex C18 15025 mm10 m; A: water (FA), B: ACN, B %: 16%-46% over 10 min] to afford the tittle compound (8.85 mg, 23% yield) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.23 (s, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.06 (s, 1H), 4.74 (br s, 1H), 4.66 (br dd, J=3.2, 11.2 Hz, 1H), 4.56 (br d, J=14.8 Hz, 2H), 4.50 (br d, J=11.2 Hz, 1H), 4.37-4.24 (m, 1H), 3.70-3.54 (m, 1H), 3.52-3.38 (m, 2H), 3.27-3.14 (m, 2H), 2.54-2.39 (m, 1H), 2.26-2.03 (m, 4H), 2.03-1.92 (m, 3H), 1.91-1.73 (m, 6H), 1.29 (d, J=9.4 Hz, 3H), 0.81 (q, J=7.1 Hz, 3H); LCMS (ESI, M+1): m/z=622.3 Example 816 ##STR00634## 7-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decan-4-one 2,2-dioxide ##STR00635## [1090] Step A. 1-benzyl 3-methyl 3-(sulfamoylamino) piperidine-1,3-dicarboxylate: To a solution of 1-benzyl 3-methyl 3-aminopiperidine-1,3-dicarboxylate (1.35 g, 1.0 equiv) in THF (10 mL) were added TEA (1.87 g, 4.0 equiv) and sulfamoyl chloride (1.07 g, 2.0 equiv) at 0 C. The reaction was stirred at 0 C. for 10 minutes and 50 C. for 24 hours. The mixture was concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (400 mg, 11% yield) as yellow oil. [1091] Step B. benzyl 4-oxo-2-thia-1,3,7-triazaspiro[4.5]decane-7-carboxylate 2,2-dioxide: To a solution of NaOMe (349 mg, 6.0 equiv) in MeOH (2 mL) was added into a solution of 1-benzyl 3-methyl 3-(sulfamoylamino) piperidine-1,3-dicarboxylate (400 mg, 1.0 equiv) in MeOH (1.5 mL) slowly. The reaction was stirred at 68 C. for 18 hours. The mixture was concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (80 mg, 13% yield) as yellow solid; LCMS (ESI, M+23): m/z=362.0. [1092] Step C. 2-thia-1,3,7-triazaspiro[4.5]decan-4-one 2,2-dioxide: To a mixture of Pd/C (25.0 mg, 10% purity) in MeOH (1 mL) was added benzyl 4-oxo-2-thia-1,3,7-triazaspiro[4.5]decane-7-carboxylate 2,2-dioxide (60.0 mg, 1.0 equiv) slowly under N.sub.2 atmosphere. The reaction was degassed and purged with H.sub.2 3 times. The reaction was stirred under H.sub.2 (15 Psi) at 30 C. for 1 hour. The mixture was filtered and concentrated to afford the title compound (30.0 mg, crude) as white solid. [1093] Step D. 7-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decan-4-one 2,2-dioxide: To a solution of 7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) and 2-thia-1,3,7-triazaspiro[4.5]decan-4-one 2,2-dioxide (45.6 mg, crude) in DMF (0.1 mL) were added DIEA (54.8 mg, 4.0 equiv) and 4 molecular sieve (10 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 16%-46%, 10 min] and prep-HPLC [column: Waters Xbridge C18 15050 mm10 um; mobile phase: [water (NH.sub.4HCO.sub.3)-ACN]; B %: 17%-47%, 10 min] to afford the title compound (11.3 mg, 15% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.15 (s, 1H), 7.81 (ddd, J=1.2, 5.6, 9.2 Hz, 1H), 7.43-7.35 (m, 2H), 7.26-7.19 (m, 1H), 5.68-5.47 (m, 1H), 4.81-4.55 (m, 4H), 4.54-4.39 (m, 1H), 4.16-3.95 (m, 2H), 3.93-3.80 (m, 2H), 3.49-3.38 (m, 1H), 2.62-2.41 (m, 2H), 2.87-2.40 (m, 1H), 2.37-2.22 (m, 4H), 2.15-2.01 (m, 1H), 1.93 (br dd, J=1.6, 10.8 Hz, 2H); LCMS (ESI, M+1): m/z=704.2. Example 817 ##STR00636## (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxy-7-(trifluoromethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00637## [1094] Step A. 5-(2-(4-iodophenyl) acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione: To a solution of 2-(4-iodophenyl) acetic acid (30.0 g, 1.0 equiv) and 2,2-dimethyl-1,3-dioxane-4,6-dione (18.1 g, 1.1 equiv) in acetonitrile (150 mL) were added DMAP (1.26 g, 0.09 equiv) and DIEA (31.1 g, 2.1 equiv) below 30 C. To the mixture was added pivaloyl chloride (15.2 g, 1.1 equiv) dropwise below 40 C. The reaction was stirred at 45 C. for 3 hours. The mixture was cooled to 0 C. and adjusted the pH to 5 by adding 4 M HCl (500 mL) below 15 C. The mixture was stirred at 0 C. for 1 hour. The mixture was diluted with water (1 L) and the pH of the mixture was adjusted to 2 with 4N HCl. The mixture was filtered. The filter cake was washed with water until the pH of filtrate was 56. The filter cake was the title compound (40.0 g, 89% yield) as white solid; LCMS (ESI, M1): m/z=386.9. [1095] Step B. 1,3-dihydroxy-7-iodo-2-naphthoic acid: 5-(2-(4-iodophenyl) acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (40.0 g, 1.0 equiv) was added into CF.sub.3SO.sub.3H (136 g, 8.8 equiv) in portions below 30 C. The reaction was stirred at 20 C. for 2 hours. The mixture was poured into ice water (500 mL) slowly and filtered. The filter cake was washed with water until the pH of the filtrate was 34. The filter cake was the title compound (20.0 g, 57% yield) as yellow solid; LCMS (ESI, M1): m/z=328.8. [1096] Step C. 7-iodonaphthalene-1,3-diol: A mixture of 1,3-dihydroxy-7-iodo-2-naphthoic acid (30.0 g, 1.0 equiv) in acetonitrile (600 mL) and water (450 mL) was stirred at 90 C. for 12 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO.sub.2, Petroleum ether: Ethyl acetate=5/1 to 1/1] to afford the title compound (10.0 g, 46% yield) as brown solid. [1097] Step D. 7-iodonaphthalene-1,3-diyl bis(2,2-dimethylpropanoate); To a solution of 7-iodonaphthalene-1,3-diol (4.00 g, 1.0 equiv), DIEA (9.04 g. 12.2 mL, 5.0 equiv) and DMAP (170 mg, 0.1 equiv) in THF (40 mL) was added pivaloyl chloride (5.90 g, 3.5 equiv) at 0 C. The reaction was stirred at 0 C. for 12 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO.sub.2, Petroleum ether:Ethyl acetate=1/0] to afford the title compound (4.00 g, 59% yield) as white solid. [1098] Step E. 7-(trifluoromethyl)naphthalene-1,3-diyl bis(2,2-dimethylpropanoate): To a mixture of 7-iodonaphthalene-1,3-diyl bis(2,2-dimethylpropanoate) (6.00 g, 1.0 equiv) and CuI (25.1 g, 10 equiv) in DMAC (90 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (53.3 g, 21 equiv) at 25 C. The reaction was stirred at 90 C. for 12 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO.sub.2, Petroleum ether:Ethyl acetate=1/0] to afford the title compound (2.00 g, 38% yield) as white solid. [1099] Step F. 4-hydroxy-6-(trifluoromethyl)naphthalen-2-yl pivalate: To a solution of 7-(trifluoromethyl)naphthalene-1,3-diyl bis(2,2-dimethylpropanoate) (1.00 g, 1.0 equiv) in THF (20 mL) and H.sub.2O (5 mL) was added LiOH.Math.H.sub.2O (233 mg, 2.2 equiv). The reaction was stirred at 0 C. for 1.5 hours. The mixture was diluted with water (10 mL) and adjusted the pH to 2 with 2 M HCl. The mixture was extracted with ethyl acetate (20 mL). The combined organic layers were concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether:Ethyl acetate=1/0 to 4/1] to afford the title compound (260 mg. 30% yield) as white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =11.57-10.42 (m, 1H), 8.42 (s, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.74 (dd, J=1.6, 8.4 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H), 1.34 (s, 9H). [1100] Step G. 6-(trifluoromethyl)-4-(((trifluoromethyl) sulfonyl)oxy)naphthalen-2-yl pivalate: To a solution of 4-hydroxy-6-(trifluoromethyl)naphthalen-2-yl pivalate (330 mg, 1.0 equiv) and DIEA (273 mg, 2.0 equiv) in DCM (5 mL) was added Tf.sub.2O (358 mg, 1.2 equiv) at 40 C. The reaction was stirred at 40 C. for 0.5 hours. The mixture was concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether:Ethyl acetate=100/1 to 16/1] to afford the title compound (330 mg, 66% yield) as brown solid, .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.36 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.79 (dd, J=1.6, 8.8 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 1.46-1.40 (m, 9H). [1101] Step H. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)naphthalen-2-yl pivalate: To a solution of 6-(trifluoromethyl)-4-(((trifluoromethyl) sulfonyl)oxy)naphthalen-2-yl pivalate (330 mg, 1.0 equiv), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (380 mg, 4.0 equiv) and TEA (301 mg, 4.0 equiv) in ACN (12 mL) was added Pd(dppf) C12 (54.3 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 80 C. for 2 hours. The mixture was quenched with MeOH (0.5 mL). The mixture was concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether: Ethyl acetate=100/1 to 6/1] to afford the title compound (170 mg, 25% yield) as white solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.17 (s, 1H), 7.97 (s, 1H), 7.88-7.83 (m, 1H), 7.71-7.67 (m, 1H), 7.66-7.61 (m, 1H), 1.43 (d, J=6.4 Hz, 21H). [1102] Step I. 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(trifluoromethyl)naphthalen-2-yl pivalate: To a mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (156 mg, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)naphthalen-2-yl pivalate (150 mg, 1.0 equiv) and Cs.sub.2CO.sub.3 (1.5 M in water, 3.0 equiv) in methoxycyclopentane (2.5 mL) was added CataCXium A Pd G3 (25.9 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 C. for 1 hour. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (215 mL). The combined organic layer was concentrated to afford the title compound (400 mg, crude) as white solid; LCMS (ESI, M+1): m/z=699.3. [1103] Step J. 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-(trifluoromethyl)naphthalen-2-yl pivalate: To a mixture of 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(trifluoromethyl)naphthalen-2-yl pivalate (360 mg, 1.0 equiv), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (131 mg, 2.0 equiv) and 4 molecular sieve (100 mg) in DMF (1.5 mL) was added DIEA (200 mg, 3.0 equiv). The reaction was stirred at 40 C. for 1 hour. The mixture was filtered. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (215 mL). The combined organic layers were concentrated to give the title compound (600 mg, crude) as yellow oil. [1104] Step K. (1R,5R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxy-7-(trifluoromethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-(trifluoromethyl)naphthalen-2-yl pivalate (600 mg, 1.0 equiv) in THF (8 mL) was added LiOH.Math.H.sub.2O (3 M in water, 2.0 equiv). The reaction was stirred at 15 C. for 0.5 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (215 mL). The combined organic layers were concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] and prep-HPLC [column: Unisil 3-100 C18 Ultra 15050 mm3 m; A: water (FA), B: ACN, B %: 19%-49% over 7 min] and prep-HPLC [column: Waters Xbridge BEH C18 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 52%-82% over 10 min] to afford the title compound (26.5 mg, 13% yield over three steps) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.33 (s, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 7.61 (dd, J=1.6, 8.4 Hz, 1H), 7.38 (s, 2H), 5.46-5.21 (m, 1H), 4.94 (br d, J=13.2 Hz, 1H), 4.79 (br d, J=13.2 Hz, 1H), 4.44-4.18 (m, 3H), 3.78 (br d, J=11.6 Hz, 1H), 3.54-3.32 (m, 2H), 3.30-3.20 (m, 2H), 3.10-2.98 (m, 1H), 2.46-2.10 (m, 6H), 2.07-1.97 (m, 2H), 1.96-1.85 (m, 2H), 1.84-1.77 (m, 1H), 1.40 (td, J=3.2, 14.0 Hz, 1H); LCMS (ESI, M+1): m/z=642.3. Example 818 ##STR00638## (3R)-1-(2-((1-((dimethylamino)methyl)-2,3-dimethylcyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00639## [1105] Step A. 4,5-dimethyl-1,3,2-dioxathiolane 2-oxide: To a solution of butane-2,3-diol (1.00 g, 1.0 equiv) in DCM (10 mL) was added SOCl.sub.2 (1.72 g, 1.3 equiv). The reaction was degassed, purged with N.sub.2 for 3 times and stirred at 40 C. for 2 hours. The mixture was poured into ice-water (10 mL) and stirred for 30 minutes, and then extracted with DCM (230 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated to afford the title compound (1.50 g, crude) as a yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =5.16-4.95 (m, 2H), 1.33-1.28 (m, 6H). [1106] Step B. 4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide: To a solution of 4,5-dimethyl-1,3,2-dioxathiolane 2-oxide (10.0 g, 1.0 equiv) in a mixed solvent of DCM (30 mL) and ACN (30 mL) was added a solution of RuCl.sub.3 (15.2 mg, 0.001 equiv) in H.sub.2O (60 mL) dropwise, followed by addition of NaIO.sub.4 (17.3 g, 1.1 equiv) in portions at 0 C. The reaction was stirred at 25 C. for 12 hours. The mixture was poured into ice-water (30 mL) and stirred for 30 min, and then extracted with DCM (230 mL). The combined organic layers were washed with brine (24 mL), dried over sodium sulfate, concentrated under vacuum and purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 0 50% Ethylacetate/Petroleum ethergradient@48 mL/min) to afford the title compound (10.5 g, 94% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =5.26-5.00 (m, 2H), 1.54-1.41 (m, 6H). [1107] Step C. dimethyl 2,3-dimethylcyclopropane-1,1-dicarboxylate; To a solution of dimethyl propanedioate (6.77 g, 1.2 equiv) in DMF (60 mL) was added NaH (4.27 g, 60% purity, 2.5 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hour. 4,5-Dimethyl-1,3,2-dioxathiolane 2,2-dioxide (6.50 g, 1.0 equiv) was added at 0 C. The reaction was stirred at 80 C. for 11.5 hours under N.sub.2 atmosphere. The mixture was poured into ice-water (300 mL) and stirred for 30 minutes, and then extracted with ethyl acetate (2300 mL). The combined organic layers were washed with brine (2200 mL), dried over sodium sulfate, concentrated under vacuum and purified by flash silica gel chromatography (ISCO; 80 g SepaFlash Silica Flash Column, Eluent of 0 20% Ethylacetate/Petroleum ethergradient@150 mL/min) to afford the title compound (3.60 g, 45% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =3.75 (s, 3H), 3.71 (s, 3H), 1.85-1.77 (m, 2H), 1.15-1.11 (m, 6H). [1108] Step D. 1-(methoxycarbonyl)-2,3-dimethylcyclopropanecarboxylic acid: To a solution of dimethyl 2,3-dimethylcyclopropane-1,1-dicarboxylate (1.60 g, 1.0 equiv) in MeOH (16 mL) was added NaOH aqueous solution (2 M, 5.16 mL, 1.2 equiv). The reaction was stirred at 25 C. for 1 hour. The mixture was acidified with 1M HCl until pH=2, diluted with H.sub.2O (50 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (1.48 g, crude) as a white solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =3.87-3.80 (m, 3H), 2.21-2.10 (m, 2H), 1.24-1.20 (m, 6H). [1109] Step E. methyl 1-(dimethylcarbamoyl)-2,3-dimethylcyclopropanecarboxylate; A mixture of 1-(methoxycarbonyl)-2,3-dimethylcyclopropanecarboxylic acid (925 mg, 1.0 equiv), N-methylmethanamine (876 mg, 2.0 equiv, HCl salt), HATU (4.08 g, 2.0 equiv) and DIEA (3.47 g, 5.0 equiv) in DCM (10 mL) was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 25 C. for 12 hours. The mixture was poured into ice-water (30 mL) and stirred for 5 minutes, and then extracted with ethyl acetate (60 mL). The organic phase was washed with brine (30 mL), dried over sodium sulfate, concentrated under vacuum and purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 050% Ethylacetate/Petroleum ethergradient@36 mL/min) to afford the title compound (800 mg, 75% yield) as a yellow oil. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =3.67-3.57 (m, 3H), 2.98-2.87 (m, 3H), 2.86-2.76 (m, 3H), 1.73-1.61 (m, 2H), 1.22-1.12 (m, 6H). [1110] Step F. (1-((dimethylamino)methyl)-2,3-dimethylcyclopropyl)methanol: To a mixture of methyl 1-(dimethylcarbamoyl)-2,3-dimethylcyclopropanecarboxylate (1.00 g, 1.0 equiv) in THF (10 mL) was added LiAlH.sub.4 (890 mg, 5.0 equiv) in portions at 0 C. The reaction was stirred at 25 C. for 1 hour. The mixture was quenched with saturated Na.sub.2SO.sub.4 aqueous solution (6 mL), filtered and the filtrate was dried over sodium sulfate, concentrated to afford the title compound (737 mg, crude) as a yellow oil. [1111] Step G. (3R)-1-(2-((1-((dimethylamino)methyl)-2,3-dimethylcyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-[2-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol (433 mg, 1.0 and (1-((dimethylamino)methyl)-2,3-dimethylcyclopropyl)methanol (200 mg, 0.97 equiv) in THF (4 mL) was added NaHMDS (1 M, 983 L, 1.5 equiv) dropwise at 0 C. The reaction was stirred at 10 C. for 1 hour under N.sub.2 atmosphere. The mixture was quenched by addition of saturated NH.sub.4Cl aqueous solution (10 mL) at 0 C., diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (210 mL), dried over sodium sulfate, concentrated and purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 22%-52% over 10 min] to afford the title compound (152 mg, 36% yield) as a white solid; LCMS (ESI, M+1): m/z=650.3. [1112] Step H. (3R)-1-(2-((1-((dimethylamino)methyl)-2,3-dimethylcyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A mixture of (3R)-1-(2-((1-((dimethylamino)methyl)-2,3-dimethylcyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (120 mg, 1.0 equiv) in HCl/MeOH (4 M, 1 mL) was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 10 C. for 1 hour under N.sub.2 atmosphere. The mixture was quenched by addition of saturated NH.sub.4Cl aqueous solution (10 mL) at 0 C., diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (210 mL), dried over sodium sulfate, concentrated and purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 16%-46% over 10 min] to afford the title compound (54.4 mg, 59% yield) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.25 (d, J=2.8 Hz, 1H), 8.62-8.52 (m, 1H), 7.70 (dd, J=6.0, 9.2 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.28 (t, J=9.2 Hz, 1H), 7.08 (s, 1H), 4.69-4.60 (m, 3H), 4.32 (br t, J=12.8 Hz, 1H), 3.72-3.59 (m, 1H), 3.56-3.44 (m, 1H), 2.99-2.82 (m, 2H), 2.79-2.59 (m, 6H), 2.56-2.40 (m, 1H), 2.31-2.11 (m, 2H), 1.97-1.73 (m, 3H), 1.31 (d, J=9.2 Hz, 3H), 1.18 (br d, J=5.2 Hz, 6H), 1.13-1.00 (m, 2H), 0.83 (q, J=7.2 Hz, 3H); .sup.19F NMR (376 MHZ, METHANOL-d.sub.4) =121.12 (br s, 1F), 139.82 (br s, 1F); LCMS (ESI, M+1): m/z=606.4. Example 819 ##STR00640## 4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-3-(2-hydroxycyclobutane-1-carboxamido)-N,N-dimethyl-1H-pyrazole-1-carboxamide ##STR00641## [1113] Step A. dimethyl (1R,2R)-cyclobutane-1,2-dicarboxylate: To a solution of (1R,2R)-cyclobutane-1,2-dicarboxylic acid (500 mg, 1.0 equiv) in MeOH (5 mL) was added sulphuric acid (460 mg, 1.4 equiv). The reaction was stirred at 40 C. for 16 hours. The mixture was concentrated under reduced pressure, diluted with water (50 mL) and extracted with ethyl acetate (50 mL3). The combined organic layers were washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (515 mg, 86% yield) as yellow oil; .sup.1H NMR (400 MHZ, CDCl.sub.3) =3.69 (s, 6H), 3.33-3.47 (m, 2H), 2.13-2.20 (m, 4H). [1114] Step B. (1R,2R)-2-(methoxycarbonyl)cyclobutane-1-carboxylic acid: To a solution of dimethyl (1R,2R)-cyclobutane-1,2-dicarboxylate (500 mg, 1.0 equiv) in dioxane (8 mL) and H.sub.2O (8 mL) was added NaOH (1 M, 2.90 mL, 1.0 equiv). The reaction was stirred at 25 C. for 3 hours. The mixture was adjusted to pH=2-3 with 1M HCl (5 mL) and extracted with ethyl acetate (40 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=5/1 to 1/1) to afford the title compound (360 mg, 78% yield) as yellow oil; .sup.1H NMR (400 MHz, CDCl.sub.3) =3.66-3.78 (m, 3H), 3.39-3.52 (m, 2H), 2.17-2.30 (m, 4H). [1115] Step C. methyl (1R,2R)-2-(chlorocarbonyl)cyclobutane-1-carboxylate: To a solution of (1R,2R)-2-(methoxycarbonyl)cyclobutane-1-carboxylic acid (350 mg, 1.0 equiv) and oxalyl chloride (308 mg, 1.1 equiv) in DCM (6 mL) was added DMF (51.7 mg, 0.32 equiv) at 0 C. The reaction was stirred at 25 C. for 2 hours. The mixture was concentrated under reduced pressure to afford the title compound (350 mg, 89.55% yield) as yellow oil. [1116] Step D. methyl (1R,2R)-2-propionylcyclobutane-1-carboxylate: A mixture of methyl (1R,2R)-2-(chlorocarbonyl)cyclobutane-1-carboxylate (350 mg, 1.0 equiv) and 1,1-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (72.51 mg, 0.05 eq) in toluene (5 mL) was degassed and purged with N.sub.2 for 3 times. ZnEt.sub.2 (1 M, 2.38 mL, 1.2 equiv) was added to above mixture at 0 C. The reaction was stirred at 25 C. for 3 hours under N.sub.2 atmosphere. The mixture was quenched with water (5 mL) at 0 C. and extracted with ethyl acetate (5 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=5/1) to afford the title compound (150 mg, 44% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CDCl.sub.3) =3.67-3.73 (m, 3H), 3.33-3.57 (m, 2H), 2.37-2.47 (m, 2H), 2.05-2.20 (m, 4H), 1.03-1.08 (m, 3H). [1117] Step E. 2-propionylcyclobutane-1-carboxylic acid: To a solution of methyl (1R,2R)-2-propionylcyclobutane-1-carboxylate (3.00 g, 1.0 equiv) in THF (20 mL) and H.sub.2O (10 mL) was added KOH (2.97 g, 3.0 equiv). The reaction was stirred at 25 C. for 3 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/1) to afford the title compound (2.00 g, 73% yield) as a yellow oil; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =12.08-12.14 (m, 1H), 3.38-3.49 (m, 1H), 3.13-3.23 (m, 1H), 2.41 (dd, J=7.2, 1.2 Hz, 2H), 1.96-2.05 (m, 4H), 0.92 (t, J=7.2 Hz, 3H). [1118] Step F. tert-butyl((1-(dimethylcarbamoyl)-3-(2-propionylcyclobutane-1-carboxamido)-1H-pyrazol-4-yl)methyl)carbamate: To a solution of tert-butyl((3-amino-1-(dimethylcarbamoyl)-1H-pyrazol-4-yl)methyl)carbamate (200 mg, 1.0 equiv) and (2-propionylcyclobutane-1-carboxylic acid (551 mg, 5.0 equiv) in DCM (10 mL) were added DIEA (365 mg, 4.0 equiv) and HATU (537 mg, 2.0 equiv). The reaction was stirred at 25 C. for 3 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (200 mg, 67% yield) as yellow oil; LCMS (ESI, M+1): m/z=422.4. [1119] Step G. 2-((4-(((tert-butoxycarbonyl)amino)methyl)-1-(dimethylcarbamoyl)-1H-pyrazol-3-yl)carbamoyl)cyclobutyl propionate: To a solution of tert-butyl((1-(dimethylcarbamoyl)-3-(2-propionylcyclobutane-1-carboxamido)-1H-pyrazol-4-yl)methyl)carbamate (200 mg, 1.0 equiv) and trifluoroacetic anhydride (1.49 g, 15 equiv) in DCM (20 mL) was added H.sub.2O.sub.2 (807 mg, 30% purity, 15 equiv) at 0 C. The reaction was stirred at 25 C. for 3 hours. The mixture was quenched with aqueous sodium sulfite solution (60 mL) at 0 C., adjusted to pH=8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (60 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (200 mg, 96% yield) as yellow solid; LCMS (ESI, M+1): m/z=438.2. [1120] Step H. 2-((4-(aminomethyl)-1-(dimethylcarbamoyl)-1H-pyrazol-3-yl)carbamoyl)cyclobutyl propionate: To a solution of 2-((4-(((tert-butoxycarbonyl)amino)methyl)-1-(dimethylcarbamoyl)-1H-pyrazol-3-yl)carbamoyl)cyclobutyl propionate (150 mg, 1.0 equiv) in dioxane (3 mL) was added HCl/dioxane (4 M, 4.2 equiv) at 0 C. The reaction was stirred at 25 C. for 1 hour. The mixture was concentrated under reduced pressure to afford the title compound (100 mg, 86% yield) as yellow oil; LCMS (ESI, M+1): m/z=338.0 [1121] Step I. 2-((1-(dimethylcarbamoyl)-4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1H-pyrazol-3-yl)carbamoyl)cyclobutyl propionate: To a mixture of 2-((4-(aminomethyl)-1-(dimethylcarbamoyl)-1H-pyrazol-3-yl)carbamoyl)cyclobutyl propionate (30.0 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(trifluoromethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (52.7 mg, 1.0 equiv) in MeCN (1 mL) and DMF (1 mL) were added and K.sub.3PO.sub.4 (189 mg, 10 eq) and 4 molecular sieves (300 mg). The reaction was stirred at 60 C. for 1 hour. The mixture was filtered and purified by prep-HPLC [Waters xbridge 15025 mm 10 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; B %: 31%-61%, 8 min] to afford the title compound (20 mg, 27% yield) as yellow solid; LCMS (ESI, M+1): m/z=830.5. [1122] Step J. 4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-3-(2-hydroxycyclobutane-1-carboxamido)-N,N-dimethyl-1H-pyrazole-1-carboxamide: To a solution of 2-((1-(dimethylcarbamoyl)-4-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1H-pyrazol-3-yl)carbamoyl)cyclobutyl propionate (15.0 mg, 1.0 equiv) in MeOH (1 mL) was added K.sub.2CO.sub.3 (0.1 M, 0.7 mL, 4.0 equiv). The reaction was stirred at 25 C. for 0.5 hours. The mixture was quenched with HCOOH (0.5 M, 0.5 mL, 10 equiv) at 25 C., filtered and purified by prep-HPLC [Phenomenex luna C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 12%-42%, 8 min] to afford the title compound (1.97 mg, 12% yield, HCOOH) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.12-9.17 (m, 1H), 8.46-8.58 (m, 1H), 8.16-8.27 (m, 1H), 7.63-7.72 (m, 1H), 7.28-7.33 (m, 1H), 7.20-7.28 (m, 1H), 6.99-7.06 (m, 1H), 5.45-5.54 (m, 1H), 5.26-5.44 (m, 1H), 4.65-4.76 (m, 2H), 4.30-4.49 (m, 2H), 3.50-3.68 (m, 1H), 3.35 (br s, 4H), 3.13 (br s, 8H), 2.41-2.53 (m, 3H), 2.27-2.34 (m, 1H), 2.20-2.25 (m, 1H), 2.08 (br d, J=6.4 Hz, 3H), 1.96 (br dd, J=10.8, 6.4 Hz, 1H), 1.73-1.84 (m, 1H), 0.73-0.82 (m, 3H); LCMS (ESI, M+1): m/z=774.8. Example 820 ##STR00642## (3R)-1-(7-(5,6-dimethylbenzo[d]isothiazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00643## [1123] Step A. 1-bromo-5-fluoro-2,3-dimethylbenzene: To a mixture of 1,3-dibromo-5-fluoro-2-methylbenzene (3.5 g, 1 equiv), potassium trifluoro(methyl) borate (2.07 g, 1.3 equiv) in dioxane (50 mL) and H.sub.2O (10 mL) were added 1,1-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (956 mg, 0.1 equiv) and K.sub.2CO.sub.3 (3.61 g, 2 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 C. for 12 hours. The mixture diluted with petroleum ether (100 mL) and washed with brine (2100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified with column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=1/0) to afford the title compound (1.8 g, crude) as light yellow oil. [1124] Step B. 2-bromo-6-fluoro-3,4-dimethylbenzaldehyde: To a solution of 1-bromo-5-fluoro-2,3-dimethylbenzene (7 g, 1 equiv) in THF (150 mL) was added LDA (2 M, 22.4 mL, 1.3 equiv) at 78 C. The reaction was stirred at 78 C. for 0.5 hours. The mixture was added a solution of DMF (2.77 g, 1.1 equiv) in THF (4 mL) at 78 C. The reaction was stirred at 78 C. for 0.5 hours. The mixture was quenched with aqueous NH.sub.4Cl solution (100 mL) and extracted with ethyl acetate (2200 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=1/0 to 20/1) to afford the title compound (0.9 g, 11% yield) as yellow solid; LCMS (ESI, M+1, M+3): m/z=231.0, 233.0. [1125] Step C. 4-bromo-5,6-dimethylbenzo[d]isothiazole; A mixture of 2-bromo-6-fluoro-3,4-dimethylbenzaldehyde (0.9 g, 1 equiv) and NH.sub.3.Math.H.sub.2O (5 mL, 28% purity, 9.33 equiv) in 2-methoxyethanol (5 mL) was added Sulfur (125 mg, 1 equiv). The reaction was stirred at 90 C. for 12 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (320 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified with column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=1/0 to 10/1) to afford the title compound (600 mg, 34% yield) as yellow solid; LCMS (ESI, M+1, M+3): m/z=242.0, 244.0. [1126] Step D. 5,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isothiazol: To a solution of 4-bromo-5,6-dimethyl-1,2-benzothiazole (300 mg, 1.0 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (503 mg, 1.6 equiv) in dioxane (5 mL) were added KOAc (365 mg, 3.0 equiv) and PCy.sub.3 Pd G2 (73.2 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 C. for 6 hours. The mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (120 mg, 31% yield) as red solid; LCMS (ESI, M+1): m/z=290.0. [1127] Step E. (3R)-1-(7-(5,6-dimethylbenzo[d]isothiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (100 mg, 1.0 equiv) and 5,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isothiazol (79.6 mg, 1.2 equiv) in THF (0.5 mL) were added K.sub.3PO.sub.4 (1.5 M in H.sub.2O, 459 L, 3.0 equiv) and CataCXium A Pd G3 (16.7 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 60 C. for 2 hours. The mixture was diluted with H.sub.2O (10 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: water (FA)-CAN; B %: 14%-44% over 10 minutes] to afford the title compound (62.7 mg, 48% yield, 0.81 HCOOH) as yellow solid; .sup.1H NMR (400 MHz, METHANOL-d.sub.4) =9.35 (d, J=8.8 Hz, 1H), 8.48 (d, J=5.6 Hz, 1H), 8.02 (s, 1H), 4.62 (s, 3H), 4.36-4.33 (m, 1H), 3.69-3.56 (m, 3H), 3.45-3.34 (m, 1H), 3.22-3.18 (m, 2H), 2.54 (s, 3H), 2.32-2.23 (m, 5H), 2.22-2.10 (m, 5H), 2.08-2.00 (m, 2H), 1.90-1.82 (m, 1H), 1.79-1.73 (m, 2H), 1.29 (s, 3H); LCMS (ESI, M+1): m/z=563.2. Example 821 ##STR00644## (3R)-1-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00645## [1128] Step A. 4-bromo-5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazole: To a mixture of 4-bromo-5,6-dimethyl-1H-benzo[d][1,2,3]triazole (20.0 g, 1.0 equiv) in tetrahydrofuran (200 mL) was added NaH (5.31 g, 60% purity, 1.0 equiv). The reaction was stirred at 0 C. for 1 hour. (2-(chloromethoxy)ethyl)trimethylsilane (29.5 g, 2.0 equiv) was added into above mixture. The reaction was stirred at 0 C. for 3 hours. The mixture was quenched with H.sub.2O (20 mL) at 0 C. and extracted with EtOAc (3100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=20/1 to 5/1] to afford the title compound (14.5 g, 45% yield) as yellow solid; LCMS (ESI, M+1, M+3): m/z=356.0, 358.0. [1129] Step B. 5,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazole: To a solution of 4-bromo-5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (12.0 g, 1.0 equiv) and 4,4,4,4,5,5,5,5-octamethyl-2,2-bi (1,3,2-dioxaborolane) (12.8 g, 1.5 equiv) in dioxane (120 mL) were added KOAc (9.92 g, 3.0 equiv) and Pd(dppf)Cl.sub.2 (3.70 g, 0.15 equiv). The reaction was degassed and purged with nitrogen 3 times. The mixture was stirred at 100 C. for 12 hours. The mixture was diluted with H.sub.2O (100 mL) and extracted with EtOAc (3100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (7.00 g, 24% yield) as white solid; LCMS (ESI, M+1): m/z=404.2. [1130] Step C. (3R)-1-(7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (170 mg, 1.0 equiv) and 5,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (227 mg, 1.5 equiv) in methoxycyclopentane (2 mL) and H.sub.2O (0.5 mL) were added cataCXium A Pd G3 (40.9 mg, 0.15 equiv) and Cs.sub.2CO.sub.3 (336 mg, 3.0 equiv). The reaction was degassed and purged with nitrogen 3 times. The mixture was stirred at 90 C. for 6 hours. The mixture was diluted with H.sub.2O (5 mL) and extracted with ethyl acetate (315 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 31% yield) as white solid; LCMS (ESI, M+1): m/z=695.3. [1131] Step D. (3R)-1-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (100 mg, 1.0 equiv) in dichloromethane (1 mL) was added 2,2,2-trifluoroacetic acid (164 mg, 10 equiv). The reaction was stirred at 25 C. for 12 hours. The mixture was concentrated. The residue was diluted with water (2 mL). The mixture was adjusted to pH=10 with NaOH solution (10% w/w) at 0 C. and extracted with dichloromethane (32 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 9%-39% over 10 min] to afford the title compound (40.4 mg, 49% yield, 0.78 HCOOH) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.47-9.17 (m, 1H), 8.55-8.28 (m, 1H), 7.92-7.66 (m, 1H), 5.59-5.40 (m, 1H), 4.71-4.48 (m, 3H), 4.40-4.31 (m, 1H), 3.91-3.58 (m, 4H), 3.52-3.33 (m, 1H), 2.68-2.43 (m, 5H), 2.39-2.21 (m, 6H), 2.19-2.06 (m, 2H), 1.91-1.72 (m, 3H), 1.34-1.22 (m, 3H); LCMS (ESI, M+1): m/z=565.3. Example 822 ##STR00646## (6S)-4-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol [1132] Synthesized according to Example 821. The title compound was obtained as white solid (FA salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.64 (s, 1H), 7.80 (s, 1H), 4.60-4.47 (m, 4H), 4.22-4.12 (m, 1H), 4.05-3.97 (m, 1H), 3.95-3.81 (m, 2H), 3.74-3.63 (m, 2H), 3.51-3.41 (m, 2H), 3.12-3.02 (m, 2H), 2.54 (s, 3H), 2.31-2.26 (m, 3H), 2.26-2.18 (m, 2H), 2.15-2.02 (m, 4H), 2.01-1.92 (m, 2H), 1.29 (s, 3H); LCMS (ESI, M+1): m/z=563.4. Example 823 ##STR00647## 7-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione ##STR00648## [1133] Step A. 7-(7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a mixture of 7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (Synthesized according to Example 732 step A-B, 150 mg, 1.0 equiv), 1,3,7-triazaspiro[4.5]decane-2,4-dione (76.7 mg, 2.0 equiv) and 4 molecular sieve (50.0 mg) in DMF (1 mL) was added DIEA (87.9 mg, 3.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (110 mg, 66% yield) as yellow solid; LCMS (ESI, M+1): m/z=731.1. [1134] Step B. 7-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-(hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a mixture of 7-(7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 equiv) in dichloromethane (0.5 mL) was added TFA (1.54 g, 99 equiv) at 0 C. The reaction was stirred at 20 C. for 1 hour. The mixture was adjusted pH to 8 with saturated NaHCO.sub.3 aqueous solution (20 mL) and extracted with dichloromethane (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex C18 7530 mm3 m; A: water (FA), B: ACN, B %: 5%-35% over 7 min] to afford the title compound (13.4 mg, 16% yield, 0.67 HCOOH) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.23 (s, 1H), 7.80 (s, 1H), 4.67-4.56 (m, 3H), 4.51-4.29 (m, 1H), 3.90-3.69 (m, 2H), 3.67-3.56 (m, 2H), 3.25-3.11 (m, 2H), 2.60-2.50 (m, 3H), 2.35-2.22 (m, 6H), 2.22-2.12 (m, 4H), 2.12-2.02 (m, 3H), 2.02-1.91 (m, 2H); LCMS (ESI, M+1): m/z=601.3. Example 824 ##STR00649## 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-3-azabicyclo[3.2.1]octane-1-carboxamide ##STR00650## [1135] Step A. methyl 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1-carboxylate: To a mixture of methyl 3-azabicyclo[3.2.1]octane-1-carboxylate (320 mg, 1.2 equiv, HCl) and DIEA (670 mg, 4.0 equiv) in DMF (2 mL) was added 4 molecular sieve (25 mg). The reaction was stirred at 20 C. for 0.1 hours. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (768 mg, 1.0 equiv) was added into the above mixture. The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by reversed-phase (0.1% FA condition) to afford the title compound (500 mg, 52% yield, 90% purity) as yellow solid; LCMS (ESI, M+1): m/z=662.2. [1136] Step B. 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1-carboxylic acid: To a solution of methyl 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1-carboxylate (450 mg, 1.0 equiv) in H.sub.2O (0.9 mL) and THF (4.5 mL) was added NaOH (136 mg, 5.0 equiv). The reaction mixture was stirred at 20 C. for 12 hours. The mixture was adjusted pH to 6 by 1 N HCl aqueous at 0 C. and purified by reversed-phase (0.1% formic acid condition) to afford the title compound (130 mg, 29.5% yield) as white solid; LCMS (ESI, M+1): m/z=648.2. [1137] Step C. 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-3-azabicyclo[3.2.1]octane-1-carboxamide: To a solution of 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1-carboxylic acid (30 mg, 1.0 equiv) and TEA (37 mg, 8.0 equiv) in DMF (0.3 mL) were added EDCI (11 mg, 1.2 equiv) and HOBt (12 mg, 2.0 equiv). The reaction was stirred at 20 C. for 0.1 hours. N-methylmethanamine (2 M, 232 L, 10.0 equiv) was added into the mixture. The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified with reversed-phase HPLC (column: Phenomenex Luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 16%-46%, 10 minutes) to afford the title compound (20 mg, 63% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.13-9.03 (m, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.26 (t, J=9.2 Hz, 1H), 7.06 (dd, J=2.8, 8.8 Hz, 1H), 5.52-5.24 (m, 2H), 4.49-4.19 (m, 3H), 3.98-3.84 (m, 1H), 3.69-3.32 (m, 7H), 3.23-2.89 (m, 4H), 2.56-2.35 (m, 3H), 2.35-2.24 (m, 2H), 2.22-2.03 (m, 6H), 2.00-1.81 (m, 3H), 1.59-1.42 (m, 1H), 0.86-0.72 (m, 3H); LCMS (ESI, M+1): m/z=675.5. Example 825 ##STR00651## (1R,5R,6R)-3-(7-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00652## [1138] Step A. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole: To a mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (20.7 mg, 1.0 equiv) and 5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole (20.0 mg, 1.0 equiv) in Methoxy cyclopentane (4 mL) and H.sub.2O (1.3 mL) were added CataCXium A Pd G3 (3.43 mg, 0.10 equiv) and Cs.sub.2CO.sub.3 (46.1 mg, 3.0 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 80 C. for 12 hours. The mixture was filtered and purified by reversed-phase HPLC (0.1% FA condition) to afford the title compound (9.00 mg, 24% yield) as yellow solid; LCMS (ESI, M+1): m/z=701.2. [1139] Step B. (1R,5R,6R)-3-(7-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole (20.0 mg, 1.0 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (7.26 mg, 2.0 equiv) in DMF (1 mL) were added DIEA (22.1 mg, 6.0 equiv) and 4 molecular sieve (2.00 mg). The reaction was stirred at 60 C. for 2 hours. The mixture was filtered and purified by reversed-phase HPLC [water (FA, 0.1%)/acetonitrile] to afford the title compound (20.0 mg, 93% yield) as yellow solid; LCMS (ESI, M+1): m/z=728.7. [1140] Step C. (1R,5R,6R)-3-(7-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: A mixture of (1R,5R,6R)-3-(7-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (15.0 mg, 1.0 equiv) in TFA (578 mg, 246 equiv) was stirred at 20 C. for 0.5 hour. The mixture was concentrated. The residue was diluted with water (1 mL). The mixture was adjusted to pH=7 with saturated NaHCO.sub.3 (10 mL) and extracted with ethyl acetate (5 mL3). The combined organic layers and dried over by anhydrous sodium sulfate, concentrated, and purified with prep-HPLC (column: Phenomenex luna C18 150 25 mm10 um; mobile phase: [water (FA)-ACN]; B %: 18%-48%, 10 min) to afford the title compound (6.03 mg, 45% yield, 0.17 HCOOH) as yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.39-9.30 (m, 1H), 8.24 (s, 1H), 8.01 (dd, J=6.0, 9.2 Hz, 1H), 7.72 (s, 1H), 7.33 (dt, J=1.6, 9.2 Hz, 1H), 5.44-5.23 (m, 1H), 5.09-5.00 (m, 1H), 4.79 (br s, 1H), 4.42-4.23 (m, 3H), 3.90-3.76 (m, 1H), 3.57-3.36 (m, 2H), 3.27 (br d, J=7.6 Hz, 1H), 3.12-3.00 (m, 1H), 2.65 (br dd, J=7.2, 14.8 Hz, 1H), 2.46-2.37 (m, 2H), 2.36-2.14 (m, 5H), 2.06-1.79 (m, 5H), 1.43 (br d, J=13.6 Hz, 1H), 0.92-0.80 (m, 3H); LCMS (ESI, M+1): m/z=644.2. Example 826 ##STR00653## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(methoxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00654## [1141] Step A. (3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine: To a solution of ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (6.00 g, 1.0 equiv) and TEA (2.96 g, 2.0 equiv) in DCM (100 mL) was added TrtCl (6.12 g, 1.5 equiv). The reaction was stirred at 25 C. for 12 hours. The mixture was diluted with water (50 mL) and extracted with DCM (3 50 mL). The combined organic layers were washed with brine (350 mL), dried over sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (3.60 g, 38% yield) as a yellow oil. [1142] Step B. ((3S,7aS)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol: To a solution of (3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine (2.00 g, 1.0 equiv) in DMF (20 mL) was added CsF (6.99 g, 15 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered, the filtrate was concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (0.80 g, 63% yield) as a yellow oil; LCMS (ESI, M+1): m/z=414.2. [1143] Step C. (3S,7aS)-3-(hydroxymethyl)-7a-((trityloxy)methyl) octahydropyrrolizine 4-oxide: To a solution of ((3S,7aS)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol (250 mg, 1.0 equiv) in DCM (3 mL) was added m-CPBA (147 mg, 1.2 equiv). The reaction was stirred at 25 C. for 2 hours. The mixture was quenched by addition of saturated NaHCO.sub.3 aqueous solution (2.5 mL) and extracted with DCM (10 mL). The combined organic layers were washed with saturated sodium bicarbonate aqueous solution (10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (230 mg, crude) as a white solid; LCMS (ESI, M+1): m/z=430.2. [1144] Step D. (3S,7aS)-3-(methoxymethyl)-7a-((trityloxy)methyl) octahydropyrrolizine 4-oxide: To a solution of (3S,7aS)-3-(hydroxymethyl)-7a-((trityloxy)methyl) octahydropyrrolizine 4-oxide (460 mg, 1.0 equiv) in DMF (5 mL) was added NaH (64.3 mg, 60% purity, 1.5 equiv). The mixture was stirred at 0 C. for 30 minutes. MeI (228 mg, 1.5 equiv) was added. The reaction was stirred at 0 C. for 2 hours. The mixture was quenched by addition of ice-water (15 mL) and extracted with ethyl acetate (215 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.3.Math.H.sub.2O), B: ACN, B %: 44%-74% over 9 min] to afford the title compound (130 mg, 26% yield) as a yellow solid; LCMS (ESI, M+1): m/z=444.2. [1145] Step E. (3S,7aS)-3-(methoxymethyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine: To a solution of (3S,7aS)-3-(methoxymethyl)-7a-((trityloxy)methyl) octahydropyrrolizine 4-oxide (30.0 mg, 1.0 equiv) in MeOH (0.6 mL) was added Pd/C (5.00 mg, 10% purity) under N.sub.2 atmosphere. The suspension was degassed, purged with H.sub.2 for 3 times and stirred at 25 C. for 12 hours under H.sub.2 (15 Psi) atmosphere. The mixture was filtered through Celite and washed with MeOH (10 mL). The filtrate was concentrated to afford the title compound (25.0 mg, crude) as a yellow solid; LCMS (ESI, M+1): m/z=428.2. [1146] Step F. ((3S,7aS)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol: To a solution of (3S,7aS)-3-(methoxymethyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine (25.0 mg, 1.0 equiv) in DCM (0.3 mL) was added TFA (156 uL). The reaction was stirred at 20 C. for 2 hours. The mixture was concentrated to afford the title compound (25.0 mg, crude) as a yellow solid, which was used directly for the next step without further purification. [1147] Step G. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A mixture of ((3S,7aS)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (21.0 mg, 1.2 equiv), 4 molecular sieve (5 mg) and t-BuONa (36.3 mg, 4.0 equiv) in toluene (0.5 mL) was stirred at 0 C. for 10 minutes. (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50.0 mg, 1.0 equiv) was added. The reaction was stirred at 0 C. for 1 hour. The mixture was quenched with H.sub.2O (10 mL) at 0 C. and extracted with ethyl acetate (310 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, concentrated and purified with prep-HPLC [column: Phenomenex luna C18 7530 mm3 um; A: water (FA), B: ACN, B %: 24%-44% over 8 min] to afford the title compound (15.0 mg, 23% yield) as a white solid; LCMS (ESI, M+1): m/z=678.5. [1148] Step H. (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (10.0 mg, 1 equiv) in MeOH (0.2 mL) was added HCl/MeOH (4 M, 200 uL) at 0 C. The reaction was stirred at 25 C. for 0.5 hour. The mixture was concentrated, diluted with MeCN (0.5 mL) and adjusted to PH7 with 10% NH.sub.3.Math.H.sub.2O. The mixture was directly purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 19%-49% over 10 min] to afford the title compound (6.00 mg, 62% yield) as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.29-9.17 (m, 1H), 8.55 (s, 1H), 7.75-7.62 (m, 1H), 7.31 (t, J=2.8 Hz, 1H), 7.25 (dt, J=1.6, 9.2 Hz, 1H), 7.06 (s, 1H), 4.64-4.42 (m, 3H), 4.39-4.24 (m, 2H), 3.69-3.56 (m, 2H), 3.50-3.41 (m, 2H), 3.39 (d, J=1.6 Hz, 1H), 3.34 (d, J=4.8 Hz, 2H), 3.21-2.92 (m, 2H), 2.54-2.40 (m, 1H), 2.35-1.71 (m, 13H), 1.34-1.25 (m, 3H), 0.88-0.75 (m, 3H); LCMS (ESI, M+1): m/z=634.3. Example 827 ##STR00655## (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00656## [1149] Step A. (3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)methanol: To a solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.0 equiv) in THF (8.0 mL) was added LAH (222 mg, 2.5 equiv) at 0 C. The reaction was stirred at 60 C. for 1 hour. The mixture was quenched with water (0.2 mL), 15% NaOH solution (0.2 mL) and water (0.6 mL) at 0 C. The mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was dried, filtered, concentrated and purified with prep-TLC (SiO.sub.2, methylene chloride/methanol=5:1) to afford the title compound (200 mg, 67% yield)) as colorless oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =4.67 (br s, 1H), 3.76-3.69 (m, 1H), 3.65-3.59 (m, 1H), 3.07 (d, J=8.8 Hz, 1H), 2.96 (d, J=8.8 Hz, 1H), 2.43-2.36 (m, 2H), 2.32 (s, 3H), 1.27 (td, J=4.0, 8.0 Hz, 1H), 1.02 (t, J=4.4 Hz, 1H), 0.49 (dd, J=4.4, 8.0 Hz, 1H). [1150] Step B. (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)methanol (50.0 mg, 1.0 equiv) in THF (2.0 mL) was added t-BuOK (1.0 M, 2.2 equiv). The reaction was stirred at 20 C. for 0.5 hours. The mixture was added to the solution of (3R)-1-[2-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol (145 mg, 0.7 equiv) in THF (2.0 mL). The reaction was stirred at 60 C. for 5 hours. The mixture was quenched with water (0.2 mL), concentrated and purified with prep-HPLC [column: Phenomenex C18 7530 mm3 um; mobile phase: water (FA)-ACN; B %: 15%-45%, 7 min] to afford the title compound (40.0 mg, 16% yield) as white solid; LCMS (ESI, M+1): m/z=620.0 [1151] Step C. (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol (20.0 mg, 1.0 equiv) in ACN (1 mL) was added HCl.Math.dioxane (4 M, 1.0 equiv). The reaction was stirred at 0 C. for 1 hour. The mixture was concentrated and purified with prep-HPLC [column: Phenomenex C18 7530 mm3 um; mobile phase: [water (FA)-ACN]; B %: 12%-42%, 5 min] to afford the title compound (4.2 mg, 22% yield, HCOOH salt) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.22 (s, 1H), 8.52 (s, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.06 (s, 1H), 4.68-4.50 (m, 4H), 4.38-4.21 (m, 1H), 3.68-3.50 (m, 2H), 3.50-3.36 (m, 2H), 3.26 (br d, J=10.4 Hz, 1H), 3.20-3.10 (m, 1H), 2.71 (s, 3H), 2.57-2.39 (m, 1H), 2.30-2.07 (m, 2H), 1.91-1.68 (m, 4H), 1.29 (d, J=10.0 Hz, 3H), 1.15-0.91 (m, 2H), 0.81 (q, J=7.6 Hz, 3H); LCMS (ESI, M+1): m/z=576.4. Example 828 ##STR00657## (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-methyl-3-azabicyclo[5.1.0]octan-1-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00658## [1152] Step A. 2-(pent-4-en-1-yl) isoindoline-1,3-dione: To a solution of 5-bromopent-1-ene (4.0 g, 1.0 equiv) in DMF (30 mL) were added K.sub.2CO.sub.3 (11.1 g, 3.0 equiv) and isoindoline-1,3-dione (4.74 g, 1.2 equiv). The reaction was stirred at 20 C. for 12 hours. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (2 300 mL). The combined organic layers were purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=20/1 to 3/1] to afford the title compound (5.6 g, 96% yield) as yellow oil; LCMS (ESI, M+1): m/z=216.1. [1153] Step B. diethyl 2-(3-(1,3-dioxoisoindolin-2-yl) propyl)cyclopropane-1,1-dicarboxylate: To a solution of 2-(pent-4-en-1-yl) isoindoline-1,3-dione (1.5 g, 1.0 equiv) in DCM (20 mL) were added dropwise PhCl (1.57 g, 1.41 mL, 2.0 equiv) and Rh.sub.2(OAc).sub.4 (308 mg, 0.1 equiv) at 25 C., and then diethyl 2-diazopropanedioate (1.56 g, 1.2 equiv) was added dropwise at 60 C. The reaction was stirred at 60 C. for 1 hour. Then diethyl 2-diazopropanedioate (1.56 g, 1.2 equiv) was added dropwise at 60 C. The resulting mixture was stirred at 60 C. for 11 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2100 mL). The combined layer was purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=10/1 to 1/1] to afford the title compound (2.4 g, 69% yield) as white solid; LCMS (ESI, M+1): m/z=374.1. [1154] Step C. ethyl 2-oxo-3-azabicyclo[5.1.0]octane-1-carboxylate: To a solution of diethyl 2-(3-(1,3-dioxoisoindolin-2-yl) propyl)cyclopropane-1,1-dicarboxylate (1.0 g, 1.0 equiv) in MeOH (10 mL) was added N.sub.2H.sub.4.Math.H.sub.2O (410 mg, 98% purity, 3.0 equiv). The reaction was stirred at 60 C. for 12 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (230 mL). The combined layers were washed with brine (40 mL), dried, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=5/1 to 1/1] to afford the title compound (200 mg, 37% yield) as yellow oil; LCMS (ESI, M+1): m/z=198.2. [1155] Step D. (3-azabicyclo[5.1.0]octan-1-yl)methanol: To a solution of ethyl 2-oxo-3-azabicyclo[5.1.0]octane-1-carboxylate (200 mg, 1.0 equiv) in THF (5 mL) was added LiAlH.sub.4 (57.7 mg, 3.0 equiv). The reaction was stirred at 40 C. for 3 hours. The mixture was quenched with water (10 mL) at 25 C., and purified with prep-TLC [SiO.sub.2, dichloromethane/methanol=10:1] to afford the title compound (120 mg, 82% yield) as white solid; LCMS (ESI, M+1): m/z=142.1. [1156] Step E. (3-methyl-3-azabicyclo[5.1.0]octan-1-yl)methanol: To a solution of 3-azabicyclo[5.1.0]octan-1-ylmethanol (60.0 mg, 1.0 equiv) in DMF (1 mL) were added K.sub.2CO.sub.3 (29.4 mg, 1 equiv) and MeI (30.2 mg, 1.0 equiv). The reaction was stirred at 25 C. for 2 hours. The mixture was concentrated and purified with prep-TLC [SiO.sub.2, dichloromethane/methanol=10:1] to afford the title compound (64 mg, 95% yield) as white solid; LCMS (ESI, M+1): m/z=156.0. [1157] Step F. (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((3-methyl-3-azabicyclo[5.1.0]octan-1-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3-methyl-3-azabicyclo[5.1.0]octan-1-yl)methanol (32 mg, 1.0 equiv) in THF (3 mL) was added dropwise t-BuONa (1 M, 600 L, 3 equiv) at 0 C. After addition, the mixture was stirred at this temperature for 0.5 hours, and then (3R)-1-[2-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol (109 mg, 1.0 equiv) was added. The reaction was stirred at 0 C. for 0.5 hours. The mixture was concentrated and purified with prep-TLC [SiO.sub.2, petroleum ether/ethyl acetate=0:1] to afford the title compound (30 mg, 22% yield) as yellow solid; LCMS (ESI, M+1): m/z=648.4. [1158] Step G. (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-methyl-3-azabicyclo[5.1.0]octan-1-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((3-methyl-3-azabicyclo[5.1.0]octan-1-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (30.0 mg, 1.0 equiv) in HCl.Math.dioxane (2.0 mL). The reaction was stirred at 0 C. for 1 hour. The mixture was filtered and concentrated and purified with prep-HPLC [column: 3_Phenomenex Luna C18 7530 mm3 um; mobile phase: [water (FA)-ACN]; B %: 20%-40%, 8 min] to afford the title compound (3.8 mg, 12% yield) as white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.25 (d, J=4.4 Hz, 1H), 8.48 (s, 1H), 7.76 (dd, J=5.6, 9.2 Hz, 1H), 7.43-7.27 (m, 2H), 7.03 (s, 1H), 4.85-4.63 (m, 1H), 4.57-4.33 (m, 3H), 4.22-4.00 (m, 2H), 3.18 (s, 4H), 2.70-2.63 (m, 3H), 2.32 (br d, J=2.0 Hz, 3H), 2.26-1.84 (m, 7H), 1.76-1.58 (m, 4H), 1.17 (d, J=10.0 Hz, 3H), 0.80-0.69 (m, 3H); LCMS (ESI, M+1): m/z=604.4. Example 829 ##STR00659## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-((1-methyl-1H-imidazol-5-yl)methyl) pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00660## [1159] Step A. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-((1-methyl-1H-imidazol-5-yl)methyl) pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (60.0 mg, 1.0 equiv) and 1-methyl-5-(pyrrolidin-3-ylmethyl)-1H-imidazole (41.8 mg, 2.5 equiv) in DMF (1 mL) were added 4 molecular sieve (10.0 mg, 1.0 equiv) and K.sub.3PO.sub.4 (215 mg, 10.0 equiv). The reaction was stirred at 60 C. for 2 hours. The mixture was filtered and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 35%-65%, 9 min] to afford the title compound (13.4 mg, 20% yield) as off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.31 (br s, 1H), 8.25 (br s, 1H), 7.69 (dd, J=5.6, 8.8 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.26 (t, J=9.2 Hz, 1H), 7.21 (br s, 1H), 7.04 (br d, J=4.8 Hz, 1H), 5.69-5.42 (m, 1H), 4.76-4.60 (m, 3H), 4.45-4.11 (m, 3H), 3.92-3.77 (m, 6H), 3.50-3.39 (m, 1H), 3.03-2.91 (m, 2H), 2.88-2.77 (m, 1H), 2.77-2.63 (m, 1H), 2.63-2.55 (m, 1H), 2.54-2.23 (m, 6H), 2.21-2.09 (m, 2H), 2.03-1.88 (m, 1H), 0.84-0.73 (m, 3H); LCMS (ESI, M+1): m/z=658.4. Example 830 ##STR00661## 4-(4-(3-(1H-1,2,3-triazol-1-yl) azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ##STR00662## [1160] Synthesized according to Example 829. The title compound was obtained as white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.26 (d, J=2.0 Hz, 1H), 8.69-8.40 (m, 1H), 8.23 (d, J=1.6 Hz, 1H), 7.82 (s, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.26 (br t, J=8.8 Hz, 1H), 7.09-7.01 (m, 1H), 5.51-5.22 (m, 2H), 4.74-4.58 (m, 4H), 4.51-4.31 (m, 2H), 4.29-4.08 (m, 3H), 3.18-3.02 (m, 1H), 2.56-2.36 (m, 2H), 2.33-1.89 (m, 11H), 1.64-1.43 (m, 1H), 0.87-0.72 (m, 3H); LCMS (ESI, M+1): m/z=659.4. Example 831 ##STR00663## 4-(4-((1R,5S)-8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ##STR00664## [1161] Synthesized according to Example 829. The title compound was obtained as white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.08 (s, 1H), 8.51 (br s, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.44-7.16 (m, 2H), 7.05 (d, J=2.4 Hz, 1H), 5.56-5.21 (m, 1H), 4.59 (s, 5H), 4.46-4.30 (m, 2H), 3.75 (br d, J=6.4 Hz, 2H), 3.42 (br d, J=2.4 Hz, 4H), 3.18-3.09 (m, 1H), 3.08-2.97 (m, 1H), 2.85-2.69 (m, 2H), 2.54-2.43 (m, 3H), 2.24-2.13 (m, 2H), 2.08 (br d, J=4.4 Hz, 2H), 2.04-1.93 (m, 3H), 1.68 (br d, J=8.8 Hz, 2H), 0.85-0.73 (m, 3H); LCMS (ESI, M+1): m/z=695.4. Example 832 ##STR00665## (1R,5R,6R)-3-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00666## [1162] Step A. (1R,5R,6R)-3-(7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (76.9 mg, 2.0 equiv) in DMF (0.5 mL) was added DIEA (117 mg, 3.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified with reversed-phase HPLC [C18, 0.1% formic acid condition] to afford the title compound (140 mg, 67% yield) as white solid; LCMS (ESI, M+1): m/z=689.4. [1163] Step B. (1R,5R,6R)-3-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (130 mg, 1.0 equiv) in DCM (0.5 mL) was added TFA (770 mg, 35 equiv). The reaction was stirred at 0 C. for 1 hours. The mixture was concentrated and diluted with H.sub.2O (5 mL). The mixture was adjusted pH to 8 with saturated Na.sub.2CO.sub.3 aqueous solution (3 mL) and extracted with DCM (210 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex Luna C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 8%-38%, 9 min] to afford the title compound (46.7 mg, 43% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.36 (s, 1H), 8.53 (s, 1H), 7.81 (s, 1H), 4.97-4.92 (m, 1H), 4.84-4.81 (m, 1H), 4.60 (s, 2H), 4.41-4.28 (m, 1H), 3.88-3.72 (m, 1H), 3.67-3.48 (m, 3H), 3.26-3.14 (m, 2H), 2.55 (s, 3H), 2.42 (br s, 1H), 2.35-2.22 (m, 7H), 2.21-2.00 (m, 6H), 1.98-1.90 (m, 1H), 1.87-1.78 (m, 1H), 1.45-1.32 (m, 1H); LCMS (ESI, M+1): m/z=559.4. Example 833 ##STR00667## 5-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione [1164] Synthesized according to Example 832. The title compound was obtained as white solid (FA salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.38 (s, 1H), 7.81 (s, 1H), 4.68-4.63 (m, 4H), 4.40-4.32 (m, 2H), 3.83-3.74 (m, 2H), 3.66-3.60 (m, 2H), 3.27-3.16 (m, 2H), 2.55 (s, 3H), 2.34-2.29 (m, 2H), 2.29-2.27 (s, 3H), 2.24-2.17 (m, 2H), 2.16-2.11 (m, 2H), 2.10-2.03 (m, 2H); LCMS (ESI, M+1): m/z=572.2. Example 834 ##STR00668## 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1-carboxamide ##STR00669## [1165] Step A. 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1-carboxamide: To a solution of 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1-carboxylic acid (30.0 mg, 1.0 equiv) and NH.sub.4Cl (24.8 mg, 10 equiv) in DMF (0.3 mL) were added EDCI (10.6 mg, 1.2 equiv), HOBt (12.5 mg, 2.0 equiv) and TEA (37.5 mg, 8.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 40%-70%, 8 min] to afford the title compound (12.9 mg, 42% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.11 (d, J=1.2 Hz, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.33-7.20 (m, 2H), 7.06 (t, J=2.4 Hz, 1H), 5.50-5.28 (m, 1H), 5.11-4.99 (m, 1H), 4.68-4.59 (m, 1H), 4.51-4.33 (m, 2H), 3.78-3.47 (m, 3H), 3.46-3.36 (m, 2H), 3.20-3.07 (m, 1H), 2.62-2.30 (m, 4H), 2.28-2.04 (m, 6H), 2.01-1.85 (m, 4H), 1.68-1.52 (m, 1H), 0.84-0.75 (m, 3H); LCMS (ESI, M+1): m/z=647.2. Example 835 ##STR00670## ((3S,7aR)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-hydroxy-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate ##STR00671## [1166] Step A. 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol: To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.00 g, 1.0 equiv) and DIEA (1.54 g, 3.0 equiv) in DCM (10 mL) was added 6-azaspiro[3.5]nonan-2-ol (559 mg, 1.0 equiv). The reaction was stirred at 40 C. for 1 hour. The mixture was diluted with water (50 mL), extracted with ethyl acetate (350 mL), washed with brine (50 mL), dried, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=5/1 to 2/1] to afford the title compound (800 mg, 56% yield) as a white solid; LCMS (ESI, M+1): m/z=357.1. [1167] Step B. 2,7-dichloro-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidine: To a solution of 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (800 mg, 1.0 equiv) and TsOH (77.1 mg, 0.2 equiv) in DCM (10 mL) was added DHP (282 mg, 1.5 equiv). The reaction was stirred at 20 C. for 16 hours. The mixture was quenched by saturated sodium bicarbonate solution (50 mL) at 0 C., extracted with DCM (50 3 mL), washed with brine (50 mL), dried, concentrated and purified with prep-TLC [SiO.sub.2, petroleum ether/ethyl acetate=1/1] to afford the title compound (700 mg, 71% yield) as white solid; LCMS (ESI, M+1): m/z=441.1. [1168] Step C. 2-(((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-chloro-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidine: To a solution of ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (650 mg, 1.0 equiv), 4 molecular sieve (50 mg) in toluene (10 mL) was added t-BuONa (2 M, 2.38 mL, 3.0 equiv) at 0 C. for 0.5 hours, and then mixture was added 2,7-dichloro-8-fluoro-4- (2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidine (700 mg, 1.0 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hour under N.sub.2 atmosphere. The mixture was quenched by water (50 mL at 0 C.), extracted with DCM (3 50 mL), washed with brine (50 mL), dried, concentrated and purified with column chromatography [SiO.sub.2, methylene chloride: methyl alcohol=10:1] to afford the title compound (700 mg, 54% yield) as a yellow solid; LCMS (ESI, M+1): m/z=814.3. [1169] Step D. ((3S,7aR)-7a-(((7-chloro-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol: To a solution of t 2-(((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-chloro-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidine (700 mg, 1.0 equiv) in DMF (8 mL) was added CsF (2.61 g, 20.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was diluted with water (20 mL), extracted with ethyl acetate (320 mL), washed with brine (20 mL), dried and concentrated to afford the title compound (300 mg, crude) as a yellow solid; LCMS (ESI, M+1): m/z=576.2. [1170] Step E. ((3S,7aR)-7a-(((7-chloro-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-(((7-chloro-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol (280 mg, 1.0 equiv) and TEA (148 mg, 3.0 equiv) in DCM (5 mL) was added (4-nitrophenyl) carbonochloridate (196 mg, 2.0 equiv) at 0 C. The reaction was stirred at 25 C. for 2 hours, then TEA (98.4 mg, 2.0 equiv) and N-methylmethanamine (2 M, 729 L, 3.0 equiv) was added at 0 C. The reaction was stirred at 25 C. for 2 hours. The mixture was diluted with water (30 mL), extracted with DCM (330 mL), washed with brine (30 mL), dried, concentrated and purified with prep-TLC [SiO.sub.2, methylene dichloride:methyl alcohol=10:1] to afford the title compound (300 mg, 95% yield) as a yellow oil; LCMS (ESI, M+1): m/z=647.4. [1171] Step F. ((3S,7aR)-7a-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-(((7-chloro-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (300 mg, 1.0 equiv), Ad.sub.2nBuP Pd G.sub.3 (33.8 mg, 0.1 equiv) and Cs.sub.2CO.sub.3 (453, 3.0 equiv) in water (1 mL) and CPME (5 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (285 mg, 1.2 equiv), The reaction was stirred at 100 C. for 2 hours under N.sub.2 atmosphere. The mixture was diluted with water (30 mL), extracted with DCM (330 mL), washed with brine (30 mL), dried, concentrated and purified with prep-TLC [SiO.sub.2, methylene dichloride:methyl alcohol=10:1] to afford the title compound (200 mg, 43% yield) as yellow solid; [1172] Step G. ((3S,7aR)-7a-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (50.0 mg, 1.0 equiv) in DMF (2 mL) was added CsF (228 mg, 30 equiv). The mixture was stirred at 20 C. for 2 hours. The reaction mixture was diluted with water (20 mL), extracted with DCM (320 mL), washed with brine (20 mL), dried, and concentrated to afford the title compound (50 mg, crude) as a yellow oil; LCMS (ESI, M+1): m/z=841.4. [1173] Step H. ((3S,7aR)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(2-hydroxy-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate (60.0 mg, 1.0 equiv) in ACN (2 mL) was added HCl.Math.dioxane (4 M, 2 mL). The reaction was stirred at 0 C. for 0.5 hours. The reaction mixture was quenched by NaHCO.sub.3, adjusted pH to 7 at 0 C., diluted with water (20 mL), extracted with methylene dichloride (320 mL), washed with brine (20 mL), dried, concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: [water (NH.sub.4HCO.sub.3)-ACN]; B %: 38%-68%, 8 min] to afford the title compound (7.80 mg, 15% yield) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =8.99 (d, J=7.2 Hz, 1H), 7.86 (dd, J=5.6, 9.2 Hz, 1H), 7.37-7.29 (m, 2H), 7.25-7.20 (m, 1H), 4.68-4.55 (m, 1H), 4.38-4.16 (m, 3H), 4.15-3.86 (m, 6H), 3.51-3.37 (m, 1H), 3.04 (td, J=5.2, 10.0 Hz, 2H), 2.92 (br d, J=18.4 Hz, 6H), 2.83 (br dd, J=5.2, 10.4 Hz, 1H), 2.41-2.27 (m, 1H), 2.25-2.18 (m, 2H), 2.07-1.99 (m, 1H), 1.97-1.87 (m, 3H), 1.82 (br s, 5H), 1.71 (br dd, J=7.2, 11.6 Hz, 3H); LCMS (ESI, M+1): m/z=713.3. Example 836 ##STR00672## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-1,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00673## [1174] Step A. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(1,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (150 mg, 1.0 equiv) and 1,6-dioxa-9-azaspiro[3.6]decane (109 mg, 3.0 equiv) in DMF (1 mL) were added 4 molecular sieve (10.0 mg, 1.0 equiv) and K.sub.3PO.sub.4 (537 mg, 10 equiv). The reaction was stirred at 60 C. for 2 hours. The mixture was filtered and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 30%-60%, 9 min] to afford the title compound (41.6 mg, 29% yield) as off-white solid; LCMS (ESI, M+1): m/z=636.3. [1175] Step B. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-1,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (41.6 mg) was separated by SFC [Column: Cellulose-4 504.6 mm I.D., 3 um Mobile phase: Phase A for CO.sub.2, and Phase B for EtOH (0.05% DEA); Gradient elution: 40% EtOH (0.05% DEA) in CO.sub.2 Flow rate: 3 mL/min; Detector: PDA Column Temp: 35C; Back Pressure: 100 Bar] to afford the title compound (6.44 mg, 4% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.54 (s, 1H), 7.68 (dd, J=5.8, 9.2 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.06 (dd, J=2.5, 10.4 Hz, 1H), 5.43-5.20 (m, 1H), 4.69-4.53 (m, 4H), 4.40-4.32 (m, 1H), 4.30-4.16 (m, 2H), 4.13-3.95 (m, 4H), 3.92-3.80 (m, 1H), 3.29-3.17 (m, 3H), 3.03 (dt, J=5.6, 9.2 Hz, 1H), 2.77-2.65 (m, 1H), 2.62-2.43 (m, 2H), 2.39-2.20 (m, 2H), 2.20-2.11 (m, 2H), 2.05-1.88 (m, 3H), 0.80 (td, J=7.2, 17.2 Hz, 3H); LCMS (ESI, M+1): m/z=636.5. Example 837 ##STR00674## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-1,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00675## [1176] Step A. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-1,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (41.6 mg) was separated by SFC [Column: Cellulose-4 504.6 mm I.D., 3 um Mobile phase: Phase A for CO.sub.2, and Phase B for EtOH (0.05% DEA); Gradient elution: 40% EtOH (0.05% DEA) in CO.sub.2 Flow rate: 3 mL/min; Detector: PDA Column Temp: 35C; Back Pressure: 100 Bar] to afford the title compound (5.70 mg, 3% yield) as a yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.62 (s, 1H), 7.69 (dd, J=6.0, 9.2 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.26 (t, J=9.6 Hz, 1H), 7.09-7.03 (m, 1H), 5.65-5.40 (m, 1H), 4.73-4.52 (m, 6H), 4.27-4.14 (m, 1H), 4.13-3.99 (m, 4H), 3.94-3.71 (m, 4H), 3.38 (br dd, J=4.0, 9.6 Hz, 1H), 2.78-2.67 (m, 1H), 2.66-2.43 (m, 4H), 2.42-2.34 (m, 1H), 2.33-2.23 (m, 2H), 2.22-2.07 (m, 2H), 0.86-0.74 (m, 3H); LCMS (ESI, M+1): m/z=636.5. Example 838 ##STR00676## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-thia-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00677## [1177] Step A. 6-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-thia-6-azaspiro[3.5]nonane: To a mixture of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (66.0 mg, 1.0 equiv) and 1-thia-6-azaspiro[3.5]nonane (23.7 mg, 0.9 equiv, HCl salt) in DCM (0.6 mL) were added DIEA (75.8 mg, 4.0 equiv) and 4 molecular sieve (50 mg). The reaction was stirred at 0 C. for 30 minutes. The mixture was quenched with water (5 mL) and extracted with DCM (25 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=2:1) to afford the title compound (32.0 mg, 39% yield) as yellow solid. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.47 (d, J=6.4 Hz, 1H), 7.70 (dd, J=5.6, 8.8 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J=2.4 Hz, 1H), 5.36-5.25 (m, 2H), 4.75-4.50 (m, 1H), 4.41-4.22 (m, 1H), 4.02-3.82 (m, 1H), 3.52 (d, J=0.8 Hz, 3H), 3.50-3.38 (m, 1H), 3.24-3.05 (m, 2H), 2.82-2.63 (m, 2H), 2.59-2.44 (m, 1H), 2.38-2.26 (m, 1H), 2.23-2.11 (m, 1H), 2.04-1.99 (m, 1H), 1.89 (br d, J=4.4 Hz, 2H), 0.85 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=557.1. [1178] Step B. 6-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-thia-6-azaspiro[3.5]nonane: To a mixture of 6-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-thia-6-azaspiro[3.5]nonane (50.0 mg, 1.0 equiv) and 4 molecular sieve (50 mg, 1.0 equiv) in toluene (0.5 mL) was added t-BuONa (25.9 mg, 3.0 equiv). The reaction was stirred at 0 C. for 10 minutes. To the mixture was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (15.7 mg, 1.1 equiv). The reaction was stirred at 0 C. for 1 hour. The mixture was quenched with H.sub.2O (10 mL) at 0 C. and extracted with ethyl acetate (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 24%-57%, 9 min) to afford the title compound (18.0 mg, 30% yield) as white solid; LCMS (ESI, M+1): m/z=680.3. [1179] Step C. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(1-thia-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of 6-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-thia-6-azaspiro[3.5]nonane (21.0 mg, 1.0 equiv) in DCM (1 mL) was added TFA (500 uL). The reaction was stirred at 0 C. for 2 hours. The mixture was concentrated under vacuum. The residue was diluted with water (1 mL). The mixture was adjusted to pH=7 with saturated NaHCO.sub.3 (3 mL) and extracted with ethyl acetate (3 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 24%-44%, 10 min) to afford the title compound (6.00 mg, 30% yield) as yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.44-9.28 (m, 1H), 8.53 (br d, J=2.8 Hz, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.40-7.19 (m, 2H), 7.10 (br d, J=2.4 Hz, 1H), 5.56-5.24 (m, 1H), 4.64 (br d, J=13.2 Hz, 1H), 4.51-4.27 (m, 3H), 4.05-3.88 (m, 1H), 3.58-3.37 (m, 4H), 3.21-2.99 (m, 3H), 2.82-2.63 (m, 2H), 2.54-2.32 (m, 3H), 2.31-1.94 (m, 7H), 1.82 (br d, J=3.6 Hz, 2H), 0.80 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=636.3. Example 839 ##STR00678## 5-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [1180] Synthesized according to Example 832. The title compound was obtained as white solid (FA salt). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) =9.37-9.23 (m, 1H), 8.57-8.52 (m, 1H), 7.93-7.71 (m, 1H), 6.86-6.76 (m, 1H), 5.32-5.24 (m, 2H), 4.57 (s, 2H), 4.56-4.46 (m, 4H), 3.64-3.51 (m, 2H), 3.37-3.34 (m, 3H), 3.22-3.14 (m, 2H), 3.12-3.05 (m, 3H), 2.58-2.52 (m, 3H), 2.51-2.41 (m, 2H), 2.34-2.23 (m, 5H), 2.22-1.99 (m, 6H); LCMS (ESI, M+1): m/z=640.4. Example 840 ##STR00679## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-((2-hydroxyethoxy)methyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00680## [1181] Step A. tert-butyl 1-((2-(benzyloxy) ethoxy)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (300 mg, 1.0 equiv) in DMAC (3.00 mL) was added NaH (149 mg, 60% purity, 3.0 equiv) at 0 C. The mixture was stirred at 0 C. for 0.5 hours. Then ((2-iodoethoxy)methyl)benzene (977 mg, 3.0 equiv) was added. The reaction was stirred at 25 C. for 2 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (137 mg, 28% yield) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.38-7.28 (m, 5H), 4.58 (br s, 2H), 3.89 (br d, J=11.2 Hz, 1H), 3.82-3.70 (m, 1H), 3.62 (br d, J=4.4 Hz, 4H), 3.42-3.35 (m, 2H), 2.88-2.69 (m, 2H), 2.31-2.16 (m, 1H), 1.77-1.63 (m, 2H), 1.63-1.49 (m, 3H), 1.46 (s, 9H), 1.43-1.38 (m, 1H); LCMS (ESI, M55): m/z=320.2. [1182] Step B. 1-((2-(benzyloxy) ethoxy)methyl)-3-azabicyclo[3.2.1]octane: To a solution of tert-butyl 1-((2-(benzyloxy) ethoxy)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (130 mg, 1.0 equiv) in acetonitrile (1.00 mL) was added HCl.Math.dioxane (4 M, 2.00 mL). The reaction mixture was stirred at 20 C. for 1 hour. The mixture was concentrated under vacuum to afford the title compound (110 mg, crude, HCl salt) as yellow oil; LCMS (ESI, M+1): m/z=276.3. [1183] Step C. 4-(4-(1-((2-(benzyloxy) ethoxy)methyl)-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (150 mg, 1.0 equiv), DIEA (164 mg, 5.0 equiv), and 4 molecular sieve (30.0 mg) in DMF (1.50 mL) 1-((2-(benzyloxy) ethoxy)methyl)-3-azabicyclo[3.2.1]octane (103 mg, 1.3 equiv, HCl). The reaction mixture was stirred at 40 C. for 16 hours. The mixture was filtered and the filtrate was purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (103 mg, 50% yield) as yellow solid; LCMS (ESI, M+1): m/z=768.4. [1184] Step D. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(1-((2-hydroxyethoxy)methyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of 4-(4-(1-((2-(benzyloxy) ethoxy)methyl)-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (80 mg, 1.0 equiv) in MeOH (5.00 mL) was added Pd(OH).sub.2/C (50.0 mg, 20% purity) under N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The reaction was stirred at 20 C. for 5 hours under H.sub.2 (15 Psi). The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified with prep-HPLC [Waters Xbridge 15025 mm5 m: A: water (NH.sub.4HCO.sub.3), B: CAN, B %: 48%-78% over 8 min] to afford the title compound (5.52 mg, 8.0% yield) as yellow solid; .sup.1H NMR (400 MHz, METHANOL-d4) =9.09 (d, 1H), 7.73-7.62 (m, 1H), 7.34-7.20 (m, 2H), 7.07 (br s, 1H), 5.42-5.25 (m, 1H), 4.78-4.61 (m, 2H), 4.41-4.20 (m, 2H), 3.75-3.61 (m, 3H), 3.59-3.47 (m, 5H), 3.29-3.18 (m, 2H), 3.16-2.99 (m, 1H), 2.55-2.40 (m, 2H), 2.39-2.23 (m, 2H), 2.22-2.12 (m, 2H), 2.08-1.97 (m, 2H), 1.97-1.43 (m, 8H), 0.87-0.75 (m, 3H); LCMS (ESI, M+1): m/z=678.5. Example 841 ##STR00681## (1R,5R,6R)-3-(7-(6-(difluoromethyl)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00682## [1185] Step A. (5-bromonaphthalen-2-yl)methanol: To a solution of methyl 5-bromo-2-naphthoate (100 mg, 1.0 equiv) in THF (2 mL) was added LAH (28.6 mg, 2.0 equiv) at 40 C. in portions. The reaction was stirred at 40 C. for 1 hour. The mixture was quenched with H.sub.2O (0.2 mL), 15% NaOH solution (0.2 mL), H.sub.2O (0.6 mL), The residue was filtered and the filtrate was concentrated under vacuum to afford the title compound (50.0 mg, crude) as white solid. [1186] Step B: 5-bromo-2-naphthaldehyde: To a solution of (5-bromonaphthalen-2-yl)methanol (1.16 g, 1.0 equiv) in dichloromethane (20 mL) was added Dess-Martin (2.49 g, 1.2 equiv) at 25 C. The reaction was stirred at 25 C. for 1 hour. The mixture was quenched with saturated Na.sub.2SO.sub.3 (15 mL) and extracted with dichloromethane (20 mL). The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=50/1 to 10/1) to afford the title compound (476 mg, 41% yield) as a yellow solid. .sup.1H NMR (400 MHZ, DMSO-d6) =10.20 (s, 1H), 8.67 (s, 1H), 8.26 (dd, J=8.8, 15.2 Hz, 2H), 8.10-8.03 (m, 2H), 7.59 (t, J=8.0 Hz, 1H). [1187] Step C: 1-bromo-6-(difluoromethyl)naphthalene: A mixture of 5-bromo-2-naphthaldehyde (470 mg, 1.0 equiv) and BAST (6.41 g, 14 equiv) was stirred at 25 C. for 1 hour. The reaction was diluted with water (6 mL) and extracted with ethyl acetate (8 mL). The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=50/1 to 10/1) to afford the title compound (370 mg, 72% yield) as a yellow oil. .sup.1H NMR (400 MHZ, DMSO-d6) =8.29-8.22 (m, 2H), 8.12 (d, J=8.0 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.25 (t, J=55.6 Hz, 1H). [1188] Step D: (6-(difluoromethyl)naphthalen-1-yl)trimethylstannane: A mixture of 1-bromo-6-(difluoromethyl)naphthalene (311 mg, 1.0 equiv), trimethyl(trimethylstannyl) stannane (3.96 g, 10 equiv) and Pd(PPh.sub.3).sub.4 (279 mg, 0.2 equiv) in toluene (20 mL) was degassed under vacuum and purged with N.sub.2 three times. The reaction was stirred at 100 C. for 14 hours. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (SiO.sub.2, petroleum ether) to afford the title compound (380 mg, 92% yield) as colourless oil. [1189] Step E 7-(6-(difluoromethyl)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (140 mg, 1.0 equiv), [6-(difluoromethyl)-1-naphthyl]-trimethyl-stannane (217 mg, 2.0 equiv), BINAP (39.7 mg, 0.2 equiv), CuI (24.3 mg, 0.4 equiv) in toluene (10 mL) was added Pd(dppf)Cl.sub.2 (23.3 mg, 0.1 equiv). The mixture was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 100 C. for 16 hours under N.sub.2 atmosphere. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL). The organic layer was dried over sodium sulfate, concentrated and purified by reversed-phase HPLC (0.1% FA condition) to afford the title compound (49.0 mg, 20% yield) as a brown solid. LCMS (ESI, M+1): m/z=581.3. [1190] Step F (1R,5R,6R)-3-(7-(6-(difluoromethyl)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 7-(6-(difluoromethyl)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (49 mg, 1.0 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (21.5 mg, 2.0 equiv) in DMF (2.0 mL) was added DIEA (32.7 mg, 3.0 equiv) and 4 molecular sieve (40.0 mg) at 40 C. The mixture was warmed to 40 C. and stirred for 14 hours. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL). [1191] The organic layer was dried over sodium sulfate, filtered and concentrated and purified by prep-HPLC [column: Waters Xbridge 15050 mm10 m; A: water (NH.sub.4HCO.sub.3), B: ACN; B %: 50%-80% over 10 min] to afford the title compound (9.20 mg, 18% yield) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.33 (s, 1H), 8.22-8.14 (m, 2H), 7.83 (br d, J=9.2 Hz, 1H), 7.79-7.71 (m, 2H), 7.62 (d, J=8.8 Hz, 1H), 6.95 (t, J=56.8 Hz, 1H), 5.52-5.29 (m, 1H), 4.97 (br s, 1H), 4.51-4.42 (m, 1H), 4.40-4.30 (m, 2H), 3.80 (br d, J=12.4 Hz, 1H), 3.60-3.40 (m, 4H), 3.22-3.08 (m, 1H), 2.52-2.32 (m, 3H), 2.30-2.19 (m, 3H), 2.17-2.06 (m, 2H), 2.05-1.89 (m, 2H), 1.87-1.77 (m, 1H), 1.45-1.35 (m, 1H); LCMS (ESI, M+1): m/z=608.4. Example 842 ##STR00683## (1R,5S,8R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-ol ##STR00684## [1192] Step A. (1R,5S,8R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-ol: The mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv) and (1R,5S,8s)-3-azabicyclo[3.2.1]octan-8-ol (21.5 mg, 1.5 equiv, HCl) in DMF (0.5 mL) were added DIEA (109 mg, 10 equiv) and 4 molecular sieve (10.0 mg, 1.0 equiv). The reaction was stirred at 60 C. for 12 hours. The mixture was filtered and purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 um; mobile phase: [water (NH.sub.4HCO.sub.3)-ACN]; B %: 30%-60%, 11 min) to afford the title compound (11.8 mg, 22% yield) as yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.04 (s, 1H), 7.67 (dd, J=5.6, 8.8 Hz, 1H), 7.37-7.16 (m, 2H), 7.06 (d, J=2.4 Hz, 1H), 5.48-5.18 (m, 1H), 4.74-4.68 (m, 2H), 4.36-4.12 (m, 3H), 3.64 (br t, J=9.6 Hz, 2H), 3.26-3.11 (m, 3H), 3.07-2.94 (m, 1H), 2.48 (br s, 1H), 2.40-2.07 (m, 6H), 2.05-1.82 (m, 5H), 1.53 (br d, J=9.6 Hz, 2H), 0.87-0.71 (m, 3H); LCMS (ESI, M+1): m/z=620.3. Example 843 ##STR00685## (1R,5S,8R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-(trifluoromethyl)-3-azabicyclo[3.2.1]octan-8-ol [1193] Synthesized according to Example 842. The title compound was obtained as white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.94 (br s, 1H), 9.15 (s, 1H), 7.76 (dd, J=6.4, 8.8 Hz, 1H), 7.42-7.26 (m, 2H), 7.02 (d, J=2.0 Hz, 1H), 6.85 (s, 1H), 5.41-5.12 (m, 1H), 4.50 (br t, J=13.6 Hz, 2H), 4.23-3.93 (m, 4H), 3.14-2.97 (m, 3H), 2.89-2.77 (m, 1H), 2.45-2.30 (m, 3H), 2.19-1.98 (m, 4H), 1.91-1.72 (m, 5H), 1.63 (br d, J=8.0 Hz, 2H), 0.72 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=688.0. Example 844 ##STR00686## 4-(4-(3-azabicyclo[3.2.2]nonan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [1194] Synthesized according to Example 842. The title compound was obtained as orange solid; .sup.1H NMR (400 MHz, METHANOL-d.sub.4) =9.05 (s, 1H), 7.74-7.61 (m, 1H), 7.37-7.19 (m, 2H), 7.06 (d, J=2.4 Hz, 1H), 5.44-5.19 (m, 1H), 4.36-4.31 (m, 1H), 4.30-4.17 (m, 4H), 3.27-3.12 (m, 3H), 3.06-2.96 (m, 1H), 2.55-2.42 (m, 1H), 2.39-2.08 (m, 6H), 2.06-1.94 (m, 2H), 1.93-1.73 (m, 9H), 0.94-0.68 (m, 3H); LCMS (ESI, M+1): m/z=618.4. Example 845 ##STR00687## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5S,8S)-8-(hydroxymethyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00688## [1195] Synthesized according to Example 842. The title compound was obtained as yellow solid (FA salt). .sup.1H NMR (400 MHZ, METHANOL-d4) =9.09 (s, 1H), 8.51 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.34-7.20 (m, 2H), 7.06 (d, J=2.4 Hz, 1H), 5.51-5.27 (m, 1H), 4.78 (br d, J=12 Hz, 2H), 4.49-4.41 (m, 1H), 4.40-4.33 (m, 1H), 3.69-3.58 (m, 2H), 3.56-3.36 (m, 5H), 3.17 (br d, J=5.2 Hz, 1H), 2.34 (br s, 5H), 2.28-2.05 (m, 5H), 2.02-1.91 (m, 1H), 1.87-1.73 (m, 2H), 1.55 (br d, J=10.4 Hz, 2H), 0.79 (dt, J=2.4, 7.2 Hz, 3H). LCMS (ESI, M+1): m/z=634.3 Example 846 ##STR00689## (1R,5S,8R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-methyl-3-azabicyclo[3.2.1]octan-8-ol [1196] Synthesized according to Example 842. The title compound was obtained as yellow solid. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.16-9.69 (m, 1H), 9.15 (s, 1H), 7.76 (dd, J=6.0, 9.2 Hz, 1H), 7.39-7.30 (m, 2H), 7.02 (d, J=2.0 Hz, 1H), 5.36-5.18 (m, 1H), 5.07 (s, 1H), 4.40-4.30 (m, 2H), 4.13 (dd, J=6.8, 10.4 Hz, 1H), 4.09-3.99 (m, 3H), 3.08 (br d, J=9.6 Hz, 2H), 3.01 (s, 1H), 2.87-2.77 (m, 1H), 2.39-2.29 (m, 1H), 2.19-2.09 (m, 2H), 2.05 (br d, J=2.0 Hz, 1H), 2.01 (br s, 1H), 1.91-1.74 (m, 5H), 1.74-1.66 (m, 2H), 1.43 (br d, J=12.4 Hz, 2H), 1.23 (s, 3H), 0.72 (t, J=7.6 Hz, 3H); LCMS (ESI, M+1): m/z=634.7. Example 847 ##STR00690## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5S,8S)-8-(2-hydroxyethyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [1197] Synthesized according to Example 842. The title compound was obtained as yellow solid (FA salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.15 (s, 1H), 8.53 (br s, 1H), 7.67 (dd, J=6.0, 8.8 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 5.49-5.25 (m, 1H), 4.50 (br t, J=11.2 Hz, 2H), 4.42-4.37 (m, 1H), 4.35-4.28 (m, 1H), 3.91 (br dd, J=8.8, 11.6 Hz, 2H), 3.76 (t, J=6.4 Hz, 2H), 3.37 (br d, J=6.4 Hz, 3H), 3.16-3.06 (m, 1H), 2.55-2.26 (m, 5H), 2.24-2.13 (m, 2H), 2.07 (q, J=6.4 Hz, 4H), 1.95 (br dd, J=4.0, 6.8 Hz, 2H), 1.89-1.80 (m, 2H), 1.61 (br d, J=10.0 Hz, 2H), 0.79 (dt, J=2.4, 7.2 Hz, 3H); LCMS (ESI, M+1): m/z=648.4. Example 848 ##STR00691## (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-ol ##STR00692## [1198] Synthesized according to Example 842. The title compound was obtained as yellow solid (FA salt). .sup.1H NMR (400 MHZ, DMSO-d6) =9.15 (s, 1H), 7.75 (dd, J=6.0, 9.2 Hz, 1H), 7.44-7.28 (m, 2H), 7.02 (d, J=2.0 Hz, 1H), 5.36-5.18 (m, 1H), 4.33 (br s, 2H), 4.13 (dd, J=6.0, 10.0 Hz, 1H), 4.08-3.88 (m, 4H), 3.04-3.04 (m, 1H), 3.14-3.03 (m, 2H), 3.00 (s, 1H), 2.85-2.78 (m, 1H), 2.39-2.29 (m, 1H), 2.20-1.94 (m, 6H), 1.89-1.61 (m, 5H), 1.54-1.34 (m, 2H), 0.72 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=620.2 Example 849 ##STR00693## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-methylene-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00694## [1199] Step A. (1R,5S)-8-methylene-3-azabicyclo[3.2.1]octane: A mixture of (1R,5S)-tert-butyl 8-methylene-3-azabicyclo[3.2.1]octane-3-carboxylate (300 mg, 1.34 mmol, 1.0 equiv) and HCl.Math.dioxane (4 M, 1.0 equiv) in MeCN (0.5 mL) was stirred at 20 C. for 0.5 hour. The mixture was concentrated to afford the title compound (200 mg, crude) as yellow solid. [1200] Step B. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((1R,5S)-8-methylene-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv) and (1R,5S)-8-methylene-3-azabicyclo[3.2.1]octane (10.4 mg, 1.0 equiv) in DMF (0.5 mL) were added DIEA (65.4 mg, 6.0 equiv) and 4 molecular sieve (10 mg). The reaction was stirred 40 C. for 12 hours. The mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 25%-55%, 10 min) to afford the title compound (21.7 mg, 94% yield, 0.41 HCOOH) as yellow solid .sup.1H NMR (400 MHz, DMSO-d6) =9.09 (s, 1H), 8.24 (s, 1H), 7.76 (dd, J=6.0, 9.2 Hz, 1H), 7.44-7.21 (m, 2H), 7.11-6.89 (m, 1H), 5.38-5.16 (m, 1H), 4.87-4.66 (m, 3H), 4.22-4.00 (m, 2H), 3.67-3.59 (m, 2H), 3.14-2.89 (m, 4H), 2.86-2.78 (m, 1H), 2.77-2.68 (m, 2H), 2.41-1.96 (m, 6H), 1.89-1.56 (m, 7H), 0.72 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=616.7. Example 850 ##STR00695## (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-3-azabicyclo[3.2.1]octane-8-carboxamide ##STR00696## [1201] Step A. (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (300 mg, 1.0 equiv) and (1R,5S,8r)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (194. mg, 2.0 equiv, HCl) in DMF (0.1 mL) were added DIEA (654 mg, 10 equiv) and 4 molecular sieve (10.0 mg). The reaction was stirred at 60 C. for 12 hours. The mixture was filtered and purified by prep-HPLC (column: Welch Xtimate C18 150 25 mm5 um; mobile phase: [water (NH.sub.3H.sub.2O)-ACN]; B %: 10%-40%, 8 min) to afford the title compound (115 mg, 33% yield) as yellow solid; LCMS (ESI, M+1): m/z=648.4. [1202] Step B. (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-3-azabicyclo[3.2.1]octane-8-carboxamide: To a solution of (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50.0 mg, 1.0 equiv) and methanamine (10.4 mg, 2.0 equiv, HCl) in DMF (0.5 mL) were added HATU (88.1 mg, 3.0 equiv) and DIEA (59.9 mg, 6.0 equiv). The reaction was stirred at 25 C. for 0.5 hour. The mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18 15025 mm10 m; mobile phase: [water (FA)-ACN]; B %: 20%-50%, 10 min) to afford the title compound (15.9 mg, 30% yield, 0.5 HCOOH) as off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.09 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.35-7.20 (m, 2H), 7.05 (d, J=2.4 Hz, 1H), 5.59-5.34 (m, 1H), 4.78 (br d, J=3.6 Hz, 2H), 4.55-4.41 (m, 2H), 3.76-3.47 (m, 5H), 3.27-3.20 (m, 1H), 2.82 (s, 1H), 2.76-2.66 (m, 5H), 2.59-2.36 (m, 3H), 2.34-2.25 (m, 1H), 2.24-2.13 (m, 3H), 2.11-1.96 (m, 1H), 1.92-1.82 (m, 2H), 1.55 (br d, J=8.8 Hz, 2H), 0.79 (dt, J=2.8, 7.2 Hz, 3H); LCMS (ESI, M+1): m/z=661.4. Example 851 ##STR00697## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-azaspiro[2.5]octane-1-carbonitrile ##STR00698## [1203] Synthesized according to Example 842. The title compound was obtained as yellow solid. .sup.1HNMR (400 MHZ, METHANOL-d.sub.4) =0.81 (br t, J=6.8 Hz, 3H), 1.13-1.21 (m, 1H), 1.32-1.46 (m, 1H), 1.81-1.89 (m, 1H), 1.90-2.00 (m, 1H), 2.02-2.15 (m, 4H), 2.16-2.31 (m, 3H), 2.33-2.41 (m, 1H), 2.42-2.70 (m, 3H), 3.36 (br s, 1H), 3.64-4.14 (m, 6H), 4.27-4.44 (m, 1H), 4.48-4.68 (m, 2H), 5.37-5.65 (m, 1H), 7.08 (br s, 1H), 7.28 (t, J=9.2 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.70 (dd, J=9.2, 5.6 Hz, 1H), 8.42 (br s, 1H), 9.11 (d, J=3.6 Hz, 1H); LCMS (ESI, M+1): m/z=629.4. Example 852 ##STR00699## (R)-1-(2-(((3S,7aS)-3-((cyclobutylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00700## [1204] Step A. (3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine: To a solution of ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (16.0 g, 1 equiv) and TEA (7.90 g, 2.0 equiv) in DCM (160 mL) was added [chloro(diphenyl)methyl]benzene (16.3 g, 1.5 equiv). The reaction was stirred at 25 C. for 12 hours. The mixture was diluted with water (20 mL) and extracted with DCM (330 mL). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (25.0 g, 98% yield) as yellow oil liquid. [1205] Step B. ((3S,7aS)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol: To a solution of (3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine (24.0 g, 1.0 equiv) in DMF (300 mL) was added CsF (83.9 g, 15 equiv) in one portion under N.sub.2. The reaction was stirred at 40 C. for 6 hours. The mixture was concentrated to remove DMF and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (3.30 g, 20% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =7.61-7.17 (m, 15H), 3.94-3.72 (m, 3H), 3.59-3.43 (m, 3H), 3.41-3.32 (m, 1H), 3.31 (s, 1H), 2.14-1.79 (m, 8H); LCMS (ESI, M+1): m/z=414.5. [1206] Step C. (3S,7aS)-3-((cyclobutylmethoxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine: To a solution of ((3S,7aS)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol (470 mg, 1.0 equiv) in THF (2.5 mL) and DMF (2.5 mL) was added NaH (282 mg, 60% purity, 6.2 equiv) at 0 C. under N.sub.2. The reaction was stirred at 0 C. for 1 hour. Then (bromomethyl)cyclobutane (508 mg, 3 equiv) was added. The reaction was stirred at 0-25 C. for 47 hours. The mixture was quenched by water (5.0 mL) at 0 C. and extracted with ethyl acetate (33.0 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (85 mg, 16% yield) as yellow oil. .sup.1H NMR (400 MHZ, CDCl.sub.3-d) =7.46 (br d, J=7.6 Hz, 6H), 7.37-7.28 (m, 6H), 7.27-7.20 (m, 3H), 3.88-3.73 (m, 2H), 3.71-3.55 (m, 2H), 3.54-3.43 (m, 2H), 3.22-3.07 (m, 2H), 3.05-2.86 (m, 1H), 2.61-2.48 (m, 1H), 2.13-1.53 (m, 14H). [1207] Step D. ((3S,7aS)-3-((cyclobutylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol: To a solution of (3S,7aS)-3-((cyclobutylmethoxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine (110 mg, 1.0 equiv) in DCM (1.1 mL) was added TFA (260 mg, 10 equiv). The reaction was stirred at 0-25 C. for 12 hours. The mixture was diluted with water (2.0 mL) and extracted with ethyl acetate (32.0 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (Al.sub.2O.sub.3, petroleum ether/ethyl acetate=10/1 to 1/1, dichloromethane/methanol=15:1) to afford the title compound (55 mg, crude) as yellow oil. [1208] Step E. (R)-1-(2-(((3S,7aS)-3-((cyclobutylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (80.0 mg, 1.0 equiv) and ((3S,7aS)-3-((cyclobutylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (43.4 mg, 1.2 equiv) in toluene (0.80 mL) was added t-BuONa (2.0 M, 151 L, 2.0 equiv) at 0 C. The reaction was stirred at 0 C. for 1 hour. The mixture was diluted with water (2.0 mL) and extracted with ethyl acetate (32.0 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (95 mg, crude) as yellow oil; LCMS (ESI, M+1): m/z=732.3. [1209] Step F. (R)-1-(2-(((3S,7aS)-3-((cyclobutylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(2-(((3S,7aS)-3-((cyclobutylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (95.0 mg, 1.0 equiv) in MeCN (0.95 mL) was added HCl.Math.dioxane (4.0 M, 1.9 mL, 59 equiv) at 0 C. The reaction was stirred at 0 C. for 1 hour. The mixture was quenched with iced saturated NaHCO.sub.3 solution (5.0 mL) dropwise at 0 C. and extracted with ethyl acetate (33.0 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum and purified by reversed-phase HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 24%-54%, 10 min] to afford the title compound (12.5 mg, 13% yield, HCOOH) as an off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.26 (d, J=1.2 Hz, 1H), 7.70 (dd, J=6.0, 9.2 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.27 (t, J=9.6 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 5.06 (br s, 1H), 4.71-4.62 (m, 1H), 4.57-4.49 (m, 1H), 4.35 (br dd, J=9.2, 12.8 Hz, 1H), 4.07-3.95 (m, 1H), 3.76-3.67 (m, 2H), 3.66-3.59 (m, 1H), 3.53-3.48 (m, 2H), 3.46 (br s, 1H), 3.36 (br s, 2H), 2.67-2.54 (m, 1H), 2.52-2.42 (m, 1H), 2.37-2.23 (m, 3H), 2.20-2.10 (m, 3H), 2.08-1.93 (m, 7H), 1.89-1.71 (m, 6H), 1.31 (d, J=8.8 Hz, 3H), 0.88-0.75 (m, 3H); LCMS (ESI, M+1): m/z=688.7. Example 853 ##STR00701## (R)-1-(2-(((3S,7aS)-3-(ethoxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00702## [1210] Step A. (3S,7aS)-3-(ethoxymethyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine: To a suspension of NaH (58.03 mg, 1.45 mmol, 60% purity, 1.2 equiv) in THF (5 mL) and DMF (5 mL) was added ((3S,7aS)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol (500 mg, 1.0 equiv) in one portion at 0 C. under N.sub.2. The reaction was stirred at 0 C. for 30 minutes. To above mixture was added iodoethane (283 mg, 1.5 equiv). The reaction was warmed to 20 C. and stirred for 12 hours. The mixture was diluted with ice water (4 mL), adjusted to pH=1 with con. HCl, extracted with ethyl acetate (15 mL3), washed with brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (200 mg, 36% yield) as white solid; LCMS (ESI, M+1): m/z=442.3. [1211] Step B. ((3S,7aS)-3-(ethoxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol: To a mixture of (3S,7aS)-3-(ethoxymethyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine (200 mg, 1.0 equiv) in DCM (2 mL) was added TFA (516 mg, 10 equiv) in one portion under N.sub.2. The reaction was stirred at 20 C. for 12 hours. The mixture was concentrated, dissolved in MeOH (5 mL), neutralized with solid NaHCO.sub.3, filtered and purified by column chromatography (Al.sub.2O.sub.3, Petroleum ether/Ethyl acetate=1/0 to 0:1) to afford the title compound (90 mg, 99% yield) as yellow solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =3.60-3.54 (m, 1H), 3.52-3.40 (m, 4H), 3.29-3.19 (m, 3H), 2.96-2.74 (m, 2H), 1.98-1.91 (m, 1H), 1.83-1.54 (m, 6H), 1.53-1.40 (m, 1H), 1.15-1.07 (m, 3H). [1212] Step C. (R)-1-(2-(((3S,7aS)-3-(ethoxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of ((3S,7aS)-3-(ethoxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (239 mg, 1.0 equiv) in toluene (1 mL) was added t-BuONa (2 M, 2.0 equiv) in one portion at 0 C. under N.sub.2. The reaction was stirred at 0 C. for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (330 mL). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 25%-45%, 58 min] to afford the title compound (90 mg. 27% yield) as yellow solid; LCMS (ESI, M+1): m/z=692.8. [1213] Step D. (R)-1-(2-(((3S,7aS)-3-(ethoxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (R)-1-(2-(((3S,7aS)-3-(ethoxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (80.0 mg, 1.0 equiv) in ACN (0.8 mL) was added HCl/dioxane (4 M, 6.9 equiv) in one portion at 0 C. under N.sub.2. The reaction was stirred at 20 C. for 1 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (330 mL). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 20%-50%, 10 min] to afford the title compound (15.9 mg, 21% yield, HCOOH) as pink solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.25 (s, 1H), 8.55 (s, 1H), 7.71-7.65 (m, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.29-7.22 (m, 1H), 7.06 (s, 1H), 4.65-4.60 (m, 1H), 4.55 (br s, 1H), 4.50-4.44 (m, 1H), 4.34 (br t, J=11.6 Hz, 1H), 3.99-3.85 (m, 1H), 3.75-3.67 (m, 2H), 3.63 (br d, J=11.2 Hz, 1H), 3.59-3.51 (m, 2H), 3.49-3.41 (m, 1H), 3.22-3.16 (m, 1H), 2.53-2.41 (m, 1H), 2.36-2.28 (m, 1H), 2.27-2.13 (m, 3H), 2.12-2.00 (m, 3H), 1.99-1.85 (m, 4H), 1.84-1.75 (m, 2H), 1.30 (d, J=9.2 Hz, 3H), 1.24-1.14 (m, 3H), 0.86-0.75 (m, 3H); LCMS (ESI, M+1): m/z=648.7. Example 854 ##STR00703## 5-chloro-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol ##STR00704## [1214] Step A. 1-(1-(((7-chloro-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine: To a mixture of 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (2.00 g, 1.0 equiv) and [1-[(dimethylamino)methyl]cyclopropyl]methanol (753 mg, 1.0 equiv) in dioxane (20 mL) was added DIEA (2.26 g, 3.0 equiv). The reaction was stirred at 90 C. for 2 hours. The mixture was concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (436 mg, 12% yield, FA salt) as yellow oil; .sup.1H NMR (400 MHz, DMSO-d6) =9.01 (s, 1H), 4.42-4.29 (m, 4H), 4.26 (s, 2H), 4.18-4.12 (m, 1H), 3.81 (br d, J=13.6 Hz, 1H), 2.35-2.29 (m, 4H), 2.22 (s, 6H), 2.13-2.02 (m, 2H), 1.88-1.77 (m, 2H), 0.69-0.63 (m, 2H), 0.47-0.42 (m, 2H); LCMS (ESI, M+1): m/z=436.2. [1215] Step B. 1-(1-(((7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine: To a mixture of 1-(1-(((7-chloro-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine (200 mg, 1.0 equiv), CuI (26.2 mg, 0.3 equiv) and ((5-chloro-6-fluoro-4-(trimethylstannyl)naphthalen-2-yl)oxy)triisopropylsilane (592 mg, 2.5 equiv) in toluene (3 mL) were added BINAP (57.1 mg, 0.2 equiv) and [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.6 mg, 0.1 equiv). The reaction was stirred at 90 C. for 16 hours under N.sub.2. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (220 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (151 mg, 28.4% yield) as yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.28-9.17 (m, 1H), 7.73 (br d, J=6.0 Hz, 2H), 7.40 (br s, 2H), 4.63-4.54 (m, 2H), 4.46-4.35 (m, 3H), 4.31-4.18 (m, 3H), 3.63-3.45 (m, 2H), 2.66-2.59 (m, 2H), 2.51-2.46 (m, 2H), 2.10-2.04 (m, 2H), 1.54 (s, 6H), 1.35-1.30 (m, 3H), 1.13 (d, J=7.2 Hz, 18H), 0.98-0.81 (m, 4H); LCMS (ESI, M+1): m/z=752.4. [1216] Step C. 5-chloro-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol: To a solution of 1-(1-(((7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine (130 mg, 1.0 equiv) in DMF (1 mL) was added CsF (105 mg, 4.0 equiv). The reaction was stirred at 25 C. for 1 hour. The mixture was filtered and purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 16%-46%, 10 min] to afford the title compound (6.35 mg. 5.9% yield) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.27 (d, J=10.4 Hz, 1H), 7.82 (dd, J=5.6, 9.2 Hz, 1H), 7.47-7.39 (m, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 4.73-4.64 (m, 1H), 4.63-4.58 (m, 2H), 4.57-4.49 (m, 2H), 4.46-4.37 (m, 2H), 3.82 (dd, J=5.2, 13.6 Hz, 1H), 3.51-3.42 (m, 1H), 2.94-2.75 (m, 2H), 2.71-2.53 (m, 6H), 2.52-2.45 (m, 1H), 2.36-2.24 (m, 1H), 2.09-1.91 (m, 2H), 1.89-1.76 (m, 1H), 0.90-0.82 (m, 2H), 0.69 (br s, 2H); LCMS (ESI, M+1): m/z=596.5. Example 855 ##STR00705## 7-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide ##STR00706## [1217] Step A. 7-(7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: To a solution of 7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and 2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (130 mg, 1.5 equiv) in DMF (0.5 mL) was added DIEA (176 mg, 3.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (300 mg, 83% yield) as yellow solid; LCMS (ESI, M+1): m/z=753.4. [1218] Step B. 7-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: To a solution of 7-(7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (100 mg, 1.0 equiv) in THF (1 mL) was added TBAF (1M, 0.7 mL, 5.0 equiv). The reaction was stirred at 50 C. for 12 hours. The mixture was concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 22%-52% over 8 min] to afford the title compound (5.01 mg, 5.6% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.19 (s, 1H), 7.79 (s, 1H), 4.54-4.31 (m, 4H), 3.48 (s, 2H), 3.30-3.13 (m, 4H), 2.93-2.80 (m, 2H), 2.55-2.49 (m, 3H), 2.29-2.22 (m, 3H), 2.20-2.10 (m, 2H), 2.08-1.90 (m, 7H), 1.89-1.79 (m, 3H); LCMS (ESI, M+1): m/z=623.5. Example 856 ##STR00707## 7-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one ##STR00708## [1219] Step A. 7-(7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one: To a mixture of 7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and 1,3,9-triazaspiro[4.5]decan-2-one (141 mg, 2.0 equiv) in DMF (1 mL) were added 4 molecular sieve (50 mg) and DIEA (176 mg, 3.0 equiv). The reaction was stirred at 50 C. for 12 hours. The mixture was filtered and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (150 mg, 45% yield) as yellow solid; LCMS (ESI, M+1): m/z=717.5. [1220] Step B. 7-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(1-(hydroxymethyl)-5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one: To a mixture of 7-(7-(5,6-dimethyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one (60.0 mg, 1.0 equiv) in THF (0.5 mL) was added TBAF (1 M, 418 L, 5.0 equiv) at 0 C. The reaction was stirred at 50 C. for 12 hours. The mixture was diluted with water (1 mL) and extracted with dichloromethane/methanol=10/1 (32 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (60.0 mg, 96% yield); LCMS (ESI, M+1): m/z=617.2. [1221] Step C. 7-(7-(5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one: To a solution of 7-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(1-(hydroxymethyl)-5,6-dimethyl-1H-benzo[d][1,2,3]triazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one (60.0 mg, 1.0 equiv) in THF (0.2 mL) was added NH.sub.3.Math.H.sub.2O (455 mg, 25% purity, 33 equiv). The reaction was stirred at 20 C. for 24 hours. The mixture was diluted with water (2 mL) and extracted with dichloromethane (33 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 19%-49% over 8 min] and prep-HPLC [Phenomenex Luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 5%-35% over 9 min] to afford the title compound (7.73 mg, 13% yield, 0.72 HCOOH) as green solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.22 (s, 1H), 7.80 (s, 1H), 4.65-4.48 (m, 3H), 4.36-4.06 (m, 2H), 4.03-3.81 (m, 2H), 3.60-3.50 (m, 2H), 3.44 (br d, J=9.6 Hz, 1H), 3.14 (td, J=5.6, 11.2 Hz, 2H), 2.54 (s, 3H), 2.28 (s, 3H), 2.27-2.18 (m, 2H), 2.18-2.05 (m, 4H), 2.05-1.80 (m, 6H); LCMS (ESI, M+1): m/z=587.4. Example 857 ##STR00709## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-((2-methoxyethoxy)methyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00710## [1222] Step A. tert-butyl 1-((2-methoxyethoxy)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (500 mg, 1.0 equiv) in DMAC (10 mL) was added NaH (249 mg, 60% purity, 3.0 equiv) portionwise at 0 C. The reaction was stirred at 0 C. for 0.5 hours. 1-bromo-2-methoxyethane (576 mg, 2.0 equiv) was added at 0 C. The reaction was stirred at 25 C. for 3 hours. The mixture was quenched with water (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, concentrated and purified with column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=15/1 to 3/1) to afford the title compound (470 mg, 76% yield) as colourless oil. [1223] Step B. 1-((2-methoxyethoxy)methyl)-3-azabicyclo[3.2.1]octane: To a solution of tert-butyl 1-((2-methoxyethoxy)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (200 mg, 1.0 equiv) in MeCN (3 mL) was added HCl/dioxane (4 M, 7 mL, 42 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hours. The mixture was concentrated to afford the title compound (157 mg, crude, HCl) as white solid. [1224] Step C. 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-((2-methoxyethoxy)methyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine: To a solution of 1-((2-methoxyethoxy)methyl)-3-azabicyclo[3.2.1]octane (153 mg, 1.9 equiv, HCl) in DMF (0.5 mL) was added DIEA (221 mg, 5.0 equiv) and 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (150 mg, 1.0 equiv) at 25 C. The reaction was stirred at 40 C. for 14 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated to afford the title compound (183 mg, crude) as yellow oil. [1225] Step D. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-((2-methoxyethoxy)methyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-((2-methoxyethoxy)methyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine (183 mg, 1.0 equiv) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (161 mg, 1.5 equiv) in methoxycyclopentane (10 mL) was added cataCXium A Pd G3 (49.5 mg, 0.2 equiv) and K.sub.3PO.sub.4 (1.5 M, 680 L, 3.0 equiv). The mixture was degassed and purged with N.sub.2 3 times. The reaction was stirred at 80 C. for 3 hours under N.sub.2 atmosphere. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, concentrated and purified with column chromatography (SiO.sub.2, Dichloromethane:Methanol=50/1 to 10/1) followed by prep-HPLC (column: Waters Xbridge 15025 mm5 um; mobile phase: A: water (NH.sub.4HCO.sub.3; B: ACN; B %: 60% to 90% over 8 min). to afford the title compound (105 mg, 44% yield) as yellow solid; SFC: column: Chiralcel OD-3 50 4.6 mm I.D., 3 m, mobile phase 60% EtOH (0.05% DEA) in CO2, flow rate: 3 mL/min, detector: 220 nm, tR.sub.1: 0.511 min, tR.sub.2: 1.603 min; .sup.1H NMR (400 MHZ, methanol-d4) =9.07 (d, J=3.2 Hz, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.24 (t, J=9.6 Hz, 1H), 7.06 (s, 1H), 5.43-5.19 (m, 1H), 4.77-4.65 (m, 2H), 4.37-4.18 (m, 2H), 3.65-3.52 (m, 7H), 3.51-3.45 (m, 1H), 3.36 (s, 3H), 3.27-3.12 (m, 3H), 3.06-2.96 (m, 1H), 2.54-2.41 (m, 2H), 2.40-2.09 (m, 4H), 2.05-1.95 (m, 2H), 1.94-1.75 (m, 3H), 1.70-1.48 (m, 4H), 0.85-0.76 (m, 3H); LCMS (ESI, M+1): m/z=692.4. Example 858 ##STR00711## (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-3-azabicyclo[3.2.1]octane-8-carboxamide ##STR00712## [1226] Step A. (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-3-azabicyclo[3.2.1]octane-8-carboxamide: To a solution of (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50.0 mg, 1.0 equiv), dimethylamine (6.96 mg, 2.0 equiv, 2M in THF) in DMF (0.5 mL) were added HATU (88.0 mg, 3.0 equiv), and DIEA. The reaction was stirred at 20 C. for 12 hours. The mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 15%-45%, 0 min). to afford the title compound (14.6 mg, 27% yield, 0.19 HCOOH) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.10 (s, 1H), 8.55-8.43 (m, 1H), 7.74-7.62 (m, 1H), 7.35-7.18 (m, 2H), 7.06 (br s, 1H), 5.54-5.31 (m, 1H), 4.81-4.73 (m, 2H), 4.53-4.36 (m, 2H), 3.85-3.71 (m, 2H), 3.67-3.42 (m, 3H), 3.22 (s, 5H), 2.94 (s, 3H), 2.64 (br s, 2H), 2.56-2.34 (m, 3H), 2.31-2.09 (m, 4H), 1.98 (br d, J=5.2 Hz, 3H), 1.57 (br d, J=8.4 Hz, 2H), 0.85-0.75 (m, 3H); LCMS (ESI, M+1): m/z=675.5. Example 859 ##STR00713## 2-((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide ##STR00714## [1227] Step A. 2-((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl) acetic acid: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (300 mg, 1.0 equiv) and 2-((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl) acetic acid (208 mg, 2.0 equiv, HCl) in DMF (0.1 mL) were added DIEA (196 mg, 3.0 equiv) and 4 molecular sieve (10 mg). The reaction was stirred at 60 C. for 12 hours. The mixture was filtered and purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 um; mobile phase: [water (NH.sub.4HCO.sub.3)-ACN]; B %: 18%-48%, 11 min) to afford title compound (90.0 mg, 26% yield) as yellow solid. LCMS (ESI, M+1): m/z=662.6. [1228] Step B. 2-((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide: To a mixture of 2-((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl) acetic acid (50.0 mg, 1.0 equiv) and NH.sub.4Cl (40.4 mg, 10 equiv) in DMF (0.3 mL) were added HATU (86.2 mg, 3.0 equiv) and DIEA (97.7 mg, 10 equiv). The reaction was stirred at 25 C. for 0.5 hour. The mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 15%-45%, 10 min) to afford the title compound (17.1 mg, 32% yield, 0.51 HCOOH) as yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.29-9.05 (m, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.41-7.19 (m, 2H), 7.06 (d, J=2.0 Hz, 1H), 5.62-5.35 (m, 1H), 4.65-4.44 (m, 5H), 3.98-3.78 (m, 2H), 3.76-3.63 (m, 3H), 2.75 (d, J=7.6 Hz, 1H), 2.67-2.54 (m, 1H), 2.52-2.45 (m, 2H), 2.40-2.15 (m, 8H), 2.13-2.02 (m, 1H), 1.93-1.81 (m, 2H), 1.68-1.52 (m, 2H), 0.79 (dt, J=2.8, 7.2 Hz, 3H); LCMS (ESI, M+1): m/z=661.0. Example 860 ##STR00715## 2-((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-N,N-dimethylacetamide ##STR00716## [1229] Step A. 2-((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-N,N-dimethylacetamide: To a mixture of 2-((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl) acetic acid (30.0 mg, 1.0 equiv) and dimethylamine (20.4 mg, 2M in THF) in DMF (0.1 mL) were added HATU (51.7 mg, 3.0 equiv) and DIEA (58.6 mg, 10 equiv). The reaction was stirred at 25 C. for 0.5 hour. The mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 18%-48%, 0 min) to afford the title compound (10.7 mg, 33% yield, 0.3 HCOOH) as yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.26-9.08 (m, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.35-7.20 (m, 2H), 7.06 (d, J=2.4 Hz, 1H), 5.58-5.35 (m, 1H), 4.62-4.43 (m, 5H), 4.00-3.88 (m, 1H), 3.76 (br s, 3H), 3.21-3.06 (m, 4H), 3.00-2.91 (m, 4H), 2.65-2.41 (m, 3H), 2.41-2.12 (m, 8H), 2.12-1.99 (m, 1H), 1.94-1.80 (m, 2H), 1.68-1.51 (m, 2H), 0.79 (dt, J=2.8, 7.2 Hz, 3H); LCMS (ESI, M+1): m/z=689.7. Example 861 ##STR00717## 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide ##STR00718## [1230] Step A. 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide: To a solution of (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50 mg, 1 equiv) and DIEA (59.8 mg, 6 equiv) in DMF (0.5 mL) were added HATU (88 mg, 3 equiv) and NH.sub.4Cl (6.19 mg, 1.5 equiv). The reaction was stirred at 20 C. for 0.5 hour. The mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 15%-45%, 10 min) to afford the title compound (16.1 mg, 30% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.06 (s, 1H), 7.68 (dd, J=5.6, 8.8 Hz, 1H), 7.40-7.17 (m, 2H), 7.06 (d, J=2.4 Hz, 1H), 5.40-5.22 (m, 1H), 4.81-4.74 (m, 2H), 4.38-4.20 (m, 2H), 3.69 (br t, J=8.4 Hz, 2H), 3.27-3.17 (m, 2H), 3.10-2.96 (m, 1H), 2.85 (s, 1H), 2.73 (br s, 2H), 2.55-2.42 (m, 1H), 2.39-2.12 (m, 4H), 2.03-1.96 (m, 2H), 1.89 (br s, 2H), 1.57 (br d, J=8.8 Hz, 2H), 1.38-1.23 (m, 2H), 0.86-0.76 (m, 3H); LCMS (ESI, M+1): m/z=647.6. Example 862 ##STR00719## ##STR00720## [1231] Step A. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((1R,5S,8S)-8-methyl-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((1R,5S)-8-methylene-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (150 mg, 1 equiv) in MeOH (5 mL) was added Pd/C (10% purity, 10 mg). The reaction was degassed and purged with H.sub.2 3 times. The reaction was stirred at 20 C. for 10 min under H.sub.2 at 15 psi. The mixture was filtered and purified by prep-HPLC (column: Welch Ultimate C18 150*25 mm*5 um; mobile phase: [water (FA)-ACN]; B %: 27%-57%, 10 min) to afford the title compound (54.4 mg, 35% yield, 0.2 HCOOH) as yellow solid. .sup.1H NMR (400 MHZ, DMSO-d6) =10.26-9.52 (m, 1H), 9.34-9.02 (m, 1H), 8.19 (s, 1H), 7.76 (dd, J=6.0, 9.2 Hz, 1H), 7.47-7.22 (m, 2H), 7.02 (d, J=2.0 Hz, 1H), 5.45-5.15 (m, 1H), 4.59-4.23 (m, 2H), 4.17-3.96 (m, 2H), 3.82 (br t, J=13.2 Hz, 1H), 3.60-3.53 (m, 1H), 3.16-2.97 (m, 4H), 2.88-2.76 (m, 1H), 2.42-2.28 (m, 1H), 2.19-1.98 (m, 6H), 1.91-1.66 (m, 6H), 1.54-1.25 (m, 4H), 0.72 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=618.5. Example 863 ##STR00721## 2-((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-N-methylacetamide ##STR00722## [1232] Step A. 2-((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-N-methylacetamide: To a mixture of 2-((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl) acetic acid (60.0 mg, 1.0 equiv) and methanamine (61.2 mg, 10 equiv, HCl) in DMF (0.6 mL) were added HATU (345 mg, 10 equiv) and DIEA (35.2 mg, 3.0 equiv). The reaction was stirred at 25 C. for 0.5 hour. The mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 15%-45%, 10 min) to afford the title compound (5.70 mg, 9% yield, 0.38 HCOOH) as white solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.20-9.08 (m, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.36-7.16 (m, 2H), 7.06 (d, J=2.4 Hz, 1H), 5.55-5.36 (m, 1H), 4.55 (br s, 5H), 3.95-3.89 (m, 1H), 3.69-3.53 (m, 3H), 2.81-2.74 (m, 3H), 2.72 (br d, J=7.6 Hz, 2H), 2.61-2.41 (m, 3H), 2.34-2.15 (m, 7H), 2.14-1.98 (m, 2H), 1.88 (br d, J=6.0 Hz, 2H), 1.63 (br d, J=8.4 Hz, 2H), 0.87-0.72 (m, 3H); LCMS (ESI, M+1): m/z=675.5. Example 864 ##STR00723## (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocan-3-yl)dimethylphosphine oxide ##STR00724## [1233] Step A. tert-butyl 3-hydroxyazocane-1-carboxylate: To a solution of tert-butyl 3-oxoazocane-1-carboxylate (800 mg, 1.0 equiv) in MeOH (8 mL) was added NaBH.sub.4 (266 mg, 2.0 equiv) at 0 C. slowly. The reaction was stirred at 0 C. for 2 hours. The mixture was quenched with saturated NH.sub.4Cl (5 mL), concentrated and extracted with ethyl acetate (33 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the title compound (800 mg, crude) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =3.99-3.81 (m, 1H), 3.68-3.50 (m, 1H), 3.49-3.13 (m, 3H), 2.03-1.80 (m, 3H), 1.79-1.56 (m, 5H), 1.49 (s, 9H). [1234] Step B. tert-butyl 3-iodoazocane-1-carboxylate: To a solution of tert-butyl 3-hydroxyazocane-1-carboxylate (800 mg, 1.0 equiv), imidazole (356 mg, 1.5 equiv) and PPh.sub.3 (1.37 g, 1.5 equiv) in DCM (16 mL) was added I.sub.2 (1.33 g, 1.5 equiv) in portions. The reaction was stirred at 25 C. for 5 hours. The mixture was concentrated and purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 025% Ethyl acetate/Petroleum ethergradient@15 mL/min) to afford the title compound (750 mg, 63% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =4.70-4.48 (m, 1H), 3.63-3.13 (m, 4H), 2.52-2.11 (m, 4H), 1.82-1.63 (m, 4H), 1.50 (d, J=11.7 Hz, 9H). [1235] Step C. tert-butyl 3-(dimethylphosphoryl) azocane-1-carboxylate: To a solution of methylphosphonoylmethane (345 mg. 2.0 equiv) in THF (3 mL) was added NaHMDS (1 M, 4.42 mL, 2.0 equiv) dropwise at 0 C. The mixture was stirred at 0 C. for 1 hour. tert-butyl 3-iodoazocane-1-carboxylate (750 mg, 1.0 equiv) was added. The reaction was stirred at 20 C. for 11 hours. The mixture was concentrated and purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 18%-48% over 10 min] to afford the title compound (176 mg, 28% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =3.68-3.49 (m, 1H), 3.44-3.36 (m, 1H), 3.35-3.24 (m, 2H), 2.19-1.89 (m, 2H), 1.77-1.57 (m, 7H), 1.47 (s, 12H), 1.45-1.41 (m, 3H). [1236] Step D. azocan-3-yldimethylphosphine oxide: To a solution of tert-butyl 3-(dimethylphosphoryl) azocane-1-carboxylate (160 mg, 1.0 equiv) in dioxane (0.8 mL) was added HCl/dioxane (4 M, 800 L, 5.79 equiv). The reaction was stirred at 25 C. for 2 hours. The mixture was concentrated to afford the title compound (120 mg, crude, HCl salt) as a yellow oil. [1237] Step E. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) azocan-3-yl)dimethylphosphine oxide: A mixture of azocan-3-yldimethylphosphine oxide (50.0 mg, 1.0 equiv, HCl salt), 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (84.0 mg, 0.8 equiv), K.sub.3PO.sub.4 (113 mg, 3.0 equiv) and 4 molecular sieve (50 mg) in DMF (0.5 mL) was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 60 C. for 2 hours under N.sub.2 atmosphere. The mixture was filtered, and then the filtrate was concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (ammonia hydroxide v/v), B: ACN, B %: 30%-60% over 9 min] to afford the title compound (21.0 mg, 17% yield) as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.13 (br d, J=5.4 Hz, 1H), 7.67 (br dd, J=6.1, 8.7 Hz, 1H), 7.30 (br s, 1H), 7.25 (br t, J=9.3 Hz, 1H), 7.05 (br d, J=12.2 Hz, 1H), 5.39-5.21 (m, 1H), 4.42-4.17 (m, 4H), 4.17-3.98 (m, 2H), 3.29-3.12 (m, 3H), 3.07-2.95 (m, 1H), 2.48 (td, J=7.1, 14.5 Hz, 2H), 2.37-2.10 (m, 5H), 2.09-1.93 (m, 6H), 1.86 (br d, J=1.1 Hz, 3H), 1.70-1.56 (m, 1H), 1.50 (br d, J=12.3 Hz, 6H), 0.80 (br d, J=6.5 Hz, 3H); LCMS (ESI, M+1): m/z=682.5. Example 865 ##STR00725## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbonitrile ##STR00726## [1238] Step A. 5-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbonitrile: To a mixture of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (45.6 mg, 1.0 equiv) and 4 molecular sieve (10.0 mg, 1.0 equiv) in DMF (1 mL) was added DIEA (39.2 mg, 3.0 equiv) at 40 C. The reaction mixture was stirred for 5 minutes. Then 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbonitrile (15.0 mg, 1.0 equiv) was added to the mixture and stirred at 40 C. for 30 minutes. The mixture was diluted with H.sub.2O (30 mL) and extracted with ethyl acetate (230 mL), washed with brine (10 mL), dried, concentrated and purified with prep-TLC [SiO.sub.2, dichloromethane/methanol=10/1] to afford the title compound (40.0 mg, 70% yield) as a white solid; LCMS (ESI, M+1): m/z=562.3 [1239] Step B. 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbonitrile: To a mixture of 5-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbonitrile (40.0 mg, 1.0 equiv), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (28.3 mg, 2.5 equiv) and 4 molecular sieve (10.0 mg, 1.0 equiv) in DMF (1 mL) was added DIEA (27.6 mg, 3.0 equiv). The reaction mixture was stirred at 60 C. for 12 hours. The mixture was diluted with H.sub.2O (30 mL) and extracted with ethyl acetate (2 30 mL), washed with brine (10 mL), dried, concentrated and purified with prep-TLC [SiO.sub.2, dichloromethane/methanol=10/1] to afford the title compound (30.0 mg, 61% yield) as a white solid; LCMS (ESI, M+1): m/z=685.4. [1240] Step C. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbonitrile: To a solution of 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbonitrile (30 mg, 1.0 equiv) in MeCN (1 mL) was added HCl.Math.dioxane (4M, 1 mL). The reaction mixture was stirred at 0 C. for 30 minutes. The mixture was adjusted with NaHCO.sub.3 to PH7. The mixture was filtered and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 76%-76%, 9 min] to afford the title compound (4.95 mg, 20% yield) as off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.22 (s, 1H), 7.95 (s, 1H), 7.66 (br dd, J=5.2, 8.8 Hz, 1H), 7.33-7.19 (m, 2H), 7.04 (br d, J=1.2 Hz, 1H), 5.42-5.22 (m, 3H), 4.54 (br d, J=3.2 Hz, 4H), 4.35 (q, J=10.8 Hz, 2H), 3.19 (s, 2H), 3.09-2.95 (m, 1H), 2.52-1.85 (m, 9H), 0.85-0.74 (m, 3H); LCMS (ESI, M+1): m/z=641.4. Example 866 ##STR00727## 4-(4-((5aS,8aR)-4,5a-dimethyloctahydrocyclopenta[e][1,4]diazepin-1(2H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ##STR00728## [1241] Step A. 2-chloro-4-((5aS,8aR)-4,5a-dimethyloctahydrocyclopenta[e][1,4]diazepin-1(2H)-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine: To a solution of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (64.2 mg, 0.8 equiv) and (5aS,8aR)-4,5a-dimethyldecahydrocyclopenta[e][1,4]diazepine (30.0 mg, 1.0 equiv) in ACN (2.0 mL) were added DIEA (69.1 mg, 3.0 equiv) and 4 molecular sieve (10.0 mg). The mixture was stirred at 0 C. for 0.5 hours. The mixture was filtered and extracted with ethyl acetate (230 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, concentrated and purified with prep-HPLC [column: Phenomenex Luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 22%-52%, 9 min] to afford the title compound (20.0 mg, 19% yield) as a white solid. [1242] Step B. 4-((5aS,8aR)-4,5a-dimethyloctahydrocyclopenta[e][1,4]diazepin-1(2H)-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine: To a solution of 2-chloro-4-((5aS,8aR)-4,5a-dimethyloctahydrocyclopenta[e][1,4]diazepin-1(2H)-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (20.0 mg, 1.0 equiv) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (16.4 mg, 3.0 equiv) in THF (2 mL) were added DIEA (22.2 mg, 5.0 equiv) and 4 molecular sieve (20.0 mg). The mixture was stirred at 60 C. for 12 hours. The mixture was filtered and extracted with ethyl acetate (230 mL). The combined organic layers were washed with brine (10 mL), dried, concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 um, mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 75%-100%, 9 min] to afford the title compound (10 mg, 41% yield) as a white solid. [1243] Step C. 4-(4-((5aS,8aR)-4,5a-dimethyloctahydrocyclopenta[e][1,4]diazepin-1(2H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a solution of 4-((5aS,8aR)-4,5a-dimethyloctahydrocyclopenta[e][1,4]diazepin-1(2H)-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (10.0 mg, 1.0 equiv) in ACN (2.4 mL) was added HCl.Math.dioxane (4 M, 0.5 mL). The mixture was stirred at 0 C. for 0.5 hours. The mixture was quenched with saturated NaHCO.sub.3 aqueous solution (20 mL), extracted with ethyl acetate (310 mL), dried, concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 60%-90%, 9 min] to afford the title compound (2.50 mg, 26% yield, 96% purity) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.07 (d, J=2.4 Hz, 1H), 7.69 (dd, J=5.6, 8.8 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.26 (t, J=9.6 Hz, 1H), 7.04 (dd, J=2.4, 19.6 Hz, 1H), 5.60-5.42 (m, 1H), 4.74-4.50 (m, 8H), 4.32-4.26 (m, 1H), 3.79-3.65 (m, 2H), 3.23-2.92 (m, 3H), 2.57-2.23 (m, 10H), 1.91-1.65 (m, 3H), 1.46 (d, J=4.4 Hz, 4H), 1.36-1.22 (m, 2H), 0.85-0.74 (m, 3H); LCMS (ESI, M+1): m/z=661.5. Example 867 ##STR00729## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N, 1-trimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxamide ##STR00730## [1244] Step A. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (255 mg, 0.6 equiv) and methyl 1-methyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-3-carboxylate (130 mg, 1.0 equiv) in DMF (2.0 mL) were added K.sub.3PO.sub.4 (1.52 g, 10 equiv) and 4 molecular sieve (100 mg, 10 equiv). The reaction was stirred at 60 C. for 2 hours. The mixture was filtered and extracted with ethyl acetate (230 mL). The combined organic layers were washed with brine (10 mL), dried, concentrated and purified with prep-HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 17%-47%, 10 min] to afford the title compound (50.0 mg, 10% yield) as a white solid. [1245] Step B. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N,1-trimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxamide: To a solution of 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid (20.0 mg, 1.0 equiv) in DMF (1 mL) were added HATU (17.3 mg, 1.5 equiv) and TEA (9.20 mg, 3.0 equiv). The mixture was stirred at 20 C. for 2 hours. Then to the reaction was added dimethylamine (2 M, 75.8 L) and the mixture was stirred at 20 C. for 2 hours. The mixture was filtered and extracted with ethyl acetate (230 mL). The combined organic layers were washed with brine (10 mL), dried, concentrated and purified by prep-HPLC [column: 3_Phenomenex Luna C18 7530 mm3 um; mobile phase: [water (FA)-ACN]; B %: 21%-41%, 8 min] to afford the title compound (4 mg, 19% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =11.54 (br t, J=7.2 Hz, 3H), 10.28-10.12 (m, 4H), 10.09-9.83 (m, 4H), 9.19 (br s, 4H), 8.89-8.75 (m, 6H), 8.46-8.26 (m, 3H), 7.81-7.64 (m, 4H), 7.01-6.76 (m, 3H), 5.37-5.20 (m, 1H), 5.14-4.95 (m, 2H), 4.66 (dd, J=6.0, 8.8 Hz, 1H), 3.90-3.76 (m, 1H), 2.87 (br s, 1H); LCMS (ESI, M+1): m/z=687.5. Example 868 ##STR00731## 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00732## [1246] Step A. 7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv), CuI (26.0 mg, 0.3 equiv) and ((5-chloro-6-fluoro-4-(trimethylstannyl)naphthalen-2-yl)oxy)triisopropylsilane (353 mg, 1.5 equiv) in toluene (3 mL) were added BINAP (56.8 mg, 0.2 equiv) and [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.4 mg, 0.1 equiv). The reaction was stirred at 90 C. for 16 hours under N.sub.2. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by reversed phase flash chromatography [Phenomenex luna C18 15025 mm10 um; water (0.1% FA)/acetonitrile] to afford the title compound (171 mg, 46.2% yield) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.25 (s, 1H), 7.70 (dd, J=5.6, 8.8 Hz, 1H), 7.37-7.30 (m, 2H), 7.27 (s, 2H), 7.24 (s, 1H), 5.42-5.21 (m, 1H), 5.17-4.97 (m, 2H), 3.43-3.13 (m, 3H), 3.07-2.95 (m, 1H), 2.36-2.09 (m, 3H), 2.03-1.89 (m, 3H), 1.38 (br s, 3H), 1.13 (d, J=7.4 Hz, 18H); LCMS (ESI, M+1): m/z=755.3. [1247] Step B. 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a mixture of 7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (80.0 mg, 1.0 equiv) and 1,6-dioxa-9-azaspiro[3.6]decane (38.1 mg, 2.0 equiv, HCl) in DMF (1 mL) were added K.sub.3PO.sub.4 (112 mg, 5.0 equiv) and 4 molecular sieve (80 mg). The reaction was stirred at 100 C. for 7 hours. The mixture was filtered and the filtrate was purified by prep-HPLC [column: Phenomenex Luna C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 13%-43%, 9 min] to afford the title compound (7.9 mg, 11% yield, HCOOH) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.65-9.52 (m, 1H), 7.88-7.79 (m, 1H), 7.48-7.34 (m, 2H), 7.24 (dd, J=2.4, 9.6 Hz, 1H), 5.58-5.35 (m, 1H), 4.71-4.36 (m, 6H), 4.30-4.15 (m, 1H), 4.12 (br s, 4H), 3.95-3.80 (m, 1H), 3.77-3.45 (m, 4H), 2.79-2.67 (m, 1H), 2.63-2.36 (m, 3H), 2.29 (br d, J=8.8 Hz, 1H), 2.24-2.14 (m, 2H), 2.12-1.96 (m, 1H); LCMS (ESI, M+1): m/z=642.6. Example 869 ##STR00733## 4-(4-(8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ##STR00734## [1248] Step A. 4-(4-(8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv) and 8,8-difluoro-3-azabicyclo[3.2.1]octane (31.0 mg, 2.0 equiv, HCl) in DMF (0.2 mL) were added DIEA (109 mg, 10 equiv) and 4 molecular sieve (5.00 mg, 1.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by reversed-phase HPLC (column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 22%-52%, 10 min) and purified by reversed-phase HPLC (column: Welch Xtimate C18 15025 mm5 um; mobile phase: [water(NH.sub.3H.sub.2O)-ACN]; B %: 45%-75%, 8 min) to afford the title compound (3.67 mg, 6.7% yield) as blue solid; .sup.1HNMR (400 MHz, CHLOROFORM-d) =9.06-8.92 (m, 1H), 7.65-7.44 (m, 1H), 7.25-7.17 (m, 2H), 7.12-6.93 (m, 1H), 5.45-5.18 (m, 1H), 4.77-4.61 (m, 2H), 4.33-4.25 (m, 1H), 3.90-3.72 (m, 2H), 3.41-3.17 (m, 2H), 3.09-2.95 (m, 1H), 2.52-2.33 (m, 3H), 2.31-2.11 (m, 3H), 2.06-1.89 (m, 5H), 1.34-1.26 (m, 4H), 0.92-0.78 (m, 4H); LCMS (ESI, M+1): m/z=640.0. Example 870 ##STR00735## (R)-1-(2-(((3S,7aS)-3-((cyclopropylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00736## [1249] Step A. (3S,7aS)-3-((cyclopropylmethoxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine: To a mixture of ((3S,7aS)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol (500 mg, 1.0 equiv) in THF (2 mL) and DMF (2 mL) was added NaH (96.7 mg, 60% purity, 2.0 equiv). The reaction was stirred at 0-25 C. for 0.5 hours. To the mixture was added (iodomethyl)cyclopropane (330 mg, 1.5 equiv). The reaction was stirred at 25 C. for 11.5 hours. The mixture was quenched with H.sub.2O (5 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by reversed phase flash chromatography [Phenomenex luna C18 15025 mm10 um; water (0.1% FA)/acetonitrile] to afford the title compound (415 mg, 71% yield) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =7.27 (s, 5H), 7.14-7.06 (m, 7H), 7.06-6.99 (m, 3H), 3.50 (dd, J=6.4, 9.6 Hz, 1H), 3.35 (br s, 1H), 3.09 (d, J=6.8 Hz, 2H), 3.05-2.82 (m, 2H), 2.73 (br d, J=6.0 Hz, 2H), 2.48 (br s, 1H), 1.93 (br dd, J=6.8, 12.0 Hz, 1H), 1.65-1.56 (m, 2H), 1.53 (br d, J=5.6 Hz, 2H), 1.43 (br s, 2H), 1.32-1.22 (m, 1H), 0.91-0.79 (m, 1H), 0.37-0.28 (m, 2H), 0.01 (q, J=4.8 Hz, 2H); LCMS (ESI, M+1): m/z=468.4. [1250] Step B. ((3S,7aS)-3-((cyclopropylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol: To a mixture of (3S,7aS)-3-((cyclopropylmethoxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine (415 mg, 1.0 equiv) in DCM (4 mL) was added TFA (1.01 g, 10 equiv). The reaction was stirred at 0-25 C. for 12 hours. The mixture was concentrated, dissolved in MeOH (2 mL), neutralized with solid NaHCO.sub.3 and filtered. The filtrate was concentrated and purified by column chromatography (Al.sub.2O.sub.3, Petroleum ether:Ethyl acetate=5:1 to 0:1 to Dichloromethane:Methanol=20:1) to afford the title compound (210 mg, 95% yield) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =3.67 (dd, J=7.6, 10.0 Hz, 1H), 3.40-3.34 (m, 2H), 3.33-3.29 (m, 3H), 2.94-2.89 (m, 1H), 2.76-2.65 (m, 2H), 2.07-1.96 (m, 3H), 1.80-1.71 (m, 3H), 1.65-1.60 (m, 2H), 1.12-1.01 (m, 1H), 0.58-0.49 (m, 2H), 0.20 (q, J=4.8 Hz, 2H). [1251] Step C. (R)-1-(2-(((3S,7aS)-3-((cyclopropylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of ((3S,7aS)-3-((cyclopropylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (101 mg, 1.1 equiv) and (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (215 mg, 1.0 equiv) in toluene (1 mL) was added t-BuONa (2 M, 4.0 equiv). The reaction was stirred at 0 C. for 1 hour. The mixture was quenched with H.sub.2O (5 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to afford the title compound (460 mg, 95% yield) as yellow solid; [1252] Step D. (R)-1-(2-(((3S,7aS)-3-((cyclopropylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (R)-1-(2-(((3S,7aS)-3-((cyclopropylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (450 mg, 1.0 equiv) in ACN (3 mL) was added HCl/dioxane (4 M, 38 equiv). The reaction was stirred at 25 C. for 0.5 hours. The mixture was concentrated, dissolved in MeOH (3 mL), neutralized with solid NaHCO.sub.3 and filtered. The filtrate was concentrated and purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 21%-51%, 10 min] to afford the title compound (84.9 mg, 19% yield, HCOOH) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.27 (d, J=3.2 Hz, 1H), 7.69 (dd, J=6.0, 8.8 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.26 (t, J=9.2 Hz, 1H), 7.05 (br s, 1H), 4.70-4.57 (m, 4H), 4.42-4.31 (m, 1H), 4.24-4.11 (m, 1H), 3.86-3.77 (m, 1H), 3.75-3.60 (m, 2H), 3.60-3.52 (m, 1H), 3.50-3.37 (m, 3H), 2.50-2.33 (m, 3H), 2.27-2.13 (m, 4H), 2.11-1.98 (m, 4H), 1.93-1.74 (m, 3H), 1.31 (d, J=8.4 Hz, 3H), 1.10-0.98 (m, 1H), 0.81 (td, J=7.2, 14.0 Hz, 3H), 0.49 (br d, J=7.6 Hz, 2H), 0.19 (br t, J=3.2 Hz, 2H); LCMS (ESI, M+1): m/z=674.6. Example 871 ##STR00737## (3R)-1-(7-(5,6-dimethyl-1H-indol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00738## [1253] Step A. 5,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole: To a mixture of 4-bromo-5,6-dimethyl-1H-indole (100 mg, 1.0 equiv), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (571 mg, 10 equiv) and (1,1-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (32.6 mg, 0.1 equiv) in MeCN (1.0 mL) was added TEA (135 mg, 3.0 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 C. for 12 hours. The mixture was filtered and purified by reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile] to afford the title compound (96 mg, 73% yield) as yellow oil; LCMS (ESI, M+1): m/z=272.1. [1254] Step B. (R)-1-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of 7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv) and (R)-3-methylpiperidin-3-ol (109 mg, 2.0 equiv) in DMF (1.0 mL) were added DIEA (1.23 g, 20 equiv) and 4 molecular sieve (20.0 mg, 1.0 equiv). The reaction was stirred 60 C. for 12 hours. The mixture was filtered and purified by reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile] to afford the title compound (160 mg, 62% yield) as yellow solid. LCMS (ESI, M+1): m/z=436.1. [1255] Step C. (3R)-1-(7-(5,6-dimethyl-1H-indol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (R)-1-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (120 mg, 1.0 equiv) and 5,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (90.0 mg, 1.2 equiv) in H.sub.2O (3.0 mL) and THF (10 mL) were added CataCXium A Pd G3 (20.1 mg, 0.1 equiv) and K.sub.3PO.sub.4 (176 mg, 3.0 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred 60 C. for 2 hours. The mixture was washed with water (2 mL) and extracted with EtOAc (2 mL3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified with HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 8%-38%, 10 min) to afford the title compound (23.1 mg, 14% yield, 0.59 HCOOH) as yellow solid. .sup.1H NMR (400 MHz, METHANOL-d4) =9.27 (d, J=5.6 Hz, 1H), 7.36 (s, 1H), 7.13 (d, J=3.2 Hz, 1H), 5.97 (dd, J=3.2, 7.6 Hz, 1H), 4.66-4.56 (m, 3H), 4.33 (br d, J=13.2 Hz, 1H), 3.64 (br dd, J=1.6, 13.6 Hz, 1H), 3.53 (td, J=5.6, 11.2 Hz, 2H), 3.48-3.40 (m, 1H), 3.13 (td, J=6.4, 11.2 Hz, 2H), 2.45 (s, 3H), 2.31-2.31 (m, 1H), 2.31-2.22 (m, 1H), 2.20-2.14 (m, 4H), 2.14-2.06 (m, 3H), 2.06-1.93 (m, 3H), 1.90-1.74 (m, 3H), 1.29 (s, 3H); LCMS (ESI, M+1): m/z=545.3. Example 872 ##STR00739## 7-(7-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane ##STR00740## [1256] Step A. 7-(7-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole (9.00 mg, 1.0 equiv) and 2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (4.91 mg, 2.0 equiv) in DMF (0.2 mL) were added DIEA (16.6 mg, 10 equiv) and 4 molecular sieve (1.00 mg, 1.0 equiv). The mixture was stirred at 60 C. for 12 hours. The mixture was filtered and purified by reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile] to afford the title compound (6.00 mg, 52% yield) as yellow solid. LCMS (ESI, M+1): m/z=792.5. [1257] Step B. 7-(7-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: A mixture of 7-(7-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (12.0 mg, 1.0 equiv) in TFA (308 mg, 0.2 mL, 178 equiv) was stirred at 25 C. for 0.5 hour. The mixture was concentrated. The residue was diluted with water (1 mL). The mixture was adjusted to pH=7 with saturated NaHCO.sub.3 (10 mL) and extracted with EtOAc (2 mL3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 15%-45%, 10 min) to afford the title compound (2.09 mg, 18% yield, 0.34 HCOOH) as yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.21 (d, J=7.2 Hz, 1H), 8.24 (d, J=3.2 Hz, 1H), 8.01 (br dd, J=5.6, 8.8 Hz, 1H), 7.87-7.62 (m, 1H), 7.33 (t, J=9.6 Hz, 1H), 5.41-5.33 (m, 1H), 4.41 (br t, J=11.2 Hz, 2H), 3.95-3.78 (m, 2H), 3.75-3.57 (m, 2H), 3.46-3.38 (m, 2H), 3.26-3.06 (m, 3H), 2.72-2.60 (m, 1H), 2.52-2.17 (m, 5H), 2.15-1.78 (m, 7H), 0.95-0.78 (m, 3H); LCMS (ESI, M+1): m/z=708.6. Example 873 ##STR00741## ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl dibutylcarbamate ##STR00742## [1258] Step A. (R)-1-(2-(((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (302 mg, 1.3 equiv) and 4 molecular sieve (10.0 mg, 1.0 equiv) in DMF (1 mL) was added t-BuONa (2 M, 2.0 equiv). The reaction mixture was stirred at 0 C. for 40 minutes. (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (300 mg, 1.0 equiv) was added into the mixture. The reaction was stirred at 0 C. for 40 minutes. The mixture was diluted with water (10 mL) and extracted with EtOAc (330 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, DCM/MeOH=10/1] to afford the title compound (400 mg, 70% yield) as yellow solid. LCMS (ESI, M+1): m/z=902.3 [1259] Step B. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(hydroxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(2-(((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (400 mg, 1.0 equiv) in DMF (5 mL) was added CsF (1.01 g, 15 equiv). The reaction was stirred at 25 C. for 24 hours. The mixture was diluted with EtOAc (20 mL), washed with brine (20 mL3). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, DCM/MeOH=10/1] to afford the title compound (180 mg, 61% yield) as off-red solid. LCMS (ESI, M+1): m/z=664.3 [1260] Step C. ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl dibutylcarbamate: To a mixture of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(hydroxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (90.0 mg, 1.0 equiv) in THF (1.5 mL) was added TEA (137 mg, 0.2 mL, 10 equiv). The reaction was stirred at 25 C. for 4 minutes. 4-nitrophenyl carbonochloridate in THF (0.5 mL) was added into the mixture at 0 C. The reaction was stirred at 40 C. for 5 hours. TEA (137 mg, 0.2 mL, 10 equiv) and N-butylbutan-1-amine (52.6 mg, 0.7 mL, 3.0 equiv) were added into above mixture. The reaction was stirred at 80 C. for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 ml). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, DCM/MeOH=10/1] to afford the title compound (30 mg, 27% yield) as yellow oil; LCMS (ESI, M+1): m/z=819.3. [1261] Step D. ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl dibutylcarbamate: To a solution of ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl dibutylcarbamate (30 mg, 1.0 equiv) in MeCN (1 mL) was added HCl.Math.dioxane (4 M, 1.0 mL). The reaction was stirred at 0 C. for 30 minutes. The mixture was adjusted pH-7 with NaHCO.sub.3 solution. The mixture was filtered and purified with prep-HPLC (column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water (NH.sub.4HCO.sub.3)-ACN]; B %: 80%-100%, 8 min) to afford the title compound (12.5 mg, 44% yield) as yellow solid; .sup.1HNMR (400 MHZ, METHANOL-d4) =9.22 (d, J=2.4 Hz, 1H), 7.69 (dd, J=6.0, 9.2 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H), 7.27 (t, J=9.6 Hz, 1H), 7.08 (t, J=2.4 Hz, 1H), 4.61 (br s, 1H), 4.55 (br d, J=13.2 Hz, 1H), 4.37-4.21 (m, 3H), 4.10-4.04 (m, 1H), 4.03-3.96 (m, 1H), 3.71-3.57 (m, 1H), 3.54-3.43 (m, 1H), 3.26 (br s, 4H), 3.11-3.02 (m, 2H), 2.88-2.78 (m, 1H), 2.58-2.41 (m, 1H), 2.30-2.12 (m, 3H), 2.11-2.01 (m, 1H), 2.00-1.86 (m, 4H), 1.85-1.75 (m, 4H), 1.74-1.65 (m, 1H), 1.60-1.49 (m, 4H), 1.36-1.27 (m, 7H), 0.94 (t, J=7.2 Hz, 6H), 0.87-0.78 (m, 3H); LCMS (ESI, M+1): m/z=775.3. Example 874 ##STR00743## ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl butyl(methyl)carbamate ##STR00744## [1262] Step A. ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl butyl(methyl)carbamate: To a mixture of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(hydroxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (90.0 mg, 1.0 equiv) in THF (1.5 mL) was added TEA (137 mg, 0.2 mL, 10 equiv). The reaction was stirred at 25 C. for 4 minutes. 4-nitrophenyl carbonochloridate in THF (0.5 mL) was added into the mixture at 0 C. The reaction was stirred at 40 C. for 5 hours. TEA (137 mg, 0.2 mL, 10 equiv) and N-methylbutan-1-amine (35.5 mg, 3.0 equiv) were added into above mixture. The reaction was stirred at 80 C. for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 ml). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, DCM/MeOH=10/1] to afford the title compound (30.0 mg, 28% yield) as yellow oil; LCMS (ESI, M+1): m/z=777.3. [1263] Step B. ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl butyl(methyl)carbamate: To a solution of ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl butyl(methyl)carbamate (30.0 mg, 1.0 equiv) in MeCN (1 mL) was added HCl.Math.dioxane (4M, 1 mL). The reaction mixture was stirred at 0 C. for 30 minutes. The mixture was adjusted pH=7 with NaHCO.sub.3 solution. The mixture was filtered and purified with prep-HPLC (column: Phenomenex C18 75*30 mm*3 um; mobile phase: [water (FA)-ACN]; B %: 2%-32%, 7 min) to afford the title compound (20 mg, 71% yield) as white solid; .sup.1H NMR (400 MHz, METHANOL-d4) =9.24 (d, J=2.4 Hz, 1H), 7.70 (dd, J=5.6, 9.2 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H), 7.27 (t, J=9.2 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 4.57 (br d, J=15.6 Hz, 2H), 4.44-4.27 (m, 3H), 4.25-4.12 (m, 1H), 4.07 (br dd, J=6.4, 10.8 Hz, 1H), 3.73-3.57 (m, 1H), 3.54-3.45 (m, 1H), 3.26 (br d, J=6.4 Hz, 3H), 3.08-2.97 (m, 1H), 2.95-2.84 (m, 3H), 2.48 (br dd, J=7.2, 14.8 Hz, 1H), 2.36-2.09 (m, 4H), 2.07-1.96 (m, 3H), 1.95-1.73 (m, 6H), 1.51 (br s, 2H), 1.37-1.22 (m, 5H), 0.93 (t, J=7.2 Hz, 3H), 0.87-0.78 (m, 3H); LCMS (ESI, M+1): m/z=733.2. Example 875 ##STR00745## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(4-(hydroxymethyl)hexahydropyrrolo[3,4-c]pyrrol-2 (1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00746## [1264] Step A. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(4-(hydroxymethyl)hexahydropyrrolo[3,4-c]pyrrol-2 (1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a mixture of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (59.2 mg, 1.0 equiv) and (octahydropyrrolo[3,4-c]pyrrol-1-yl)methanol (20.0 mg, 1.0 equiv, 2 HCl salt) in DMF (0.5 mL) were added DIEA (60.1 mg, 5.0 equiv) and 4 molecular sieve (50 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 3%-33%, 10 min) to afford the title compound (15.0 mg, 25% yield) as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.28 (s, 1H), 8.49 (br s, 2H), 7.68 (br dd, J=6.0, 8.8 Hz, 1H), 7.32 (br d, J=2.0 Hz, 1H), 7.25 (br t, J=9.2 Hz, 1H), 7.05 (br d, J=2.0 Hz, 1H), 5.59-5.34 (m, 1H), 4.54 (br s, 2H), 4.33 (br s, 2H), 4.27-4.08 (m, 2H), 3.97-3.54 (m, 7H), 3.44-3.33 (m, 2H), 3.27 (br s, 1H), 3.12 (br s, 1H), 2.68-2.37 (m, 3H), 2.35-2.05 (m, 5H), 0.89-0.62 (m, 3H); LCMS (ESI, M+1): m/z=635.1. Example 876 ##STR00747## (3R)-1-(7-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00748## [1265] Step A. (3R)-1-(7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 1.0 equiv) and 6-chloro-5-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazole (268 mg, 1.3 equiv) in toluene (5 mL) were added K.sub.3PO.sub.4 (1.5 M, 917 L, 3.0 equiv) and APhos Pd G3 (29.1 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The mixture was stirred at 60 C. for 12 hours. The mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (320 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography with prep-TLC [SiO.sub.2, DCM:MeOH=10:1] to afford the title compound (150 mg, 38% yield) as a yellow solid; LCMS (ESI, M+1): m/z=722.4. [1266] Step B. (3R)-1-(7-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (112 mg, 1.0 equiv) in DCM (0.5 mL) was added TFA (1.54 g, 1.0 mL, 97 equiv) at 0 C. The reaction was stirred at 25 C. for 5 hours. The mixture was concentrated. The residue was diluted with water (1 mL). The mixture was adjusted to pH=7 with saturated NaHCO.sub.3 (5 mL) and extracted with DCM (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex Synergi C18 15025 mm10 m; A: water (NH.sub.4HCO.sub.3), B: ACN; B %: 25%-55% over 8 min] to afford the title compound (36.9 mg, 43% yield) as a light yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.31 (d, J=5.8 Hz, 1H), 7.83-7.79 (m, 1H), 7.77 (s, 1H), 4.59-4.49 (m, 1H), 4.39-4.23 (m, 3H), 3.70-3.57 (m, 1H), 3.53-3.42 (m, 1H), 3.16-3.04 (m, 2H), 2.77-2.65 (m, 2H), 2.24-2.00 (m, 4H), 1.99-1.70 (m, 9H), 1.31 (d, J=8.6 Hz, 3H), 0.96-0.81 (m, 1H), 0.71-0.57 (m, 1H), 0.33-0.20 (m, 1H), 0.14-0.02 (m, 1H); LCMS (ESI, M+1): m/z=592.3. Example 877 ##STR00749## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aR)-3-(methoxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00750## [1267] Step A. (3R,7aR)-3-(hydroxymethyl)-7a-((trityloxy)methyl) octahydropyrrolizine 4-oxide: To a solution of ((3R,7aR)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol (500 mg, 1.0 equiv) in DCM (6 mL) was added m-CPBA (295 mg, 85% purity, 1.2 equiv). The reaction was stirred at 25 C. for 2 hours. The mixture was quenched by addition of saturated NaHCO.sub.3 aqueous solution (0.5 mL) and extracted with DCM (10 mL). The organic layer was washed with saturated NaHCO.sub.3 aqueous solution (10 mL) and brine (10 mL), dried over sodium sulfate and concentrated to afford the title compound (520 mg, crude) as a white solid; LCMS (ESI, M+1): m/z=430.1. [1268] Step B. (3R,7aR)-3-(methoxymethyl)-7a-((trityloxy)methyl) octahydropyrrolizine 4-oxide: To a solution of (3R,7aR)-3-(hydroxymethyl)-7a-((trityloxy)methyl) octahydropyrrolizine 4-oxide (520 mg, 1.0 equiv) in DMF (5 mL) was added NaH (72.6 mg, 60% purity, 1.5 equiv). The mixture was stirred at 0 C. for 30 minutes. MeI (258 mg, 1.5 equiv) was added. The reaction was stirred at 0 C. for 2 hours. The mixture was quenched by addition of ice-water (15 mL) and extracted with ethyl acetate (215 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.3.Math.H.sub.2O), B: ACN, B %: 45%-75% over 9 min] to afford the title compound (80.0 mg, 15% yield) as a yellow solid; LCMS (ESI, M+1): m/z=444.2. [1269] Step C. (3R,7aR)-3-(methoxymethyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine: To a solution of (3R,7aR)-3-(methoxymethyl)-7a-((trityloxy)methyl) octahydropyrrolizine 4-oxide (80.0 mg, 1.0 equiv) in MeOH (1 mL) was added Pd/C (10.0 mg, 10% purity) under N.sub.2 atmosphere. The reaction was degassed and purged with H.sub.2 for 3 times and stirred at 25 C. for 12 hours under H.sub.2 (15 Psi) atmosphere. The mixture was filtered through Celite and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated to afford the title compound (75.0 mg, crude) as a yellow solid; LCMS (ESI, M+1): m/z=428.3. [1270] Step D. ((3R,7aR)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol: To a solution of (3R,7aR)-3-(methoxymethyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine (75.0 mg, 1.0 equiv) in DCM (0.6 mL) was added TFA (0.3 mL), and then the mixture was stirred at 20 C. for 2 hours. The mixture was concentrated under reduced pressure to afford the title compound (75.0 mg, crude) as a yellow solid. [1271] Step E. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3R,7aR)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A mixture of ((3R,7aR)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (38.5 mg, 1.1 equiv), 4 molecular sieve (50 mg) and t-BuONa (72.7 mg, 4.0 equiv) in toluene (1 mL) was stirred at 0 C. for 10 minutes. (S)-2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) was added. The reaction was stirred at 0 C. for additional 1 hour. The mixture was quenched with H.sub.2O (10 mL) at 0 C. and extracted with ethyl acetate (310 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, concentrated and purified by prep-HPLC [column: Phenomenex Luna C18 7530 mm3 m; A: water (FA), B: ACN, B %: 25%-45% over 8 min] to afford the title compound (25.0 mg, 19% yield) as a white solid; LCMS (ESI, M+1): m/z=678.4. [1272] Step F. (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aR)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3R,7aR)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (20.0 mg, 1.0 equiv) in MeOH (200 uL) was added HCl/MeOH (4 M, 200 uL) at 0 C. The mixture was stirred at 25 C. for 0.5 hour. The mixture was concentrated, diluted with MeCN (0.5 mL) and adjusted to pH= 7 with 10% NH.sub.3.Math.H.sub.2O. The mixture was directly purified by prep-HPLC [column: Phenomenex Luna C18 7530 mm3 m; A: water (FA), B: ACN, B %: 18%-48% over 7 min] to afford the title compound (15.0 mg, 78% yield) as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.29-9.15 (m, 1H), 8.55 (s, 1H), 7.72-7.61 (m, 1H), 7.33-7.29 (m, 1H), 7.25 (br t, J=9.2 Hz, 1H), 7.06 (s, 1H), 4.66-4.43 (m, 2H), 4.39-4.23 (m, 2H), 3.70-3.50 (m, 2H), 3.49-3.41 (m, 2H), 3.38 (d, J=3.6 Hz, 1H), 3.34 (d, J=2.8 Hz, 2H), 3.17-2.90 (m, 2H), 2.52-2.40 (m, 1H), 2.36-1.67 (m, 14H), 1.32-1.25 (m, 3H), 0.87-0.75 (m, 3H); LCMS (ESI, M+1): m/z=634.4. Example 878 ##STR00751## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(fluoromethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00752## [1273] Step A. ((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methyl benzoate: To a solution of ((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (2.60 g, 1.0 equiv) and TEA (1.28 g, 2.0 equiv) in DCM (26 mL) was added B.sub.2Cl (1.34 g, 1.5 equiv) at 0 C. The reaction was stirred at 25 C. for 12 hours. The mixture was diluted with DCM (100 mL), dried over sodium sulfate, concentrated and purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 030% Ethyl acetate/Petroleum ethergradient@80 mL/min) to afford the title compound (2.30 g, 71% yield) as a yellow oil. [1274] Step B. ((3R,7aS)-3-(hydroxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methyl benzoate: To a solution of ((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methyl benzoate (8.00 g, 1.0 equiv) in DMF (100 mL) was added CsF (35.5 g, 15.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (2.60 g, 61% yield) as a yellow oil; LCMS (ESI, M+1): m/z=276.1. [1275] Step C. ((3R,7aS)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methyl benzoate: To a solution of ((3R,7aS)-3-(hydroxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methyl benzoate (500 mg, 1.0 equiv) in DCM (15 mL) was added MOST (954 mg, 3.0 equiv) at 0 C. carefully. The reaction was stirred at 20 C. for 72 hours. The mixture was diluted with ice-cold sat. NaHCO.sub.3 aqueous solution (100 mL) and extracted with DCM (250 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified by SFC separation [column: DAICEL CHIRALPAK AD, 25030 mm, 10 m; A: CO.sub.2, B: IPA (0.1% NH3H2O), B %: 20% B over 5.4 min] to afford the title compound (75.0 mg, 27% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.05 (d, J=8.0 Hz, 2H), 7.61-7.52 (m, 1H), 7.49-7.40 (m, 2H), 4.40 (d, J=5.6 Hz, 1H), 4.28 (d, J=5.6 Hz, 1H), 4.09 (s, 2H), 3.14-2.92 (m, 2H), 2.78 (td, J=5.6, 10.8 Hz, 1H), 2.13 (br dd, J=6.4, 11.6 Hz, 1H), 2.07-1.97 (m, 1H), 1.92-1.83 (m, 4H), 1.78-1.58 (m, 5H); LCMS (ESI, M+1): m/z=278.1. [1276] Step D. ((3R,7aS)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol: To a solution of ((3R,7aS)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methyl benzoate (70.0 mg, 1.0 equiv) in MeOH (1 mL) was added NaOMe methanol solution (5 M, 101 L, 2.0 equiv). The reaction was stirred at 0 C. for 0.5 hour. The mixture was quenched with water (1 mL) and concentrated to afford the title compound (40.0 mg, crude) as a yellow oil. [1277] Step E. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of ((3R,7aS)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (40.0 mg, 1.0 equiv) and (3R)-1-[2-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol (73.3 mg, 0.6 equiv) in toluene (1 mL) was added t-BuONa (44.4 mg, 2.0 equiv) at 0 C. The reaction was stirred at 0 C. for 1 hour. The mixture was concentrated and purified by prep-HPLC [column: Phenomenex luna C18 7530 mm3 m; A: water (FA), B: ACN, B %: 20%-50% over 7 min] to afford the title compound (27.0 mg, 18% yield) as a yellow solid; LCMS (ESI, M+1): m/z=666.2. [1278] Step F. (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (27.0 mg, 1.0 equiv) in MeOH (0.2 mL) was added HCl/MeOH (2 M, 180 L, 8.9 equiv). The reaction was stirred at 0 C. for 2 hours. The mixture was concentrated and purified by prep-HPLC [column: Phenomenex luna C18 7530 mm3 m; A: water (FA), B: ACN, B %: 15%-45% over 7 min] to afford the title compound (8.39 mg, 32% yield) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.23 (br s, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.06 (s, 1H), 4.67-4.52 (m, 3H), 4.46-4.38 (m, 2H), 4.31 (br t, J=12.8 Hz, 1H), 3.72-3.55 (m, 1H), 3.51-3.36 (m, 2H), 3.29-3.18 (m, 1H), 3.17-3.02 (m, 1H), 2.56-2.40 (m, 1H), 2.38-2.24 (m, 1H), 2.23-2.13 (m, 2H), 2.13-1.97 (m, 4H), 1.97-1.83 (m, 4H), 1.82-1.73 (m, 2H), 1.29 (d, J=10.0 Hz, 3H), 0.81 (q, J=7.6 Hz, 3H); LCMS (ESI, M+1): m/z=622.4. Example 879 ##STR00753## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(fluoromethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00754## [1279] Step A. ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methyl benzoate: To a solution of ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (3.00 g, 1.0 equiv) and TEA (1.48 g, 2.0 equiv) in DCM (30 mL) was added B.sub.2Cl (1.55 g, 1.5 equiv) at 0 C. The reaction was stirred at 25 C. for 12 hours. The mixture was diluted with DCM (100 mL), dried over sodium sulfate, concentrated and purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 030% Ethyl acetate/Petroleum ethergradient@80 mL/min) to afford the title compound (2.40 g, 64% yield) as a yellow oil. [1280] Step B. ((3S,7aR)-3-(hydroxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methyl benzoate: To a solution of ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methyl benzoate (2.40 g, 1.0 equiv) in DMF (240 mL) was added CsF (10.6 g, 15.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (1.04 g, 66% yield) as a yellow oil. [1281] Step C. ((3S,7aR)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methyl benzoate: To a solution of ((3S,7aR)-3-(hydroxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methyl benzoate (500 mg, 1.0 equiv) in DCM (15 mL) was added MOST (954 mg, 3.0 equiv) at 0 C. carefully. The reaction was stirred at 20 C. for 72 hours. The mixture was diluted with ice-cold sat. NaHCO.sub.3 aqueous solution (20 mL) and extracted with DCM (310 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition], followed by SFC separation [column: DAICEL CHIRALPAK AD, 25030 mm, 10 m; A: CO2, B: MeOH (0.1% NH.sub.3H.sub.2O), B %: 20% B over 4.6 min] to afford the title compound (75.0 mg, 27% yield) as a yellow oil; LCMS (ESI, M+1): m/z=278.2. [1282] Step D. ((3S,7aR)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol: To a solution of ((3S,7aR)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methyl benzoate (160 mg, 1.0 equiv) in MeOH (1.5 mL) was added NaOMe methanol solution (5 M, 231 L, 2.0 equiv). The reaction was stirred at 0 C. for 0.5 hour. The mixture was quenched with water (1 mL), and then concentrated to afford the title compound (40.0 mg, crude) as a yellow oil. [1283] Step E. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of ((3S,7aR)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (20.0 mg, 1.0 equiv) and (3R)-1-[2-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol (48.9 mg, 0.8 equiv) in toluene (0.5 mL) was added t-BuONa (22.2 mg, 2.0 equiv). The reaction was stirred at 0 C. for 1 hour. The mixture was concentrated to afford the title compound (75.0 mg, crude) as a yellow solid. [1284] Step F. (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(fluoromethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (75.0 mg, 1.0 equiv) in MeOH (0.5 mL) was added HCl/MeOH (2 M, 0.5 mL, 8.9 equiv). The reaction was stirred at 0 C. for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC [column: Phenomenex luna C18 7530 mm3 m; A: water (FA), B: ACN, B %: 15%-45% over 7 min] to afford the title compound (3.62 mg, 5% yield) as a yellow solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.22 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.06 (s, 1H), 4.92 (br s, 1H), 4.65-4.46 (m, 3H), 4.44-4.25 (m, 3H), 3.70-3.58 (m, 1H), 3.53-3.40 (m, 1H), 3.29-3.07 (m, 2H), 3.07-2.91 (m, 1H), 2.57-2.36 (m, 1H), 2.35-2.09 (m, 3H), 2.09-1.90 (m, 4H), 1.89-1.75 (m, 5H), 1.29 (d, J=10.4 Hz, 3H), 0.81 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=622.4. Example 880 ##STR00755## (3R)-1-(7-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00756## [1285] Step A. (3R)-1-(7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 1.0 equiv) and 6-chloro-5-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazole (237 mg, 1.2 equiv) in toluene (2 mL) and water (0.5 mL) were added APhos Pd G3 (42.0 mg, 0.15 equiv) and K.sub.2CO.sub.3 (280 mg, 3.0 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 60 C. for 12 hours. The mixture was diluted with H.sub.2O (5 mL) and extracted with ethyl acetate (315 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (150 mg, 45% yield) as white solid; LCMS (ESI, M+1): m/z=740.5. [1286] Step B. (3R)-1-(7-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (120 mg, 1.0 equiv) in dichloromethane (1 mL) was added 2,2,2-trifluoroacetic acid (164 mg, 10 equiv). The reaction was stirred at 25 C. for 12 hours. The mixture was concentrated. The residue as diluted with water (2 mL). The mixture was adjusted to pH=10 with NaOH solution (10% w/w) at 0 C. and extracted with dichloromethane (32 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 13%-43% over 10 min] to afford the title compound (26.5 mg, 27% yield, HCOOH salt) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.33 (d, J=6.4 Hz, 1H), 7.79 (d, J=12.4 Hz, 2H), 5.49-5.27 (m, 1H), 5.44-4.57 (m, 1H), 4.46-4.29 (m, 3H), 3.64 (dd, J=13.6, 17.2 Hz, 1H), 3.53-3.34 (m, 4H), 3.13, (J=5.4, 9.8 Hz, 1H), 2.55-1.95 (m, 8H), 1.94-1.75 (m, 3H), 1.31 (d, J=8.0 Hz, 3H), 0.95-0.83 (m, 1H), 0.69-0.56 (m, 1H), 0.27-0.24 (m, 1H), 0.13-0.03 (m, 1H); LCMS (ESI, M+1): m/z=610.4. Example 881 ##STR00757## 5-(7-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide ##STR00758## [1287] Step A. 5-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.00 g, 1.0 equiv) and N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (742 mg, 1.5 equiv) in DMF (3 mL) was added DIEA (921 mg, 3.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (400 mg, 32% yield) as yellow solid; LCMS (ESI, M+1): m/z=529.3. [1288] Step B. 5-(7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a mixture of 5-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (200 mg, 1.0 equiv) and 6-chloro-5-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazole (204 mg, 1.2 equiv) in toluene (2.0 mL) and H.sub.2O (756 L) was added Aphos-Pd-G3 (27.5 mg, 0.10 equiv) and K.sub.3PO.sub.4 (241 mg, 3 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 60 C. for 12 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (410 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=5/1 to dichloromethane/methanol=5/1] and reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 29% yield) as yellow solid; LCMS (ESI, M+1): m/z=815.3. [1289] Step C 5-(7-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 5-(7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (80 mg, 1.0 equiv) in DCM (0.5 mL) was added TFA (0.5 mL). The reaction was stirred at 0 C. for 0.5 hours. The mixture was quenched with saturated NaHCO.sub.3 aqueous (5 mL) at 0 C. and extracted with EtOAc (45 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was dissolved in THF (0.2 mL). NH.sub.3.Math.H.sub.2O (0.4 mL, 25% purity) was added. The reaction was stirred at 20 C. for 4 hours. The mixture was diluted with water (2 mL) and extracted with EtOAc (33 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN; B %: 10%-40%, over 10 min] to afford the title compound (29.5 mg, 50% yield, 0.50 HCOOH) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.31 (s, 1H), 7.81 (s, 1H), 7.78 (s, 1H), 6.79 (s, 1H), 5.38-5.22 (m, 2H), 4.60 (br s, 2H), 4.53-4.43 (m, 4H), 3.45-3.37 (m, 2H), 3.34 (s, 3H), 3.08 (s, 3H), 3.06-2.97 (m, 2H), 2.47 (br d, J=5.2 Hz, 2H), 2.26-2.15 (m, 2H), 2.12-1.99 (m, 5H), 1.98-1.89 (m, 2H), 0.93-0.86 (m, 1H), 0.64-0.57 (m, 1H), 0.30-0.20 (m, 1H), 0.11-0.01 (m, 1H); LCMS (ESI, M+1): m/z=685.2. Example 882 ##STR00759## 5-(7-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide ##STR00760## [1290] Step A. 5-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1.0 equiv) and N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (356 mg, 1.5 equiv) in DMF (1.5 mL) was added DIEA (442 mg, 3.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition]. to afford the title compound (500 mg, 80% yield) as yellow solid; LCMS (ESI, M+1): m/z=547.3. [1291] Step B. 5-(7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a mixture of 5-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (200 mg, 1.0 equiv) and 6-chloro-5-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazole (197 mg, 1.2 equiv) in toluene (2 mL) and H.sub.2O (731 L) were added Aphos-Pd-G3 (26.6 mg, 0.10 equiv) and K.sub.3PO.sub.4 (233 mg, 3 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 60 C. for 12 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (410 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=5/1 to dichloromethane/methanol=5/1] and reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 30% yield) as yellow solid; LCMS (ESI, M+1): m/z=833.4. [1292] Step C. 5-(7-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 5-(7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (80 mg, 1.0 equiv) in DCM (0.5 mL) was added TFA (0.5 mL). The reaction was stirred at 0 C. for 0.5 hours. The mixture was quenched with saturated NaHCO.sub.3 aqueous (5 mL) at 0 C. and extracted with EtOAc (45 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was diluted with THF (0.2 mL) and NH.sub.3.Math.H.sub.2O (0.4 mL 25% purity). The reaction was stirred at 20 C. for 12 hours. The mixture was diluted with water (2 mL) and extracted with EtOAc (33 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (NH.sub.4HCO.sub.3), B: ACN; B %: 34%-64%, over 10 min] to afford the title compound (58.5 mg, 76% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.27 (s, 1H), 7.81 (s, 1H), 7.77 (d, J=1.2 Hz, 1H), 6.78 (s, 1H), 5.41-5.20 (m, 3H), 4.59-4.54 (m, 2H), 4.53-4.38 (m, 2H), 4.34-4.20 (m, 2H), 3.34 (s, 3H), 3.30-3.14 (m, 3H), 3.08 (s, 3H), 3.03-2.99 (m, 1H), 2.52-2.40 (m, 2H), 2.36-2.24 (m, 1H), 2.23-2.17 (m, 1H), 2.17-2.10 (m, 1H), 2.07-1.95 (m, 3H), 1.95-1.83 (m, 1H), 0.96-0.81 (m, 1H), 0.66-0.53 (m, 1H), 0.32-0.18 (m, 1H), 0.13-0.02 (m, 1H); LCMS (ESI, M+1): m/z=703.2. Example 883 ##STR00761## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-azaspiro[bicyclo[3.2.1]octane-8,2-[1,3]dioxolan]-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00762## [1293] Step A. (1R,5S)-3-benzyl-3-azaspiro[bicyclo[3.2.1]octane-8,2-[1,3]dioxolane]; To a solution of (1R,5S)-3-benzyl-3-azabicyclo[3.2.1]octan-8-one (300 mg, 1 equiv) and ethane-1,2-diol (86.5 mg, 1.0 equiv) in toluene (3 mL) was added TsOH.Math.H.sub.2O (26.5 mg, 0.1 equiv). The reaction was stirred at 100 C. for 12 hours. The mixture was diluted with H.sub.2O (5 mL) and extracted with EtOAc (35 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (200 mg, 55% yield) as yellow oil. [1294] Step B. (1R,5S)-3-azaspiro[bicyclo[3.2.1]octane-8,2-[1,3]dioxolane]: To a solution of (1R,5S)-3-benzyl-3-azaspiro[bicyclo[3.2.1]octane-8,2-[1,3]dioxolane] (200 mg, 1.0 equiv) and NH.sub.3.Math.MeOH (4 M, 0.2 mL) in MeOH (2 mL) was added Pd/C (50.0 mg, 10% purity) under nitrogen atmosphere. The reaction was degassed and purged with H.sub.2 3 times. The reaction was stirred under H.sub.2 (15 Psi) at 20 C. for 1 hour. The mixture was filtered and concentrated under reduced pressure to afford the title compound (80 mg, 60% yield) as white solid. [1295] Step C. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5S)-3-azaspiro[bicyclo[3.2.1]octane-8,2-[1,3]dioxolan]-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (100 mg, 1.0 equiv) and (1R,5S)-3-azaspiro[bicyclo[3.2.1]octane-8,2-[1,3]dioxolane] (42.8 mg, 1.5 equiv) in what solvent? were added DIEA (218 mg, 10 equiv) and 4 molecular sieve (10 mg). The reaction was stirred at 60 C. for 12 hours. The mixture was filtered and purified by prep-HPLC (column: Waters xbridge 15025 mm10 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 50%-80%, 10 min) to afford the title compound (5.48 mg, 51% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.21-9.03 (m, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.32-7.21 (m, 2H), 7.08-7.02 (m, 1H), 5.39-5.22 (m, 1H), 4.75-4.64 (m, 3H), 4.34-4.29 (m, 1H), 4.27-4.21 (m, 1H), 4.11-3.96 (m, 5H), 3.26-3.16 (m, 3H), 3.01 (dt, J=6.0, 9.2 Hz, 1H), 2.55-2.44 (m, 1H), 2.35-2.05 (m, 6H), 2.03-1.84 (m, 5H), 1.56 (br d, J=9.6 Hz, 2H), 0.78-0.78 (m, 1H), 0.80 (dt, J=2.0, 7.2 Hz, 2H); LCMS (ESI, M1): m/z=662.2. Example 884 ##STR00763## (5R)-7-(7-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione ##STR00764## [1296] Step A. 5-ethyl-6-fluoro-4-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole: To a solution of 7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (50 mg, 1.0 equiv), 5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole (50.4 mg, 1.0 equiv) and Cs.sub.2CO.sub.3 (1.5 M, 3.0 equiv) in Methoxy cyclopentane (2 mL) was added CataCXium A Pd G3 (8.65 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 80 C. for 5 hours. The mixture was added H.sub.2O (5 mL) and extracted with ethyl acetate (5 mL3). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography (C18, 0.1% formic acid condition) to afford the title compound (17.0 mg, 19% yield) as yellow oil; LCMS (ESI, M+1): m/z=683.3. [1297] Step B. (5R)-7-(7-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole (15.0 mg, 1.0 equiv) and (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (15 mg, 4.04 equiv) in DMAc (1.5 mL) were added 4 molecular sieve (2.0 mg) and CsF (33.4 mg, 10.0 equiv). The reaction was stirred at 40 C. for 1.5 hours. The mixture was filtered and purified by reversed phase flash chromatography (C18, 0.1% formic acid condition) to afford the title compound (15 mg, 91% yield) as yellow oil; LCMS (ESI, M+1): m/z=752.6. [1298] Step C. (5R)-7-(7-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of (5R)-7-(7-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (15.0 mg, 1.0 equiv) in DCM (0.5 mL) was added TFA (770 mg, 0.5 mL). The reaction was stirred at 20 C. for 0.5 hour. The mixture was concentrated at 25 C. The residue was diluted with water (1 mL). The mixture was adjusted to pH=7 with saturated NaHCO.sub.3 (10 mL) and extracted with ethyl acetate (5 mL3). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC (column: Phenomenex Luna C18 15025 mm10 um; mobile phase: [water (FA)-ACN]; B %: 11%-41% over 12 min) to afford the title compound (2.89 mg, 21% yield, 0.52 HCOOH) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.25 (s, 1H), 8.26 (s, 1H), 8.03 (dd, J=6.0, 9.6 Hz, 1H), 7.70 (d, J=2.8 Hz, 1H), 7.34 (t, J=9.6 Hz, 1H), 4.74-4.63 (m, 2H), 4.53-4.47 (m, 2H), 3.96-3.79 (m, 2H), 3.46-3.40 (m, 2H), 3.10-2.96 (m, 2H), 2.70-2.56 (m, 1H), 2.43-2.34 (m, 1H), 2.32-2.16 (m, 4H), 2.14-2.03 (m, 5H), 2.01-1.92 (m, 3H), 0.92-0.80 (m, 3H); LCMS (ESI, M+1): m/z=668.3. Example 885 ##STR00765## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(methoxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00766## [1299] Step A. (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin: To a solution of ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (9.00 g, 1.0 equiv) and TEA (4.45 g, 2.0 equiv) in DCM (100 mL) was added TrtCl (9.19 g, 1.5 equiv). The reaction was stirred at 25 C. for 12 hours. The mixture was diluted with water (50 mL) and extracted with DCM (3 50 mL). The combined organic layers were washed with brine (350 mL), dried over sodium sulfate and concentrated to afford the title compound (12.0 g, crude) as a yellow oil. [1300] Step B. ((3S,7aR)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol: To a solution of (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin (1.00 g, 1.0 equiv) in DMF (10 mL) was added CsF (2.33 g, 10 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (350 mL). The combined organic layers were washed with brine (350 mL), dried over sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (500 mg, 79% yield) as a yellow oil. [1301] Step C. (3S,7aR)-3-(methoxymethyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine: To a solution of ((3S,7aR)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol (200 mg, 1.0 equiv) in DMF (2 mL) was added NaH (38.7 mg, 60% purity, 2.0 equiv) at 0 C. The mixture was stirred at 0 C. for 30 minutes. MeI (103 mg, 1.5 equiv) was added. The reaction was stirred at 0 C. for 2 hours. The reaction was quenched by addition of ice-water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, concentrated and purified by prep-HPLC [column: Phenomenex luna C18 7530 mm3 m; A: water (FA), B: ACN, B %: 27%-47% over 8 min] to afford the title compound (120 mg, 56% yield) as a yellow oil; LCMS (ESI, M+1): m/z=428.3. [1302] Step D. ((3S,7aR)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol: To a solution of (3S,7aR)-3-(methoxymethyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine (100 mg, 1.0 equiv) in DCM (0.8 mL) was added TFA (400 uL, 23.1 equiv). The reaction was stirred at 20 C. for 2 hours. The mixture was concentrated to afford the title compound (100 mg, crude) as a yellow solid. [1303] Step E. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A mixture of ((3S,7aR)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (29.8 mg, 1.0 equiv), 4 molecular sieve (5 mg) and t-BuONa (61.8 mg, 4.0 equiv) in toluene (1 mL) was stirred at 0 C. for 10 minutes. (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (85.0 mg, 1.0 equiv) was added. The reaction was stirred at 0 C. for 1 hour. The mixture was quenched with water (10 mL) at 0 C. and extracted with ethyl acetate (310 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, concentrated under vacuum and purified by prep-HPLC [column: YMC Triart C18 15025 mm5 m; A: water (FA), B: ACN, B %: 40%-60% over 8 min] to afford the title compound (30.0 mg, 27% yield) as a white solid; LCMS (ESI, M+1): m/z=678.5. [1304] Step F. (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To of (R)-1-(7-(8-ethyl-7-fluoro-3-a solution (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (20.0 mg, 1.0 equiv) in MeOH (0.2 mL) was added HCl/MeOH (4 M, 0.2 mL) at 0 C. The reaction was stirred at 25 C. for 0.5 hours. The mixture was concentrated, diluted with MeCN (0.5 mL) and adjusted to pH= 7 with 10% NH.sub.3.Math.H.sub.2O. The mixture was directly purified by prep-HPLC [column: YMC Triart C18 15025 mm5 m; A: water (FA), B: ACN, B %: 20%-50% over 8.5 min] to afford the title compound (14.0 mg, 74% yield) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.26 (s, 1H), 8.56 (br d, J=2.0 Hz, 1H), 7.70 (dd, J=5.9, 9.0 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.27 (t, J=9.4 Hz, 1H), 7.08 (s, 1H), 4.61 (br s, 5H), 4.44 (br s, 1H), 4.33 (br t, J=14.8 Hz, 1H), 3.72-3.58 (m, 1H), 3.57-3.42 (m, 3H), 3.34 (br s, 3H), 2.54-2.42 (m, 1H), 2.39-1.74 (m, 13H), 1.31 (d, J=10.0 Hz, 3H), 0.88-0.77 (m, 3H); LCMS (ESI, M+1): m/z=634.3. Example 886 ##STR00767## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(methoxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00768## [1305] Step A. (3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine: To a solution of ((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (6.00 g, 1.0 equiv) and TEA (2.96 g, 2.0 equiv) in DCM (60 mL) was added TrtCl (6.12 g, 1.5 equiv). The reaction was stirred at 25 C. for 12 hours. The mixture was washed with water (50 mL) and extracted with DCM (2 30 mL). The combined organic layers were dried over sodium sulfate and concentrated to afford the title compound (9.00 g, crude) as a yellow oil. [1306] Step B. ((3R,7aS)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol: To a solution of (3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine (9.00 g, 1.0 equiv) in DMF (90 mL) was added CsF (31.5 g, 15 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and the filtrate was directly purified by reversed-phase HPLC (0.1% FA condition) to afford the title compound (4.00 g, 70% yield) as a yellow oil. [1307] Step C. (3R,7aS)-3-(methoxymethyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine: To a solution of ((3R,7aS)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol (100 mg, 1.0 equiv) in DMF (1 mL) was added NaH (19.3 mg, 60% purity, 2.0 equiv). The mixture was stirred at 0 C. for 30 minutes. MeI (34.3 mg, 1.0 equiv) was added. The reaction was stirred at 25 C. for 12 hours. The mixture was quenched by addition of ice-water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, concentrated and purified by prep-HPLC [column: Phenomenex luna C18 7530 mm3 m; A: water (FA), B: ACN, B %: 22%-52% over 7 min] to afford the title compound (50.0 mg, 47% yield) as a white solid; LCMS (ESI, M+1): m/z=428.4. [1308] Step D. ((3R,7aS)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol: To a solution of (3R,7aS)-3-(methoxymethyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine (50.0 mg, 1.0 equiv) in DCM (0.4 mL) was added TFA (200 uL, 23.1 equiv). The reaction was stirred at 20 C. for 12 hours. The mixture was concentrated to afford the title compound (50.0 mg, crude) as a yellow solid. [1309] Step E. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A mixture of ((3R,7aS)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (38.5 mg, 1.0 equiv), 4 molecular sieve (2 mg) and t-BuONa (79.9 mg, 4.0 equiv) in toluene (1 mL) was stirred at 0 C. for 10 minutes. (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (110 mg, 1.0 equiv) was added. The reaction was stirred at 0 C. for 1 hour. The mixture was quenched with H.sub.2O (10 mL) at 0 C. and extracted with ethyl acetate (310 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, concentrated and purified by prep-HPLC [column: YMC Triart C18 15025 mm5 m; A: water (FA), B: ACN, B %: 24%-54% over 8 min] to afford the title compound (25.0 mg, 17% yield) as a white solid; LCMS (ESI, M+1): m/z=678.5. [1310] Step F. (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(methoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (15.0 mg, 1.0 equiv) in MeOH (0.15 mL) was added HCl/MeOH (4 M, 300 uL) at 0 C. The mixture was stirred at 25 C. for 0.5 hour. The mixture was concentrated under reduced pressure at 30 C., diluted with MeCN (0.5 mL) and adjusted to pH= 7 with 10% NH.sub.3.Math.H.sub.2O. The mixture was directly purified by prep-HPLC [column: Phenomenex luna C18 15025 mm5 m; A: water (FA), B: ACN, B %: 47%-54% over 8 min] prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 17%-47%, min) to afford the title compound (8.00 mg, 55% yield) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.24 (d, J=5.6 Hz, 1H), 8.64-8.48 (m, 1H), 7.70 (dd, J=6.0, 8.8 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.27 (t, J=9.2 Hz, 1H), 7.13-7.00 (m, 1H), 4.61 (br s, 3H), 4.45-4.28 (m, 3H), 3.71-3.57 (m, 1H), 3.50 (br d, J=5.2 Hz, 3H), 3.36 (d, J=6.8 Hz, 3H), 3.24-3.05 (m, 2H), 2.48 (qd, J=7.2, 14.4 Hz, 1H), 2.35-2.13 (m, 3H), 2.12-1.95 (m, 4H), 1.94-1.75 (m, 6H), 1.31 (d, J=9.2 Hz, 3H), 0.90-0.77 (m, 3H); LCMS (ESI, M+1): m/z=634.3. Example 887 ##STR00769## (R)-7-(7-((R)-6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione ##STR00770## ##STR00771## [1311] Step A. 6-chloro-4-fluoro-5-((1S,2R)-2-methylcyclopropyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazole: To a mixture of 6-chloro-4-fluoro-5-iodo-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazole (10.0 g, 1.0 equiv) and 4,4,5,5-tetramethyl-2-((1S,2R)-2-methylcyclopropyl)-1,3,2-dioxaborolane (8.53 g, 2.0 equiv) in dioxane (75 mL) and H.sub.2O (25 mL) were added K.sub.3PO.sub.4 (14.9 g, 3.0 equiv) and Pd(dppf)Cl.sub.2 (1.71 g, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 100 C. for 12 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (330 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (4.70 g, 54% yield) as yellow liquid; LCMS (ESI, M+1): m/z=355.0. [1312] Step B. 6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-ol: To a solution of 6-chloro-4-fluoro-5-((1S,2R)-2-methylcyclopropyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazole (3.00 g, 1.0 equiv) and 2-(methylsulfonyl) ethan-1-ol (4.20 g, 4.0 equiv) in DMAc (30 mL) was added NaH (2.03 g, 60% purity, 6.0 equiv) portion-wise at 0 C. The reaction was stirred at 40 C. for 12 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (330 mL). The combined organic layers were washed with brine (350 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=0/1 to 10/1] to afford the title compound (1.50 g, 50% yield) as yellow liquid; LCMS (ESI, M+1): m/z=353.1. [1313] Step C. 6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl trifluoromethanesulfonate: To a solution of 6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-ol (4.10 g, 1.0 equiv) and DIEA (6.07 mL, 3.0 equiv) in DCM (40 mL) was added Tf.sub.2O (3.83 mL, 2.0 equiv) at 70 C. The reaction was stirred at 70 C. for 0.5 hours. The mixture was diluted with water (40 mL) and extracted with DCM (330 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 5/1] to afford the title compound (4.50 g, 78% yield) as yellow liquid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) 7.97 (d, J=6.8 Hz, 1H), 7.71 (dd, J=0.8, 9.2 Hz, 1H), 5.70 (d, J=5.6 Hz, 2H), 3.63-3.50 (m, 2H), 1.61-1.55 (m, 1H), 1.54-1.38 (m, 1H), 1.38-1.32 (m, 2H), 1.01-0.97 (m, 1H), 0.93-0.86 (m, 2H), 0.84-0.62 (m, 2H), 0.05 (d, J=4.0 Hz, 9H); LCMS (ESI, M+1): m/z=485.0. [1314] Step D. 6-chloro-5-((1S,2R)-2-methylcyclopropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazole: To a mixture of 6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl trifluoromethanesulfonate (500 mg, 1.0 equiv), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi (1,3,2-dioxaborolane) (314 mg, 1.2 equiv) and KOAc (202 mg, 2.0 equiv) in MeCN (10 mL) was added P(Cy.sub.3)-Pd-G3 (75.7 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 C. for 6 hours. The mixture was diluted with ethyl acetate (40 mL) and filtered, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (850 mg, 44% yield) as yellow liquid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =8.12 (d, J=0.8 Hz, 1H), 7.65 (d, J=0.8 Hz, 1H), 5.67 (s, 2H), 3.55-3.45 (m, 2H), 1.47 (d, J=10.8 Hz, 12H), 1.32 (d, J=5.6 Hz, 3H), 1.27-1.26 (m, 1H), 0.92-0.78 (m, 5H), 0.01-0.10 (m, 9H); LCMS (ESI, M+1): m/z=463.2. [1315] Step E. 7-((R)-6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of 7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv), 6-chloro-5-((1S,2R)-2-methylcyclopropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazole (121 mg, 1.1 equiv) and K.sub.3PO.sub.4 (1.5 M, 475 L, 3.0 equiv) in toluene (2 mL) was added APhos-Pd-G3 (15.1 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 70 C. for 4 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (35 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [Al.sub.2O.sub.3, Petroleum ether/Ethyl acetate=20/1 to 0/1] to afford the title compound (85.0 mg, 16% yield) as yellow solid; LCMS (ESI, M+1): m/z=721.6. [1316] Step F. (R)-7-(7-((R)-6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a mixture of 7-((R)-6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (85 mg, 1.0 equiv), (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (39.9 mg, 2.0 equiv) and 4 molecular sieve (50 mg) in DMF (1 mL) was added DIEA (61.6 L, 3.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (50 mg, 53% yield) as yellow solid; LCMS (ESI, M+1): m/z=790.4. [1317] Step G. (R)-7-(7-((R)-6-chloro-1-(hydroxymethyl)-5-((1S,2R)-2-methylcyclopropyl)-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of (R)-7-(7-((R)-6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (40.0 mg, 1.0 equiv) in DCM (0.25 mL) was added TFA (0.5 mL, 133 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hours. The mixture was adjusted pH to 8 with saturated NaHCO.sub.3 aqueous solution (5 mL) and extracted with ethyl acetate (35 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to afford the title compound (35 mg, 99% yield) as yellow solid; LCMS (ESI, M+1): m/z=690.4. [1318] Step H. (R)-7-(7-((R)-6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of (R)-7-(7-((R)-6-chloro-1-(hydroxymethyl)-5-((1S,2R)-2-methylcyclopropyl)-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (30 mg, 1.0 equiv) in THF (0.01 mL) was added NH.sub.3.Math.H.sub.2O (5.46 g, 6.00 mL, 25% purity, 896 equiv). The reaction was stirred at 20 C. for 2 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (33 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex C18 7530 mm3 m; A: water (FA), B: ACN, B %: 12%-42% over 7 min] to afford the title compound (9.32 mg, 32% yield, HCOOH salt) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.34-9.12 (m, 1H), 7.99-7.59 (m, 2H), 4.69-4.57 (m, 2H), 4.50 (br d, J=8.0 Hz, 1H), 4.01-3.69 (m, 3H), 3.58-3.46 (m, 2H), 3.13 (br d, J=5.6 Hz, 2H), 2.36-1.90 (m, 12H), 1.81-1.65 (m, 1H), 1.10-0.72 (m, 3H), 0.64 (br d, J=4.4 Hz, 1H), 0.54-0.11 (m, 2H); LCMS (ESI, M+1): m/z=660.3. Example 888 ##STR00772## (3R)-1-(7-(5,6-dimethyl-1H-benzo[d]imidazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00773## [1319] Step A. 2-bromo-3,4-dimethyl-6-nitroaniline: To a solution of 4,5-dimethyl-2-nitroaniline (10.0 g, 1.0 equiv) in acetonitrile (200 mL) was added NBS (11.8 g, 1.1 equiv). The reaction was stirred at 20 C. for 2 hours. The mixture was concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc (4100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated to afford the title compound (15.0 g, crude) as yellow solid. [1320] Step B. 3-bromo-4,5-dimethylbenzene-1,2-diamine: To a solution of 2-bromo-3,4-dimethyl-6-nitroaniline (15.0 g, 1.0 equiv) and NH.sub.4Cl (13.1 g, 4.0 equiv) in ethyl alcohol (300 mL) and H.sub.2O (150 mL) was added Zn powder (16.2 g, 4.1 equiv) slowly. The reaction was stirred at 60 C. for 30 minutes and 80 C. for 2 hours. The mixture was filtered. The filtrate was adjusted to pH=8 with saturated NaHCO.sub.3 aqueous (100 mL) at 0 C. and extracted with EtOAc (480 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=3/1 to 1/1] to afford the title compound (10.0 g, 76% yield) as yellow solid; .sup.1H NMR (400 MHz, CHLOROFORM-d) =6.50 (s, 1H), 3.56 (br s, 4H), 2.29 (s, 3H), 2.21 (s, 3H). [1321] Step C. 4-bromo-5,6-dimethyl-1H-benzo[d]imidazole: A mixture of 3-bromo-4,5-dimethylbenzene-1,2-diamine (4.00 g, 1.0 equiv) in HCOOH (40 mL) was stirred at 100 C. for 2 hours. The mixture was concentrated. The mixture was adjusted to pH=8 with saturated Na.sub.2CO.sub.3 aqueous (100 mL) and extracted with EtOAc (480 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, Petroleum ether/Ethyl acetate=1/1 to 0/1] to afford the title compound (3.20 g, 73% yield) as yellow solid; LCMS (ESI, M+1, M+3): m/z=224.9, 226.9. [1322] Step D. 4-bromo-N,N,5,6-tetramethyl-1H-benzo[d]imidazole-1-sulfonamide: To a solution of 4-bromo-5,6-dimethyl-1H-benzo[d]imidazole (2.50 g, 1.0 equiv) in DMAc (30 mL) was added NaH (1.33 g, 60% purity, 3.0 equiv) slowly at 0 C. for 0.5 hours. The reaction was stirred at 0 C. for 0.5 hours. Then dimethylsulfamoyl chloride (2.39 g, 1.5 equiv) was added into the mixture at 0 C. The reaction was stirred at 0 C. for 0.5 hours. The mixture was diluted with water (30 mL) at 0 C. and extracted with EtOAc (430 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (3.50 g, 93% yield) as yellow solid; LCMS (ESI, M+1, M+3): m/z=331.9, 333.9. [1323] Step E. (1-(N,N-dimethylsulfamoyl)-5,6-dimethyl-1H-benzo[d]imidazol-4-yl) boronic acid: To a mixture of 4,4,4,4,5,5,5,5-octamethyl-2,2-bi (1,3,2-dioxaborolane) (4.59 g, 3.0 equiv), 4-bromo-N,N,5,6-tetramethyl-1H-benzo[d]imidazole-1-sulfonamide (2.00 g, 1.0 equiv) and KOAc (1.18 g, 2.0 equiv) in toluene (30 mL) was added P(Cy.sub.3) Pd G3 (391 mg, 0.10 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 100 C. for 12 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (430 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% NH.sub.3.Math.H.sub.2O condition] to afford the title compound (500 mg, 25% yield) as yellow solid; LCMS (ESI, M+1): m/z=298.0. [1324] Step F. 4-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-N,N,5,6-tetramethyl-1H-benzo[d]imidazole-1-sulfonamide: To a mixture of (R)-1-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (100 mg, 1.0 equiv) and (1-(N,N-dimethylsulfamoyl)-5,6-dimethyl-1H-benzo[d]imidazol-4-yl) boronic acid (102 mg, 1.5 equiv) in toluene (2 mL) and H.sub.2O (459 L) were added K.sub.3PO.sub.4 (146 mg, 3.0 equiv) and Aphos-Pd-G3 (14.6 mg, 0.10 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 60 C. for 12 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (45 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 63% yield) as yellow solid; LCMS (ESI, M+1): m/z=653.2. [1325] Step G. (3R)-1-(7-(5,6-dimethyl-1H-benzo[d]imidazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of 4-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-N,N,5,6-tetramethyl-1H-benzo[d]imidazole-1-sulfonamide (130 mg, 1.0 equiv) in EtOH (0.5 mL) was added HCl (12 M, 2 mL). The reaction was stirred at 50 C. for 2 hours. The mixture was quenched with saturated Na.sub.2CO.sub.3 aqueous (10 mL) at 0 C. and extracted with EtOAc (45 mL). The combined organic layers was dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, Dichloromethane:Methanol=10/1] and prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN; B %: 0%-30%, over 10 min] twice to afford the title compound (6.57 mg, 5.5% yield, 0.73 HCOOH) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.30 (s, 1H), 8.05 (s, 1H), 7.57 (s, 1H), 4.60 (br s, 3H), 4.34 (br d, J=13.2 Hz, 1H), 3.67-3.55 (m, 3H), 3.50-3.38 (m, 1H), 3.24-3.12 (m, 2H), 2.49 (s, 3H), 2.34-2.24 (m, 2H), 2.23-2.20 (m, 3H), 2.20-2.13 (m, 3H), 2.13-1.99 (m, 4H), 1.93-1.84 (m, 1H), 1.84-1.74 (m, 2H), 1.30 (s, 3H); LCMS (ESI, M+1): m/z=546.4. Example 889 ##STR00774## 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-3-azabicyclo[3.2.1]octane-1-carboxamide ##STR00775## [1326] Step A. methyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1-carboxylate: To a mixture of methyl 3-azabicyclo[3.2.1]octane-1-carboxylate (609 mg, 1.3 equiv, HCl) and DIEA (1.60 mL, 4.0 equiv) in DMF (4 mL) was added 4 molecular sieve (50 mg). The reaction was stirred at 20 C. for 10 minutes. 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1 g, 1.0 equiv) was added into the mixture. The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified with reversed phase (0.1% FA condition) to afford the title compound (900 mg, 76% yield) as yellow solid; LCMS (ESI, M+1): m/z=508.2. [1327] Step B. 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1-carboxylic acid: To a solution of methyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1-carboxylate (400 mg, 1.0 equiv) in THF (5 mL) and H.sub.2O (1 mL) was added NaOH (157 mg, 5.0 equiv) at 0 C. The reaction was stirred at 20 C. for 1 hour. The mixture was adjusted pH to 6 by 1 N HCl aqueous at 0 C. and purified with reversed phase (0.1% FA condition) to afford the title compound (235 mg, 56% yield) as yellow solid; LCMS (ESI, M+1): m/z=494.1. [1328] Step C. 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-3-azabicyclo[3.2.1]octane-1-carboxamide: To a solution of 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1-carboxylic acid (135 mg, 1.0 equiv) in DMF (2 mL) were added TEA (442 mg, 16.0 equiv) and T3P (1.64 g, 50% purity, 9.4 equiv) dropwise at 0 C. The reaction was stirred at 0 C. for 0.1 hours. methanamine (284 mg, 10.0 equiv, HCl) was added into above mixture. The reaction was stirred at 20 C. for 1 hour. The mixture was added saturated NaHCO.sub.3 aqueous (16 mL) at 0 C. and extracted with EtOAc (84 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (220 mg, crude) as yellow solid; LCMS (ESI, M+1): m/z=507.2. [1329] Step D. 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-3-azabicyclo[3.2.1]octane-1-carboxamide: To a solution of 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-3-azabicyclo[3.2.1]octane-1-carboxamide (200 mg, 1.0 equiv) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (162 mg, 1.3 equiv) in methoxycyclopentane (4 mL) were added CataCXium A Pd G3 and K.sub.3PO.sub.4 (1.5 M, 789 L, 3.0 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 80 C. for 4 hours. The mixture was diluted with water (3 mL) and extracted with EtOAc (44 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed-phase (0.1% FA condition) and prep-HPLC (column: Waters Xbridge 15025 mm5 um; mobile phase: [water (NH.sub.4HCO.sub.3)-ACN]; B %: 43%-73%, 8 minutes) to afford the title compound (95 mg, 36% yield) as white solid; 1H NMR (400 MHZ, METHANOL-d4) =9.08 (d, J=1.6 Hz, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.32-7.20 (m, 2H), 7.06 (t, J=2.4 Hz, 1H), 5.43-5.19 (m, 1H), 5.06-4.90 (m, 2H), 4.58 (br s, 1H), 4.38-4.21 (m, 2H), 3.73-3.50 (m, 2H), 3.26-3.17 (m, 2H), 3.01 (dt, J=5.6, 9.2 Hz, 1H), 2.77 (d, J=2.8 Hz, 3H), 2.59-2.41 (m, 2H), 2.40-2.10 (m, 4H), 2.09-1.94 (m, 4H), 1.88 (br s, 4H), 1.70-1.51 (m, 1H), 0.80 (br t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=661.4. Example 890 ##STR00776## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-(hydroxymethyl)hexahydropyrrolo[3,4-c]pyrrol-2 (1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00777## [1330] Step A. tert-butyl 4-(hydroxymethyl)hexahydropyrrolo[3,4-c]pyrrole-2 (1H)-carboxylate: To a solution of (octahydropyrrolo[3,4-c]pyrrol-1-yl)methanol (200 mg, 1.0 equiv, 2 HCl salt) and TEA (564 mg, 6.0 equiv) in DCM (2 mL) and MeOH (2 mL) were added Boc.sub.2O (223 mg, 1.1 equiv). The reaction was stirred at 25 C. for 12 hours. The mixture was concentrated to afford the title compound (220 mg, crude) as a yellow solid. [1331] Step B. tert-butyl 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-(hydroxymethyl)hexahydropyrrolo[3,4-c]pyrrole-2 (1H)-carboxylate: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (289 mg, 1.0 equiv) and tert-butyl 4-(hydroxymethyl)hexahydropyrrolo[3,4-c]pyrrole-2 (1H)-carboxylate (220 mg, 2.0 equiv) in DMF (2 mL) were added DIEA (293 mg, 5.0 equiv) and 4 molecular sieve (200 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was concentrated and purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 47%-77%, 9 min) to afford the title compound (18.0 mg, 45% yield) as a white solid; LCMS (ESI, M+1): m/z=735.4. [1332] Step C. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(1-(hydroxymethyl)hexahydropyrrolo[3,4-c]pyrrol-2 (1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of tert-butyl 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-(hydroxymethyl)hexahydropyrrolo[3,4-c]pyrrole-2 (1H)-carboxylate (15.0 mg, 1.0 equiv) in DCM (0.1 mL) was added HCl.Math.dioxane (4 M, 75.00 uL). The reaction was stirred at 25 C. for 0.5 hours. The mixture was concentrated and purified by prep-HPLC (column: Phenomenex C18 75*30 mm*3 um; mobile phase: [water (FA)-ACN]; B %: 2%-32%, 7 min) to afford the title compound (2.70 mg, 21% yield) as off-white solid. .sup.1HNMR (400 MHZ, METHANOL-d4) =9.34-9.19 (m, 1H), 8.48 (br d, J=1.2 Hz, 1H), 7.69 (dd, J=6.0, 9.2 Hz, 1H), 7.39-7.20 (m, 2H), 7.08-6.95 (m, 1H), 5.52-5.29 (m, 2H), 5.14-5.00 (m, 3H), 4.47-4.28 (m, 2H), 4.25-4.09 (m, 1H), 4.08-3.97 (m, 1H), 3.88 (br dd, J=1.6, 13.2 Hz, 1H), 3.74-3.52 (m, 3H), 3.49-3.38 (m, 2H), 3.22-3.05 (m, 2H), 2.62-2.40 (m, 1H), 2.39-2.28 (m, 1H), 2.25-2.06 (m, 4H), 2.01-1.87 (m, 1H), 1.18 (t, J=7.2 Hz, 2H), 0.85-0.75 (m, 3H): LCMS (ESI, M+1): m/z=635.4. Example 891 ##STR00778## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-(methoxymethyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00779## [1333] Step A. tert-butyl 1-(methoxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (100 mg, 1.0 equiv) in DMAc (2 mL) was added NaH (49.7 mg, 60% purity, 3.0 equiv) portionwise at 0 C. The reaction was stirred at 0 C. for 0.5 hours. MeI (118 mg, 2.0 equiv) was added at 0 C. The mixture was stirred at 25 C. for 3 hours. The mixture was quenched with water (5 mL) at 0 C. and extracted with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated to afford the title compound (105 mg, crude) as yellow oil. [1334] Step B. 1-(methoxymethyl)-3-azabicyclo[3.2.1]octane: To a solution of tert-butyl 1-(methoxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (105 mg, 1.0 equiv) in MeCN (2 mL) was added HCl/dioxane (4 M, 4 mL, 39 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hours. The mixture was concentrated to afford the title compound (63.0 mg, crude, HCl) as white solid. [1335] Step C. 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-(methoxymethyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine: To a solution of 1-(methoxymethyl)-3-azabicyclo[3.2.1]octane (52.4 mg, 1.5 equiv, HCl) and 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (80.0 mg, 1.0 equiv) in DMF (1 mL) was added DIEA (118 mg, 5.0 equiv) at 25 C. The reaction was stirred at 40 C. for 14 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated to afford the title compound (90.0 mg, crude) as yellow oil. [1336] Step D. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-(methoxymethyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: A mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-(methoxymethyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine (90.0 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (86.4 mg, 1.5 equiv), cataCXium A Pd G3 (26.5 mg, 0.2 equiv) and K.sub.3PO.sub.4 (1.5 M, 364 L, 3.0 equiv) in methoxycyclopentane (5 mL) was degassed and purged with N.sub.2 3 times. The reaction was stirred at 80 C. for 3 hours under N.sub.2 atmosphere. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate, concentrated. The residue was purified by column chromatography (SiO.sub.2, Dichloromethane:Methanol=100/1 to 10/1), and further purified by prep-HPLC (column: Phenomenex luna C18 15025 mm10 um; mobile phase: A: water (FA), B: ACN; B %: 28% to 48% over 9 min). to afford the title compound (27.6 mg, 23% yield) as white solid; .sup.1H NMR (400 MHz, methanol-d4) =9.09 (d, J=4.4 Hz, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 5.55-5.24 (m, 1H), 4.75-4.71 (m, 1H), 4.50-4.34 (m, 2H), 3.66-3.38 (m, 8H), 3.36 (d, J=4.8 Hz, 3H), 3.21-3.12 (m, 1H), 2.54-2.45 (m, 2H), 2.44-2.29 (m, 2H), 2.28-2.17 (m, 2H), 2.16-2.05 (m, 2H), 2.04-1.93 (m, 1H), 1.89-1.73 (m, 2H), 1.69-1.46 (m, 4H), 0.86-0.74 (m, 3H); LCMS (ESI, M+1, M/2+1): m/z=648.3, 324.7. Example 892 ##STR00780## (3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)methyl dimethylcarbamate ##STR00781## [1337] Step A. tert-butyl 1-(((dimethylcarbamoyl)oxy)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (100 mg, 1.0 equiv) in DMAc (2.00 mL) was added NaH (49.7 mg, 60% purity, 3.0 equiv) portionwise at 0 C. The mixture was stirred at 0 C. for 0.5 hours. N,N-dimethylcarbamoyl chloride (89.1 mg, 2.0 equiv) was added at 0 C. The reaction was stirred at 25 C. for 3 hours. The mixture was quenched by water (5 mL) at 0 C. and extracted with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate, concentrated to afford the title compound (150 mg, crude) as yellow solid. [1338] Step B. (3-azabicyclo[3.2.1]octan-1-yl)methyl dimethylcarbamate: To a solution of tert-butyl 1-(dimethylcarbamoyloxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (100 mg, 1.0 equiv) in ACN (1.5 mL) was added HCl/dioxane (4 M, 80.0 uL, 1.0 equiv) at 0 C. The reaction was stirred at 25 C. for 0.5 hours. The mixture was concentrated to afford the title compound (77.0 mg, crude) as a yellow solid. [1339] Step C. (3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)methyl dimethylcarbamate: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (90 mg, 1.0 equiv) and 3-azabicyclo[3.2.1]octan-1-ylmethyl N,N-dimethylcarbamate (76.5 mg, 1.5 equiv, HCl) in DMF (1.00 mL) was added DIEA (79.5 mg, 3.0 equiv). The reaction was stirred at 40 C. for 14 hours. The mixture was diluted with water (1 mL) and extracted with ethyl acetate (3 mL). The organic layer was dried over sodium sulfate, concentrated to afford the title compound (130 mg, crude) as yellow oil. LCMS (ESI, M+1): m/z=551.1. [1340] Step D. (3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)methyl dimethylcarbamate: To a solution of (3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)methyl dimethylcarbamate (130 mg, 61% purity, 1.0 equiv) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (68.25 mg, 1.5 equiv) in methoxycyclopentane (3.00 mL) was added cataCXium A Pd G3 (21.0 mg, 0.2 equiv) and aqueous K.sub.3PO.sub.4 (1.5 M, 288 L, 3.0 equiv). The mixture was degassed and purged with N.sub.2 for 3 times. The mixture was stirred at 80 C. for 3 hours under N.sub.2 atmosphere. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (4 mL). The organic layer was dried over sodium sulfate, concentrated and purified by prep-HPLC [column: Phenomenex lun 15025 mm10 m; A: water (FA), B: ACN; B %: 24%-54% over 10 min] to afford the title compound (32.1 mg, 31% yield, HCOOH) as a white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.10 (d, J=3.6 Hz, 1H), 7.67 (dd, J=5.6, 9.2 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.08-7.02 (m, 1H), 5.47-5.20 (m, 1H), 4.79-4.66 (m, 2H), 4.41-4.25 (m, 2H), 4.22-4.05 (m, 2H), 3.63 (td, J=5.6, 11.6 Hz, 1H), 3.53 (td, J=7.8, 12.3 Hz, 1H), 3.46-3.32 (m, 2H), 3.30-3.23 (m, 1H), 3.08 (dt, J=5.8, 9.6 Hz, 1H), 2.93 (br d, J=12.4 Hz, 6H), 2.55-2.44 (m, 2H), 2.43-2.31 (m, 1H), 2.31-2.24 (m, 1H), 2.23-2.12 (m, 2H), 2.09-2.00 (m, 2H), 1.98-1.79 (m, 3H), 1.74-1.64 (m, 2H), 1.63-1.52 (m, 2H), 0.84-0.74 (m, 3H). LCMS (ESI, M+1): m/z=705.3. Example 893 ##STR00782## 2-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-2-azabicyclo[3.1.1]heptan-4-ol ##STR00783## [1341] Step A. tert-butyl 4-oxo-2-azabicyclo[3.1.1]heptane-2-carboxylate: To a solution of 2-azabicyclo[3.1.1]heptan-4-one (100 mg, 1.0 equiv) and TEA (376 uL, 3 equiv) in DCM (1.5 mL) were added N,N-dimethylpyridin-4-amine (21.3 mg, 0.2 equiv) and Boc.sub.2O (393 mg, 2 equiv). The reaction was stirred at 25 C. for 1 hour. The mixture was diluted with H.sub.2O (5 mL) and extracted with DCM (10 mL3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (160 mg, 84% yield) as yellow solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =4.67-4.63 (m, 1H), 4.12-4.08 (m, 2H), 2.90 (q, J=5.6 Hz, 1H), 2.68-2.61 (m, 2H), 1.84 (br s, 2H), 1.41 (s, 9H). [1342] Step B. tert-butyl 4-hydroxy-4-methyl-2-azabicyclo[3.1.1]heptane-2-carboxylate: To a solution of tert-butyl 4-oxo-2-azabicyclo[3.1.1]heptane-2-carboxylate (80 mg, 1 equiv) in THF (1 mL) was added MeMgBr (1 M, 568 L, 1.5 equiv) at 0 C. The reaction was stirred at 25 C. for 2 hours. The mixture was quenched with saturated NH.sub.4Cl solution (5 mL) and extracted with DCM (10 mL3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 050% Ethylacetate/Petroleum ethergradient@20 mL/min) to afford the title compound (47 mg, crude) as light yellow oil. [1343] Step C. 4-methyl-2-azabicyclo[3.1.1]heptan-4-ol: To a solution of tert-butyl 4-hydroxy-4-methyl-2-azabicyclo[3.1.1]heptane-2-carboxylate (40 mg, 1 equiv) in DCM (1 mL) was added TFA (0.5 mL, 38 equiv). The reaction was stirred at 25 C. for 2 hours. The mixture was concentrated under reduced pressure to afford the title compound (23 mg, crude) as white oil. [1344] Step D. 2-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-2-azabicyclo[3.1.1]heptan-4-ol: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30 mg, 1 equiv) and 4-methyl-2-azabicyclo[3.1.1]heptan-4-ol (6.44 mg, 1 equiv) in DMF (1 mL) was added K.sub.3PO.sub.4 (21.5 mg, 2 equiv). The reaction was stirred at 60 C. for 2 hours. The mixture was filtered and purified by prep-HPLC (column: Boston Green ODS 150*30 mm*5 um; mobile phase: [water (FA)-ACN]; B %: 20%-50%, 6 min) to afford the title compound (4.25 mg, 13% yield, 0.39HCOOH) as white solid. .sup.1H NMR (400 MHZ, CD.sub.3OD) =8.94 (br s, 1H), 7.71-7.65 (m, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.29-7.21 (m, 1H), 7.09-7.02 (m, 1H), 5.45-5.26 (m, 1H), 4.48-4.13 (m, 5H), 3.50-3.37 (m, 1H), 3.11-3.04 (m, 1H), 2.67-1.81 (m, 15H), 1.48-1.27 (m, 3H), 0.86-0.75 (m, 3H); LCMS (ESI, M+1): m/z=620.3. Example 894 ##STR00784## ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl decyl(methyl)carbamate ##STR00785## [1345] Step A. ((3S,7aR)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl decyl(methyl)carbamate: To a solution of ((3S,7aR)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol (200 mg, 1.0 equiv) and TEA (245 mg, 5.0 equiv) in THF (10 mL) was added (4-nitrophenyl) carbonochloridate (195 mg, 2.0 equiv) dropwise at 40 C. After stirring at 40 C. for 3 hours, a solution of N-methyldecan-1-amine; hydrochloride (110 mg, 1.1 equiv) in DMF (0.5 mL) was added to the mixture. The reaction was stirred at 80 C. for 9 hours. The mixture was diluted with H.sub.2O (30 mL) and extracted with ethyl acetate (2 30 mL). Combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-TLC (SiO.sub.2, Petroleum ether/Ethyl acetate=5/1) to afford the title compound (150 mg, 51% yield) as yellow solid; LCMS (ESI, M+1): m/z=611.6. [1346] Step B. ((3S,7aR)-7a-(hydroxymethyl) hexahydro-1H-pyrrolizin-3-yl)methyl decyl(methyl)carbamate: To a solution of ((3S,7aR)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl decyl(methyl)carbamate (196 mg, 1 equiv) in DCM (5 mL) was added TFA (4.62 g, 126 equiv). The reaction was stirred at 25 C. for 18 hours. The mixture was concentrated under reduced pressure to afford the title compound (189 mg, crude) as yellow oil which used for the next step without further purification; LCMS (ESI, M+1): m/z=369.3. [1347] Step C. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (100 mg, 1.0 equiv) in DMSO (2 mL) was added KF (220 mg, 3.79 mmol, 20 equiv). The reaction was stirred at 120 C. for 0.5 hours. The mixture was diluted with EtOAc (20 mL). The combined organic layers were washed with brine (20 mL3), dried over anhydrous sodium sulfate, concentrated, and purified with flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 010% Dichloromethane/Methanol @15 ml/min) to afford the title compound (92 mg, 74% yield) as yellow oil; (ESI, M+1): m/z=513.1 [1348] Step D. ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl decyl(methyl)carbamate: To a solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (92.0 mg, 1 equiv) and ((3S,7aR)-7a-(hydroxymethyl) hexahydro-1H-pyrrolizin-3-yl)methyl decyl(methyl)carbamate (86.0 mg, 1.0 equiv) in THF (1 mL) was added t-BuOK (1 M, 420 L, 3 equiv). The reaction was stirred at 0 C. for 1 hour. The mixture was quenched with addition H.sub.2O (10 mL) and extracted with DCM (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with flash silica gel chromatography ((ISCO: 4 g SepaFlash Silica Flash Column, Eluent of 010% Dichloromethane/Methanol @15 ml/min) to afford the title compound (69 mg, 43% yield) as a yellow oil; LCMS (ESI, M+1): m/z=861.3. [1349] Step E. ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl decyl(methyl)carbamate: To a mixture of ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methyl decyl(methyl)carbamate (69 mg, 1.0 equiv) in dioxane (1 mL) was added HCl.Math.dioxane (4 M, 0.5 mL). The mixture was stirred at 25 C. for 2 hours. The mixture was concentrated and purified by prep-HPLC (column: O-Welch C18 150*30 mm*5 um; mobile phase: [water (FA)-ACN]; B %: 25%-65%, 10 min) to afford the title compound (4.07 mg, 6.1% yield, 0.23 HCOOH) as a white solid; 1H NMR (400 MHZ, METHANOL-d4) =9.27-9.17 (m, 1H), 8.56-8.47 (m, 1H), 7.71-7.64 (m, 1H), 7.33-7.29 (m, 1H), 7.28-7.22 (m, 1H), 7.12-7.02 (m, 1H), 4.55-4.50 (m, 1H), 4.46-4.25 (m, 3H), 4.24-4.09 (m, 1H), 4.08-3.96 (m, 1H), 3.71-3.57 (m, 1H), 3.53-3.41 (m, 1H), 3.29-3.08 (m, 4H), 3.06-2.79 (m, 4H), 2.53-2.39 (m, 1H), 2.33-1.74 (m, 13H), 1.61-1.43 (m, 2H), 1.37-1.19 (m, 17H), 1.02-0.68 (m, 6H). LCMS (ESI, M+1): m/z=817.5. Example 895 ##STR00786## (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(isopropoxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00787## [1350] Step A. (3S,7aS)-3-(isopropoxymethyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine: To a mixture of ((3S,7aS)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol (500 mg, 1.0 equiv) in THF (10 mL) was added NaH (483 mg, 60% purity, 10 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hour. 2-iodopropane (4.11 g, 20 equiv) was added into above mixture. The reaction was stirred at 60 C. for 12 hours. The mixture was diluted with water (15 mL) and extracted with EtOAc (8 mL3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile] to afford the title compound (90.0 mg, 16% yield) as yellow oil; LCMS (ESI, M+1): m/z=456.2. [1351] Step B. ((3S,7aS)-3-(isopropoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol: A mixture of (3S,7aS)-3-(isopropoxymethyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine (50.0 mg, 1.0 equiv) in TFA (1.54 g, 123. equiv) was stirred at 0 C. for 0.5 hour. The mixture was concentrated. The residue was diluted with MeOH. To the mixture was added NaHCO.sub.3 (200 mg). The mixture was stirred at 25 C. for 0.5 hour. The mixture was filtered and concentrated to afford the title compound (125 mg, crude) as white solid. [1352] Step C. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(isopropoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of ((3S,7aS)-3-(isopropoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methanol (120 mg, 1.5 equiv) and (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (198 mg, 1.0 equiv) in THF (1.0 mL) was added t-BuONa (1 M, 750 L, 2.0 equiv) at 40 C. The reaction was stirred at 25 C. for 12 hours. The mixture was diluted with water (2 mL) and extracted with EtOAc (2 mL3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile] to afford the title compound (32.0 mg, 12% yield) as yellow solid; LCMS (ESI, M+1): m/z=706.6. [1353] Step D. (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S. 7aS)-3-(isopropoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A mixture of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(isopropoxymethyl) hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (30.0 mg, 1.0 equiv) in HCl.Math.MeOH (2 M, 1.5 mL, 70 equiv) was stirred at 0 C. for 0.5 hour. The mixture was concentrated. The residue was diluted with water (1 mL). The mixture was adjusted to pH=7 with saturated NaHCO.sub.3 (10 mL) and extracted with ethyl acetate (2 mL3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B %: 23%-53%, 10 min) to afford the title compound (3.03 mg, 10% yield, 0.27 HCOOH) as white solid. .sup.1H NMR (400 MHZ, METHANOL-d4) =9.22 (s, 1H), 7.68 (dd, J=5.2, 8.8 Hz, 1H), 7.37-7.19 (m, 2H), 7.06 (t, J=2.4 Hz, 1H), 4.61-4.44 (m, 2H), 4.42-4.25 (m, 2H), 3.67 (br d, J=4.8 Hz, 2H), 3.65-3.57 (m, 2H), 3.52-3.34 (m, 2H), 3.19-2.96 (m, 2H), 2.53-2.37 (m, 1H), 2.31-2.07 (m, 4H), 2.04-1.68 (m, 9H), 1.29 (d, J=9.6 Hz, 3H), 1.17 (dt, J=2.4, 4.0 Hz, 6H), 0.81 (td, J=7.2, 11.2 Hz, 3H); LCMS (ESI, M+1): m/z=662.3. Example 896 ##STR00788## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00789## [1354] Step A. ethyl(S)-2-methylene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate: Ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (10 g) was separated by SFC [column: DAICEL CHIRALPAK IK (250 mm50 mm, 10 um); mobile phase: CO.sub.2-i-PrOH (0.1% NH.sub.3H.sub.2O); B %: 0%, isocratic elution mode] to afford the title compound (4.4 g, 41% yield) as light yellow gum; LCMS (ESI, M+1): m/z=210.1. [1355] Step B. (S)-(2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol: To a solution of ethyl(S)-2-methylene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (3.40 g, 1.0 equiv) in THF (34 mL) was added dropwise DIBAL-H (1M, 162 mL) at 0 C. The reaction was stirred at 0 C. for 5 hours. The mixture was quenched with water (8 mL), 15% NaOH (8 mL) and water (24 mL) at 0 C., and then diluted with EtOAc (500 mL). NaSO.sub.4 (60 g) was added to the mixture. The mixture was stirred for 0.16 hours and filtered. The filter cake was washed with EtOAc (200 mL). The filtrate was concentrated and purified with column chromatography [Al.sub.2O.sub.3, petroleum ether/ethyl acetate=1/0 to 0/1] to afford the title compound (1.02 g, 41% yield) as light yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =4.92 (br d, J=10.4 Hz, 2H), 3.66 (br d, J=14.4 Hz, 1H), 3.36-3.22 (m, 3H), 3.17-3.06 (m, 1H), 2.73-2.61 (m, 1H), 2.51-2.45 (m, 1H), 2.36-2.30 (m, 1H), 1.96-1.85 (m, 2H), 1.85-1.66 (m, 2H). [1356] Step C (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (1.26 g, 1.0 equiv) and DIEA (1.09 g, 3.0 equiv) in DCM (13 mL) was added a solution of (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (356 mg, 1.0 equiv) in DCM (2 mL) dropwise at 40 C. The reaction was stirred at 40 C. for 1 hour. The mixture was quenched with water (40 mL) at 20 C. and extracted with DCM (2 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=10/1 to 1/1] to afford the title compound (1.38 g, 91% yield) as yellow solid; LCMS (ESI, M+1): m/z=541.2. [1357] Step D. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (690 mg, 1.0 equiv) and(S)-(2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (586 mg, 3.0 equiv) in DMF (1 mL) was added DIEA (824 mg, 5.0 equiv). The reaction was stirred at 80 C. for 12 hours. The mixture was quenched with water (20 mL) at 20 C. and extracted with EtOAc (220 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Phenomenex luna C18 15040 mm15 um; mobile phase: water (FA)-ACN; gradient: 22%-52% B over 15 min] to afford the title compound (400 mg, 47% yield) as white solid; LCMS (ESI, M+1): m/z=658.5. [1358] Step E. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 equiv) in MeOH (5 mL) was added HCl.Math.MeOH (4M, 5 mL) at 0 C. The reaction was stirred at 0 C. for 6 hours. The mixture was concentrated, dissolved in MeOH (3 mL), adjusted to pH-7 with solid NaHCO.sub.3 and filtered. The filtrate was concentrated and purified with prep-HPLC [column: C18 15030 mm; mobile phase: water (FA)-ACN; gradient: 12%-42% B over 7 min] to afford the title compound (71.5 mg, 76% yield, 0.75 HCOOH) as white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.12-9.73 (m, 1H), 9.42-9.20 (m, 1H), 7.77 (br dd, J=6.0, 8.0 Hz, 1H), 7.44-7.27 (m, 2H), 7.13-6.98 (m, 1H), 4.93 (br s, 2H), 4.89-4.77 (m, 1H), 4.76-4.66 (m, 1H), 4.63-4.54 (m, 1H), 4.24-4.09 (m, 2H), 4.05-3.96 (m, 1H), 3.80-3.70 (m, 1H), 3.63-3.56 (m, 1H), 3.28-3.15 (m, 2H), 3.08-2.97 (m, 1H), 2.65-2.57 (m, 2H), 2.42-2.30 (m, 3H), 2.21-2.04 (m, 3H), 2.03-1.95 (m, 1H), 1.93-1.75 (m, 3H), 1.75-1.60 (m, 2H), 1.32-1.21 (m, 1H), 0.80-0.68 (m, 3H); LCMS (ESI, M+1): m/z=614.4. Example 897 ##STR00790## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00791## [1359] Step A. ethyl (R)-2-methylene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate: Ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (10 g) was separated by SFC [column: DAICEL CHIRALPAK IK (250 mm50 mm, 10 m); mobile phase: CO.sub.2-i-PrOH (0.1% NH.sub.3.Math.H.sub.2O); B %: 0%, isocratic elution mode] to afford the title compound (4.40 g, 42% yield) as light yellow gum; LCMS (ESI, M+1): m/z=210.1. [1360] Step B. (R)-(2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol: To a solution of ethyl (R)-2-methylene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (3.40 g, 1.0 equiv) in THF (34 mL) was added dropwise DIBAL-H (1M, 162 mL) at 0 C. The reaction was stirred at 0 C. for 5 hours. The mixture was quenched with water (8 mL), 15% NaOH (8 mL) and water (24 mL) at 0 C., and then diluted with EtOAc (500 mL). anhydrous NaSO.sub.4 (60 g) was added to the mixture. The mixture stirred for 0.16 hours and filtered. The filter cake was washed with EtOAc (200 mL). The filtrate was concentrated and purified with column chromatography [Al.sub.2O.sub.3, petroleum ether/ethyl acetate=1/0 to 0/1] to afford the title compound (790 mg, 32% yield) as light yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =4.91 (br d, J=10.8 Hz, 2H), 3.64 (br d, J=14.4 Hz, 1H), 3.33-3.23 (m, 3H), 3.14-3.04 (m, 1H), 2.69-2.62 (m, 1H), 2.50-2.43 (m, 1H), 2.37-2.29 (m, 1H), 1.96-1.84 (m, 2H), 1.83-1.64 (m, 2H). [1361] Step C. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (690 mg, 1.0 equiv) and (R)-(2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (586 mg, 3.0 equiv) in DMF (1 mL) was added DIEA (824 mg, 5.0 equiv). The reaction was stirred at 80 C. for 12 hours. The mixture was quenched with water (20 mL) at 20 C. and extracted with EtOAc (220 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Phenomenex luna C18 15040 mm15 um; mobile phase: water (FA)-ACN; gradient: 22%-52% B over 15 min] to afford the title compound (500 mg, 59% yield) as a white solid; LCMS (ESI, M+1): m/z=658.4. [1362] Step D. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 equiv) in MeOH (5 mL) was added HCl.Math.MeOH (4M, 5 mL) at 0 C. The reaction was stirred at 0 C. for 6 hours. The mixture was concentrated, dissolved in MeOH (3 mL), adjusted to pH=7 with solid NaHCO.sub.3 and filtered. The filtrate was concentrated and purified with prep-HPLC [column: C18 15030 mm; mobile phase: water (FA)-ACN; gradient: 12%-42% B over 7 min] to afford the title compound (37.0 mg, 39% yield, 0.60 HCOOH) as white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.23-9.72 (m, 1H), 9.36-9.23 (m, 1H), 7.76 (dd, J=6.0, 9.2 Hz, 1H), 7.38-7.30 (m, 2H), 7.03 (dd, J=2.4, 14.4 Hz, 1H), 4.90 (br s, 2H), 4.86-4.76 (m, 1H), 4.75-4.66 (m, 1H), 4.62-4.54 (m, 1H), 4.20-4.11 (m, 1H), 4.08-3.97 (m, 2H), 3.78-3.68 (m 1H), 3.57 (br d, J=14.0 Hz, 1H), 3.21 (br d, J=14.4 Hz, 2H), 3.04-2.98 (m, 1H), 2.64-2.56 (m, 2H), 2.36 (br d, J=18.4 Hz, 3H), 2.19-2.02 (m, 3H), 2.01-1.94 (m, 1H), 1.91-1.73 (m, 3H), 1.72-1.61 (m, 2H), 1.24 (br d, J=11.6 Hz, 1H), 0.77-0.65 (m, 3H); LCMS (ESI, M+1): m/z=614.4. Example 898 ##STR00792## 10-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-oxa-1,3,10-triazaspiro[4.6]undecan-2-one ##STR00793## [1363] Step A. 10-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-oxa-1,3,10-triazaspiro[4.6]undecan-2-one: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (80 mg, 1.0 equiv) and 7-oxa-1,3,10-triazaspiro[4.6]undecan-2-one (34.7 mg, 1.5 equiv) in DMF (1 mL) were added K.sub.3PO.sub.4 (86 mg, 3.0 equiv) and 4 molecular sieve (80 mg). The reaction was stirred at 60 C. for 16 hours. The mixture was filtered and purified by prep-HPLC [column: Phenomenex luna C1815025 mm10 um; mobile phase: water (FA)-ACN; B %: 10%-40%, 10 min] to afford the title compound (25.9 mg, 28% yield, HCOOH) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.34-9.22 (m, 1H), 7.72-7.64 (m, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.29-7.21 (m, 1H), 7.05 (dd, J=2.4, 5.6 Hz, 1H), 5.60-5.38 (m, 1H), 5.24-5.11 (m, 1H), 4.65-4.58 (m, 1H), 4.52-4.43 (m, 1H), 4.42-4.37 (m, 1H), 4.29-4.18 (m, 2H), 4.16-4.09 (m, 1H), 4.01 (ddd, J=5.6, 8.4, 14.0 Hz, 1H), 3.86-3.73 (m, 3H), 3.72-3.54 (m, 3H), 3.43-3.34 (m, 2H), 2.59-2.40 (m, 3H), 2.34-2.27 (m, 1H), 2.25-2.15 (m, 3H), 2.13-2.05 (m, 1H), 0.87-0.76 (m, 3H); LCMS (ESI, M+1): m/z=664.4. Example 899 ##STR00794## ethyl 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-3-azabicyclo[3.2.1]octane-1-carboxylate ##STR00795## [1364] Step A. ethyl 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-3-azabicyclo[3.2.1]octane-1-carboxylate: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (130 mg, 1.0 equiv) and ethyl 8,8-difluoro-3-azabicyclo[3.2.1]octane-1-carboxylate (168 mg, 3.0 equiv, HCl) in DMF (1.3 mL) were added 4 molecular sieve (75.0 mg) and K.sub.3PO.sub.4 (140 mg, 3.0 equiv) in one portion under N.sub.2. The reaction was stirred at 40 C. for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (330 mL). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified by prep-HPLC [column: Phenomenex Luna C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 26%-56%, 10 min] to afford the title compound (14.2 mg, 8.6% yield, HCOOH) as an off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.12 (s, 1H), 7.72-7.65 (m, 1H), 7.31 (d, J=2.6 Hz, 1H), 7.25 (t, J=9.4 Hz, 1H), 7.08-7.02 (m, 1H), 5.45-5.26 (m, 1H), 5.04-4.95 (m, 1H), 4.77-4.67 (m, 1H), 4.43-4.34 (m, 2H), 4.31-4.24 (m, 2H), 4.16-4.01 (m, 2H), 3.45-3.37 (m, 1H), 3.15-3.06 (m, 1H), 2.70-2.70 (m, 1H), 2.65-2.55 (m, 1H), 2.49-2.39 (m, 2H), 2.37-2.27 (m, 2H), 2.23-2.14 (m, 2H), 2.11-1.89 (m, 6H), 1.71-1.59 (m, 1H), 1.32 (t, J=7.2 Hz, 3H), 0.83-0.76 (m, 3H); LCMS (ESI, M+1): m/z=712.2. Example 900 ##STR00796## 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00797## [1365] Step A. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (260 mg, 1.0 equiv) and 4 molecular sieve (100 mg) in DMF (1 mL) was added piperidine (299 mg, 8.0 equiv). The reaction was stirred at 25 C. for 1 hour. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] and prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 23%-53% over 10 min] to afford the title compound (62.8 mg, 24% yield, 0.26 HCOOH) as off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.03 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.33-7.18 (m, 2H), 7.06 (d, J=2.8 Hz, 1H), 5.47-5.27 (m, 1H), 4.47-4.28 (m, 2H), 4.06 (br s, 4H), 3.55-3.35 (m, 3H), 3.12 (dt, J=6.0, 9.6 Hz, 1H), 2.54-2.28 (m, 3H), 2.26-2.13 (m, 2H), 2.12-2.03 (m, 2H), 2.02-1.91 (m, 1H), 1.85 (br s, 6H), 0.80 (dt, J=1.2, 7.2 Hz, 3H); LCMS (ESI, M+1): m/z=578.4. Example 901 ##STR00798## 4-(4-(8,8-difluoro-1-(hydroxymethyl)-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ##STR00799## [1366] Step A. 4-(4-(8,8-difluoro-1-(hydroxymethyl)-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (200 mg, 1.0 equiv) and (8,8-difluoro-3-azabicyclo[3.2.1]octan-1-yl)methanol (179 mg, 3.0 equiv) in DMF (2 mL) were added 4 molecular sieve (50.0 mg) and K.sub.3PO.sub.4 (215 mg, 3.0 equiv) in one portion under N.sub.2. The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by prep-HPLC [column: Phenomenex luna C18 150 25 mm10 um; mobile phase: water (FA)-ACN; B %: 25%-45%, 58 min] to afford the title compound (57.6 mg, 24.21% yield, HCOOH) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.16 (d, J=4.0 Hz, 1H), 7.71-7.66 (m, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.26 (t, J=9.6 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 5.56-5.37 (d, J=52.8 Hz, 1H), 5.01-4.89 (m, 2H), 4.59-4.47 (m, 2H), 4.03-3.93 (m, 1H), 3.92-3.81 (m, 1H), 3.79 (s, 2H), 3.75 (m, 1H), 3.68-3.63 (m, 1H), 3.61-3.55 (m, 1H), 3.28 (br s, 1H), 2.63-2.51 (m, 2H), 2.48 (br s, 1H), 2.44-2.37 (m, 1H), 2.36-2.28 (m, 1H), 2.24-2.15 (m, 3H), 2.12-2.01 (m, 1H), 2.00-1.88 (m, 1H), 1.85-1.74 (m, 2H), 1.72-1.59 (m, 1H), 0.84-0.76 (m, 3H); F NMR (400 MHZ, METHANOL-d.sub.4) =72.48, 123.05, 173.72; LCMS (ESI, M+1): m/z=670.1. Example 902 ##STR00800## (R)-1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-3-ol ##STR00801## [1367] Step A. (R)-1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-3-ol: To a mixture of 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (70.0 mg, 1.0 equiv), (R)-piperidin-3-ol (38.8 mg, 3.0 equiv) and 4 molecular sieve (30 mg) in DMF (1 mL) was added DIEA (49.6 mg, 3.0 equiv). The reaction was stirred at 40 C. for 1 hour. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] and prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 12%-42% over 10 min] to afford the title compound (12.5 mg, 17% yield, 0.42HCOOH) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.15 (d, J=6.0 Hz, 1H), 8.18-8.07 (m, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.75-7.65 (m, 1H), 7.63-7.55 (m, 2H), 7.55-7.44 (m, 1H), 4.46 (s, 2H), 4.25 (br d, J=13.2 Hz, 1H), 4.10-3.94 (m, 3H), 3.92-3.79 (m, 1H), 3.43-3.34 (m, 2H), 3.04-2.92 (m, 2H), 2.24-2.14 (m, 2H), 2.13-1.97 (m, 6H), 1.96-1.87 (m, 2H), 1.81-1.71 (m, 2H); LCMS (ESI, M+1): m/z=548.3. Example 903 ##STR00802## (S)-1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) piperidin-3-ol [1368] Synthesized according to Example 902. The title compound was obtained as white solid (FA salt). .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.15 (d, J=6.0 Hz, 1H), 8.20-8.08 (m, 1H), 8.04-7.96 (m, 1H), 7.73-7.65 (m, 1H), 7.63-7.57 (m, 2H), 7.54-7.48 (m, 1H), 4.43 (s, 2H), 4.31-4.18 (m, 1H), 4.10-3.94 (m, 3H), 3.91-3.77 (m, 1H), 3.38-3.32 (m, 2H), 3.01-2.88 (m, 2H), 2.25-2.13 (m, 2H), 2.12-1.94 (m, 6H), 1.94-1.83 (m, 2H), 1.81-1.70 (m, 2H); LCMS (ESI, M+1): m/z=548.3. Example 904 ##STR00803## (R)-1-(2-(((3S,7aS)-3-((cyclopentylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00804## [1369] Step A. cyclopent-1-en-1-ylmethanol: To a solution of methyl cyclopent-1-ene-1-carboxylate (5.0 g, 1.0 equiv) in THF (50 mL) was added DIBAL-H (1 M, 43.6 mL, 1.1 equiv). The reaction was stirred at 78 C. for 3 hours. After completion, the mixture was diluted with THF (100 mL), warmed up to 0 C., quenched with H.sub.2O (1.75 mL), 15% NaOH aqueous solution (1.75 mL) and H.sub.2O (4.36 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate 10:1 to 5:1) to afford the title compound (1.1 g, 27% yield) as colorless oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =5.61 (br d, J=1.6 Hz, 1H), 4.18 (s, 2H), 2.39-2.27 (m, 4H), 1.97-1.86 (m, 2H), 1.72 (br s, 1H). [1370] Step B. 1-(bromomethyl)cyclopent-1-ene: To a solution of cyclopent-1-en-1-ylmethanol (500 mg, 1.0 equiv) in DCM (5 mL) was added PBr.sub.3 (5.52 g, 4.0 equiv). The reaction was stirred at 0 C. for 2 hours. The mixture was quenched with ice water (5 mL), saturated NaHCO.sub.3 (10 mL) and extracted with dichloromethane (210 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to afford the title compound (300 mg, crude) as green oil. [1371] Step C. (3S,7aS)-3-((cyclopent-1-en-1-ylmethoxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine: To a solution of ((3S,7aS)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizin-3-yl)methanol (514 mg, 1.0 equiv) in THF (3 mL) and DMF (3 mL) was added NaH (99.4 mg, 60% purity, 2.0 equiv). The reaction was stirred at 0 C. for 0.5 hours. 1-(bromomethyl)cyclopentene (300 mg, 1.5 equiv) was added and the reaction was stirred at 0-25 C. for 11.5 hours. The mixture was quenched with H.sub.2O (5 mL) and extracted with ethyl acetate (215 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuum and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (260 mg, 41% yield) as yellow oil; LCMS (ESI, M+1): m/z=494.4. [1372] Step D. ((3S,7aS)-3-((cyclopent-1-en-1-ylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol: To a solution of (3S,7aS)-3-((cyclopent-1-en-1-ylmethoxy)methyl)-7a-((trityloxy)methyl) hexahydro-1H-pyrrolizine (260 mg, 1.0 equiv) in DCM (3 mL) was added TFA (601 mg, 10 equiv). The reaction was stirred at 0-25 C. for 16 hours. The mixture was concentrated, dissolved in MeOH (3 mL), neutralized with solid NaHCO.sub.3.and filtered. The filtrate was concentrated under vacuum and purified by column chromatography (Al.sub.2O.sub.3, Petroleum ether:Ethyl acetate=10:1 to 0:1 to Dichloromethane:Methanol=20:1) to afford the title compound (60 mg, 41% yield) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =5.64 (br s, 1H), 4.06 (s, 2H), 3.72-3.62 (m, 2H), 3.09-3.01 (m, 1H), 2.88-2.73 (m, 2H), 2.10-1.95 (m, 6H), 1.91 (br d, J=7.6 Hz, 2H), 1.83 (br dd, J=4.0, 8.8 Hz, 6H), 1.61-1.57 (m, 2H). [1373] Step E. (R)-1-(2-(((3S,7aS)-3-(cyclopent-1-en-1-ylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of ((3S,7aS)-3-((cyclopent-1-en-1-ylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (60 mg, 1.0 equiv) and (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (126 mg, 1.0 equiv) in toluene (1 mL) was added t-BuONa (2 M, 477 L, 4.0 equiv). The reaction was stirred at 0 C. for 2 hours. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under vacuum and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (60 mg, 24% yield) as yellow solid; LCMS (ESI, M+1): m/z=744.5. [1374] Step F. (R)-1-(2-(((3S,7aS)-3-((cyclopentylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(2-(((3S,7aS)-3-((cyclopent-1-en-1-ylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (60 mg, 1.0 equiv) in MeOH (1 mL) was added Pd/C (10 mg, 10% purity) under N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The reaction was stirred under H.sub.2 (15 Psi) at 25 C. for 1 hour. The mixture was filtered and concentrated to afford the title compound (30 mg, 29% yield.) as white solid; LCMS (ESI, M+1): m/z=746.5. [1375] Step G. (R)-1-(2-(((3S,7aS)-3-((cyclopentylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(2-(((3S,7aS)-3-((cyclopentylmethoxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (30 mg, 1.0 equiv) in acetonitrile (0.5 mL) was added HCl.Math.dioxane (4 M, 1 mL, 99 equiv). The reaction was stirred at 25 C. for 1 hour. The mixture was concentrated, dissolved in MeOH (1 mL), neutralized with solid NaHCO.sub.3 and filtered. The filtrate was concentrated under vacuum and purified by prep-HPLC [column: Waters xbridge 15025 mm10 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; B %: 52%-82%, 10 min] to afford the title compound (3.3 mg, 11% yield) as yellow solid; .sup.1H NMR (400 MHz, METHANOL-d.sub.4) =9.24-9.13 (m, 1H), 7.72-7.60 (m, 1H), 7.35-7.19 (m, 2H), 7.09-6.99 (m, 1H), 5.03-4.97 (m, 1H), 4.71-4.62 (m, 2H), 4.43-4.22 (m, 3H), 3.72-3.53 (m, 3H), 3.52-3.40 (m, 2H), 3.38-3.33 (m, 1H), 3.26 (br s, 1H), 3.02-2.79 (m, 2H), 2.53-2.40 (m, 1H), 2.23-2.14 (m, 3H), 2.01 (br dd, J=2.8, 7.6 Hz, 1H), 1.86 (br dd, J=6.0, 11.2 Hz, 4H), 1.80-1.66 (m, 5H), 1.63-1.42 (m, 4H), 1.28 (br dd, J=3.6, 9.6 Hz, 6H), 0.88-0.71 (m, 3H); LCMS (ESI, M+1): m/z=702.2. Example 905 ##STR00805## 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-N,N-dimethyl-3-azabicyclo[3.2.1]octane-1-carboxamide ##STR00806## [1376] Step A. tert-butyl 1-(dimethylcarbamoyl)-8,8-difluoro-3-azabicyclo[3.2.1]octane-3-carboxylate: To a mixture of 3-(tert-butoxycarbonyl)-8,8-difluoro-3-azabicyclo[3.2.1]octane-1-carboxylic acid (200 mg, 1.0 equiv) and DIEA (266 mg, 3.0 equiv) in DMF (1 mL) was added HATU (392 mg, 1.5 equiv). After stirring at 25 C. for 0.5 hours, Me.sub.2NH (2 M, 1.03 mL, 3.0 equiv) was added. The reaction was stirred for 2 hours under N.sub.2 atmosphere. The mixture was concentrated under reduced pressure and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (140 mg, 64% yield) as a yellow solid; LCMS (ESI, M+1): m/z=318.9 [1377] Step B. 8,8-difluoro-N,N-dimethyl-3-azabicyclo[3.2.1]octane-1-carboxamide: To a solution of tert-butyl 1-(dimethylcarbamoyl)-8,8-difluoro-3-azabicyclo[3.2.1]octane-3-carboxylate (130 mg, 1.0 equiv) in MeOH (2.0 mL) was added HCl.Math.MeOH (4 M, 2 mL, 19.6 equiv) at 0 C. The reaction was stirred at 0 C. for 1 hour. The mixture was concentrated under reduced pressure, diluted with MeOH (6 mL), adjusted to pH=10 by solid NaHCO.sub.3, filtered and concentrated to afford the title compound (100 mg, crude) as yellow solid; LCMS (ESI, M+1): m/z=219.2. [1378] Step C. 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-N,N-dimethyl-3-azabicyclo[3.2.1]octane-1-carboxamide: To a mixture of 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl 4-methylbenzenesulfonate (35.0 mg, 1.0 equiv) and 8,8-difluoro-N,N-dimethyl-3-azabicyclo[3.2.1]octane-1-carboxamide (38.7 mg, 3.0 equiv) in DMF (0.5 mL) were added K.sub.3PO.sub.4 (125 mg, 10 equiv) and 4 molecular sieve (10 mg, 1.0 equiv). The reaction was stirred at 60 C. for 16 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC [neutral condition; column: Phenomenex Luna C18 15025 mm10 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; B %: 40%-70%, 10 min] to afford the title compound (15.1 mg, 35.4% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.13-9.05 (m, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.05 (dd, J=2.4, 12.8 Hz, 1H), 5.42-5.22 (m, 2H), 4.51-4.38 (m, 1H), 4.35-4.27 (m, 2H), 4.27-4.20 (m, 1H), 3.74 (br d, J=14.1 Hz, 1H), 3.29-3.22 (m, 3H), 3.18 (br d, J=6.0 Hz, 3H), 3.02 (dt, J=5.6, 9.2 Hz, 3H), 2.65-2.53 (m, 1H), 2.53-2.41 (m, 2H), 2.38-2.19 (m, 2H), 2.18-2.02 (m, 4H), 2.01-1.84 (m, 4H), 1.53-1.40 (m, 1H), 0.79 (td, J=7.6, 20.0 Hz, 3H); F NMR (400 MHZ, METHANOL-d4) =114.08, 121.10, 124.04, 138.65, 173.55; LCMS (ESI, M+1): m/z=711.1. Example 906 ##STR00807## 7-(8-fluoro-7-(8-(hydroxymethyl)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide ##STR00808## [1379] Step A. 7-(8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: To a mixture of 8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)naphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (180 mg, 1.0 equiv) in DMF (0.1 mL) were added rac-(R)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (65.9 mg, 1.2 equiv), 4 molecular sieve (50 mg) and DIEA (371 mg, 500 L, 10 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (80 mg, 37% yield) as a yellow solid; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =9.10-9.00 (m, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.96-7.88 (m, 1H), 7.75-7.39 (m, 4H), 4.55-4.22 (m, 5H), 4.11-4.03 (m, 1H), 4.02-3.85 (m, 1H), 3.87-3.59 (m, 2H), 3.58-3.39 (m, 2H), 3.34-3.12 (m, 4H), 2.73-2.64 (m, 2H), 2.20-2.07 (m, 3H), 2.02-1.85 (m, 5H), 1.82-1.59 (m, 5H), 1.55-1.31 (m, 5H); LCMS (ESI, M+1): m/z=718.3. [1380] Step B. 7-(8-fluoro-7-(8-(hydroxymethyl)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: A solution of 7-(8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (60 mg, 1.0 equiv) and TFA (0.3 mL) was stirred at 0 C. for 1 hour. The mixture was added and diluted with acetonitrile (1.0 ml) and neutralized with solid NaHCO.sub.3, filtered, and purified by prep-HPLC [column: UniSil 3-100 C18 Ultra 15025 mm3 m; A: water (FA), B: ACN, B %: 17%-37% over 10 min], followed by prep-HPLC [column: Waters Xbridge BEH C18 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 25%-55% over 9 min] to afford the title compound (10 mg, 18.1% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.09 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.78-7.76 (m, 1H), 7.63-7.52 (m, 2H), 7.51-7.44 (m, 1H), 4.63-4.57 (m, 2H), 4.47-4.40 (m, 1H), 4.39-4.32 (m, 2H), 4.31-4.26 (m, 1H), 3.88-3.77 (m, 1H), 3.74-3.65 (m, 1H), 3.45-3.39 (m, 1H), 3.20 (dd, J=5.2, 12.0 Hz, 1H), 3.17-3.08 (m, 2H), 2.81-2.69 (m, 2H), 2.02-2.15 (m, 4H), 2.00-1.84 (m, 6H), 1.82-1.71 (m, 2H); LCMS (ESI, M+1): m/z=634.3. Example 907 ##STR00809## (1S,5R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-N-methyl-3-azabicyclo[3.2.1]octane-1-carboxamide ##STR00810## [1381] Step A. tert-butyl 8,8-difluoro-1-(methylcarbamoyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of 3-(tert-butoxycarbonyl)-8,8-difluoro-3-azabicyclo[3.2.1]octane-1-carboxylic acid (200 mg, 1.0 equiv) and DIEA (266 mg, 3.0 equiv) in DMF (2.0 mL) was added HATU (392 mg, 1.5 equiv) at 0-5 C. The reaction was stirred at 0-25 C. for 0.5 hours. To the mixture was added methanamine (2.0 M, 1.0 mL, 3.0 equiv) at 0 C. The reaction was stirred at 0-25 C. for 4 hours. The mixture was diluted with water (6.0 mL) and extracted with ethyl acetate (3 3.0 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 41% yield) as light yellow solid; LCMS (ESI, M55): m/z=249.0. [1382] Step B. 8,8-difluoro-N-methyl-3-azabicyclo[3.2.1]octane-1-carboxamide: To a solution of tert-butyl 8,8-difluoro-1-(methylcarbamoyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (100 mg, 1.0 equiv) in MeOH (1.0 mL) was added HCl.Math.MeOH (4.0 M, 1.0 mL, 12 equiv) at 0-5 C. The reaction was stirred at 0-5 C. for 5 hours. The mixture was concentrated under reduced pressure, dissolved in MeOH (1.0 mL), adjusted to pH=9 with solid NaHCO.sub.3 and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (80 mg, crude) as yellow solid. [1383] Step C. 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-N-methyl-3-azabicyclo[3.2.1]octane-1-carboxamide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (40.0 mg, 1.0 equiv) and 8,8-difluoro-N-methyl-3-azabicyclo[3.2.1]octane-1-carboxamide (27.6 mg, 2.0 equiv) in DMF (1.0 mL) were added K.sub.3PO.sub.4 (71.7 mg, 5.0 equiv) and 4 molecular sieve (10.0 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by reversed-phase HPLC [column: Phenomenex luna C18 15025 mm10 um; mobile phase: water (FA)-ACN; B %: 16%-46%, 10 min] to afford the title compound (11.0 mg, 21% yield, HCOOH) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.13 (s, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.29-7.22 (m, 1H), 7.05 (t, J=3.2 Hz, 1H), 5.53-5.32 (m, 1H), 5.08-4.93 (m, 1H), 4.75 (dt, J=1.6, 10.8 Hz, 1H), 4.55-4.41 (m, 2H), 4.14-3.96 (m, 2H), 3.62-3.44 (m, 1H), 3.63-3.44 (m, 2H), 3.21 (dt, J=5.6, 10 Hz, 1H), 2.82 (d, J=3.6 Hz, 3H), 2.68-2.57 (m, 1H), 2.55-2.34 (m, 3H), 2.34-2.20 (m, 3H), 2.20-2.09 (m, 3H), 2.03 (br d, J=5.6 Hz, 3H), 0.85-0.74 (m, 3H); F NMR (400 MHZ, METHANOL-d4) =112.440, 121.071, 128.148, 138.836, 173.900; LCMS (ESI, M+1): m/z=697.4. Example 908 ##STR00811## 2-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)acetamide ##STR00812## [1384] Step A. tert-butyl 1-(((methylsulfonyl)oxy)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (300 mg, 1.0 equiv) and TEA (3.77 g, 30 equiv) in THF (5.0 mL) was added methylsulfonyl methanesulfonate (2.17 g, 10 equiv). The reaction was stirred at 25 C. for 2 hours. The mixture was diluted with cold water (15 mL) and extracted with ethyl acetate (35.0 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound (397 mg, crude) as a yellow oil. [1385] Step B. tert-butyl 1-(cyanomethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of tert-butyl 1-(((methylsulfonyl)oxy)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (397 mg, 1.0 equiv) in DMSO (6.0 mL) were added KI (309 mg, 1.5 equiv) and KCN (425 mg, 5.3 equiv). The reaction was stirred at 100 C. for 5 hours. The mixture was quenched with water (24 mL) at 25 C. and extracted with ethyl acetate (310 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=20/1 to 5/1) to afford the title compound (120 mg, 38% yield) as a yellow oil; .sup.1H NMR (400 MHZ, CDCl.sub.3) =3.99-3.67 (m, 2H), 2.90-2.64 (m, 2H), 2.41 (s, 2H), 2.36-2.22 (m, 1H), 1.91-1.75 (m, 1H), 1.75-1.60 (m, 3H), 1.57-1.51 (m, 2H), 1.46 (s, 9H). [1386] Step C. tert-butyl 1-(2-amino-2-oxoethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of tert-butyl 1-(cyanomethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (50.0 mg, 1.0 equiv) and K.sub.2CO.sub.3 (55.2 mg, 2.0 equiv) in DMSO (1.3 mL) was added H.sub.2O.sub.2 (212 mg, 9.4 equiv). The reaction was stirred at 60 C. for 6 hours. The mixture was diluted with cold water (6.0 mL) and extracted with EtOAc (34.0 mL). The combined organic layers were washed with saturated Na.sub.2SO.sub.3 solution (2 mL), brine (2 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford the title compound (50.0 mg, crude) as a colorless oil. [1387] Step D. 2-(3-azabicyclo[3.2.1]octan-1-yl)acetamide: To a solution of tert-butyl 1-(2-amino-2-oxoethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (50.0 mg, 1.0 equiv) in MeOH (0.50 mL) was added HCl.Math.MeOH (4.0 M, 0.50 mL, 11 equiv). The reaction was stirred at 0-5 C. for 6 hours. The mixture was concentrated under reduced pressure, diluted with MeOH (2.0 mL), adjusted to pH=7-8 with solid NaHCO.sub.3 and filtered. The filtrate was concentrated to afford the title compound (60 mg, crude) as a light yellow solid. [1388] Step E. 2-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)acetamide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30.0 mg, 1.0 equiv) and 2-(3-azabicyclo[3.2.1]octan-1-yl)acetamide (17.7 mg, 2.0 equiv) in DMF (0.30 mL) were added 4 molecular sieve (20.0 mg) and K.sub.3PO.sub.4 (33.5 mg, 3.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and the filtrate was purified by prep-HPLC [column: Waters xbridge 15025 mm 10 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; B %: 37%-67%, 10 min] to afford the title compound (5.92 mg, 7.3% yield) as an off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.08 (s, 1H), 7.75-7.62 (m, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.12-7.03 (m, 1H), 5.41-5.24 (m, 1H), 5.07-4.98 (m, 2H), 4.39-4.22 (m, 2H), 3.72-3.61 (m, 1H), 3.52-3.40 (m, 2H), 3.26-3.16 (m, 2H), 3.08-2.97 (m, 1H), 2.53-2.45 (m, 2H), 2.42-2.34 (m, 2H), 2.25 (br d, J=16.4 Hz, 1H), 2.21-2.13 (m, 2H), 2.07-1.93 (m, 3H), 1.88 (br d, J=12.0 Hz, 2H), 1.79-1.71 (m, 2H), 1.69-1.60 (m, 1H), 1.59-1.48 (m, 1H), 1.35-1.28 (m, 1H), 0.86-0.74 (m, 3H); LCMS (ESI, M+1): m/z=661.2. Example 909 ##STR00813## 3-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)-N-methylpropanamide ##STR00814## ##STR00815## [1389] Step A. tert-butyl 1-formyl-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (2.0 g, 1.0 equiv) in DCM (40 mL) was added DMP (5.27 g, 1.5 equiv). The reaction was stirred at 0 C. for 2 hours. The mixture was quenched with saturated aqueous NaHCO.sub.3 (2 mL) and extracted with DCM (32 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel chromatography (Petroleum ether/Ethyl acetate 50/1, 3/1) to afford the title compound (2 g, crude) as colorless oil. [1390] Step B. tert-butyl(E)-1-(3-ethoxy-3-oxoprop-1-en-1-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of ethyl 2-diethoxyphosphorylacetate (2.25 g, 1.2 equiv) in THF (20 mL) was added NaH (501 mg, 60% purity, 1.5 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hours. tert-butyl 1-formyl-3-azabicyclo[3.2.1]octane-3-carboxylate (2.0 g, 1.0 equiv) was added. The reaction was stirred at 25 C. for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (320 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated to afford the title compound (2.23 g, 86% yield) as yellow oil. [1391] Step C. tert-butyl 1-(3-ethoxy-3-oxopropyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of tert-butyl(E)-1-(3-ethoxy-3-oxoprop-1-en-1-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate (2.23 g, 1.0 equiv) in MeOH (20 mL) was added Pd/C (500 mg, 10% purity) under N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The reaction was stirred under H.sub.2 (15 Psi) for 0.5 hours at 25 C. The mixture was filtered and the filtrate was concentrated in vacuum to afford the title compound (1.60 g, 71% yield) as colorless oil; .sup.1H NMR (400 MHZ, chloroform-d) =4.20-4.06 (m, 2H), 3.94-3.58 (m, 2H), 2.88-2.51 (m, 2H), 2.39-2.25 (m, 2H), 2.25-2.14 (m, 1H), 1.79-1.60 (m, 5H), 1.52 (br s, 1H), 1.46 (s, 9H), 1.39-1.30 (m, 2H), 1.26 (br t, J=7.2 Hz, 3H). [1392] Step D. ethyl 3-(3-azabicyclo[3.2.1]octan-1-yl) propanoate: To a solution of tert-butyl 1-(3-ethoxy-3-oxopropyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (200 mg, 1.0 equiv) in acetonitrile (1 mL) was added HCl.Math.dioxane (4 M, 2.0 mL, 12 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hours. The mixture was concentrated in vacuum to afford the title compound (150 mg, crude, HCl) as colorless oil. [1393] Step E. ethyl 3-(3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl) propanoate: To a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (150 mg, 1.0 equiv), DIEA (152 mg, 5.0 equiv) and ethyl 3-(3-azabicyclo[3.2.1]octan-1-yl) propanoate (146 mg, 2.5 equiv, HCl) in DMF (0.5 mL) was added 4 molecular sieve (50 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (110 mg, 62% yield) as a yellow solid; LCMS (ESI, M+1): m/z=748.4. [1394] Step F. 3-(3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl) propanoic acid: To a solution of ethyl 3-(3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl) propanoate (110 mg, 1.0 equiv) in MeOH (1 mL) was added LiOH (2 M, 294 L, 4.0 equiv). The reaction was stirred at 25 C. for 3 hours. The mixture was acidified with 1M HCl (0.5 mL) and extracted with ethyl acetate (31 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated to afford the title compound (110 mg, crude) as a yellow solid. [1395] Step G. 3-(3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)-N-methylpropanamide: To a mixture of 3-(3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl) propanoic acid (80 mg, 1.0 equiv) and methanamine hydrochloride (15 mg, 2.0 equiv) in DMF (1 mL) were added HATU (63.4 mg, 1.5 equiv) and DIEA (71.8 mg, 5.0 equiv). The reaction was stirred at 25 C. for 0.5 hours. The mixture was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (40 mg, 46% yield) as a yellow solid; LCMS (ESI, M+1): m/z=733.5. [1396] Step H. 3-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)-N-methylpropanamide: To a solution of 3-(3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)-N-methylpropanamide (35 mg, 1.0 equiv) in MeCN (0.2 mL) was added HCl.Math.dioxane (4 M, 0.4 mL, 33 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hours. The mixture was concentrated, diluted with acetonitrile (1.0 ml), neutralized with solid NaHCO.sub.3, concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (ammonia hydroxide v/v), B: ACN, B %: 37%-67% over 8 min] to afford the title compound (7.21 mg, 21% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.05 (d, J=2.0 Hz, 1H), 7.65 (dd, J=5.6, 8.8 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.23 (t, J=9.2 Hz, 1H), 7.05 (t, J=2.4 Hz, 1H), 5.39-5.22 (m, 1H), 4.69-4.57 (m, 2H), 4.37-4.19 (m, 2H), 3.71-3.61 (m, 1H), 3.44-3.34 (m, 2H), 3.29-3.16 (m, 3H), 3.07-2.95 (m, 1H), 2.72 (d, J=2.4 Hz, 3H), 2.54-2.42 (m, 2H), 2.35-2.22 (m, 3H), 2.21-2.10 (m, 2H), 2.05-1.95 (m, 2H), 1.94-1.73 (m, 5H), 1.70-1.43 (m, 4H), 0.85-0.75 (m, 3H); LCMS (ESI, M+1): m/z=689.5. Example 910 ##STR00816## 3-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)propanamide ##STR00817## [1397] Step A. 3-(3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl) propanamide: To a mixture of 3-(3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl) propanoic acid (50 mg, 1.0 equiv) in DMF (0.5 mL) were added NH.sub.4Cl (7.43 mg, 2.0 equiv), HATU (39.6 mg, 1.5 equiv) and DIEA (44.9 mg, 5.0 equiv). The reaction was stirred at 25 C. for 0.5 hours. The mixture was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (20 mg, 37% yield) as yellow solid; LCMS (ESI, M+1): m/z=719.4. [1398] Step B. 3-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl) propanamide: To a solution of 3-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl) propanamide (15 mg, 1.0 equiv) in acetonitrile (0.2 mL) was added HCl.Math.dioxane (4.0 M, 306 L, 59 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hours. The mixture was concentrated, diluted with MeCN (1 ml) and neutralized with solid NaHCO.sub.3. The mixture was filtered, concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 38%-68% over 9 min]. The desired fractions were collected and concentrated under vacuum to remove acetonitrile. The aqueous layers was lyophilized to afford the title compound (3.21 mg, 22% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.07 (d, J=2.4 Hz, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.07 (t, J=2.8 Hz, 1H), 5.41-5.21 (m, 1H), 4.74-4.60 (m, 2H), 4.36-4.20 (m, 2H), 3.73-3.62 (m, 1H), 3.44-3.34 (m, 2H), 3.30-3.18 (m, 3H), 3.08-2.97 (m, 1H), 2.55-2.43 (m, 2H), 2.38-2.23 (m, 3H), 2.22-2.12 (m, 2H), 2.07-1.95 (m, 2H), 1.95-1.74 (m, 5H), 1.72-1.60 (m, 2H), 1.59-1.45 (m, 2H), 0.87-0.74 (m, 3H); LCMS (ESI, M+1): m/z=675.5. Example 911 ##STR00818## 2-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)-N,N-dimethylacetamide ##STR00819## [1399] Step A. 2-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.1]octan-1-yl) acetic acid: A mixture of tert-butyl 1-(cyanomethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (350 mg, 1.0 equiv), NaOH (10 M, 1.50 mL, 10.7 equiv) in EtOH (1.5 mL) was stirred at 80 C. for 48 hours under N.sub.2 atmosphere. The mixture was adjusted to pH=5 with HCl (2 M), extracted with EtOAc (50 mL3), washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford the title compound (300 mg, crude) as a yellow oil. LCMS (ESI, M1): m/z=268.0 [1400] Step B. tert-butyl 1-(2-(dimethylamino)-2-oxoethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of 2-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.1]octan-1-yl) acetic acid (40 mg, 1.0 equiv) and DIEA (86.4 mg, 4.50 equiv) in DMF (1.0 mL) was added HATU (169 mg, 3.0 equiv). The reaction mixture was stirred at 25 C. for 1 hour. N-methylmethanamine (2 M, 446 L, 6.0 equiv) was added. The reaction was stirred at 25 C. for 12 hours. The mixture was extracted with EtOAc (20 mL3), washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by reversed-phase HPLC (0.1% FA condition) to afford the title compound (30 mg, 62% yield) as a yellow oil. .sup.1H NMR (400 MHZ, CHLOROFORM-d) =3.92-3.71 (m, 2H), 3.03 (s, 3H), 2.94 (s, 3H), 2.87-2.72 (m, 2H), 2.50-2.33 (m, 2H), 2.20 (br d, J=18.8 Hz, 1H), 1.72-1.53 (m, 6H), 1.46 (s, 9H); LCMS (ESI, M+1): m/z=297.1. [1401] Step C. 2-(3-azabicyclo[3.2.1]octan-1-yl)-N,N-dimethylacetamide: To a solution of tert-butyl 1-(2-(dimethylamino)-2-oxoethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (35 mg, 1.0 equiv) in MeOH (0.2 mL) was added HCl.Math.MeOH (4.0 M, 13 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hours. The mixture was concentrated in vacuum to afford the title compound (27.0 mg, crude, HCl) as yellow solid; LCMS (ESI, M+1): m/z=196.7. [1402] Step D. 2-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)-N,N-dimethylacetamide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30 mg, 1.0 equiv) and 2-(3-azabicyclo[3.2.1]octan-1-yl)-N,N-dimethylacetamide (23.6 mg, 2.0 equiv, HCl) in DMF (0.5 mL) were added DIEA (32.7 mg, 5.0 equiv) and 4 molecular sieve (10.0 mg, 1.0 equiv). The reaction was stirred at 40 C. for 12 hours. K.sub.3PO.sub.4 (21.5 mg, 2.0 equiv) was added. The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 48%-78% over 9 min] to afford the title compound (9.18 mg, 25% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.09 (d, J=5.2 Hz, 1H), 7.67 (dd, J=6.0, 8.8 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.24 (t, J=9.6 Hz, 1H), 7.07 (dd, J=2.4, 7.2 Hz, 1H), 5.44-5.20 (m, 1H), 4.73-4.62 (m, 2H), 4.41-4.18 (m, 2H), 3.67-3.56 (m, 1H), 3.56-3.44 (m, 1H), 3.27-3.15 (m, 3H), 3.11 (s, 3H), 3.06-2.98 (m, 1H), 2.93 (s, 3H), 2.73-2.54 (m, 2H), 2.52-2.41 (m, 2H), 2.25-2.10 (m, 3H), 2.05-1.96 (m, 2H), 1.95-1.79 (m, 4H), 1.78-1.70 (m, 1H), 1.65-1.50 (m, 2H), 1.36-1.26 (m, 1H), 0.86-0.75 (m, 3H); LCMS (ESI, M+1): m/z=689.4. Example 912 ##STR00820## amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophene-3- ##STR00821## [1403] Step A. (E)-N-(3-cyano-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophen-2-yl)-N,N-dimethylformimidamide: To a solution of (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (160 mg, 1.0 equiv) and (E)-N-(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)-N,N-dimethylformimidamide (150 mg, 1.2 equiv) in DMAc (4 mL) were added K.sub.3PO.sub.4 (1.5 M in H.sub.2O, 660 L, 3.0 equiv) and Brettphos Pd G4 (30.4 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 80 C. for 4.5 hours. The mixture was diluted with H.sub.2O (10 mL) and extracted with EtOAc (410 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [water (FA, 0.1%)/acetonitrile=3/2] to afford the title compound (40.0 mg, 18% yield) as light yellow solid; LCMS (ESI, M+1): m/z=665.2. [1404] Step B 2-amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophene-3-carbonitrile: To a solution of (E)-N-(3-cyano-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophen-2-yl)-N,N-dimethylformimidamide (40 mg, 1.0 equiv) in DMAc (1 mL) was added K.sub.3PO.sub.4 (1.5 M in H.sub.2O, 1 mL). The reaction was stirred at 80 C. for 1 hour. The mixture was diluted with H.sub.2O (6 mL) and extracted with EtOAc (43 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Waters xbridge 15025 mm10 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; B %: 37%-67% over 10 minutes] to afford the title compound (5.63 mg, 35% yield) as green solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.20 (s, 1H), 7.41 (dd, J=5.2, 8.4 Hz, 1H), 7.05 (t, J=8.8 Hz, 1H), 5.38-5.23 (m, 1H), 4.51-4.47 (m, 1H), 4.34-4.22 (m, 3H), 3.65-3.61 (m, 1H), 3.49-3.39 (m, 1H), 3.28-3.17 (m, 3H), 3.05-2.95 (m, 1H), 2.25-2.12 (m, 4H), 2.01-1.74 (m, 6H), 1.27 (s, 3H); LCMS (ESI, M+1): m/z=610.2. Example 913 ##STR00822## 3-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)-N,N-dimethylpropanamide ##STR00823## [1405] Step A. 3-(3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)-N,N-dimethylpropanamide: To a solution of 3-(3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl) propanoic acid (60 mg, 1.0 equiv) and N-methylmethanamine (2.0 M, 2.0 equiv) in DMF (0.5 mL) was added HATU (47.5 mg, 1.5 equiv) and DIEA (32.3 mg, 3.0 equiv). The reaction was stirred at 25 C. for 0.5 hours. The mixture was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (27 mg, 43% yield) as a white solid; LCMS (ESI, M+1): m/z=747.8. [1406] Step B. 3-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)-N,N-dimethylpropanamide: To a solution of 3-(3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)-N,N-dimethylpropanamide (22 mg, 1.0 equiv) in MeCN (0.2 mL) was added HCl.Math.dioxane (4.0 M, 68 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hours. The mixture was basified with saturated aqueous NaHCO.sub.3 (0.5 mL) and extracted with ethyl acetate (33 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 45%-75% over 9 min] to afford the title compound (2.52 mg, 12% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.11-9.03 (m, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (t, J=9.2 Hz, 1H), 7.06 (d, J=2.8 Hz, 1H), 5.40-5.20 (m, 1H), 4.66 (br d, J=11.2 Hz, 2H), 4.35-4.22 (m, 2H), 3.71-3.62 (m, 1H), 3.50-3.38 (m, 2H), 3.25-3.14 (m, 3H), 3.10 (s, 3H), 3.04-2.99 (m, 1H), 2.95 (s, 3H), 2.55-2.43 (m, 4H), 2.28-2.12 (m, 3H), 2.04-1.96 (m, 2H), 1.92-1.76 (m, 5H), 1.71-1.50 (m, 4H), 0.86-0.75 (m, 3H); LCMS (ESI, M+1): m/z=703.4. Example 914 ##STR00824## 2-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)-N-methylacetamide ##STR00825## [1407] Step A. tert-butyl 1-(2-(methylamino)-2-oxoethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of 2-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.1]octan-1-yl) acetic acid (150 mg, 1.0 equiv) and methanamine;hydrochloride (75.2 mg, 2.0 equiv) in DMF (1.0 mL) were added DIEA (360 mg, 5.0 equiv) and HATU (318 mg, 1.5 equiv). The reaction was stirred at 25 C. for 0.5 hours. The mixture was quenched with water (3 mL) and extracted with ethyl acetate (3 3 mL). The combined the organic layers were dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified with reversed phase flash chromatography [water (0.1% FA)/acetonitrile] to afford the title compound (97 mg. 62% yield,) as a yellow solid. LCMS (ESI, M1): m/z=283.3. [1408] Step B. 2-(3-azabicyclo[3.2.1]octan-1-yl)-N-methylacetamide: To a solution of tert-butyl 1-(2-(methylamino)-2-oxoethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (80 mg, 1.0 equiv) in MeOH (0.5 mL) was added HCl/MeOH (4.0 M, 14 equiv) at 0 C. The reaction was stirred at 25 C. for 0.5 hours. The reaction was concentrated to afford the title compound (61 mg, crude, HCl) as a yellow solid; LCMS (ESI, M+1): m/z=182.7. [1409] Step C. 2-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-1-yl)-N-methylacetamide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (80 mg, 1.0 equiv) and 2-(3-azabicyclo[3.2.1]octan-1-yl)-N-methylacetamide (51 mg, 1.7 equiv, HCl) in DMF (1 mL) was added 4 molecular sieve (40 mg, 1.0 equiv) and K.sub.3PO.sub.4 (143 mg, 5.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was filtered and purified by prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 38%-68% over 9 min] to afford the title compound (9.45 mg, 10% yield) as a white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.07 (s, 1H), 7.67 (dd, J=5.6, 8.8 Hz, 1H), 7.34-7.19 (m, 2H), 7.06 (dd, J=2.4, 5.2 Hz, 1H), 5.44-5.20 (m, 1H), 5.09-4.95 (m, 2H), 4.38-4.21 (m, 2H), 3.69-3.56 (m, 1H), 3.47-3.39 (m, 1H), 3.30-3.12 (m, 3H), 3.09-2.97 (m, 1H), 2.73 (s, 3H), 2.55-2.44 (m, 2H), 2.43-2.33 (m, 2H), 2.33-2.11 (m, 4H), 2.06-1.96 (m, 2H), 1.95-1.79 (m, 3H), 1.77-1.67 (m, 2H), 1.66-1.49 (m, 2H), 0.89-0.71 (m, 3H); LCMS (ESI, M+1): m/z=675.5. Example 915 ##STR00826## (5R)-7-(7-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione ##STR00827## [1410] Step A. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv), 5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole (348 mg, 1.2 equiv) and K.sub.3PO.sub.4 (1.5 M in water, 3.0 equiv) in toluene (7 mL) was added and Aphos Pd G3 (45.2 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 70 C. for 16 hours. The mixture was diluted with H.sub.2O (10 mL) and extracted with ethyl acetate (215 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (160 mg, 29% yield) as a yellow solid; LCMS (ESI, M+1): m/z=701.2. [1411] Step B. (5R)-7-(7-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole (150 mg, 1.0 equiv) and (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (72.0 mg, 2 equiv) in DMF (0.5 mL) was added DIEA (55.3 mg, 2.0 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was diluted with H.sub.2O (10 mL) and extracted with ethyl acetate (215 mL). The combined organic layers were washed with brine (35 mL), dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 61% yield) a yellow oil; LCMS (ESI, M+1): m/z=770.3. [1412] Step C. (5R)-7-(7-(5-ethyl-6-fluoro-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of (5R)-7-(7-(5-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (90.0 mg, 1.0 equiv) in DCM (2 mL) was added TFA (4 ml) at 0 C. The reaction was stirred at 20 C. for 0.5 hours. The mixture was diluted with NaHCO.sub.3 aqueous (10 mL) and extracted with ethyl acetate (215 mL). The combined organic layer was concentrated and purified with prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 11%-41% over 10 min] and lyophilized to afford the title compound (17.9 mg, 21% yield, 0.45 HCOOH) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.25 (s, 1H), 8.26 (s, 1H), 8.02 (dd, J=6.0, 9.2 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.34 (t, J=9.6 Hz, 1H), 5.53-5.32 (m, 1H), 4.73-4.49 (m, 3H), 4.48-4.40 (m, 2H), 3.93-3.74 (m, 2H), 3.66-3.45 (m, 3H), 3.25-3.16 (m, 1H), 2.73-2.53 (m, 1H), 2.46-2.34 (m, 2H), 2.32-2.22 (m, 2H), 2.19-1.93 (m, 6H), 0.86 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=686.2. Example 916 ##STR00828## (R)-2-amino-7-fluoro-4-(8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophene-3-carbonitrile ##STR00829## [1413] Step A. (R)-1-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of 7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (350 mg, 1.0 equiv) and DIEA (215 mg, 2.0 equiv) in DMF (3 mL) was added (3R)-3-methylpiperidin-3-ol (144 mg, 1.5 equiv) at 40 C. The reaction was stirred at 40 C. for 14 hours. The mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (180 mg, 48% yield) as light yellow solid; LCMS (ESI, M+1): m/z=436.2. [1414] Step B. (R,E)-N-(3-cyano-7-fluoro-4-(8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophen-2-yl)-N,N-dimethylformimidamide: To a solution of (R)-1-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (160 mg, 1.0 equiv) and (E)-N-(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)-N,N-dimethylformimidamide (160 mg, 1.2 equiv) in DMAc (4 mL) were added K.sub.3PO.sub.4 (1.5 M in H.sub.2O, 3.0 equiv) and Brettphos Pd G4 (33.8 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 80 C. for 4.5 hours. The mixture was diluted with H.sub.2O (10 mL) and extracted with EtOAc (410 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (160 mg, 55% yield) as brown solid; LCMS (ESI, M+1): m/z=647.3. [1415] Step C. (R)-2-amino-7-fluoro-4-(8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophene-3-carbonitrile: To a solution of (R,E)-N-(3-cyano-7-fluoro-4-(8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophen-2-yl)-N,N-dimethylformimidamide (150 mg, 1.0 equiv) in DMAc (2 mL) was added K.sub.3PO.sub.4 (1.5 M in H.sub.2O, 1.50 mL). The reaction was stirred at 80 C. for 0.5 hours. The mixture was diluted with H.sub.2O (6 mL) and extracted with EtOAc (45 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC [column: Phenomenex luna C18 150 25 mm10 m; A: water (FA), B: ACN, B %: 11%-41% over 10 minutes] to afford the title compound (50.1 mg, 35% yield, 0.88 HCOOH) as yellow solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.27 (s, 1H), 7.43 (dd, J=5.2, 8.4 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H), 4.64-4.60 (s, 2H), 4.60-4.56 (m, 1H), 4.34-4.30 (m, 1H), 3.70-3.58 (m, 3H), 3.49-3.38 (m, 1H), 3.28-3.17 (m, 2H), 2.33-2.29 (m, 2H), 2.25-2.01 (m, 7H), 1.92-1.71 (m, 3H), 1.29 (s, 3H); LCMS (ESI, M+1): m/z=592.2. Example 917 ##STR00830## (R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00831## [1416] Step A. (R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a suspension of (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (700 mg, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (500 mg, 1.2 equiv) and K.sub.3PO.sub.4 (1.5 M, 3.08 mL, 3.0 equiv) in methoxycyclopentane (10 mL) was added AdanBuP Pd G3 (196 mg, 0.20 equiv). The reaction was degassed and purged with nitrogen for 3 times. The reaction was stirred at 70 C. for 16 hours. The mixture was diluted with water (10 mL) and extracted with dichloromethane (415 mL). The combined organic layers were washed with brine (310 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Waters Xbridge Prep OBD C18 15040 mm10 um; mobile phase: A: water (NH.sub.4HCO.sub.3), B: ACN, 25%-55% over 10 min] and prep-HPLC [Phenomenex luna C18 15040 mm15 m, A: water (FA), B: ACN, 12%-42% over 15 min] to afford the title compound (130 mg, 14% yield) as yellow solid; .sup.1H NMR (400 MHZ, DMSO) =9.30 (s, 1H), 8.18 (s, 1H), 7.82-7.80 (m, J=8.4 Hz, 1H), 7.57-7.54 (m, J=12.0 Hz, 1H), 7.45 (m, 1H), 7.30-7.23 (m, 3H), 5.36-5.22 (d, 1H), 4.39-4.35 (d, 1H), 4.17-4.04 (m, 3H), 3.62-2.75 (m, 6H), 2.07 (m, J=2.0 Hz, 1H), 2.02 (m, 3H), 1.78-1.66 (m, 6H), 1.18 (s, 3H); LCMS (ESI, M+1): m/z=562.4. Example 918 ##STR00832## (R)-1-(2-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol Example 919 ##STR00833## (R)-1-(2-(((R)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00834## [1417] Step A: ethyl 2-(difluoromethylene)-5-oxohexahydro-1H-pyrrolizine-7a-carboxylate: To a mixture of ethyl 2,5-dioxohexahydro-1H-pyrrolizine-7a-carboxylate and 2-((difluoromethyl) sulfonyl)pyridine (7.13 g, 1.3 equiv) in DMF (60 mL) was added a solution of t-BuOK (5.74 g, 1.8 equiv) in DMF (10 mL) at 40 C. under N.sub.2. The reaction was stirred at 40 C. for 2 hours and 20 C. for 1 hour. The mixture was quenched with NH.sub.4Cl (50 mL) and 3M HCl (60 mL). The reaction was stirred at 20 C. for 30 minutes. The mixture was extracted with ethyl acetate (320 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified with silica gel chromatography and reversed phase flash chromatography to afford the title compound (1.30 g, 44% yield) as yellow oil, .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =4.35-4.31 (m, 1H), 4.24-4.18 (m, 2H), 3.74 (d, J=14.4 Hz, 1H), 3.13 (d, J=15.6 Hz, 1H), 2.81-2.72 (m, 1H), 2.63 (t, J=12.0 Hz, 1H), 2.48-2.36 (m, 2H), 2.71-2.08 (m, 1H), 1.29-1.25 (m, 3H). [1418] Step B: (2-(difluoromethylene) hexahydro-1H-pyrrolizin-7a-yl)methanol: To a solution of ethyl 2-(difluoromethylene)-5-oxohexahydro-1H-pyrrolizine-7a-carboxylate (1.00 g, 1.0 equiv) in THF (10 mL) was added DIBAL-H (1 M, 10.0 equiv) at 70 C. The reaction was stirred at 70 C. for 1 hour. The mixture was quenched with Na.sub.2SO.sub.4.Math.10H.sub.2O at 0 C. and stirred at 20 C. for 1 hour. The mixture was filtered, concentrated and purified by silica gel chromatography to afford the title compound (300 mg, 39% yield) as yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) =3.69 (d, J=12.0 Hz, 1H), 3.40-3.29 (m, 3H), 3.15-3.13 (m, 1H), 2.67-2.64 (m, 1H), 2.49 (d, J=12.0 Hz, 1H), 2.38 (d, J=12.0 Hz, 1H), 2.00-1.95 (m, 1H), 1.89-1.84 (m, 2H), 1.71-1.76 (m, 1H). [1419] Step C. (3R)-1-(7-chloro-2-((2-(difluoromethylene) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: A mixture of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 1.00 equiv) and (2-(difluoromethylene) hexahydro-1H-pyrrolizin-7a-yl)methanol (114 mg, 1.0 equiv) in THF (4 mL) was added NaHMDS (1 M, 1.25 equiv) dropwise at 10 C. The reaction was stirred at 10 C. for 3 hours. The mixture was quenched with NH.sub.4Cl (5 mL) and extracted with ethyl acetate (2 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified with silica gel chromatography to afford the title compound (130 mg, 45% yield) as yellow solid; LCMS (ESI, M+1): m/z=484.3. [1420] Step D. (3R)-1-(2-((2-(difluoromethylene) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of (3R)-1-(7-chloro-2-((2-(difluoromethylene) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (130 mg, 1.0 equiv), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (116 mg, 1.2 equiv) and K.sub.3PO.sub.4 (171 mg, 3.0 equiv) in dioxane (2 mL) and H.sub.2O (0.5 mL) was added Pd(dtbpf) C12 (17.5 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 100 C. for 2 hrs. The mixture was diluted with ice-water (5 mL) and extracted with ethyl acetate (5 mL2). The combined organic phase was washed with brine (3 mL), dried over anhydrous sodium sulfate, concentrated, and purified with silica gel chromatography to afford the title compound (120 mg, 66% yield) as yellow solid; LCMS (ESI, M+1): m/z=682.6. [1421] Step E. (3R)-1-(2-((2-(difluoromethylene) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a mixture of compound (3R)-1-(2-((2-(difluoromethylene) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (110 mg, 1.0 equiv) in MeCN (1 mL) was added HCl.Math.dioxane (4 M, 12.4 equiv). The reaction was stirred at 20 C. for 1 hr. The mixture was concentrated and purified by prep-HPLC [column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (HCl)-ACN]; gradient: 22%-52% B over 8 min] to afford the title compound (45.6 mg, 44% yield, HCl) as yellow solid; .sup.1H NMR (400 MHz, METHANOL-d.sub.4) =9.63 (s, 1H), 7.77-7.74 (m, 1H), 7.42 (d, J=2.40 Hz, 1H), 7.33 (t, J=9.20 Hz, 1H), 7.21 (d, J=2.40 Hz, 1H), 5.00-4.94 (m, 2H), 4.63-4.57 (m, 1H), 4.49-4.45 (m, 1H), 4.17-4.14 (d, J=14.0 Hz, 1H), 3.74-3.70 (m, 1H), 3.51-3.50 (m, 1H), 3.41-3.35 (m, 1H), 3.17 (d, J=12.0 Hz, 1H), 2.99 (d, J=16.0 Hz, 1H), 2.51-2.19 (m, 8H), 1.92-1.90 (m, 3H), 1.40 (s, 3H), 0.93-0.88 (m, 3H); LCMS (ESI, M+1): m/z=638.3. [1422] Step F. (R)-1-(2-(((S)-2-(difluoromethylene) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol and (R)-1-(2-(((R)-2-(difluoromethylene) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: (3R)-1-(2-((2-(difluoromethylene) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (40 mg) was separated by SFC [column: Chiralpak IG-3 50*4.6 mm I.D., 3 um Mobile phase: Phase A for CO.sub.2, and Phase B for EtOH (0.05% DEA); Gradient elution: 30% EtOH (0.05% DEA) in CO.sub.2, Flow rate: 3 mL/min; Detector: PDA; Colum Temp: 35C; Back Pressure: 100Bar] to give two peaks [1423] Peak 1 Example 918: (R)-1-(2-(((S)-2-(difluoromethylene) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (peak1) (12.0 mg, 30% yield) .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.11 (s, 1H), 7.59-7.55 (m, 1H), 7.19 (d, J=4.00 Hz, 1H), 7.14 (t, J=12.0 Hz, 1H), 6.95 (s, 1H), 4.50-4.42 (m, 1H), 4.31-4.28 (m, 1H), 4.22-4.16 (m, 2H), 3.68 (d, J=24.0 Hz, 1H), 3.57-3.47 (m, 1H), 3.39-3.32 (m, 1H), 3.07-3.03 (m, 1H), 2.69 (d, J=16.0 Hz, 1H), 2.64-2.58 (m, 1H), 2.43-2.35 (m, 2H), 2.13-2.02 (m, 3H), 1.92-1.89 (m, 1H), 1.85-1.78 (m, 2H), 1.77-175 (m, 2H); 1.72-1.66 (m, 2H), 1.20-1.17 (m, 3H), 0.74-0.69 (m, 3H); LCMS (ESI, M+1): m/z=638.4; SFC: Rt=1.338 [1424] Peak 2 Example 919: (R)-1-(2-(((R)-2-(difluoromethylene) hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (8.20 mg, 20% yield); .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.24 (s, 1H), 7.72-7.68 (m, 1H), 7.33 (d, J=4.00 Hz, 1H), 7.27 (t, J=8.00 Hz, 1H), 7.08 (s, 1H), 4.59-4.55 (m, 1H), 4.49 (d, J=12.0 Hz, 1H), 4.40-4.29 (m, 2H), 3.96-3.92 (m, 2H), 3.69-3.62 (m, 1H), 3.55-3.45 (m, 2H), 3.28-3.25 (m, 1H), 2.89-2.83 (m, 2H), 2.62 (d, J=12.0 Hz, 1H), 2.52-2.47 (m, 1H), 2.25-2.16 (m, 3H), 2.08-1.97 (m, 3H), 1.91-1.78 (m, 3H), 1.33 (d, J=8.00 Hz, 3H); 0.86-0.80 (m, 3H); LCMS (ESI, M+1): m/z=638.4; SFC: Rt=1.815 Example 920 ##STR00835## (1R,5R,6R)-3-(7-(3-chloro-5-hydroxy-2-(cis-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00836## [1425] Step A. 7-(3-chloro-5-(methoxymethoxy)-2-(cis-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (450 mg, 1.0 equiv) and 2-(3-chloro-5-(methoxymethoxy)-2-(cis-2-methylcyclopropyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (362 mg, 1.0 equiv) in methoxycyclopentane (5 mL) and water (1.3 mL) were added CataCXium A Pd G3 (149 mg, 0.2 equiv) and Cs.sub.2CO.sub.3 (1.00 g, 3.0 equiv). The reaction was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 90 C. for 10 hours under N.sub.2 atmosphere. The mixture was diluted with water (50 mL) and extracted with EtOAc (250 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=10/1 to 0/1] to afford the title compound (320 mg, 40% yield) as yellow solid; LCMS (ESI, M+1): m/z=629.2. [1426] Step B. (1R,5R,6R)-3-(7-(3-chloro-5-(methoxymethoxy)-2-(cis-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 7-(3-chloro-5-(methoxymethoxy)-2-(cis-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (320 mg, 1.0 equiv) in DMF (6 mL) were added (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (104 mg, 2.0 equiv), DIEA (105 mg, 2.0 equiv) and 4 molecular sieve (50.0 mg). The reaction was stirred at 40 C. for 24 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (330 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, ethyl acetate/ethanol=1/0 to 1/1] to afford the title compound (277 mg, 77% yield) as yellow solid; LCMS (ESI, M+1): m/z=656.4. [1427] Step C. (1R,5R,6R)-3-(7-(3-chloro-5-hydroxy-2-(cis-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(3-chloro-5-(methoxymethoxy)-2-(cis-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (220 mg, 1.0 equiv) in acetonitrile (2 mL) was added HCl.Math.dioxane (4 M, 2 mL) at 0 C. The reaction was stirred at 0 C. for 3 hours. The mixture was concentrated, dissolved in MeOH (2 mL), adjusted to pH=7 with solid NaHCO.sub.3 and filtered. The filtrate was concentrated and purified with prep-HPLC [neutral condition; column: Waters Xbridge 15025 mm5 m; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; gradient: 40%-70% B over 9 min] to afford the title compound (73.8 mg, 48% yield) as white solid; 1HNMR (400 MHZ, DMSO-d.sub.6) =9.97 (s, 1H), 9.35-9.25 (m, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.85-6.77 (m, 1H), 5.42-5.15 (m, 1H), 4.91-4.47 (m, 3H), 4.24-4.07 (m, 2H), 3.99 (dd, J=6.4, 10.0 Hz, 1H), 3.83-3.58 (m, 1H), 3.29 (d, J=12.4 Hz, 1H), 3.15-2.97 (m, 3H), 2.88-2.76 (m, 1H), 2.32 (s, 1H), 2.16-1.98 (m, 5H), 1.90-1.63 (m, 6H), 1.23 (d, J=13.2 Hz, 1H), 1.14-0.92 (m, 1H), 0.55 (s, 4H); LCMS (ESI, M+1): m/z=612.3. Example 921 ##STR00837## 4-(4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ##STR00838## [1428] Step A. 4-(4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (100 mg, 1.0 equiv) and 1,2,3,6-tetrahydropyridine (60.6 mg, 2.3 equiv, HCl) in DMF (1 mL) were added DIEA (109 mg, 5.0 equiv) and 4 molecular sieve (10.0 mg). The reaction was stirred at 40 C. for 1.5 hours. The mixture was filtered and purified by prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA); B: ACN; B %: 17%-47% over 10 min] to afford the title compound (21.8 mg, 21% yield, HCOOH) as light yellow solid; .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) =9.11 (s, 1H), 7.76 (dd, J=6.0, 9.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.03 (d, J=2.4 Hz, 1H), 6.03-5.78 (m, 2H), 5.39-5.16 (m, 1H), 4.48 (br s, 2H), 4.22-4.12 (m, 1H), 4.11-3.97 (m, 3H), 3.13-2.99 (m, 3H), 2.86-2.80 (m, 1H), 2.46-2.29 (m, 3H), 2.21-2.08 (m, 2H), 2.08-1.95 (m, 2H), 1.89-1.71 (m, 3H), 0.73 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=576.2. Example 922 ##STR00839## 4-(4-(8-thia-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ##STR00840## [1429] Step A. 4-(4-(8-thia-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (100 mg, 1.0 equiv) and 8-thia-3-azabicyclo[3.2.1]octane (31.7 mg, 1.5 equiv) in DMF (2 mL) was added K.sub.4PO.sub.3 (120 mg, 3.4 equiv). The reaction was stirred at 60 C. for 0.5 hours. The mixture was filtered and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA); B: ACN; B %: 17%-47% over 10 min] to afford the title compound (38.4 mg, 35% yield) as off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.20 (br d, J=4.4 Hz, 1H), 7.68 (dd, J=5.6, 9.2 Hz, 1H), 7.35-7.21 (m, 2H), 7.06 (d, J=2.8 Hz, 1H), 5.51-5.25 (m, 2H), 4.66-4.50 (m, 1H), 4.48-4.24 (m, 3H), 3.57-3.37 (m, 4H), 3.19-3.03 (m, 3H), 2.59-2.39 (m, 2H), 2.38-2.06 (m, 9H), 2.02-1.87 (m, 1H), 0.91-0.71 (m, 3H); LCMS (ESI, M+1): m/z=622.3. Example 923 ##STR00841## (1R,5R,6R)-3-(2-((2,6-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00842## [1430] Step A. (1R,5R,6R)-3-(2-((2,6-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (200 mg, 1.0 equiv) and (2,6-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (98.3 mg, 1.5 equiv) in THF (1 mL) and DMF (1 mL) were added Cs.sub.2CO.sub.3 (361 mg, 3.0 equiv) and DABCO (41.5 mg, 1.0 equiv). The reaction was stirred at 20 C. for 12 hours. The mixture was diluted with water (15 mL) and extracted with DCM (315 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 40% yield) as yellow solid; LCMS (ESI, M+1): m/z=682.2. [1431] Step B. (1R,5R,6R)-3-(2-((2,6-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-((2,6-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 equiv) in DCM (1 mL) was added TFA (1.5 mL). The reaction was stirred at 20 C. for 1 hour. The mixture was poured into saturated NaHCO.sub.3 aqueous (10 mL) at 0 C. and extracted with DCM (35 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 20%-40% over 10 minutes] to afford the title compound (22.1 mg, 25% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.21-9.07 (m, 1H), 7.58 (dd, J=5.6, 9.2 Hz, 1H), 7.25-7.09 (m, 2H), 6.97 (dd, J=2.4, 15.6 Hz, 1H), 5.32 (d, J=15.6 Hz, 1H), 5.19 (d, J=14.8 Hz, 1H), 4.74-4.61 (m, 1H), 4.40-4.16 (m, 3H), 3.80-3.61 (m, 1H), 3.53-3.33 (m, 2H), 3.33-3.23 (m, 2H), 3.20-3.08 (m, 2H), 2.48-2.35 (m, 2H), 2.33-2.21 (m, 3H), 2.20-1.94 (m, 4H), 1.87-1.79 (m, 1H), 1.75-1.68 (br d, J=12.0 Hz, 1H), 1.36-1.26 (m, 1H), 0.77-0.65 (m, 3H); LCMS (ESI, M+1): m/z=638.2. Example 924 ##STR00843## (1R,5R,6R)-3-(2-((2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00844## [1432] Step A. (1R,5R,6R)-3-(2-((2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (370 mg, 1.0 equiv) and (2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (182 mg, 1.5 equiv) in DMF (2 mL) and THF (2 mL) were added Cs.sub.2CO.sub.3 (223 mg, 1.0 equiv) and 1,4-diazabicyclo[2,2,2]octane (76.7 mg, 1.0 equiv). The reaction was stirred at 25 C. for 4 hours and 40 C. for 14 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (58 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (253 mg, 53% yield) as white solid; LCMS (ESI, M+1): m/z=682.3. [1433] Step B. (1R,5R,6R)-3-(2-((2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-((2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 equiv) in DCM (1 mL) was added TFA (727 mg, 49.0 equiv) at 0 C. The reaction was stirred at 20 C. for 1 hour. The mixture was dropped into saturated NaHCO.sub.3 aqueous (10 mL) at 0 C. and extracted with DCM (410 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN, B %: 30%-60% over 8 minutes] to afford the title compound (26.9 mg, 28% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.29-9.16 (m, 1H), 7.67 (dd, J=5.6, 8.8 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.24 (dt, J=2.0, 9.2 Hz, 1H), 7.06 (dd, J=2.4, 15.2 Hz, 1H), 5.06-4.92 (m, 1H), 4.84-4.73 (m, 1H), 4.40-4.21 (m, 3H), 3.86-3.72 (m, 1H), 3.53-3.38 (m, 2H), 3.23-3.07 (m, 2H), 2.85 (q, J=8.0 Hz, 1H), 2.67-2.54 (m, 1H), 2.53-2.44 (m, 1H), 2.41 (br s, 1H), 2.33 (br d, J=14.0 Hz, 1H), 2.29-2.09 (m, 4H), 2.05-78 (m, 5H), 1.44-1.42 (m, 1H), 0.80 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=638.6. Example 925 ##STR00845## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00846## [1434] Step A. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2S,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a mixture of (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (300 mg, 1.0 equiv) and ((2S,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (142 mg, 1.5 equiv) in DMF (2 mL) and THF (2 mL) were added Cs.sub.2CO.sub.3 (542 mg, 3.0 equiv) and DABCO (62.2 mg, 1.0 equiv). The reaction was stirred at 25 C. for 3 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (215 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (60.0 mg, 15% yield) as white solid; LCMS (ESI, M+1): m/z=676.3. [1435] Step B. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2S,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (50.0 mg, 1.0 equiv) in DCM (1 mL) was added TFA (1 mL, 182 equiv) at 0 C. The reaction was stirred at 25 C. for 0.5 hours. The mixture was diluted with saturated NaHCO.sub.3 aqueous (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 15%-45% over 10 min] to afford the title compound (25.3 mg, 53% yield, 0.13 HCOOH) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.31-9.22 (m, 1H), 7.69 (dd, J=6.0, 8.8 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H), 7.29-7.21 (m, 1H), 7.12-7.00 (m, 1H), 5.10-4.97 (m, 1H), 4.82-4.62 (m, 3H), 4.40-4.28 (m, 1H), 4.21 (br d, J=2.8 Hz, 1H), 3.92-3.78 (m, 2H), 3.64 (br dd, J=7.2, 11.2 Hz, 1H), 3.58-3.44 (m, 1H), 3.37 (dd, J=2.0, 6.8 Hz, 4H), 3.29-3.23 (m, 1H), 2.58-2.38 (m, 4H), 2.30-2.19 (m, 5H), 2.08 (br dd, J=3.2, 12.8 Hz, 2H), 2.01-1.90 (m, 1H), 1.88-1.76 (m, 1H), 1.45-1.32 (m, 1H), 0.86-0.74 (m, 3H); LCMS (ESI, M+1): m/z=632.3 Example 926 ##STR00847## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00848## [1436] Step A. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (207 mg, 1.0 equiv) and ((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (98.3 mg, 1.5 eq) in THF (1 mL) and DMF (1 mL) were added Cs.sub.2CO.sub.3 (374 mg, 3.0 equiv) and DABCO (42.9 mg, 1.0 equiv). The reaction was stirred at 25 C. for 3 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (100 mg, 30% yield) as white solid; LCMS (ESI, M+1): m/z=676.4. [1437] Step B. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (50.0 mg, 1.0 equiv) in MeOH (0.5 mL) was added HCl.Math.MeOH (4 M, 0.5 mL, 27 equiv) at 0 C. The reaction was stirred at 0 C. for 0.3 hours. The mixture was adjusted to pH=7 with saturated NaHCO.sub.3 (10 mL) and extracted with DCM (210 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified with [column: Phenomenex luna C18 15025 mm10 um; mobile phase: A: water (FA), B: ACN, B %: 16%-46% over 10 min] to afford the title compound (20.9 mg, 43% yield, 0.3HCOOH) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.33-9.15 (m, 1H), 7.68 (br dd, J=6.0, 8.4 Hz, 1H), 7.37-7.19 (m, 2H), 7.06 (dd, J=2.4, 15.2 Hz, 1H), 4.48-4.27 (m, 3H), 4.17 (br s, 1H), 3.94-3.72 (m, 1H), 3.58-3.39 (m, 3H), 3.35 (s, 3H), 3.25-3.10 (m, 4H), 2.53-2.31 (m, 3H), 2.30-2.21 (m, 2H), 2.20-2.07 (m, 5H), 1.94 (br d, J=11.6 Hz, 2H), 1.86-1.78 (m, 1H), 1.44-1.32 (m, 1H), 0.79-0.79 (m, 1H), 0.80 (br d, J=5.6 Hz, 2H); LCMS (ESI, M+1): m/z=632.3. Example 927 ##STR00849## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicycle[3.2.1]octan-6-ol ##STR00850## [1438] Step A. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (300 mg, 1.0 equiv) and ((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (132 mg, 1.5 equiv) in THF (1.5 mL) and DMF (1.5 mL) were added Cs.sub.2CO.sub.3 (542 mg, 3.0 equiv) and DABCO (62.2 mg, 1.0 equiv). The reaction was stirred at 20 C. for 12 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (35 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (130 mg, 34% yield) as yellow solid; LCMS (ESI, M+1): m/z=664.3. [1439] Step B. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (120 mg, 1.0 equiv) in MeOH (0.5 mL) was added HCl.Math.MeOH (4 M, 1.0 mL). The reaction was stirred at 0 C. for 0.5 hours. The mixture was adjusted to pH=8 with saturated NaHCO.sub.3 aqueous (5.0 mL) at 0 C. and extracted with EtOAc (35 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN; B %: 24%-45% over 7 min] and lyophilized to afford the title compound (66.6 mg, 59% yield, 0.21 HCOOH) as white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.31-9.15 (m, 1H), 7.70-7.66 (m, 1H), 7.35-7.18 (m, 2H), 7.16-7.04 (m, 1H), 5.47-5.27 (m, 1H), 5.04 (br d, J=12.0 Hz, 1H), 4.81-4.72 (m, 1H), 4.52-4.40 (m, 2H), 4.32 (br dd, J=5.2, 10.4 Hz, 1H), 3.88-3.73 (m, 1H), 3.62-3.44 (m, 2H), 3.28-3.20 (m, 1H), 3.12-2.96 (m, 1H), 2.95-2.84 (m, 1H), 2.63-2.44 (m, 2H), 2.44-2.36 (m, 1H), 2.29-2.08 (m, 5H), 2.06-1.90 (m, 4H), 1.85-1.77 (m, 1H), 1.46-1.36 (m, 1H), 0.80 (dt, J=4.0, 7.2 Hz, 3H); LCMS (ESI, M+1): m/z=620.3. Example 928 ##STR00851## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00852## [1440] Step A. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((3-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (300 mg, 1.0 equiv) and (3-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (129 mg, 1.5 equiv) in THF (1.5 mL) and DMF (1.5 mL) were added Cs.sub.2CO.sub.3 (542 mg, 3.0 equiv) and DABCO (62.2 mg, 1.0 equiv). The reaction was stirred at 20 C. for 12 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (35 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (130 mg, 34% yield) as yellow solid; LCMS (ESI, M+1): m/z=660.4. [1441] Step B. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((3-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (120 mg, 1.0 equiv) in MeOH (0.5 mL) was added HCl.Math.MeOH (4 M, 1.0 mL). The reaction was stirred at 0 C. for 0.5 hours. The mixture was adjusted to pH to 8 with saturated NaHCO.sub.3 aqueous (5.0 mL) at 0 C. and extracted with EtOAc (35 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex luna C18 150 25 mm10 m; A: water (FA), B: ACN; B %: 26%-47% over 7 min] and lyophilized to afford the title compound (61.8 mg, 54% yield, 0.51 HCOOH) as white solid. .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.32-9.19 (m, 1H), 7.70-7.66 (m, 1H), 7.35-7.19 (m, 2H), 7.06 (br d, J=14.8 Hz, 1H), 5.08-4.99 (m, 1H), 4.83-4.74 (m, 1H), 4.46 (s, 2H), 4.36-4.30 (m, 1H), 3.89-3.73 (m, 1H), 3.56-3.42 (m, 1H), 3.30-3.09 (m, 3H), 2.53-2.31 (m, 3H), 2.29-2.03 (m, 7H), 2.00-1.77 (m, 5H), 1.44-1.29 (m, 4H), 0.80 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=616.3. Example 929 ##STR00853## 7-(7-(3-chloro-5-hydroxy-2-(cis-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide ##STR00854## [1442] Step A. 7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (48.0 mg, 1.0 equiv) and 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (59.7 mg, 1.0 equiv) in methoxycyclopentane (1 mL) and water (0.25 mL) were added Cs.sub.2CO.sub.3 (44.3 mg, 1.0 equiv) and CataCXium A Pd G3 (19.8 mg, 0.2 equiv). The reaction was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 90 C. for 10 hours under N.sub.2 atmosphere. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (230 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, petroleum ether/ethyl acetate=0/1] to afford the title compound (16.0 mg, 17% yield) as yellow solid; LCMS (ESI, M+1): m/z=629.3. [1443] Step B. 7-(7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: To a solution of 7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (13.0 mg, 1.0 equiv) and 2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (5.93 mg, 1.5 equiv) in DMF (1 mL) were added DIEA (8.01 mg, 3.0 equiv) and 4 molecular sieve (5 mg). The reaction was stirred at 45 C. for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, DCM/MeOH=10/1] to afford the title compound (12.0 mg, 77% yield) as yellow solid; LCMS (ESI, M+1): m/z=720.2. [1444] Step C. 7-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: To a solution of 7-(7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (10.0 mg, 1.0 equiv) in MeOH (2 mL) was added HCl.Math.MeOH (4M, 2 mL). The reaction was stirred at 0 C. for 2 hours. The mixture was concentrated, dissolved in MeOH (2 mL), adjusted to pH=7 with solid NaHCO.sub.3 and filtered. The filtration was concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; gradient: 35%-65% B over 9 min] to afford the title compound (6.58 mg, 70% yield) as off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.09 (d, J=10.4 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.84 (br d, J=4.0 Hz, 1H), 5.47-5.20 (m, 1H), 4.64-4.48 (m, 1H), 4.46-4.24 (m, 3H), 3.93-3.64 (m, 2H), 3.48-3.39 (m, 1H), 3.38-3.34 (m, 1H), 3.31-3.13 (m, 4H), 3.09-2.98 (m, 1H), 2.43-1.84 (m, 12H), 1.13 (br s, 1H), 0.67 (br s, 4H); LCMS (ESI, M+1): m/z=676.3. Example 930 ##STR00855## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00856## [1445] Step A. ethyl (E)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate: To a solution of 2-((fluoromethyl) sulfonyl)pyridine (9.12 g, 1.1 equiv) in THF (100 mL) was added KHMDS (1 M, 60.1 mL, 1.2 equiv) dropwise at 65 C. The reaction was stirred at 65 C. for 1 hour. Ethyl 2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (10 g, 1.0 equiv) in THF (50 mL) was added dropwise at 65 C. The reaction was stirred at 65 C. for 2 hours and 20 C. for 2 hours. The mixture was quenched with 0.1N HCl (30 mL) at 0 C. The pH of the mixture was adjusted to 3 with 2N HCl. The mixture was extracted with EtOAc (4100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified with column chromatography [SiO2, PE/EtOAc=2/1 to 1/1] followed by purified with prep-HPLC [column: UniSil 10-120 C18 70250 mm; A: water (FA), B: ACN; B %: 15%-45% over 20 min] to afford the title compound (860 mg, 8.6% yield) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =6.75-6.48 (m, 1H), 4.35 (br d, J=14.8 Hz, 1H), 4.23 (q, J=7.2 Hz, 2H), 3.73 (br d, J=14.8 Hz, 1H), 3.32 (br d, J=16.4 Hz, 1H), 2.87-2.74 (m, 1H), 2.73-2.62 (m, 1H), 2.53-2.39 (m, 2H), 2.15 (td, J=10.0, 13.2 Hz, 1H), 1.36-1.26 (m, 3H); LCMS (ESI, M+1): m/z=228.0. [1446] Step B. (E)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol: To a solution of ethyl (E)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (300 mg, 1.0 equiv) in THF (6.00 mL) was added DIBAL-H (1 M, 10 equiv) at 0 C. The reaction was stirred at 0 C. for 2 hours. The mixture was quenched with water (0.6 mL), then 15% NaOH (0.6 mL) and water (1.8 mL). The mixture was dried over anhydrous sodium sulfate, concentrated to afford the title compound (130 mg, crude) as yellow oil; .sup.1H NMR (400 MHZ, CHLOROFORM-d) =6.67-6.40 (m, 1H), 3.61-3.51 (m, 1H), 3.49-3.32 (m, 1H), 3.31-3.20 (m, 2H), 3.13-3.00 (m, 1H), 2.61 (td, J=7.6, 10.0 Hz, 1H), 2.56-2.35 (m, 2H), 2.03-1.65 (m, 4H); LCMS (ESI, M+1): m/z=172.1. [1447] Step C. 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine: To a solution of (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (690 mg, 1.0 equiv), TBSCl (384 mg, 2.0 equiv) and imidazole (260 mg, 3.0 equiv) in DMF (5.00 mL) was added DMAP (77.9 mg, 0.5 equiv). The reaction was stirred at 40 C. for 5 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (510 mg, 49% yield) as yellow solid; LCMS (ESI, M+1): m/z=655.3. [1448] Step D. 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine: To a solution of (E)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (39.2 mg, 1.5 equiv) in THF (2.00 mL) was added NaH (18.3 mg, 60% purity, 3.0 equiv) at 0 C. The reaction was stirred at 0 C. for 10 minutes. 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) was added. The reaction was stirred at 0-20 C. for 2 hours. The mixture quenched with water (20 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (65.0 mg, 52% yield) as yellow solid; LCMS (ESI, 1/2M+1,M+1): m/z=395.9, 790.4. [1449] Step E. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (55.0 mg, 1.0 equiv) in MeOH (2.00 mL) was added HCl.Math.MeOH (4 M, 2.00 mL) at 0 C. The reaction was stirred at 20 C. for 1.5 hours. The mixture was concentrated, basified by saturated NaHCO.sub.3 solution (20 mL) and extracted with ethyl acetate (210 mL) The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC [column: C18 15030 mm; A: water (FA),B: ACN; B %: 15%-45% 12 min] to afford the title compound (12.8 mg, 26% yield) as white solid; .sup.1H NMR (400 MHZ, DMSO-d6) =10.07-9.79 (m, 1H), 9.38-9.22 (m, 1H), 8.14 (s, 1H), 7.76 (dd, J=6.4, 8.4 Hz, 1H), 7.41-7.27 (m, 2H), 7.03 (dd, J=2.0, 14.4 Hz, 1H), 6.96-6.69 (m, 1H), 4.93-4.50 (m, 3H), 4.24-3.95 (m, 3H), 3.80-3.67 (m, 1H), 3.56 (br d, J=13.6 Hz, 1H), 3.24 (br s, 1H), 3.05-2.94 (m, 1H), 2.76-2.62 (m, 1H), 2.59-2.52 (m, 1H), 2.47-2.25 (m, 4H), 2.18-2.03 (m, 3H), 2.02-1.82 (m, 2H), 1.81-1.59 (m, 4H), 1.25 (br d, J=12.8 Hz, 1H), 0.78-0.64 (m, 3H); LCMS (ESI, 1/2M+1, M+1): m/z=316.8, 632.3. Example 931 ##STR00857## (1R,5R,6R)-3-(2-((dihydro-1H,3H-spiro[cyclopropane-1,2-pyrrolizin]-7a (5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00858## [1450] Step A. (1R,5R,6R)-3-(2-((dihydro-1H,3H-spiro[cyclopropane-1,2-pyrrolizin]-7a (5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (300 mg, 1.0 equiv) and (dihydro-1H,3H-spiro[cyclopropane-1,2-pyrrolizin]-7a (5H)-yl)methanol (139 mg, 1.5 equiv) in THF (3 mL) and DMF (3 ml) were added Cs.sub.2CO.sub.3 (542 mg, 3.0 equiv) and DABCO (62.0 mg, 1.0 equiv). The reaction was stirred at 25 C. for 3 hours. The mixture was diluted with water (15 mL) and extracted with EtOAc (215 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [0.1% formic acid condition] to afford the title compound (80.0 mg, 12% yield) as yellow solid; LCMS (ESI, M+1): m/z=672.3. [1451] Step B. (1R,5R,6R)-3-(2-((dihydro-1H,3H-spiro[cyclopropane-1,2-pyrrolizin]-7a (5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-((dihydro-1H,3H-spiro[cyclopropane-1,2-pyrrolizin]-7a (5H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (70.0 mg, 1.0 equiv) in DCM (1 mL) was added TFA (3.07 g, 258 equiv) at 0 C. The reaction was stirred at 25 C. for 0.5 hours. The mixture was concentrated under vacuum. The residue was diluted with water (1 mL). The mixture was adjusted to pH=7 with NaHCO.sub.3 aqueous (10 mL) and extracted with EtOAc (210 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 17%-47% over 10 min] to afford the title compound (5.53 mg, 8% yield, 0.70 HCOOH) as off-white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.26 (d, J=19.6 Hz, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.28-7.22 (m, 1H), 7.06 (dd, J=2.4, 16.8 Hz, 1H), 4.60 (br d, J=12.0 Hz, 4H), 4.38-4.30 (m, 1H), 3.89-3.77 (m, 1H), 3.59-3.38 (m, 3H), 3.28-3.22 (m, 1H), 3.15-3.09 (m, 1H), 2.51-2.39 (m, 2H), 2.30-2.02 (m, 9H), 1.98-1.92 (m, 1H), 1.86-1.79 (m, 1H), 1.43-1.35 (m, 1H), 0.80 (q, J=7.2 Hz, 5H), 0.74-0.67 (m, 2H); LCMS (ESI, M+1): m/z=628.3. Example 932 ##STR00859## (R)-7-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione ##STR00860## [1452] Step A. (R)-7-(7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of 7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) and (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (80.7 mg, 3.0 equiv) in DMF (3 mL) were added 4 molecular sieves (50.0 mg) and DIEA (103 mg, 5 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (230 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [0.1% FA condition] to afford the title compound (50.0 mg, 44% yield) as white solid; LCMS (ESI, M+1): m/z=698.1. [1453] Step B. (R)-7-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of (R)-7-(7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.0 equiv) in MeCN (2 mL) was added HCl.Math.dioxane (4M, 2 mL). The reaction was stirred at 0 C. for 1 hour. The mixture was concentrated, dissolved in MeOH (2 mL), adjusted to pH=7 with solid NaHCO.sub.3 and filtered. The filtrate was concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; gradient: 34%-64% B over 9 min] to afford the title compound (29.0 mg, 62% yield) as white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =10.87 (s, 1H), 9.98 (s, 1H), 9.07 (d, J=6.4 Hz, 1H), 8.70 (s, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.82 (s, 1H), 5.51-5.02 (m, 1H), 4.65-4.26 (m, 2H), 4.14-4.02 (m, 2H), 3.57-3.44 (m, 2H), 3.15-2.98 (m, 3H), 2.88-2.75 (m, 1H), 2.13 (s, 12H), 1.12-0.97 (m, 1H), 0.65-0.45 (m, 4H); LCMS (ESI, M+1): m/z=654.2. Example 933 ##STR00861## 5-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide ##STR00862## [1454] Step A. 5-(7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) and N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (66.2 mg, 2.0 equiv) in DMF (3 mL) were added 4 molecular sieve (50.0 mg) and K.sub.3PO.sub.4 (103 mg, 5.0 equiv). [1455] The reaction was stirred at 60 C. for 12 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [0.1% FA condition] to afford the title compound (35.0 mg, 30% yield) as white solid; LCMS (ESI, M+1): m/z=737.1. [1456] Step B. 5-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 5-(7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (50.0 mg, 1.0 equiv) in MeCN (1.5 mL) was added HCl.Math.dioxane (4M, 1.5 mL). The reaction was stirred at 0 C. for 1 hour. The mixture was concentrated, dissolved in MeOH (2 mL), adjusted to pH=7 with solid NaHCO.sub.3 and filtered. The filtrate was concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; gradient: 38%-68% B over 9 min] to afford the title compound (6.38 mg, 13% yield) as white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6)=9.15 (s, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 6.76 (s, 1H), 5.43-5.20 (m, 3H), 4.55 (dd, J=2.8, 6.8 Hz, 2H), 4.42 (s, 2H), 4.31-4.20 (m, 2H), 3.33 (s, 3H), 3.29-3.15 (m, 3H), 3.08 (s, 3H), 3.04-2.98 (m, 1H), 2.51-1.82 (m, 10H), 1.17-1.01 (m, 1H), 0.70-0.55 (m, 4H); LCMS (ESI, M+1): m/z=693.1. Example 934 ##STR00863## 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol ##STR00864## [1457] Step A. 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv) and 6-azaspiro[3.5]nonan-2-ol (18.1 mg, 1.5 equiv) in DMF (1 mL) were added 4 molecular sieves (50 mg) and DIEA (33.1 mg, 3.0 equiv). The reaction was stirred at 40 C. for 10 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 m; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; gradient: 40%-70% B over 9 minutes] to afford the title compound (9.48 mg, 16% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.05 (d, J=6.4 Hz, 1H), 7.67 (dd, J=6.0, 9.2 Hz, 1H), 7.33-7.20 (m, 2H), 7.07 (t, J=2.4 Hz, 1H), 4.99 (br s, 2H), 4.37-4.19 (m, 3H), 4.14-3.87 (m, 4H), 3.73 (br d, J=14.0 Hz, 1H), 3.15 (td, J=4.8, 10.0 Hz, 1H), 2.84-2.66 (m, 2H), 2.55-2.43 (m, 2H), 2.33-2.11 (m, 4H), 2.04-1.66 (m, 10H), 0.86-0.75 (m, 3H); LCMS (ESI, M+1): m/z=628.3. Example 935 ##STR00865## 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00866## [1458] Step A. 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol: To a mixture of 8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (60.0 mg, 1.0 equiv), 1-oxa-8-azaspiro[3.5]nonane (68.8 mg, 3.0 equiv, oxalic) and 4 molecular sieve (10.0 mg, 1.0 equiv) in DMF (1 mL) was added DIEA (25.8 mg, 3.0 equiv). The reaction was stirred at 60 C. for 12 hours. The mixture was diluted with H.sub.2O (2 mL) and extracted with EtOAc (32 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (50 mg, 78% yield) as yellow solid; LCMS (ESI, M+1): m/z=772.5. [1459] Step B. 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (40.0 mg, 1.0 equiv) in DMF (1 mL) was added CsF (65.5 mg, 10 equiv). The reaction was stirred at 40 C. for 12 hours. The mixture was diluted with H.sub.2O (2 mL) and extracted with EtOAc (32 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered and purified by prep-HPLC (Waters Xbridge C18 15025 mm5 m; A: water (10 mM NH.sub.4HCO.sub.3); B: ACN, B %: 35%-65% over 9 min) to afford the title compound (17.0 mg, 63% yield) as yellow solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) =9.24-8.95 (m, 1H), 7.61 (br t, J=6.4 Hz, 1H), 7.25-7.07 (m, 3H), 5.41-5.17 (m, 1H), 4.65-4.13 (m, 6H), 3.62 (br t, J=14.4 Hz, 1H), 3.50-3.14 (m, 4H), 3.05-2.94 (m, 1H), 2.84 (d, J=16.0 Hz, 1H), 2.47-2.37 (m, 2H), 2.32-2.20 (m, 3H), 2.12 (br d, J=8.0 Hz, 2H), 1.94 (dt, J=6.0, 11.6 Hz, 3H), 1.82-1.70 (m, 2H); LCMS (ESI, M+1): m/z=616.4. Example 936 ##STR00867## 5-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide ##STR00868## [1460] Step A. 5-(7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (90.0 mg, 1.0 equiv) and N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (87.7 mg, 3.0 equiv) in DMF (2 mL) were added K.sub.3PO.sub.4 (447 mg, 15 equiv) and 4 molecular sieve (50.0 mg). The reaction was stirred at 80 C. for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (310 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, dichloromethane/methanol=10/1] to afford the title compound (40.0 mg, 35% yield) as yellow solid; LCMS (ESI, M+1): m/z=749.3. [1461] Step B. 5-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 5-(7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (33.0 mg, 1.0 equiv) in MeCN (1 mL) was added HCl.Math.dioxane (4M, 1 mL) at 0 C. The reaction was stirred at 0 C. for 1 hour. The mixture was concentrated, dissolved in MeOH (2 mL), adjusted to pH=7 with solid NaHCO.sub.3 and filtered. The filtrate was concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; gradient: 40%-70% B over 9 minutes] to afford the title compound (4.62 mg, 14% yield) as white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.97 (s, 1H), 9.17 (s, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.89-6.53 (m, 3H), 5.20 (br s, 2H), 4.56-4.43 (m, 2H), 4.39-4.22 (m, 2H), 4.15-4.00 (m, 2H), 3.71 (br d, J=14.8 Hz, 1H), 3.25 (s, 3H), 3.00 (br dd, J=5.2, 9.2 Hz, 1H), 2.94 (s, 3H), 2.58-2.52 (m, 2H), 2.32 (br dd, J=4.4, 10.8 Hz, 3H), 2.05-1.55 (m, 6H), 1.30-0.93 (m, 2H), 0.73-0.46 (m, 4H); LCMS (ESI, M+1): m/z=705.4. Example 937 ##STR00869## (5R)-7-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione ##STR00870## [1462] Step A. (Z)-7-chloro-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (400 mg, 1.0 equiv) and (Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (260 mg, 1.2 equiv) in THF (6 mL) were added DIEA (654 mg, 4.0 equiv) and 4 molecular sieves (50 mg). The reaction was stirred at 40 C. for 12 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=1/0 to 5/1] to afford the title compound (410 mg, 67% yield) as yellow solid; LCMS (ESI, M+1): m/z=451.1. [1463] Step B. 7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of (Z)-7-chloro-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv) and 2-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (156 mg, 1.0 equiv) in methoxycyclopentane (4 mL) and water (1 mL) were added Cs.sub.2CO.sub.3 (434 mg, 3.0 equiv) and CataCXium A Pd G3 (64.6 mg, 0.2 equiv). The reaction was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 100 C. for 2 hours under N.sub.2 atmosphere. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, petroleum ether/ethyl acetate=1/1] to afford the title compound (68.0 mg, 19% yield) as yellow solid; LCMS (ESI, M+1): m/z=641.3. [1464] Step C. (5R)-7-(7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of 7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (68.0 mg, 1.0 equiv) and (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (26.9 mg, 1.5 equiv) in DMF (2 mL) were added DIEA (41.1 mg, 3.0 equiv) and 4 molecular sieves (20 mg) The reaction was stirred at 40 C. for 10 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [SiO.sub.2, petroleum ether/ethyl acetate=1/1] to afford the title compound (44.0 mg, 47% yield) as yellow solid; LCMS (ESI, M+1): m/z=710.3. [1465] Step D. (5R)-7-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of (5R)-7-(7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (40.0 mg, 1.0 equiv) in MeOH (2 mL) was added HCl.Math.MeOH (4M, 2 mL). The reaction was stirred at 25 C. for 2 hours. The mixture was concentrated, dissolved in MeOH (2 mL), adjusted to pH=7 with solid NaHCO.sub.3 and filtered. The filtrate was concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 m; mobile phase: water (NH.sub.4HCO.sub.3)-ACN]; gradient: 35%-65% B over 9 minutes] to afford the title compound (4.32 mg, 11% yield) as white solid, .sup.1H NMR (400 MHZ, METHANOL-d4) =9.11-9.06 (m, 1H), 7.00 (d, J=2.8 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 6.75-6.50 (m, 1H), 4.58 (br t, J=12.4 Hz, 1H), 4.44 (br d, J=13.6 Hz, 1H), 4.37-4.20 (m, 2H), 3.86-3.66 (m, 3H), 3.45 (br d, J=14.8 Hz, 1H), 3.18-3.11 (m, 1H), 2.78-2.65 (m, 2H), 2.44 (br d, J=15.6 Hz, 1H), 2.31-2.18 (m, 1H), 2.17-1.77 (m, 9H), 1.19-1.04 (m, 1H), 0.64 (br d, J=5.6 Hz, 4H); LCMS (ESI, M+1): m/z=666.3. Example 938 ##STR00871## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((Z)-2-ethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00872## [1466] Step A. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((Z)-2-ethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (120 mg, 1.0 equiv) and (Z)-(2-ethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (55.6 mg, 1.5 equiv) in DMF (0.5 mL) and THF (0.5 mL) were added Cs.sub.2CO.sub.3 (217 mg, 3.0 equiv) and DABCO (24.9 mg, 1.0 equiv). The reaction was stirred at 25 C. for 3 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (35.0 mg, 21% yield) as yellow solid; LCMS (ESI, M+1): m/z=672.4. [1467] Step B. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((Z)-2-ethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: solution To a of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((Z)-2-ethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (30.0 mg, 1.0 equiv) in DCM (0.1 mL) was added TFA (307 mg, 60 equiv) at 0 C. The reaction was stirred at 0 C. for 0.5 hours. The mixture was adjusted to pH=7 with saturated NaHCO.sub.3 (10 mL) and extracted with DCM (210 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC [column: Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN, B %: 19%-49% over 10 min] to afford the title compound (10.9 mg, 36% yield, 0.49 HCOOH) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.30-9.19 (m, 1H), 7.68 (dd, J=6.0, 8.8 Hz, 1H), 7.36-7.19 (m, 2H), 7.06 (dd, J=2.4, 15.6 Hz, 1H), 5.58-5.51 (m, 1H), 4.80-4.74 (m, 1H), 4.52-4.41 (m, 2H), 4.33 (qd, J=5.2, 10.8 Hz, 1H), 4.10-3.96 (m, 1H), 3.81 (br dd, J=12.4, 20.0 Hz, 1H), 3.65 (br d, J=13.6 Hz, 1H), 3.56-3.41 (m, 2H), 3.07-2.92 (m, 1H), 2.86 (br d, J=14.0 Hz, 1H), 2.60 (br d, J=16.0 Hz, 1H), 2.54-2.36 (m, 2H), 2.34-1.88 (m, 9H), 1.86-1.76 (m, 1H), 1.66 (br d, J=6.8 Hz, 3H), 1.44-1.33 (m, 1H), 0.79-0.79 (m, 1H), 0.80 (q, J=7.2 Hz, 2H); LCMS (ESI, M1): m/z=628.3. Example 939 ##STR00873## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((E)-2-ethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00874## [1468] Step A. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((E)-2-ethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (150 mg, 1.0 equiv) and (E)-(2-ethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (69.6 mg, 1.5 equiv) in THF (0.5 mL) and DMF (0.5 mL) were added DABCO (31.1 mg, 1.0 equiv) and Cs.sub.2CO.sub.3 (271 mg, 3.0 equiv). The reaction was stirred at 20 C. for 12 hours. The mixture was diluted with water (5.0 mL) and extracted with EtOAc (35 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (70 mg, 32% yield) as yellow solid; LCMS (ESI, M+1): m/z=672.4. [1469] Step B. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((E)-2-ethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((E)-2-ethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (65.0 mg, 1.0 equiv) in MeOH (0.3 mL) was added HCl.Math.MeOH (4 M, 1.3 mL). The reaction was stirred at 0 C. for 0.5 hours. The mixture was adjusted to pH=8 with saturated NaHCO.sub.3 aqueous (5.0 mL) at 0 C. and extracted with DCM (35 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC [Phenomenex luna C18 15025 mm10 m; A: water (FA), B: ACN; B %: 18%-48% over 10 min] and lyophilized to afford the title compound (14.0 mg, 23% yield, 0.25 HCOOH) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.32-9.21 (m, 1H), 7.70-7.66 (m, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (br t, J=9.2 Hz, 1H), 7.06 (dd, J=2.4, 15.6 Hz, 1H), 5.73-5.58 (m, 1H), 4.62-4.54 (m, 4H), 4.36-4.32 (m, 1H), 4.21-4.12 (m, 1H), 3.91-3.66 (m, 2H), 3.65-3.42 (m, 2H), 3.16-3.04 (m, 1H), 2.90 (br d, J=16.8 Hz, 1H), 2.70 (br d, J=16.0 Hz, 1H), 2.54-2.39 (m, 2H), 2.36-2.33 (m, 1H), 2.31-2.21 (m, 2H), 2.20 (br s, 4H), 1.98-1.90 (m, 1H), 1.87-1.77 (m, 1H), 1.70 (br s, 3H), 1.38 (br dd, J=2.0, 14.4 Hz, 1H), 0.80 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=628.4. Example 940 ##STR00875## 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane ##STR00876## [1470] Step A. 7-chloro-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (4.00 g, 1.0 equiv) and (2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (2.09 g, 1.2 equiv) in THF (20 mL) were added DIEA (5.89 g, 4.0 equiv) and 4 molecular sieves (500 mg). The reaction was stirred at 40 C. for 10 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO.sub.2, petroleum ether/ethyl acetate=1/0 to 5/1] to afford the title compound (3.00 g, 50% yield) as yellow solid; LCMS (ESI, M+1): m/z=433.1. [1471] Step B. 5-ethyl-6-fluoro-4-(8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of 7-chloro-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (3.00 g, 1.0 equiv) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (2.19 g, 1.0 equiv) in methoxycyclopentane (20 mL) and water (5 mL) were added Cs.sub.2CO.sub.3 (6.78 g, 3.0 equiv) and CataCXium A Pd G3 (1.01 g, 0.2 equiv). The reaction was degassed and purged with N.sub.2 for 3 times. The reaction was stirred at 100 C. for 2 hours under N.sub.2 atmosphere. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (2100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: C18 15030 mm; mobile phase: water (FA)-ACN; gradient: 30%-60% B over 7 minutes] to afford the title compound (500 mg, 9.2% yield) as yellow solid; LCMS (ESI, M+1): m/z=587.2. [1472] Step C. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv) and 2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (24.5 mg, 1.5 equiv) in DMF (1 mL) were added 4 molecular sieve (20.0 mg) and K.sub.3PO.sub.4 (54.3 mg, 3.0 equiv). The reaction was stirred at 60 C. for 4 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; gradient: 38%-68% B over 9 minutes] to afford the title compound (30.5 mg, 50% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.09 (s, 1H), 7.67 (ddd, J=3.2, 5.6, 8.8 Hz, 1H), 7.31-7.21 (m, 2H), 7.04 (dd, J=2.8, 4.8 Hz, 1H), 4.98 (br s, 2H), 4.59-4.50 (m, 1H), 4.41-4.25 (m, 3H), 3.87-3.72 (m, 2H), 3.68-3.59 (m, 1H), 3.40-3.35 (m, 1H), 3.21-3.14 (m, 2H), 2.83-2.68 (m, 2H), 2.55-2.44 (m, 2H), 2.21-1.81 (m, 10H), 0.81 (dt, J=4.0, 7.2 Hz, 3H); LCMS (ESI, M+1): m/z=678.3. Example 941 ##STR00877## 5-ethyl-6-fluoro-4-(8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol ##STR00878## [1473] Step A. 5-ethyl-6-fluoro-4-(8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (45.0 mg, 1.0 equiv) in DMF (0.5 mL) were added 1-oxa-8-azaspiro[3.5]nonane (20.3 mg, 0.8 equiv, oxalate), 4 molecular sieve (30.0 mg) and K.sub.3PO.sub.4 (50.0 mg, 3.0 equiv). The reaction was stirred at 60 C. for 3 hours. The mixture was diluted with water (4 mL) and extracted with ethyl acetate (35 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; gradient: 45%-75% B over 9 minutes] to afford the title compound (4.38 mg, 8.8% yield) as white solid; 1HNMR (400 MHZ, METHANOL-d.sub.4) =9.26 (d, J=5.2 Hz, 1H), 7.68 (dd, J=6.0, 9.2 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (t, J=9.6 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 4.98 (s, 2H), 4.70-4.52 (m, 4H), 4.50-4.38 (m, 1H), 4.36-4.26 (m, 2H), 3.90-3.71 (m, 2H), 3.54-3.41 (m, 1H), 3.18-3.11 (m, 1H), 2.83-2.68 (m, 2H), 2.57-2.44 (m, 4H), 2.33-2.24 (m, 1H), 2.23-2.12 (m, 2H), 2.06-1.79 (m, 6H), 0.86-0.79 (m, 3H); LCMS (ESI, M+1): m/z=614.3. Example 942 ##STR00879## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00880## [1474] Step A. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: solution of To a (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (31.6 mg, 2.0 equiv) in THF (2.0 mL) was added NaH (11.1 mg, 60% purity, 3.0 equiv) at 0 C. After stirring for 0.5 hours, (1R,5R,6R)-3-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (50 mg, 1.0 equiv) was added. The reaction was stirred at 0 C. for 2 hours. The mixture was quenched by NH.sub.4Cl solution (10 mL) and extracted by ethyl acetate (310 mL). The combined organic layers were dried by Na.sub.2SO.sub.4, filtered, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (190 mg, 48% yield) as yellow solid; LCMS (ESI, M+1): m/z=676.4. [1475] Step B. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (80.0 mg, 1.0 equiv) in DCM (2.0 mL) was added TFA (0.60 mL, 68 equiv). The reaction was stirred at 0 C. for 2 hours. The mixture was diluted with acetonitrile, adjusted to pH=8 with NaHCO.sub.3 aqueous solution, filtered, concentrated and purified by prep-HPLC [Daisogel SP ODS RPS 15025 mm5 um; A: water (NH.sub.4HCO.sub.3)-ACN; B: CAN, 44%-74% over 10 min] to afford the title compound (54.0 mg, 71% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.30-9.16 (m, 1H), 7.67 (dd, J=5.8, 8.8 Hz, 1H), 7.32-7.17 (m, 2H), 7.06 (dd, J=2.8, 14.7 Hz, 1H), 6.80-6.49 (m, 1H), 5.07-4.89 (m, 1H), 4.82-4.72 (m, 2H), 4.37-4.28 (m, 2H), 4.27-4.21 (m, 1H), 3.89-3.72 (m, 2H), 3.53-3.38 (m, 2H), 3.21-3.10 (m, 1H), 2.78-2.67 (m, 2H), 2.53-2.37 (m, 3H), 2.29-2.19 (m, 2H), 2.18-2.07 (m, 2H), 2.04-1.96 (m, 1H), 1.94-1.86 (m, 2H), 1.85-1.77 (m, 1H), 1.48-1.37 (m, 1H), 0.80 (q, J=7.4 Hz, 3H); LCMS (ESI, M+1): m/z=632.3. Example 943 ##STR00881## 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one ##STR00882## [1476] Step A. 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (40.0 mg, 1.0 equiv) and 1,8-diazaspiro[3.5]nonan-2-one (14.3 mg, 1.5 equiv) in DMF (1 mL) were added 4 molecular sieve (10.0 mg) and K.sub.3PO.sub.4 (43.4 mg, 3.0 equiv). The reaction was stirred at 60 C. for 2 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (210 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; gradient: 35%-65% B over 9 minutes] to afford the title compound (3.00 mg, 6.9% yield) as white solid; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =9.93 (s, 1H), 9.08 (d, J=2.0 Hz, 1H), 8.56 (br s, 1H), 7.77 (dd, J=6.0, 9.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.03 (t, J=2.8 Hz, 1H), 4.89 (br s, 2H), 4.32-3.98 (m, 4H), 3.94-3.76 (m, 1H), 3.70-3.49 (m, 2H), 3.18 (br d, J=14.0 Hz, 1H), 3.04-2.94 (m, 1H), 2.86-2.73 (m, 1H), 2.69-2.55 (m, 3H), 2.35 (br d, J=15.6 Hz, 2H), 2.19-2.05 (m, 1H), 2.03-1.93 (m, 2H), 1.91-1.64 (m, 6H), 0.73 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=627.3. Example 944 ##STR00883## (R)-1-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol ##STR00884## [1477] Step A. (R)-1-(7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of 7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (70.0 mg, 1.0 equiv) and (R)-3-methylpiperidin-3-ol (18.9 mg, 1.1 equiv, HCl) in DMF (1 mL) were added DIEA (70.6 mg, 5.0 equiv) and 4 molecular sieve (30 mg). The reaction was stirred at 40 C. for 10 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-TLC [SiO.sub.2, DCM/MeOH=10/1] to afford the title compound (75.0 mg, 98% yield) as white solid; LCMS (ESI, M+1): m/z=656.3. [1478] Step B. (R)-1-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-(3-chloro-5-(methoxymethoxy)-2-((1S,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (70.0 mg, 1.0 equiv) in MeCN (2 mL) was added HCl.Math.dioxane (4M, 2 mL). The reaction was stirred at 0 C. for 1 hour. The mixture was concentrated, dissolved in MeOH (2 mL), adjusted to pH=7 with solid NaHCO.sub.3 and filtered. The filtrate was concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; gradient: 45%-75% B over 9 minutes] to afford the title compound (30.5 mg, 46% yield) as white solid, .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.19 (d, J=13.6 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.82 (br s, 1H), 6.78-6.50 (m, 1H), 4.60-4.45 (m, 1H), 4.37-4.22 (m, 3H), 3.84 (br d, J=14.8 Hz, 1H), 3.63-3.57 (m, 1H), 3.49-3.40 (m, 2H), 3.19-3.12 (m, 1H), 2.77-2.66 (m, 2H), 2.44 (br d, J=16.0 Hz, 1H), 2.21-1.72 (m, 10H), 1.28 (d, J=2.0 Hz, 3H), 1.19-1.06 (m, 1H), 0.66 (br d, J=5.6 Hz, 4H); LCMS (ESI, M+1): m/z=612.3. Example 945 ##STR00885## (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol ##STR00886## [1479] Step A. (6S,8aS)-6-(((4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine: To a solution of 4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (50.0 mg, 1.0 equiv) in THF (1.00 mL) was added NaH (11.1 mg, 60% purity, 3.0 equiv) at 0 C. The reaction was stirred at 0 C. for 10 minutes. ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (22 mg, 1.5 equiv) in THF (1.00 mL) was added. The reaction was stirred at 0 C.-20 C. for 3 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (35.0 mg, crude) as yellow oil; LCMS (ESI, 1/2M+1, M+1): m/z=388.8, 776.4. [1480] Step B. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (6S,8aS)-6-(((4-((1R,5R,6R)-6-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (25.0 mg, 1.0 equiv) in MeOH (2.00 mL) was added HCl.Math.MeOH (4 M, 2.00 mL) at 0 C. The reaction was stirred at 0-20 C. for 3 hours. The mixture was concentrated, basified by saturated NaHCO.sub.3 solution (20 mL) and extracted with ethyl acetate (210 mL) The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 m; A: water (NH.sub.4HCO.sub.3), B: ACN; B %: 35%-65% B over 9 min] to afford the title compound (10.2 mg, 50% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d4) =9.30-9.18 (m, 1H), 7.67 (dd, J=6.0, 8.8 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.24 (dt, J=2.0, 9.6 Hz, 1H), 7.10-7.02 (m, 1H), 5.03-4.89 (m, 1H), 4.82-4.74 (m, 1H), 4.62-4.46 (m, 1H), 4.42-4.27 (m, 2H), 3.86-3.61 (m, 5H), 3.54-3.42 (m, 1H), 3.39-3.34 (m, 1H), 3.20-2.97 (m, 3H), 2.57-2.36 (m, 2H), 2.31-2.06 (m, 4H), 1.99-1.86 (m, 2H), 1.84-1.68 (m, 2H), 1.54-1.37 (m, 2H), 0.80 (q, J=7.2 Hz, 3H); LCMS (ESI, M+1): m/z=618.3. Example 946 ##STR00887## 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-((1S,2R)-2-methylcyclopropyl)phenol ##STR00888## [1481] Step A. 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-((1S,2R)-2-methylcyclopropyl)phenol: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-((1R,2S)-2-methylcyclopropyl)phenol (200 mg) was purified with SFC [column: DAICEL CHIRALPAK IC 250 mm30 mm, 10 um; mobile phase: CO.sub.2-ACN/i-PrOH (0.1% NH.sub.3H.sub.2O); B %: 50%, isocratic elution mode] to afford the title compound (58.8 mg, 29% yield) as white solid; .sup.1H NMR (400 MHZ, METHANOL-d.sub.4) =9.04 (s, 1H), 7.00 (d, J=2.6 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 6.77-6.51 (m, 1H), 4.67-4.53 (m, 2H), 4.36-4.20 (m, 2H), 3.85 (br d, J=14.8 Hz, 1H), 3.75-3.64 (m, 4H), 3.47 (br d, J=14.8 Hz, 1H), 3.22-3.11 (m, 1H), 2.78-2.66 (m, 2H), 2.44 (br d, J=15.2 Hz, 1H), 2.20-2.09 (m, 1H), 2.03-1.72 (m, 9H), 1.19-1.02 (m, 1H), 0.65 (br d, J=5.6 Hz, 4H); LCMS (ESI, M+1): m/z=609.2. Example 947 ##STR00889## 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione ##STR00890## [1482] Step A. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv) and tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (17.9 mg, 1.5 equiv) in DMF (1 mL) were added 4 molecular sieve (20 mg) and K.sub.3PO.sub.4 (54.3 mg, 3.0 equiv). The reaction was stirred at 60 C. for 4 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (210 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Waters Xbridge 15025 mm5 m; mobile phase: water (NH.sub.4HCO.sub.3)-ACN; gradient: 30%-60% B over 9 minutes] to afford the title compound (13.1 mg, 22% yield) as yellow gum; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) =11.76-10.98 (m, 1H), 10.15-9.83 (m, 1H), 9.26 (s, 1H), 7.76 (dd, J=6.0, 9.2 Hz, 1H), 7.46-7.25 (m, 2H), 7.02 (d, J=2.4 Hz, 1H), 4.90 (br s, 2H), 4.41 (br d, J=11.6 Hz, 2H), 4.28 (br d, J=2.8 Hz, 2H), 4.14-4.00 (m, 2H), 3.76-3.65 (m, 2H), 3.56 (br d, J=14.0 Hz, 1H), 3.19 (br d, J=14.0 Hz, 1H), 3.06-2.95 (m, 1H), 2.62-2.54 (m, 2H), 2.41-2.26 (m, 2H), 2.20-2.05 (m, 1H), 1.99-1.94 (m, 1H), 1.89-1.75 (m, 2H), 1.72-1.63 (m, 1H), 0.79-0.66 (m, 3H); LCMS (ESI, M+1): m/z=627.3. Example A KRas Binding Assay [1483] This Example illustrates that exemplary compounds of the present invention bind to KRas and are capable of displacing a labeled tracer ligand occupying the KRas binding site. KRas.sup.WT, KRas.sup.G12A, KRas.sup.G12C, KRas.sup.G12D, KRas.sup.G12R, KRas.sup.G12S, KRas.sup.G12V, KRas.sup.G13D, or KRas.sup.Q61H was used in the assay. [1484] The ability of a compound to bind to KRas was measured using a TR-FRET displacement assay. Biotinylated KRas (corresponding to amino acids 1-169, produced at Accelegan Inc.) was incubated with custom made Cy5 labelled tracer, terbium streptavidin (Cisbio Inc.) and compound (1% DMSO final) in buffer (50 mM HEPES, pH 7.5, 5 mM MgCl.sub.2, 0.005% Tween-20 and 1 mM DTT). After a 60-minute incubation at room temperature, the reaction was measured using a BMG LABTECH CLARIO star Plus via TR-FRET. 100 percent of control (POC) is determined by using a DMSO control and 0 POC is determined using a concentration of control compound that completely inhibits binding of the tracer to KRas. The POC values were fit to a 4-parameter IC.sub.50 equation and the IC.sub.50 values were reported (Table 1). The single point inhibition values at 10 nM were reported in Table 2. TABLE-US-00001 TABLE 1 Binding to KRas (IC.sub.50 nM) by Exemplary Compounds of Formula (I) Ex. No. G12D G12V G12R WT G13D Q61H G12A G12C G12S 524 >100000 70875 >100000 525 50680 55933 45416 >100000 >100000 >100000 93754 >100000 >100000 526 >100000 >100000 67708 527 116 150 193 528 8 3 3 529 14 21 36 530 59 66 91 531 5 <2 <2 532 9 15 24 533 72 105 119 534 7 5 2 535 17 27 44 536 5 5 9 537 407 244 263 538 2 <2 <2 539 29 9 7 540 <2 <2 <2 542 60 9 6 543 1689 152 354 544 22 3 4 545 4969 431 656 546 72 35 37 547 4 7 10 548 2 3 5 549 7 4 8 550 47 14 8 551 127 32 27 552 810 244 71 553 864 77 79 554 79 9 10 555 2027 512 2031 556 10 2 <2 557 12 6 4 558 <2 <2 <2 559 15 <2 <2 560 262 85 182 561 7 <2 <2 562 <2 3 3 563 85 100 238 564 640 16 31 565 1155 908 1032 566 3 3 <2 567 682 2430 1458 568 <2 <2 <2 569 5 <2 <2 570 12 3 <2 571 300 62 59 572 1966 266 162 574 7 5 7 575 25 7 27 576 45 10 37 577 29 606 727 578 5 8 2 579 5 6 3 580 296 81 30 581 160 39 41 582 3 11 10 583 33 14 3 584 <2 6 12 585 434 103 76 586 6 3 4 587 323 64 74 588 1775 314 621 589 38 16 12 590 2 3 2 592 790 119 281 593 72 10 7 594 91 80 53 595 194 38 85 596 805 94 434 597 867 82 194 598 820 84 66 599 2125 85 23 600 5043 880 886 601 14 12 7 602 484 243 161 603 1627 590 453 604 <2 <2 <2 <2 <2 <2 2 <2 <2 605 119 71 47 606 26 43 71 607 151 53 99 608 1247 88 267 609 <2 <2 <2 610 66 28 48 611 1529 121 127 612 4253 474 911 613 54840 21772 27461 614 805 398 701 615 1988 222 421 617 9 4 4 618 644 168 195 619 33 21 4 620 495 248 376 621 891 1290 3492 622 377 68 139 624 19 17 41 625 21 10 17 626 98785 42955 23588 627 35 12 27 628 78 107 180 629 65 15 37 630 796 93 34 631 9 12 33 632 2185 1196 1872 633 8846 2817 6611 634 2238 262 839 635 1643 454 766 636 10 3 <2 637 1218 3788 2246 638 41 34 16 639 13 2 2 640 83 16 17 641 3117 632 540 642 864 235 195 643 <2 <2 <2 644 3 <2 <2 645 313 139 257 647 1988 581 582 648 9120 6083 7370 649 85 9 38 650 14 <2 3 651 30 10 15 652 125 40 51 653 123 20 16 654 19 25 18 655 2878 291 633 656 5 6 10 657 4 <2 <2 658 224 7 65 659 462 582 1605 660 2 7 2 661 680 1743 699 662 3 <2 3 663 32 10 26 664 7 6 2 665 1981 966 1246 666 <2 2 <2 667 445 203 323 668 34 12 16 670 <2 <2 <2 671 <2 <2 <2 672 8 5 4 674 <2 <2 <2 675 32 3 <2 676 2 6 5 677 13 <2 <2 678 89 11 16 679 124 105 190 680 473 43 234 681 497 51 167 682 710 192 541 685 <2 8 6 686 21 6 5 687 405 145 175 688 357 42 160 689 1651 98 349 690 <2 <2 <2 691 5 2 6 693 509 25 38 694 106 17 38 695 4 5 8 696 <2 <2 3 697 4 6 7 698 2 <2 <2 701 4 5 9 703 5 7 14 704 5 5 11 705 12 13 30 706 3 <2 2 707 9 4 <2 708 19888 42889 39806 709 <2 <2 <2 710 2 3 4 711 <2 <2 <2 712 2 <2 <2 713 3 2 4 714 <2 <2 2 715 4 2 4 716 <2 <2 <2 717 <2 <2 <2 718 <2 <2 <2 719 <2 <2 <2 720 <2 <2 <2 721 <2 <2 <2 722 >100000 42887 30027 723 >100000 42824 27518 724 1588 404 720 419 585 612 301 185 170 725 1614 410 441 965 1119 1207 763 812 494 726 58 131 344 145 138 177 242 208 68 727 634 333 520 657 888 947 516 421 540 728 60 23 34 34 37 40 35 31 31 729 26 36 61 45 46 53 48 40 40 730 35 75 203 343 513 444 251 131 113 731 15 8 10 12 13 13 13 11 12 732 113 31 47 50 60 79 61 43 63 733 933 1048 2671 1373 1411 2284 1525 1522 1399 734 8112 11627 20598 10547 10475 11448 10304 10604 11558 735 1981 2586 3958 1840 2136 3526 2684 3126 2771 736 2331 664 640 139 93 26 173 111 75 737 13 5 7 13 12 14 10 10 8 738 17 3 2 11 10 9 11 9 9 739 3 <2 <2 <2 <2 <2 2 <2 <2 740 4 5 11 9 8 6 10 7 9 741 <2 <2 <2 <2 3 <2 2 <2 <2 742 <2 <2 <2 3 3 <2 <2 <2 2 743 8 3 20 9 9 7 8 6 8 744 <2 <2 2 745 <2 <2 <2 4 3 <2 <2 3 5 746 226 59 68 117 107 166 82 106 64 747 272 67 76 107 94 180 36 107 61 748 32 12 11 20 21 26 16 18 12 749 54 19 16 34 37 44 25 29 19 750 98 29 42 84 74 184 63 74 43 751 372 93 139 167 172 185 136 165 91 752 <2 <2 <2 753 <2 <2 2 755 16 11 9 13 11 9 14 11 11 756 11 10 17 13 13 13 14 12 13 757 12 42 101 141 238 203 82 46 43 758 5 <2 <2 <2 <2 <2 <2 <2 <2 759 8 4 6 8 7 5 8 7 7 760 76 67 170 88 72 66 91 73 76 761 8 23 74 106 177 151 65 41 33 762 2 <2 <2 <2 <2 <2 <2 <2 <2 763 70 23 18 36 36 45 25 33 20 764 5528 1660 3115 3094 2407 3931 2412 2394 1689 765 268 83 132 156 146 164 139 144 100 766 2204 988 1880 980 1206 954 1163 927 824 767 17 5 3 768 3 <2 <2 <2 <2 <2 <2 <2 <2 769 <2 <2 <2 <2 <2 <2 <2 <2 <2 770 <2 3 7 15 25 21 12 6 6 771 5 4 4 12 11 7 10 8 9 772 7 5 12 4 4 3 5 7 5 773 3 <2 2 774 2 <2 <2 775 23 4 3 776 2 2 4 777 4193 1054 1324 778 6 <2 4 779 2 <2 2 <2 <2 <2 <2 <2 <2 780 <2 <2 <2 <2 <2 <2 <2 <2 <2 781 2446 727 778 754 551 891 716 635 414 782 4650 2042 3741 4215 2548 4046 4370 2782 2573 783 2 2 5 784 1322 1924 4490 665 471 746 717 480 475 785 1300 435 787 786 423 110 160 787 4 3 6 788 2 <2 4 789 <2 <2 <2 790 11666 3744 5647 10643 7765 11001 8015 9217 5659 791 <2 <2 <2 792 2 <2 2 793 <2 <2 <2 <2 <2 794 <2 <2 <2 <2 <2 795 <2 <2 <2 <2 <2 796 <2 <2 <2 <2 <2 797 <2 <2 <2 <2 <2 798 <2 <2 <2 <2 <2 799 <2 <2 <2 <2 <2 800 <2 <2 <2 <2 <2 801 <2 <2 <2 <2 <2 802 189 116 35 2 2 803 14 9 20 11 14 805 <2 <2 3 806 <2 4 4 3 2 807 <2 3 <2 808 <2 <2 <2 809 3 4 5 5 3 5 5 3 4 810 13 4 4 811 8 2 4 812 12 4 6 813 <2 <2 4 814 <2 <2 3 815 2 <2 4 816 8 3 3 817 5 <2 2 818 3 3 8 819 1127 24 86 820 22878 51952 76178 1401 470 2126 634 591 1506 821 3890 5854 11995 151 146 196 137 146 121 822 2178 3426 9674 5417 5406 5656 4979 4076 4662 823 2223 922 1378 1417 1266 1390 1428 1305 1370 824 11 4 8 825 6 <2 3 826 <2 <2 <2 827 <2 <2 3 828 11399 12737 21440 829 939 195 460 830 5 5 12 831 42 36 38 832 17125 4554 6406 4589 3884 4607 3769 3204 2942 833 1083 3545 9157 3835 2823 3670 5126 4491 1861 834 8 3 5 835 3 <2 <2 836 24 6 4 837 <2 <2 <2 838 16 10 15 839 153 743 2908 3784 4063 3815 2382 1629 1259 840 9 4 7 841 66871 34006 62883 842 5 <2 <2 843 265 79 26 844 103 35 46 845 41 10 11 846 159 28 38 847 140 20 39 848 39 9 12 849 65 9 24 850 6 8 10 851 36 12 9 852 <2 <2 <2 853 <2 <2 <2 854 <2 <2 <2 855 10 16 31 26 12 23 21 25 18 856 1191 2197 4265 2823 2469 2830 2229 2060 2507 857 19 6 9 858 6 7 10 859 51 17 13 860 91 13 68 861 4 <2 <2 862 311 60 95 863 145 32 34 864 2133 946 1793 865 809 310 282 866 102 3525 7346 867 527 97 253 868 <2 <2 <2 869 210 116 26 870 <2 <2 <2 871 2665 4413 8950 3423 2715 4527 3690 3825 4437 873 7 7 12 874 <2 2 3 875 17 34 37 876 10 11 22 17 10 18 14 9 13 877 3 3 5 878 3 3 6 879 2 <2 3 880 5 6 12 11 7 12 9 7 8 881 2 4 11 22 25 22 14 7 7 882 2 3 8 13 15 15 9 5 5 883 53 7 12 884 <2 <2 <2 885 <2 <2 <2 886 2 2 4 887 5 3 2 888 40718 58272 62260 579 567 539 375 199 201 889 4 <2 5 891 22 6 9 892 120 26 26 893 92 43 40 894 121 119 177 895 <2 <2 <2 898 <2 <2 <2 899 692 240 66 900 4 3 3 901 99 60 20 902 834 902 876 903 9826 15134 11194 904 <2 <2 <2 905 297 394 94 906 66 247 646 907 88 23 18 908 14 6 8 909 24 7 7 910 22 8 9 911 11 3 10 912 45 69 85 914 12 3 5 915 <2 <2 <2 916 78 120 132 917 4 7 12 918 <2 <2 <2 <2 <2 919 <2 <2 <2 <2 <2 920 4 <2 2 <2 <2 921 4 2 4 2 2 922 74 13 21 18 9 923 18 4 8 7 5 924 14 4 7 7 5 925 6 2 3 4 3 926 2 <2 <2 <2 <2 927 13 4 6 7 5 928 2 <2 <2 <2 <2 929 2 <2 <2 <2 <2 930 <2 <2 <2 <2 <2 931 <2 <2 <2 <2 <2 932 <2 <2 <2 <2 <2 933 <2 <2 4 <2 <2 934 <2 <2 <2 <2 <2 935 4 4 7 7 5 936 <2 <2 3 2 <2 937 <2 <2 <2 <2 <2 938 <2 <2 <2 <2 <2 939 <2 <2 <2 <2 <2 940 <2 <2 <2 <2 <2 941 <2 <2 <2 <2 <2 943 <2 <2 <2 <2 <2 944 <2 <2 <2 <2 <2 945 6 3 3 4 <2 947 <2 <2 <2 <2 <2 TABLE-US-00002 TABLE 2 Binding to KRas (% inhibition at 10 nM) by Exemplary Compounds of Formula (I) Ex. No. G12A G13D G12C Q61H G12S WT 538 78 91 94 94 89 81 540 98 98 98 98 99 98 547 49 76 56 70 58 68 548 79 86 84 79 79 79 559 70 82 89 82 82 73 562 59 69 76 67 81 62 568 94 98 96 98 98 97 586 91 93 93 90 93 91 643 88 99 99 100 98 98 670 98 98 99 97 100 98 671 97 93 98 94 98 93 674 93 92 98 95 97 91 690 93 90 97 92 96 91 698 77 84 91 88 86 82 699 87 96 96 96 93 91 700 83 96 97 96 93 91 706 82 89 89 88 85 84 707 76 85 84 85 85 76 709 80 97 95 99 94 91 710 74 86 88 88 83 80 712 88 90 94 90 90 86 713 74 67 81 69 76 66 714 89 85 94 87 95 85 716 83 98 97 98 95 93 717 90 94 93 92 92 92 718 94 95 96 96 94 94 719 95 98 97 98 97 96 721 90 93 92 92 90 89 737 47 53 53 46 60 44 752 96 98 99 99 97 97 767 54 55 58 48 66 48 773 86 94 95 95 92 90 776 80 84 85 80 83 78 Example B [1485] Inhibition of KRas Phosphorylation of ERK (HTRF) by Exemplary Compounds of Formula (I) [1486] Cisbio HTRF Advanced PERK Assay Catalog #64AERPEH [1487] Cells: MKN1, PSN1 Procedure: [1488] Day 1: Seed 6,000 cells/well-25 l/well in 384-well white solid bottom plate; RPM1_10% FBS. Incubate overnight at 37 C./5% CO2. [1489] Day 2: Echo transfer 25 nl of 10 mM compound 10 point dilution at 1:3 (Cf-10 uM) and incubate for 3 hour at 37 C./5% CO2. [1490] Add 8.5 l/well of 4 Lysis Buffer/25 Blocking reagent (do not dump media) and incubate for 30 min at room temperature on shaker. [1491] Add conjugate mixture of 4.25 ul/well 1X-pERK-D2 and 1X-pERK-K diluted in Detection Buffer for a total of 8.5 l/well. [1492] Incubate for 4 hours at room temperature covered. [1493] Read HTRF using ClarioStar [1494] Cells: ASPC1, H727, A549, H460, HCT116, H358, H2009 [1495] Culture/Assay media: RPMI-1640+10% FBS Procedure: Cell Seeding [1496] 1. To harvest cells from flask using 0.05% Trypsin/EDTA solution. Add 10 mL of media to stop trypsinizing. Pipette the cells into a conical bottom 50 mL centrifuge tube and centrifuge 5 min1000 rpm. [1497] 2. Re-suspend the cell pellet in media, take a cell count, and then adjust the cell density using fresh media. [1498] 3. Seed 6,000 cells into cell culture plate with 50 L media. The [1499] 4. Incubate cell plate overnight in a 37 C., 5% CO2 incubator. Compound Titrations [1500] 1. Use Tecan to complete the compound addition. Compounds start from 10 uM top, 3-fold dilution, and 10 doses. The final DMSO concentration is 0.8%. Dispensed 0.2 uM Trametinib as Min control. [1501] 2. Incubate cell plate for 3 hrs in the incubator. Detection with Cisbio pERK HTRF Kit [1502] 1. Dilute 1 volume of 4 lysis buffer with 3 volumes of deionized water. Then, add 100 the blocking reagent. Keep lysis buffer on the ice. [1503] 2. At the end of the compound treatment, flick-off the media. [1504] 3. Add 35 L of lysis buffer per well using a Multidrop Combi. Then place on a plate agitator shaking at 300 rpm at 4 C. for 40 mins. [1505] 4. Make up the HTRF antibody buffer. For each assay plate, mix 50 L of d2-conjugate antibody with 950 L of detection buffer. Similarly, mix 50 L of Cryptate antibody with 950 L of detection buffer. Then mix the two diluted antibodies together. [1506] 5. Dispense 3.4 L the antibody buffer to wells of an empty assay plate. Seal the plate and centrifuge plate 30 sec1000 rpm. [1507] 6. At the end of the 4 C. lysis, centrifuge the lysate plates 3 mins1500 rpm. [1508] 7. Use the Bravo to transfer 13.6 L of lysate from cell culture plate to assay plate. Then incubate assay plate for 2 hrs at room temperature. [1509] 8. At the end of incubation, read plate on the Envision after centrifuging plate 30 sec1000 rpm. [1510] pERK IC.sub.50S were reported in Table 3 and single point % inhibitions at 100 nM were reported in Table 4. TABLE-US-00003 TABLE 3 Inhibition (HTRF IC.sub.50 nM) of KRas -mediated Phosphorylation of ERK by Exemplary Compounds of Formula (I) Ex. No. AsPC-1 H727 MKN1 HCT116 A549 H460 H358 H2009 PSN1 526 >10000 >10000 527 >10000 >10000 528 >10000 >10000 529 >10000 >10000 530 2771 4394 531 >10000 >10000 532 >10000 >10000 533 1499 1967 534 5812 1624 535 1618 2192 536 4551 3439 537 2021 1178 1483 >10000 538 3 6 4 13 6 5 3 1626 539 129 179 540 1 4 1 12 7 2 2 692 541 198 240 208 216 107 542 >10000 2330 543 >10000 1608 5952 >10000 544 455 79 25 >10000 546 1829 1012 547 49 263 16 51 7525 548 55 88 549 328 208 550 590 293 645 1372 423 >10000 551 2500 814 1465 >10000 552 9328 5299 553 5156 1627 554 2383 410 742 555 >10000 >10000 4020 >10000 556 >10000 2513 557 617 216 22 517 174 165 >10000 558 312 603 822 559 105 20 5 9493 560 3097 724 561 80 13 1 24 4 5 3 >10000 562 76 217 35 1065 496 438 >10000 563 >10000 >10000 >10000 >10000 564 >10000 >10000 565 >10000 >10000 566 760 138 72 130 47 567 >10000 >10000 568 62 33 2 29 19 17 1376 569 5112 444 69 >10000 570 1774 280 56 542 >10000 571 >10000 >10000 572 >10000 4192 573 12 15 574 3420 1127 78 >10000 575 >10000 >10000 417 >10000 576 >10000 577 8440 >10000 578 294 258 1 467 125 >10000 579 155 369 37 1776 357 481 >10000 580 >10000 >10000 476 >10000 581 1367 1172 527 >10000 582 130 328 583 5378 2498 312 >10000 584 231 981 585 4611 2056 586 94 85 25 65 3771 587 2072 3086 926 >10000 588 >10000 >10000 589 1540 731 590 505 833 494 591 1541 245 357 138 592 >10000 >10000 >10000 >10000 593 1227 391 293 >10000 594 2814 2294 2347 >10000 595 1573 1193 596 >10000 2451 597 4805 2356 598 >10000 >10000 599 >10000 >10000 600 >10000 >10000 601 376 300 26 344 133 >10000 602 5455 3870 603 >10000 >10000 604 81 71 2 425 605 1556 946 606 >10000 >10000 607 1738 1771 608 >10000 >10000 >10000 >10000 609 1393 880 92 >10000 610 884 660 1010 1303 256 662 611 4468 1948 612 >10000 >10000 613 >10000 >10000 614 >10000 >10000 615 7207 >10000 1529 >10000 616 3625 1135 617 1553 763 618 >10000 >10000 619 3621 1807 620 9681 6797 621 >10000 >10000 622 >10000 >10000 623 >10000 >10000 624 4030 3993 834 >10000 625 4739 2852 195 >10000 626 >10000 >10000 627 >10000 4555 628 3261 2809 629 >10000 >10000 630 >10000 4423 631 3130 1599 632 >10000 >10000 633 >10000 >10000 >10000 >10000 634 >10000 6210 2980 >10000 635 >10000 >10000 636 4193 1810 637 >10000 >10000 >10000 >10000 638 930 1268 639 1037 718 640 5131 889 208 >10000 641 >10000 >10000 642 >10000 >10000 2868 >10000 643 6 21 4 13 16 5 2 625 644 147 340 10 411 299 160 2616 645 4637 3720 646 8484 >10000 647 9344 >10000 648 >10000 >10000 650 1321 162 256 2411 847 >10000 651 1465 1791 546 >10000 652 2279 1392 653 >10000 >10000 654 1413 1792 655 >10000 >10000 656 1896 2378 943 3243 657 2660 659 >10000 >10000 660 8033 >10000 661 >10000 >10000 662 837 274 57 >10000 663 3654 936 664 567 351 5 152 >10000 665 1242 3125 666 184 320 18 207 >10000 667 6148 6053 668 >10000 >10000 669 >10000 4511 670 2 5 2 53 9 17 1 4685 671 28 6 7 4108 672 469 1262 541 673 115 21 674 9 21 6 191 30 69 2 >10000 675 9493 2039 676 996 5133 677 4584 678 >10000 >10000 679 >10000 9493 680 >10000 >10000 681 >10000 >10000 682 >10000 >10000 683 >10000 >10000 684 >10000 >10000 685 245 1674 9 359 1089 188 >10000 686 >10000 8835 687 >10000 >10000 688 >10000 >10000 689 >10000 >10000 690 81 37 16 7622 691 >10000 >10000 692 >10000 7028 693 >10000 >10000 694 985 605 695 1110 2692 696 690 948 123 >10000 697 1865 4749 698 87 68 17 188 141 72 4151 699 2 6 14 2 5 3 700 412 948 4 784 468 348 209 1318 701 101 476 702 32 149 703 342 982 704 53 223 705 598 1222 706 45 83 9 85 112 39 2775 707 79 24 2 4412 708 >10000 >10000 709 63 53 3 253 710 22 49 25 47 2608 711 121 196 21 247 109 6215 712 15 30 12 22 2708 713 73 59 22 102 3585 714 26 89 95 760 193 >10000 715 97 153 43 344 3623 716 39 273 9 1019 717 22 44 3 84 47 30 1816 718 17 43 2 58 37 29 1096 719 7 23 1 23 7 8 518 720 19 47 6 1756 721 15 28 2 48 19 12 956 725 >10000 >10000 726 >10000 >10000 727 >10000 >10000 728 2512 2512 >10000 >10000 729 >10000 >10000 730 >10000 >10000 731 >10000 >10000 732 >10000 >10000 737 420 79 9 7192 738 5962 1510 739 >10000 >10000 740 2626 3160 741 >10000 >10000 742 1595 292 624 1794 2608 >10000 743 3693 1099 744 2726 5730 >10000 >10000 745 867 701 511 1712 815 516 185 4278 746 2257 1344 747 3848 1265 748 788 275 749 1405 246 750 1905 1675 751 5218 3827 752 55 53 753 69 83 14 3082 754 747 516 755 >10000 >10000 756 >10000 >10000 757 9835 >10000 758 1273 1784 759 >10000 >10000 760 >10000 >10000 761 4321 1278 >10000 >10000 762 704 220 139 134 234 327 40 2550 763 1247 498 764 >10000 >10000 765 5910 2910 766 >10000 >10000 767 193 87 32 216 76 64 >10000 768 434 275 22 397 708 184 38 >10000 769 510 567 226 1240 2188 661 88 >10000 770 444 654 5 3437 3332 1717 258 >10000 771 1370 897 772 2234 2667 773 7 8 4 18 8 10 3 2676 774 852 138 123 506 924 434 121 2344 775 >10000 >10000 776 18 61 16 75 18 29 18 9009 778 84 45 779 >10000 9387 780 784 340 557 412 246 33 781 8947 >10000 783 52 187 19 9777 785 >10000 786 4957 2821 787 1668 2079 788 73 211 13 2844 789 32 116 6 1747 791 1 2 0.1 2 1 1 1 1 80 792 4 32 2 13 9 4 8 744 793 3 3 0.3 9 1 2 1 246 794 32 27 1 26 12 6 5 37 795 2 11 4 130 41 28 4 4793 796 21 12 2 37 7 8 5 797 1 4 0.0 10 3 3 1 296 798 17 19 0.3 25 3 4 3 946 799 7 20 0.9 30 9 8 4 988 800 6 3 0.3 13 3 3 1 587 801 3 12 0.1 15 7 4 1 117 802 >10000 >10000 >10000 >10000 12 >10000 32 >10000 805 13 29 1 24 23 10 8 812 806 2 364 19 129 139 107 43 29 807 32 14 3 125 808 3068 1687 653 >10000 809 871 809 57 1506 2560 918 228 >10000 810 >10000 4982 110 >10000 811 149 68 37 5667 812 743 363 68 324 922 166 177 >10000 813 1077 2548 814 485 402 176 >10000 815 32 28 22 2292 816 >10000 >10000 817 188 43 50 5106 818 135 347 61 345 212 167 121 >10000 824 165 174 167 502 143 136 69 >10000 825 180 56 36 369 83 98 50 5916 826 12 51 7 74 44 30 9 2394 827 67 242 41 180 159 92 68 >10000 828 >10000 >10000 829 >10000 >10000 830 272 267 188 7859 831 331 1081 13 >10000 834 3447 1138 87 1204 2753 797 186 >10000 835 146 72 20 137 192 72 31 1621 836 386 231 19 119 69 32 22 9789 837 4 23 3 45 11 14 6 2994 838 508 1030 222 >10000 840 575 299 38 239 422 145 180 >10000 842 479 97 1 41 56 20 9 >10000 843 6226 5295 55 305 2512 162 478 >10000 844 3329 2902 198 >10000 845 1566 1146 64 159 1191 80 241 3462 846 4473 2852 102 572 2678 238 746 >10000 847 4515 1642 270 1427 1820 582 494 >10000 848 2063 896 100 496 809 275 310 >10000 849 3093 1000 189 1779 1271 802 286 >10000 850 1454 2282 4 171 862 83 150 >10000 851 1210 932 475 397 159 264 852 35 109 5 38 68 42 12 923 853 33 67 1 36 39 23 10 1071 854 20 48 6 40 36 21 11 3691 855 >10000 >10000 857 967 352 6 410 611 144 369 >10000 858 138 375 3 21 19 7 43 >10000 859 >10000 5479 56 1259 >10000 892 1135 >10000 860 2601 1118 7 600 2763 395 455 >10000 861 1453 592 1 254 1339 173 45 >10000 862 6213 3704 196 2873 7210 1107 1683 >10000 863 >10000 4002 208 3887 >10000 1992 1365 >10000 864 >10000 >10000 865 7701 >10000 867 >10000 3410 868 17 24 21 53 61 22 12 3417 869 3597 4522 290 1204 2761 271 922 >10000 870 51 98 18 49 66 25 10 1300 872 328 1206 636 581 318 197 873 93 408 198 325 135 194 149 >10000 874 12 81 22 48 22 21 16 2070 875 >10000 >10000 >10000 >10000 >10000 >10000 876 661 1557 112 1132 1036 561 234 >10000 877 79 189 104 176 92 86 40 2153 878 43 83 16 186 125 53 52 4002 879 12 35 1 65 30 25 14 889 880 153 196 24 520 176 176 100 >10000 881 >10000 >10000 >10000 >10000 882 677 1295 521 7114 >10000 4464 429 >10000 883 1167 252 94 772 822 211 95 >10000 884 3182 2807 885 14 39 5 16 30 8 7 1325 886 40 135 22 59 73 27 18 2563 887 >10000 >10000 1241 >10000 >10000 7041 2535 >10000 889 600 129 55 188 365 134 24 >10000 890 >10000 >10000 >10000 >10000 >10000 >10000 891 621 295 73 568 658 150 382 >10000 892 2177 1630 174 992 2141 382 960 >10000 893 2098 3019 895 27 119 11 79 73 42 11 905 896 6 2 1 1 897 32 12 5 3 898 250 836 196 1012 355 252 56 >10000 899 5367 4412 6694 3534 1291 1414 900 213 240 3 504 136 96 82 >10000 901 2449 2416 19 1401 873 368 623 >10000 904 30 121 4 167 112 53 21 2510 905 4146 7438 1142 6306 2610 1347 2705 >10000 907 2045 922 137 1577 827 590 325 >10000 908 5796 2306 1731 1627 630 707 909 5161 1312 910 8165 1670 911 526 527 17 231 226 108 114 >10000 912 2308 3312 504 1829 2822 2052 800 >10000 913 580 571 211 246 112 146 914 2382 1041 461 915 94 74 14 60 51 36 9 1552 916 >10000 >10000 8968 917 149 223 151 233 198 54 918 3 17 1 12 4 5 3 490 919 14 43 3 37 19 10 14 2480 920 77 42 4 44 19 15 12 2056 921 92 86 0.4 309 68 75 33 7628 922 1380 576 923 365 125 9 >10000 924 262 118 14 >10000 925 826 302 9 >10000 926 66 29 0.7 2999 927 468 202 17 >10000 928 74 33 3 2841 929 60 163 17 137 84 41 14 397 930 13 4 0.0 3 1 931 58 59 0.9 72 17 15 5 2282 932 139 225 3 130 69 33 23 933 29 70 11 526 202 287 18 934 11 6 0.2 7 1 935 70 73 936 17 25 2 262 71 104 11 937 116 116 1 88 55 36 12 938 9 4 0.2 7 3 4 1 1 939 32 28 0.1 27 11 18 5 940 42 72 2 43 33 17 10 941 1 2 0.1 3 2 2 1 1 942 2 1 1 1 1 0.4 1 943 32 50 0.4 27 4 944 2 6 0.0 6 6 3 1 1 945 79 29 0.2 40 46 29 12 946 8 847 628 984 494 212 229 947 157 352 4 119 29 TABLE-US-00004 TABLE 4 Inhibition (HTRF % at 100 nM) of KRas -mediated Phosphorylation of ERK by Exemplary Compounds of Formula (I) Ex. No. AsPC-1 H727 H460 H358 A549 HCT116 530 18 6 15 6 533 8 7 27 8 534 6 9 19 6 535 16 8 9 3 536 9 9 537 29 2 538 100 86 539 7 1 37 18 50 13 540 101 88 97 103 108 95 543 1 5 544 13 30 46 67 59 5 547 20 33 548 38 59 38 29 549 3 6 553 0 3 0 6 559 89 98 75 55 560 5 8 10 4 15 12 561 30 74 99 99 103 63 570 38 69 26 26 573 92 94 62 53 574 19 18 576 1 2 3 15 581 24 21 582 3 15 32 13 584 20 18 11 15 14 3 586 56 42 587 6 12 593 0 4 595 12 1 3 9 604 53 47 69 94 27 64 605 7 3 20 12 607 62 9 34 24 610 31 1 10 5 643 100 87 645 4 6 646 12 6 9 2 24 9 657 24 19 18 27 2 9 660 20 41 662 22 22 666 59 24 671 60 98 60 35 673 8 53 8 88 43 16 674 63 97 74 17 676 11 4 19 4 677 8 2 690 37 79 4 20 694 3 9 8 10 695 2 1 16 13 696 21 5 697 19 5 4 1 699 95 101 80 82 700 96 103 83 86 701 15 6 20 0 702 56 7 61 37 703 4 10 47 0 704 25 21 40 47 26 19 705 6 3 0 34 29 3 707 84 88 71 47 709 88 101 62 65 710 66 37 711 78 43 712 95 52 713 60 25 714 73 16 715 42 8 716 56 71 37 34 720 70 43 80 85 64 51 733 27 10 2 7 734 18 3 3 13 735 14 31 5 2 736 3 4 5 2 737 27 8 17 39 746 2 17 19 10 747 6 6 4 5 748 6 5 7 21 749 3 5 15 20 750 1 1 16 15 1 2 751 2 50 17 10 752 27 31 44 76 31 32 753 42 76 2 23 757 10 2 758 9 23 11 20 761 11 13 762 22 36 763 13 25 11 5 765 6 13 5 28 768 23 59 30 8 770 1 12 1 10 772 19 4 22 3 773 96 99 97 90 776 84 60 778 16 36 74 64 69 49 780 12 30 8 42 21 2 781 10 24 782 5 11 783 47 12 47 62 34 31 784 19 0 9 9 785 6 2 0 9 8 5 786 1 15 8 3 19 0 787 23 33 11 8 14 9 788 45 41 47 75 38 33 789 77 43 76 97 57 55 790 9 15 [1511] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.