7- OR 8-HYDROXY-ISOQUINOLINE AND 7- OR 8-HYDROXY-QUINOLINE DERIVATIVES AS ALPHA-1-ANTITRYPSIN MODULATORS FOR TREATING ALPHA-1-ANTITRYPSIN DEFICIENCY (AATD)

Abstract

7- or 8-hydroxy-isoquinoline and 7- or 8-hydroxy-quinoline derivatives as alpha-1-antitrypsin modulators for treating alpha-1-antitrypsin deficiency (AATD).

Claims

1. A compound of Formula I: ##STR01125## a deuterated derivative of a compound of Formula I, and/or a pharmaceutically acceptable salt of any of the foregoing; wherein: R.sup.1 and R.sup.1′ are selected from hydrogen, halogen, —OH, —O(benzyl), and —NH.sub.2, wherein one of R.sup.1 and R.sup.1′ is —OH, —O(benzyl), or NH.sub.2, and other is hydrogen or halogen; W.sup.1 and W.sup.2 are each —CR.sup.x; wherein R.sup.x is hydrogen or halogen; X is selected from —C═O, —CR.sup.2, N, and —NR.sup.3; Y is selected from —C═O, —CR.sup.2, N, and —NR.sup.3, wherein if X is —C═O, then Y is —NR.sup.3, if X is —CR.sup.2, then Y is N, if X is N, then Y is —CR.sup.2, and if X is —NR.sup.3, then Y is —C═O; (z) is a double bond unless X or Y is C═O, and when X or Y is C═O, then (z) is a single bond; R.sup.2 is selected from —CN, —C(═O)OH, —C(═O)NH.sub.2, —C(═O)NHR.sub.7, —C(═O)NHCH.sub.2R.sup.7, —OCH.sub.2R.sup.7, —OR.sup.7, —NHR.sup.7, —NHCH.sub.2R.sup.7, C.sub.6 or C.sub.10 aryl, 5 to 10-membered heteroaryl, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 heteroalkyl, and 3 to 10-membered heterocyclyl, wherein the alkyl, heteroalkyl, alkenyl, heterocyclyl, aryl, or heteroaryl of R.sup.2 is optionally substituted with 1-3 groups independently selected from halogen, —C(═O)OH, and C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6 or C.sub.10 aryl, 3 to 10-membered heterocyclyl, and 5 to 10-membered heteroaryl (optionally further substituted with halogen, —OH, —OCH.sub.3, —C(═O)OH) and/or C.sub.3-C.sub.6 cycloalkyl (optionally further substituted with halogen, —OH, —OCH.sub.3, and/or —C(═O)OH), and wherein the heteroalkyl of R.sup.2 contains 1-3 heteroatoms selected from N, O, and S; R.sup.3 is selected from hydrogen, C.sub.6 or C.sub.10 aryl, C.sub.1-C.sub.8 alkyl, and C.sub.3-C.sub.8 cycloalkyl; wherein R.sup.3 is optionally substituted with 1-3 groups independently selected from ═O, —OH, —CH.sub.2OH, —C(═O)OH, NH.sub.2, C.sub.3-C.sub.6 cycloalkyl (optionally substituted with ═O, —CH.sub.2OH, and/or —C(═O)OH), and 3 to 6-membered heterocyclyl (optionally substituted with ═O, —CH.sub.2OH, and/or —C(═O)OH), and wherein the heterocyclyl of R.sup.3 contains 1-3 nitrogen atoms; and wherein R.sup.3 is optionally fused to a C.sub.3-C.sub.6 cycloalkyl; R.sup.4 is selected from halogen, —NR.sup.yR.sup.y, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 heteroalkyl, 3 to 6-membered heterocyclyl, and 5 or 6-membered heteroaryl, wherein the heteroalkyl, heterocyclyl, or heteroaryl of R.sup.4 contains 1-3 atoms selected from N, O, and S; wherein the alkyl, alkenyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, and heteroaryl of R.sup.4 is optionally substituted with 1-3 groups independently selected from halogen, ═O, —OH, —OCH.sub.3, —CH.sub.3 and —C(═O)OH; and wherein R.sup.y is independently selected from hydrogen and C.sub.1-C.sub.3 alkyl; wherein the C.sub.1-C.sub.3 alkyl of R.sup.y is optionally substituted with halogen, ═O, —OH, —OCH.sub.3, —CH.sub.3 and —C(═O)OH; R.sup.5 is selected from halogen, hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.6 or C.sub.10 aryl, —O(phenyl), 5 or 6-membered heteroaryl, C.sub.3-C.sub.6 carbocyclyl, and 3 to 6-membered heterocyclyl, wherein the heterocyclyl or heteroaryl contains 1-3 nitrogens and wherein R.sup.5 is optionally substituted with (R.sup.6).sub.n, wherein n is 1, 2, or 3; provided that R.sup.5 is not imidazolyl; R.sup.6 is each independently selected from from halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, and C.sub.1-C.sub.3 haloalkoxy; R.sup.7 is selected from C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6 or C.sub.10 aryl, C.sub.2-C.sub.8 heteroalkyl, 3 to 8-membered heterocyclyl, and 5 to 8-membered heteroaryl, wherein R.sup.7 is optionally substituted with 1-3 groups independently selected from halogen, ═O, —OH, —OCH.sub.3, —CH.sub.3, —C(═O)OH, —C(═O)NR.sup.8, —CN, —NH.sub.2, C.sub.1-C.sub.6 alkyl (optionally substituted with 1-3 groups selected from ═O, —OH, —CN, —C(═O)OH, and —NH.sub.2), C.sub.3-C.sub.6 cycloalkyl (optionally substituted with 1-3 groups selected from ═O, —OH, —CN, —C(═O)OH, and —NH.sub.2), C.sub.6 or C.sub.10 aryl (optionally substituted with 1-3 groups selected from ═O, —OH, —CN, —C(═O)OH, and —NH.sub.2), C.sub.2-C.sub.6 heteroalkyl (optionally substituted with 1-3 groups selected from ═O, —OH, —CN, —C(═O)OH, and —NH.sub.2), and 3 to 6-membered heterocyclyl (optionally substituted with 1-3 groups selected from halogen, ═O, OH, CN, COOH, and NH.sub.2), 5 or 6-membered heteroaryl (optionally substituted with 1-3 groups selected from ═O, —OH, —CN, —COOH, and —NH.sub.2), and wherein the heteroalkyl, heterocyclyl, or heteroaryl of R.sup.7 contains 1-3 atoms selected from N, O, and S; and R.sup.8 is selected from C.sub.1-C.sub.6 alkyl, C.sub.6 or C.sub.10 aryl, and wherein R.sup.8 is optionally substituted with halogen and/or —OH.

2. The compound, deuterated derivative, or pharmaceutically acceptable salt of Formula I according to claim 1, selected from compounds of Formulae Ia(i), Ia(ii), Ia(iii), Ia(iv), Ia(v), and Ia(vi): ##STR01126## ##STR01127## deuterated derivatives of Formulae Ia(i), Ia(ii), Ia(iii), Ia(iv), Ia(v), and Ia(vi), and pharmaceutically acceptable salts of any of the foregoing, wherein R.sup.1′ is selected from hydrogen and halogen and R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and n are as defined in claim 1.

3. The compound of Formula I according to claim 1, selected from compounds of Formulae Ib(i), Ib(ii), Ib(iii), Ib(iv), Ib(v), and Ib(vi): ##STR01128## ##STR01129## deuterated derivatives of Formulae Ib(i), Ib(ii), Ib(iii), Ib(iv), Ib(v), and Ib(vi), and pharmaceutically acceptable salts of any of the foregoing, wherein R.sup.1′ is selected from hydrogen and halogen and R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and n are as defined in claim 1.

4. The compound of Formula 1 according to claim 1, selected from compounds of Formulae Ic(i), Ic(ii), Ic(iii), Ic(iv), Ic(v), and Ic(vi): ##STR01130## deuterated derivatives of Formulae Ic(i), Ic(ii), Ic(iii), Ic(iv), Ic(v), and Ic(vi), and pharmaceutically acceptable salts of any of the foregoing, wherein R.sup.1 is selected from hydrogen and halogen and R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and n are as defined in claim 1.

5. The compound of Formula I according to claim 1, selected from compounds of Formulae Id(i), Id(ii), Id(iii), Id(iv), Id(v), and Id(vi): ##STR01131## deuterated derivatives of Formulae Id(i), Id(ii), Id(iii), Id(iv), Id(v), and Id(vi), and pharmaceutically acceptable salts of any of the foregoing, wherein R.sup.1 is selected from hydrogen and halogen and R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and n are as defined in claim 1.

6. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein R.sup.1 is —OH.

7. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein R.sup.1′ is —OH.

8. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein R.sup.1 is —NH.sub.2.

9. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein R.sup.1′ is —NH.sub.2.

10. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-9, wherein R.sup.3 is selected from: phenyl and C.sub.3-C.sub.8 cycloalkyl wherein R.sup.3 is optionally substituted with 1-2 groups independently selected from ═O, —OH, —CH.sub.2OH, —C(═O)OH, —NH.sub.2, C.sub.3-C.sub.6 cycloalkyl (optionally further substituted with 1-2 groups independently selected from ═O, —CH.sub.2OH, and —C(═O)OH), and 3 to 6-membered heterocyclyl (optionally further substituted with 1-3 groups independently selected from ═O, —CH.sub.2OH, and —C(═O)OH); wherein the 3 to 6-membered heterocyclyl contains 1-2 nitrogen atoms; and wherein R.sup.3 is optionally fused to a C.sub.3-C.sub.6 cycloalkyl.

11. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-9, wherein R.sup.3 is selected from: C.sub.1-C.sub.6 alkyl optionally substituted with 1-2 groups independently selected from ═O, —OH, —CH.sub.2OH, —C(═O)OH, —NH.sub.2, C.sub.3-C.sub.6 cycloalkyl (optionally further substituted with 1-2 groups independently selected from ═O, —CH.sub.2OH, and —C(═O)OH), and 3 to 6-membered heterocyclyl (optionally further substituted with 1-3 groups independently selected from ═O, —CH.sub.2OH, and —C(═O)OH), wherein the 3 to 6-membered heterocyclyl contains 1-2 nitrogen atoms; and wherein R.sup.3 is optionally fused to a C.sub.3-C.sub.6 cycloalkyl.

12. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-9, wherein R.sup.3 is selected from C.sub.4 cyclic and C.sub.8 spirocyclic alkyls optionally substituted with 1-2 groups independently selected from ═O, —OH, —CH.sub.2OH, —C(═O)OH, and —NH.sub.2.

13. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-9, wherein R.sup.3 is selected from: ##STR01132##

14. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-9, wherein R.sup.3 is hydrogen.

15. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-14, wherein R.sup.4 is selected from halogen, —NR.sup.yR.sup.y, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 heterocyclyl, and 5 or 6-membered heteroaryl, wherein the heterocyclyl or heteroaryl of R.sup.4 contains 1-2 atoms selected from N, O, and S; wherein R.sup.4 is optionally substituted with 1-3 groups independently selected from halogen, —OH, —OCH.sub.3, and —CH.sub.3; wherein R.sup.y is independently selected from hydrogen and C.sub.1-C.sub.3 alkyl; and wherein the C.sub.1-C.sub.3 alkyl of R.sup.y is optionally substituted with —OCH.sub.3.

16. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-15, wherein R.sup.4is selected from halogen, —NR.sup.yR.sup.y, C.sub.1-C.sub.6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —OH, —OCH.sub.3, and —CH.sub.3), 5 or 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from halogen, —OH, —OCH.sub.3, and —CH.sub.3), and 5-membered heteroaryl, wherein the heterocyclyl contains 1-2 heteroatoms selected from N, O, and S; and wherein R.sup.y is C.sub.1-C.sub.2 alkyl optionally substituted with —OCH.sub.3.

17. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-13, wherein R.sup.4 is selected from: ##STR01133##

18. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-17, wherein R.sup.4 is ##STR01134##

19. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-17, wherein R.sup.4 is ##STR01135##

20. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claims 1-19, wherein R.sup.5 is selected from C.sub.6 or C.sub.10 aryl, —O(phenyl), 5 or 6-membered heteroaryl, C.sub.3-C.sub.6 carbocyclyl, and 3 to 6-membered heterocyclyl.

21. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-20, wherein R.sup.5 is selected from phenyl, 5 or 6-membered heteroaryl, C.sub.3-C.sub.6 carbocyclyl, and 3 to 6-membered heterocyclyl, wherein R.sup.5 is optionally substituted with 1 or 2 groups independently selected from halogen and —CH.sub.3.

22. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-21, wherein R.sup.5 is selected from: hydrogen, Br, —CH.sub.3, ##STR01136## ##STR01137## ##STR01138##

23. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-22, wherein R.sup.5 is selected from: ##STR01139##

24. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-23, wherein R.sup.2 is selected from —OR.sub.7.

25. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-23, wherein R.sup.2 is selected from —NHR.sub.7.

26. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-23, wherein R.sup.2 is selected from —C(═O)NHR.sup.7.

27. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-23, wherein R.sup.2 is selected from —NHCH.sub.2R.sup.7.

28. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-23, wherein R.sup.2 is selected from —CN, —C(═O)OH, —C(═O)NH.sub.2, —C(═O)NHCH.sub.2R.sup.7, and —OCH.sub.2R.sup.7.

29. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 24-28, wherein R.sup.7 is selected from C.sub.1-C.sub.8 alkyl and C.sub.3-C.sub.8 cycloalkyl, each of which is optionally substituted with 1-3 groups independently selected from Br, Cl, F, —CH.sub.3, —C(═O)OH, ═O, —OCH.sub.3, and —OH.

30. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 24-28, wherein R.sup.7 is selected from C.sub.2-C.sub.8 heteroalkyl and 3 to 8-membered heterocyclyl, wherein the heteroalkyl or heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; and wherein the heteroalkyl or heterocyclyl is optionally substituted with 1-3 groups independently selected from Br, Cl, F, —CH.sub.3, —C(═O)OH, ═O, —OCH.sub.3, and —OH.

31. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 24-28, wherein R.sup.7 is selected from aryl and 3 to 8-membered heteroaryl, wherein the heteroalkyl or heterocyclyl contain 1-3 heteroatoms selected from N, O, and S; and wherein the heteroalkyl or heterocyclyl is optionally substituted with 1-3 groups independently selected from Br, Cl, F, —CH.sub.3, —C(═O)OH, ═O, —OCH.sub.3, and —OH.

32. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 24-28, wherein R.sup.7 is selected from C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.8 heteroalkyl, 3 to 8-membered heterocyclyl, phenyl, and 5 to 8-membered heteroaryl, wherein R.sup.7 is optionally substituted with 1-3 groups independently selected from halogen, ═O, —C(═O)OH, phenyl, 5 to 8-membered heteroaryl, C.sub.1-C.sub.6 alkyl (optionally further substituted with 1-3 groups selected from ═O, OH, CN, COOH, and NH.sub.2), C.sub.3-C.sub.6 cycloalkyl (optionally further substituted with 1-3 groups selected from ═O, —OH, —CN, —COOH, and —NH.sub.2), C.sub.2-C.sub.6 heteroalkyl (optionally further substituted with 1-3 groups selected from halogen, ═O, —OH, —CN, —COOH, and —NH.sub.2), and 3 to 6-membered heterocyclyl (optionally further substituted with 1-3 groups selected from ═O, —OH, —CN, —COOH, and —NH.sub.2); and wherein the heteroalkyl, heterocyclyl, or heteroaryl of R.sup.7 contains 1-3 atoms independently selected from N, O, and S.

33. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-23, wherein R.sup.2 is selected from ##STR01140## ##STR01141## ##STR01142## ##STR01143##

34. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-23, wherein R.sup.2 is selected from ##STR01144##

35. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-23, wherein R.sup.2 is selected from ##STR01145## ##STR01146##

36. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-23, wherein R.sup.2 is selected from ##STR01147## ##STR01148##

37. A compound selected from: ##STR01149## ##STR01150## ##STR01151## ##STR01152## ##STR01153## ##STR01154## ##STR01155## ##STR01156## ##STR01157## ##STR01158## ##STR01159## ##STR01160## ##STR01161## ##STR01162## ##STR01163## ##STR01164## ##STR01165## ##STR01166## ##STR01167## ##STR01168## ##STR01169## ##STR01170## ##STR01171## ##STR01172## ##STR01173## ##STR01174## ##STR01175## ##STR01176## ##STR01177## ##STR01178## ##STR01179## ##STR01180## ##STR01181## ##STR01182## ##STR01183## ##STR01184## ##STR01185## ##STR01186## ##STR01187## ##STR01188## ##STR01189## ##STR01190## ##STR01191## ##STR01192## ##STR01193## ##STR01194## ##STR01195## ##STR01196## ##STR01197## ##STR01198## ##STR01199## ##STR01200## ##STR01201## ##STR01202## ##STR01203## ##STR01204## ##STR01205## ##STR01206## ##STR01207## ##STR01208## ##STR01209## ##STR01210## ##STR01211## ##STR01212## ##STR01213## ##STR01214## ##STR01215## ##STR01216## ##STR01217## ##STR01218## ##STR01219## ##STR01220## ##STR01221## ##STR01222## ##STR01223## ##STR01224## ##STR01225## ##STR01226## ##STR01227## ##STR01228## ##STR01229## ##STR01230## ##STR01231## ##STR01232## ##STR01233## ##STR01234## ##STR01235## ##STR01236## ##STR01237## deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing.

38. A pharmaceutical composition comprising a compound according to any one of claims 1-37, a deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier.

39. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof at least one compound chosen from the compounds, deuterated derivatives, and pharmaceutically acceptable salts of any one of claims 1-37 or a pharmaceutical composition according to claim 38.

40. The method according to claim 39, wherein the patient has a Z mutation in alpha-1 antitrypsin.

41. The method according to claim 39, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

42. The method according to claim 40, wherein the patient is homozygous for Z-mutations in alpha-1 antitrypsin.

43. A method of modulating alpha-1 antitrypsin activity comprising contacting said alpha-1-antitrypsin with at least one compound chosen from the compounds, deuterated derivatives, and pharmaceutically acceptable salts according to any one of claims 1-37 or a pharmaceutical composition according to claim 38.

Description

EXAMPLES

[0339] In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.

Example 1

Synthesis of Compounds

[0340] All the specific and generic compounds, the methods for making those compounds, and the intermediates disclosed for making those compounds, are considered to be part of the disclosure.

A. Synthesis of Starting Materials

[0341] Preparations of S1-S36 describe synthetic routes to intermediates used in the synthesis of Compounds 1-361.

Preparation of S1

7-(benzyloxy)-4-(4-fluorophenyl)-3-(1-methoxy-2-methylpropan-2-yl)isoquinolin-1(2H)-one (S1)

[0342] ##STR00429##

Step 1. Synthesis of 5-benzyloxy-2-bromo-benzoic acid (C2)

[0343] To a solution of C1 (5 g, 15.57 mmol) in MeOH (20 mL) and THF (15 mL) was added aq. NaOH (15 mL of 2 M, 30.00 mmol) the resulting solution was stirred at RT for 2 hours. The solution was concentrated and neutralized with 6 M HCl (5 mL). The aqueous phase was extracted with EtOAc (30 mL×2) and the combined organic fractions were washed with brine (2×20 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to provide C2 as a white solid (4.7 g, 97%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J=3.1 Hz, 1H), 7.61 (d, J=8.9 Hz, 1H), 7.49-7.35 (m, 6H), 7.04 (dd, J=8.8, 3.1 Hz, 1H), 5.12 (s, 2H). LCMS m/z 306.94 [M+H].sup.+

Step 2. Synthesis of 5-benzyloxy-2-bromo-N,N-diethyl-benzamide (C3)

[0344] To a solution of C2 (4.7 g, 15.30 mmol) in EtOAc (50 mL) was added diethylamine (5 mL, 48.33 mmol) and a white precipitate crashed out. To this suspension was added EtOAc (25 mL) followed by dropwise addition of T3P (14.6 g of 50% w/w, 22.94 mmol) in EtOAc. The solution turned yellow in a few minutes and the solution was stirred for 2 hours. The reaction was quenched by addition of 1 M HCl (20 mL) and water (20 mL). The organic phase was separated, and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic phases were washed with water (2×20 mL), brine (1×20 mL), dried over MgSO4 and concentrated to dryness to provide C3 as a yellow oil. (5.6 g, quant.). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.50-7.32 (m, 6H), 6.91-6.84 (m, 2H), 5.17-5.00 (m, 2H), 3.85 (dq, J=14.2, 7.1 Hz, 1H), 3.32 (dq, J=14.0, 7.1 Hz, 1H), 3.15 (qd, J=7.2, 3.9 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H), 1.02 (t, J=7.1 Hz, 3H). LCMS m/z 362.09 [M+H].sup.+

Step 3. Synthesis of 5-benzyloxy-N,N-diethyl-2-[(4-fluorophenyl)methyl]benzamide (C4)

[0345] A solution of C3 (6 g, 16.56 mmol), 2-[(4-fluorophenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5 g, 21.18 mmol) and Na.sub.2CO.sub.3 (28 mL of 2M, 56.00 mmol) in dioxane (90 mL) and water (30 mL) was degassed with a stream of N.sub.2 for 5 min. Then, PdCl(dppf) (605 mg, 0.8268 mmol) was added and the solution was stirred at 100° C. for 15 hours. and kept overnight. The reaction mixture the was cooled down and EtOAc (50 mL) followed by water (20 mL) were added. The aqueous layer was separated and extracted with EtOAc (2×25 mL). The combined organic fractions were washed with brine (2×20 mL), dried over Na.sub.2SO.sub.4 and concentrated to dryness. Purification by silica gel chromatography (0-52% ethyl acetate in heptane) afforded C4 as a light-yellow oil. (5.3 g, 82%) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.49-7.31 (m, 5H), 7.21-7.08 (m, 3H), 7.00-6.91 (m, 3H), 6.80 (d, J=2.7 Hz, 1H), 5.07 (d, J=9.2 Hz, 2H), 3.91 (d, J=21.7 Hz, 2H), 3.65 (s, 1H), 3.33 (s, 1H), 2.94 (s, 1H), 2.77 (s, 1H), 1.19 (t, J=7.1 Hz, 3H), 0.92 (d, J=7.1 Hz, 3H). LCMS m/z 392.25 [M+H].sup.+

Step 4. Synthesis of 7-(benzyloxy)-4-(4-fluorophenyl)-3-(1-methoxy-2-methylpropan-2-yl)isoquinolin-1(2H)-one (S1)

[0346] To a solution of C4 (210 mg, 0.5364 mmol) and 3-methoxy-2,2-dimethyl-propanenitrile C5 (70 mg, 0.6186 mmol) in THF (2 mL) was added LDA (310 μL of 2 M, 0.62 mmol) in a dropwise fashion at 0° C. The solution was slowly warmed to RT over an hour and the reaction was quenched by the addition of water (2 mL). The mixture was concentrated in vacuo and EtOAc (50 mL) and water (10 ml) were added. The aqueous layer was separated and extracted with EtOAc (10 mL). Combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated to give S1, which was used without further purification. (230 mg, 98%) .sup.1H NMR (400 MHz, Chloroform-d) δ 10.25 (s, 1H), 7.83 (d, J=2.8 Hz, 1H), 7.40-7.31 (m, 2H), 7.13-7.06 (m, 2H), 7.06-6.92 (m, 7H), 6.85-6.78 (m, 4H), 6.67 (d, J=2.7 Hz, 2H), 6.62 (d, J=9.1 Hz, 1H), 5.06 (s, 2H), 3.88-3.62 (m, 2H), 3.33 (s, 3H), 0.94 (s, 6H). LCMS m/z 432.27 [M+H].sup.+

Preparation of S2

1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-8-fluoro-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (S2)

[0347] ##STR00430##

Step 1. Synthesis of 3-benzyloxy-2-fluoro-6-(3-methylbut-1-ynyl)benzaldehyde (C7)

[0348] In a sealed tube, a suspension of C6 (3.0 g, 9.7047 mmol) in toluene (18.0 mL) and diisopropylamine (6.0 mL) was bubbled through with nitrogen for 10 min. Bis(triphenylphosphine)palladium(II) dichloride (143 mg, 0.2032 mmol) and CuI (81 mg, 0.4253 mmol) were added and bubbled through with N.sub.2 for another 2 min. 3-methylbut-1-yne (999.00 mg, 1.5 mL, 14.666 mmol) was added and the tube was sealed, stirred and heated at 50° C. overnight. The reaction mixture was cooled to RT, diluted with EtOAc (100 mL). The organic layer was washed with 3M aq. HCl (2×30 mL), water (30 mL), brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, loaded on silica gel and concentrated under reduced pressure. The residue was purified on silica gel chromatography, eluting from 0% to 20% ethyl acetate in heptanes to give, as orange oil, C7 (2.60 g, 89%). .sup.1H NMR (300 MHz, Chloroform-d) δ 1.22-1.32 (m, 6H), 2.67-2.90 (m, 1H), 5.18 (s, 2H), 7.04-7.24 (m, 2H), 7.30-7.47 (m, 5H), 10.50 (s, 1H). .sup.19F NMR (282 MHz, Chloroform-d) δ −136.8 (d, J=9.2 Hz, 1F). LCMS m/z 297.2 [M+H].sup.+

Step 2. Synthesis of 3-benzyloxy-2-fluoro-6-(3-methylbut-1-ynyl)benzaldehyde oxime (C8)

[0349] To a solution of hydroxylamine hydrochloride (6.17 g, 88.789 mmol) in pyridine (70.416 g, 72 mL, 890.22 mmol) was added acetonitrile (80 mL) at RT. Then, the solution was stirred and heated at 50° C. and a solution of C7 (8.74 g, 29.494 mmol) in 1,2-dichloroethane (55 mL) was added. The resulting mixture was heated at 50° C. for 1 hour. The solution was cooled to RT and diluted with EtOAc (100 mL) and water (100 mL) and decanted. The organic layer was washed with aqueous solution of 3 M HCl (4×50 mL), water (50 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give, as light yellow solid, C8 (8.71 g, 85%) .sup.1H NMR (300 MHz, Chloroform-d) δ 1.28 (d, J=6.8 Hz, 6H), 2.70-2.88 (m, 1H), 5.16 (s, 2H), 6.92 (t, J=8.4 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 7.29-7.50 (m, 5H), 8.54 (s, 1H), 8.73 (br. s., 1H). .sup.19F NMR (282 MHz, Chloroform-d) δ −136.3 (d, J=9.2 Hz, 1F). LCMS m/z 312.2 [M+H].sup.+

Step 3. Synthesis of 7-benzyloxy-4-bromo-8-fluoro-3-isopropyl-2-oxido-isoquinolin-2-ium (C9)

[0350] CuBr (15.7 g, 70.292 mmol) was added to a solution of C8 (8.71 g, 27.975 mmol) in N,N-dimethylacetamide (70 mL) and the resulting mixture was heated at 60° C. for 1 hour. The reaction mixture was cooled to RT, then cooled to 0° C. and with vigorous stirring, an aqueous solution of ammonium hydroxide and water (2:1, 75 mL) was slowly added and stirred at 0° C. for 30 minutes. Then, the suspended solids were filtered and washed with water to give a tan solid. The solid was dissolved through filter paper with dichloromethane, decanted, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure and dried under vacuum. The residue was triturated in methyl tert-butylether (40 mL) for 1 hour, filtered and washed with heptanes to give C9 (8.716 g, 80%) as tan solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 1.56 (d, J=7.0 Hz, 6H), 4.11 (br. s., 1H), 5.33 (s, 2H), 7.32-7.50 (m, 6H), 7.84 (d, J=9.4 Hz, 1H), 8.87 (br. s., 1H). .sup.19F NMR (282 MHz, Chloroform-d) δ −143.8 (d, J=6.1 Hz, 1F). LCMS m/z 390.1 [M+H].sup.+

Step 4. Synthesis of 7-benzyloxy-8-fluoro-4-(4-fluorophenyl)-3-isopropyl-2-oxido-isoquinolin-2-ium (C10)

[0351] A suspension of C9 (3.0 g, 7.6875 mmol), (4-fluorophenyl)boronic acid (1.62 g, 11.578 mmol) and an aqueous solution of Na.sub.2CO.sub.3 (8.0 mL of 2M, 16.0 mmol) in DMSO (27 mL) was heated to 100° C. and sparged with N.sub.2 for 10 min. Pd(dppf)Cl.sub.2.dichloromethane (327 mg, 0.4004 mmol) was added and the reaction was sparged for 2 minutes. The reaction was stirred at 100° C. for overnight. After about 20 minutes, an additional amount of DMSO (9 mL) and water (6 mL) were added due to the formation of a crust of solids on top of the mixture and difficult agitation. The reaction mixture was cooled to RT, water (60 mL) was added, stirred at room temperature for 15 minutes and the suspension was filtered and washed with water. The residue was then dissolved with dichloromethane (through filter paper). The filtrate was decanted, dried over anhydrous sodium sulfate, filtered, loaded on silica gel and concentrated under reduced pressure. The residue was purified on silica gel chromatography, eluting from 0% to 50% ethyl acetate in dichloromethane to give C10 (1.975 g, 63%) as light pink solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 1.40 (d, J=6.8 Hz, 6H), 3.21 (br. s., 1H), 5.28 (s, 2H), 6.81 (d, J=9.1 Hz, 1H), 7.14 (t, J=8.7 Hz, 1H), 7.22 (d, J=6.8 Hz, 4H), 7.31-7.48 (m, 5H), 8.96 (s, 1H). .sup.19F NMR (282 MHz, Chloroform-d) δ −144.8 (d, J=6.1 Hz, 1F), −113.6-112.2 (m, 1F). [0352] LCMS m/z 406.2 [M+H].sup.+

Step 5. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-8-fluoro-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (S2)

[0353] A solution of C10 (1.1 g, 2.710 mmol) and DABCO (1000 mg, 8.915 mmol) in dichloromethane (25 mL) was cooled to 0° C. and was added TFAA (1.5 mL, 10.79 mmol). The mixture was then allowed to warm to room temperature and was stirred for another 1 h and the reaction was concentrated to dryness. The residue was dissolved in a minimum of DMSO and was purified by reverse phase chromatography (C18, eluting from 10 to 100% acetonitrile in water with 0.1% TFA modifier) to give S2 bis trifluoroacetate salt as a white solid (1.85 g, 68%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.93 (t, J=8.9 Hz, 1H), 7.61-7.24 (m, 10H), 5.37 (s, 2H), 4.34 (t, J=7.3 Hz, 6H), 3.63 (t, J=7.3 Hz, 6H), 2.99 (p, J=6.8 Hz, 1H), 1.27 (d, J=6.8 Hz, 6H). LCMS m/z 500.38 [M+H].sup.+

Preparation of S3

4-(4-fluorophenyl)-3-isopropyl-7-methoxy-2H-isoquinolin-1-one (S3)

[0354] ##STR00431##

Step 1. Synthesis of 2-bromo-N,N-diethyl-5-methoxy-benzamide (C12)

[0355] To a solution of C11 (5 g, 21.64 mmol) and N,N-diethylamine (7 mL, 67.67 mmol) in dichloromethane (75 mL) was added HATU (10 g, 26.30 mmol) at room temperature. After stirring for 24 hours, the reaction was quenched with by addition of water and the organic layer was washed in 1 MHCl (30 mL), water, and aqueous saturated NaHCO.sub.3. The organic layer was then concentrated in vacuo to give a light brown liquid which was purified on silica gel chromatography, eluting from 0% to 50% ethyl acetate in heptane to give C12 as a colorless oil (5.63 g, 91%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.47-7.35 (m, 1H), 6.76 (dd, J=6.3, 3.1 Hz, 2H), 3.76 (d, J=3.4 Hz, 4H), 3.38-3.22 (m, 1H), 3.14 (qt, J=7.4, 3.4 Hz, 2H), 1.25 (td, J=7.1, 3.0 Hz, 4H), 1.06 (td, J=7.2, 3.0 Hz, 3H). LCMS m/z 286.14 [M+H].sup.+

Step 2. Synthesis of N,N-diethyl-2-[(4-fluorophenyl)methyl]-5-methoxy-benzamide (C13)

[0356] A solution of C12 (2 g, 6.989 mmol), 2-[(4-fluorophenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 g, 10.59 mmol) and Na.sub.2CO.sub.3 (12 mL of 2M, 24.00 mmol) in dioxane (36 mL) and water (12 mL) was degassed with N.sub.2 for 5 minutes. Then, PdCl.sub.2(dppf) (255 mg, 0.3485 mmol) was added and the solution was heated to 80° C. for 3 hours after which time the temperature was elevated to 100° C. and the solution was stirred for another 3 hours. LCMS showed the completion. The reaction mixture was cooled down to room temperature and EtOAc (50 mL) and water (20 mL) were added. The aqueous layer was separated and extracted with EtOAc (2×25 mL). The combined organic fractions were washed with brine (2×20 mL), dried over Na.sub.2SO.sub.4 and concentrated to dryness to give dark residue, which was purified on silica gel chromatography, eluting from 0% to 40% ethyl acetate in heptane to give C13 as a light yellow oil (2 g, 90%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.20-7.06 (m, 3H), 6.94 (t, J=8.7 Hz, 2H), 6.85 (dd, J=8.5, 2.7 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H), 3.80 (s, 2H), 3.74-3.23 (m, 2H), 3.08-2.65 (m, 2H), 1.19 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.1 Hz, 3H). LCMS m/z 316.26 [M+H].sup.+

Step 3. Synthesis of 4-(4-fluorophenyl)-3-isopropyl-7-methoxy-2H-isoquinolin-1-one (S3)

[0357] To a solution of C13 (1 g, 3.171 mmol) in THF (15 mL) was added LDA (2.0 mL of 2 M, 4.0 mmol) at 0° C. The colorless solution turned purple and was stirred for another hour at 0° C. by which time isobutyronitrile (570 μL) was added dropwise and the reaction was allowed to warm up to room temperature and was stirred for a further 12 hours. The reaction solution was concentrated to dryness and NH.sub.4Cl sat. (10 mL) and EtOAc (50 mL) were added. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, then concentrated to give a residue which was purified on silica gel chromatography, eluting from 0% to 50% ethyl acetate in dichloromethane to give S3 as light yellow oil (428 mg, 43%). .sup.1H NMR (400 MHz, Chloroform-d) δ 9.79 (s, 1H), 7.87 (d, J=2.8 Hz, 1H), 7.26-7.10 (m, 5H), 6.97 (d, J=8.9 Hz, 1H), 3.95 (s, 3H), 2.86 (p, J=7.1 Hz, 1H), 1.27 (d, J=7.0 Hz, 6H). LCMS m/z 312.21 [M+H].sup.+

Preparation of S4

7-benzyloxy-4-bromo-3-isopropyl-2-oxido-isoquinolin-2-ium (S4)

[0358] ##STR00432##

Step 1. Synthesis of 5-benzyloxy-2-(3-methylbut-1-ynyl)benzaldehyde (C15)

[0359] In a three-necked flask equipped with a reflux condenser, a solution of C14 (1.99 g, 6.8352 mmol) in dioxane (10.5 mL) and TEA (7.5 mL) was sparged with N.sub.2 for 15 minutes. Bis(triphenylphosphine)palladium(II) dichloride (95 mg, 0.135 mmol) and CuI (56 mg, 0.294 mmol) were added under N.sub.2 and the reaction was further bubbled for 2 m minutes in and 3-methylbut-1-yne (531.47 g, 0.84 mL, 7.4122 mmol) was added. The reaction turned from yellow to dark brown. The reaction was stirred at 60° C. overnight, cooled to room temperature, diluted with EtOAc (30 mL), washed with 1M aq. HCl (2×30 mL), water (20 ml) and brine (20 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on a silica plug eluted with Heptane/EtOAc (95:5) to yield C15 (1.88 g, 99%) as a dark brown oil. .sup.1H NMR (300 MHz, Chloroform-d) δ 1.29 (d, J=6.8 Hz, 6H), 2.84 (dt, J=13.7, 6.8 Hz, 1H), 5.12 (s, 2H), 7.16 (dd, J=8.5, 2.6 Hz, 1H), 7.28-7.62 (m, 7H), 10.50 (s, 1H). LCMS m/z 279.2 [M+H].sup.+

Step 2. Synthesis of 5-benzyloxy-2-(3-methylbut-1-ynyl)benzaldehyde oxime (C16)

[0360] To a solution of hydroxylamine hydrochloride (834 mg, 12.002 mmol) in pyridine (9.2308 g, 9.4 mL, 116.70 mmol) was added acetonitrile (11 mL) at RT. The solution was stirred at 50° C. and a solution of C15 (1.155 g, 3.8798 mmol) in 1,2-dichloroethane (7 mL) was added. The resulting mixture was heated at 50° C. for 45 minutes. The suspension was cooled to RT and diluted with EtOAc (30 mL) and water (30 mL) and decanted. The organic layer was washed with aqueous solution of 3MHCl (2×20 mL), water (20 mL), brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The resulting product still contained pyridine. The residue was dissolved in EtOAc (30 mL) and washed with 3 MHCl (30 mL) and brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated in heptane, filtered and dried under reduced pressure to yield C16 (844 mg, 74%) as a beige solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 1.28 (s, 3H), 1.30 (s, 3H), 2.82 (dquin, J=13.7, 6.8 Hz, 1H), 5.08 (s, 2H), 6.95 (dd, J=8.7, 2.8 Hz, 1H), 7.31-7.48 (m, 7H), 7.58 (br. s., 1H), 8.59 (s, 1H). LCMS m/z 294.2 [M+H].sup.+

Step 3. Synthesis of 7-benzyloxy-4-bromo-3-isopropyl-2-oxido-isoquinolin-2-ium (S4)

[0361] CuBr (10.599 g, 47.454 mmol) was added to a solution of C16 (5.6 g, 19.089 mmol) in N,N-dimethylacetamide (95 mL) and the resulting mixture was heated at 60° C. for 45 min. The reaction mixture was cooled to room temperature, then cooled to 0° C. and with vigorous stirring, an aqueous solution of ammonium hydroxide and water (2:1, 42 mL) was slowly added and stirred at 0° C. for 30 min. Then, the suspended solids were filtered and washed with water to give a tan solid. The solid was dissolved through filter paper with dichloromethane. The organic filtrate was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and dried under vacuum. The residue was triturated in methyl tert-butylether (±20 mL), filtered and washed with heptanes and dried under reduced pressure to yield S4 (4.735 g, 67%) as an off-white powder. .sup.1H NMR (300 MHz, Chloroform-d) δ 1.55 (s, 3H), 1.58 (s, 3H), 4.13 (br. s., 1H), 5.19 (s, 2H), 6.97 (d, J=2.3 Hz, 1H), 7.30-7.55 (m, 6H), 8.06 (d, J=9.4 Hz, 1H), 8.61 (br. s., 1H). LCMS m/z 372.1 [M+H].sup.+

Preparation of S5

7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-2H-isoquinolin-1-one (S5)

[0362] ##STR00433##

Step 1. Synthesis of methyl 5-benzyloxy-2-bromo-benzoate (C18)

[0363] To a solution of C17 (25.8 g, 111.67 mmol) in anhydrous DMF (180 mL) cooled at 0° C. was added K.sub.2CO.sub.3 (33.4 g, 241.67 mmol) followed by benzyl bromide (21.570 g, 15 mL, 126.12 mmol). The mixture was stirred for 15 minutes at 0° C. then for 5 hours at RT. MTBE (1.25 L) was added and the organic phase was washed with 5% aqueous NaHCO.sub.3 (5×250 mL), water (5×250 mL) and brine (1×250 mL), dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The residue was triturated in heptanes (1×125 mL), filtered and dried to afford C18 (34.2 g, 95%) as a white solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.53 (d, J=8.7 Hz, 1H), 7.45-7.29 (m, 6H), 6.95 (dd, J=8.7, 3.0Hz, 1H), 5.06 (s, 2H), 3.93 (s, 3H). LCMS m/z 321.0 [M+H].sup.+

Step 2. Synthesis of methyl 5-benzyloxy-2-[(4-fluorophenyl)methyl]benzoate (C19)

[0364] A solution of C18 (10.0 g, 31.137 mmol), 2-[(4-fluorophenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.0 g, 42.357 mmol), Na.sub.2CO.sub.3 (60.0 mL of 2M, 120.00 mmol) in a mixture of dioxane (180 mL) and water (60 mL) was heated at 100° C. and bubbled through with nitrogen for 20 min. Then, PdCl.sub.2(dppf)⋅dichloromethane (1.28 g, 1.5674 mmol) was added and bubbled with nitrogen for 5 minutes. The reaction mixture was heated at 100° C. for 2.25 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (300 mL) and water (200 mL) and decanted. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, loaded on silica gel and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting from 5% to 20% EtOAc in heptanes to give C19 (9.68 g, 82%) as white solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 3.82 (s, 3H), 4.27 (s, 2H), 5.08 (s, 2H), 6.88-7.01 (m, 2H), 7.02-7.17 (m, 4H), 7.30-7.49 (m, 5H), 7.54 (d, J=2.6 Hz, 1H). .sup.19F NMR (282 MHz, Chloroform-d) δ −118.0-117.6 (m, 1F). LCMS m/z 351.1 [M+H].sup.+

Step 3. Synthesis of 5-benzyloxy-2-[(4-fluorophenyl)methyl]benzoic acid (C20)

[0365] Grounded NaOH (4.44 g, 111.01 mmol) was added to a mixture of C19 (9.68 g, 27.627 mmol) in a mixture of THF (35 mL), MeOH (35 mL) and water (35 mL). The reaction mixture was stirred vigorously and heated at 50° C. for 2.25 hours. The reaction mixture was concentrated under reduced pressure to remove most of the THF and MeOH, then water (50 mL) was added. 1 MHCl (100 mL) was added to acidified until pH±1-2 and extracted with EtOAc (350 mL+150 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give C20 (9.03 g, 89%) as a white solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.67 (d, J=2.1 Hz, 1H), 7.52-7.30 (m, 5H), 7.17-7.05 (m, 4H), 7.01-6.88 (m, 2H), 5.10 (s, 2H), 4.34 (s, 2H). .sup.19F NMR (282 MHz, Chloroform-d) δ −117.5-117.9 (m, 1F). LCMS m/z 359.1 [M+H].sup.+

Step 4. Synthesis of 5-benzyloxy-N,N-diethyl-2-[(4-fluorophenyl)methyl]benzamide (C4)

[0366] To a suspension of C20 (9.0 g, 26.757 mmol) in dichloromethane (85 mL) was added triethylamine (10.890 g, 15 mL, 107.62 mmol) and N-ethylethanamine (2.9694 g, 4.2 mL, 40.601 mmol). The reaction mixture was placed in a cold water bath for the slow addition of T3P (50% wt in EtOAc) (19.0 mL, 32.1 mmol) over 5 min. The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc (200 mL) and saturated Na.sub.2CO.sub.3 (75 mL). The layers were decanted and the organic layer was washed with water:brine (1:1), brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting from 0% to 40% ethyl acetate in heptanes. The oil was co-evaporated with THF (3×20 mL) and dried under vacuum to give C4 (9.77 g, 88%) as a light yellow oil. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.48-7.29 (m, 5H), 7.20-7.04 (m, 3H), 7.00-6.87 (m, 3H), 6.78 (d, J=2.6 Hz, 1H), 5.17-4.94 (m, 2H), 4.04-3.80 (m, 2H), 3.71-3.51 (m, 1H), 3.43-3.18 (m, 1H), 3.04-2.59 (m, 2H), 1.17 (t, J=7.0 Hz, 3H), 0.89 (t, J=7.0 Hz, 3H). LCMS m/z 392.3 [M+H].sup.+

Step 5. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-2H-isoquinolin-1-one (S5)

[0367] To a solution of C4 (100 mg, 0.2401 mmol) in THF (1 mL), at −20° C., was added dropwise a THF/hexanes solution of LDA (0.19 mL of 1.5 M, 0.2850 mmol) and the resulting mixture was stirred at −20° C. for 2 hours. Then, 2-methylpropanenitrile (34.650 mg, 45 μL, 0.5014 mmol) was slowly added and the reaction mixture was stirred at RT overnight. Saturated aqueous solution of ammonium chloride (5 mL) and water (5 mL) were added and extracted with EtOAc (30 mL) and decanted. The organic layer was washed with brine and concentrated under reduced pressure to give a beige solid. The residue was triturated in acetonitrile (about 5 mL), filtered and dried under vacuum to give S5 (44 mg, 47%) as white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.14 (s, 1H), 7.75 (d, J=2.6 Hz, 1H), 7.52-7.44 (m, 2H), 7.44-7.25 (m, 8H), 6.83 (d, J=8.8 Hz, 1H), 5.22 (s, 2H), 2.69-2.56 (m, 1H), 1.16 (d, J=7.0 Hz, 6H). .sup.19F NMR (282 MHz, DMSO-d.sub.6) δ −114.75-115.06 (m, 1F). LCMS m/z 388.2 [M+H].sup.+

Preparation of S6

1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (S6)

[0368] ##STR00434##

Step 1. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-2-oxido-isoquinolin-2-ium (C21)

[0369] A suspension of S4 (5 g, 13.432 mmol) and (4-fluorophenyl)boronic acid (2.82 g, 20.154 mmol), an aqueous solution of Na.sub.2CO.sub.3 (13.5 mL of 2M, 27.000 mmol) in DMSO (45 mL) was heated to 100° C. and sparged with N.sub.2 for 15minutes. PdCl.sub.2(dppf)⋅dichloromethane (565 mg, 0.6919 mmol) was added and the reaction was sparged for 2 min. The reaction was stirred at 100° C. for overnight. The reaction mixture was cooled to RT, cooled to 0° C., water (90 mL) was added, stirred at 0° C. for 20 min and the suspension was filtered and washed with water. The residue was then dissolved with dichloromethane (through filter paper). The filtrate was decanted, dried over anhydrous Na.sub.2SO.sub.4, filtered, loaded on silica gel and concentrated under reduced pressure. The residue was purified on silica gel chromatography, eluting from 0% to 60% EtOAc in dichloromethane to give C21 (4.49 g, 86%) as tan solid. .sup.1H NMR (300 MHz, Chloroform-d): δ 8.71 (s, 1H), 7.50-7.34 (m, 5H), 7.24 (d, J=6.8 Hz, 4H), 7.15-6.99 (m, 3H), 5.18 (s, 2H), 3.21 (br. s., 1H), 1.41 (d, J=7.0 Hz, 6H). .sup.19F NMR (282 MHz, Chloroform-d) δ −113.06-113.52 (m, 1F) LCMS m/z 388.2 [M+H].sup.+

Step 2. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (S6)

[0370] To a solution of C21 (2000 mg, 5.147 mmol) and DABCO (2500 mg, 22.29 mmol) in dichloromethane (40 mL) was added TFAA (2000 μL, 14.39 mmol) at 0° C. The mixture was allowed to warmed to RT and stirred for 1 h, concentrated in vacuo and the residue was purified by chromatography (C18, 10-100% MeCN:water, 0.1% TFA modifier) to give S6 bis trifluoroacetate salt (3.43 g, 83%) as an off-white solid. 1H NMR (300 MHz, DMSO-d.sub.6) δ 7.78 (d, J=2.3 Hz, 1H), 7.68 (dd, J=9.4, 2.0 Hz, 1H), 7.58-7.50 (m, 2H), 7.50-7.31 (m, 8H), 5.51 (s, 2H), 4.15 (t, J=7.3 Hz, 6H), 3.36 (t, J=7.3 Hz, 6H), 2.97-2.82 (m, 2H), 1.20 (d, J=6.7 Hz, 6H). LCMS m/z 482.37 [M+H].sup.+

Preparation of S7

7-benzyloxy-1-chloro-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (S7)

[0371] ##STR00435##

Step 1. Synthesis of 7-benzyloxy-1-chloro-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (S7)

[0372] Oxalyl chloride (1 mL of 2M, 2.000 mmol) was added to a solution of C21 (410 mg, 1.058 mmol) and DIEA (400 μL, 2.296 mmol) in dry dichloromethane (5 mL) at −78° C. The reaction was allowed to warm to 0° C. over 2 h and then quenched by the addition of methanol (˜0.5 mL). The mixture was concentrated in vacuo and the residue triturated with methanol, filtered (washing with cold methanol) and dried under vacuum to afford S7 (395 mg, 92%) as a colorless solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.69 (d, J=2.4 Hz, 1H), 7.58-7.48 (m, 2H), 7.48-7.36 (m, 3H), 7.32 (dd, J=9.2, 2.5 Hz, 1H), 7.27-7.15 (m, 5H), 5.25 (s, 2H), 2.93 (hept, J=6.7 Hz, 1H), 1.24 (d, J=6.7 Hz, 6H). LCMS m/z 0.99 [M+H].sup.+

Preparation of S8

7-benzyloxy-1,3-dichloro-4-(4-fluoro-3-methyl-phenyl)isoquinoline (S8)

[0373] ##STR00436##

Step 1. Synthesis of 1,3-dichloro-4-iodo-7-methoxy-isoquinoline (C23)

[0374] To a solution of C22 (1 g, 4.385 mmol) in THF (50 mL) was added LDA (2.6 mL of 2 M, 5.2 mmol) at room temperature and the solution was stirred for 30 min by which time the initial cloudy solution became clear. 12 (2.3 g, 9.062 mmol) was then added portion-wise and the solution was stirred for 15 hours. Water (20 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed with 1 M Na.sub.2S.sub.2O.sub.3 solution and brine, dried over MgSO.sub.4, then filtered and concentrated to give C23 as a yellow solid (1.38 g, 84%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.05 (dd, J=9.2, 0.5 Hz, 1H), 7.49-7.41 (m, 2H), 4.00 (s, 3H). LCMS m/z 354.37 [M+H].sup.+

Step 2. Synthesis of 1,3-dichloro-4-(4-fluoro-3-methyl-phenyl)-7-methoxy-isoquinoline (C24)

[0375] To a solution of C23 (1.38 g, 3.675 mmol) in 1,4-dioxane (40 mL) was added (4-fluoro-3-methyl-phenyl)boronic acid (720 mg, 4.677 mmol) and Na.sub.2CO.sub.3 (6 mL of 2M, 12.00 mmol) in water (10 mL), then the solution was degassed by bubbling with N.sub.2 for 10 min, the PdCl.sub.2(dppf)⋅dichloromethane (318 mg, 0.3894 mmol) was added and bubbled with N.sub.2 for another 5 minutes. The solution was heated to 60° C. for 15 h. EtOAc (100 mL) was added in one portion and the solution was washed with water, aq. NaHSO.sub.3 and brine. After drying over MgSO.sub.4 and filtration, the solution was concentrated to dryness and the residue was purified by MPLC: 40 g column, eluting with 0-30% EtOAc in Hexanes to give C24 desired product as white solid. (1.25 g, 97%) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.57 (d, J=2.5 Hz, 1H), 7.42 (dd, J=9.3, 0.5 Hz, 1H), 7.33 (dd, J=9.2, 2.6 Hz, 1H), 7.21-7.09 (m, 3H), 4.02 (s, 3H), 2.38 (d, J=1.9 Hz, 3H). LCMS m/z 336.1 [M+H].sup.+

Step 3. Synthesis of 1,3-dichloro-4-(4-fluoro-3-methyl-phenyl)isoquinolin-7-ol (C25)

[0376] To a solution of C24 (1.9 g, 5.531 mmol) in dichloromethane (30 mL) was added BBr.sub.3 (11.5 mL of 1M, 11.50 mmol) at 0° C. in a dropwise fashion. The solution was then allowed to warm up to room temperature slowly and stirred for 1 hour. The solution was then cooled down to 0° C. in ice bath, ice was added to quench the reaction. The solution was concentrated and the residue was loaded onto column with MeOH/dichloromethane solution. MPLC: 12 g column, eluting with 0-5% MeOH in dichloromethane to give C25 (1.75 g, 96%) LCMS m/z 322.16 [M+H].sup.+

Step 4. Synthesis of 7-benzyloxy-1,3-dichloro-4-(4-fluoro-3-methyl-phenyl)isoquinoline (S8)

[0377] To a solution of C25 (1.75 g, 5.315 mmol) and K.sub.2CO.sub.3 (1.5 g, 10.85 mmol) in DMF (20 mL) was added BnBr (700 μL, 5.885 mmol) and the solution was stirred at room temperature for 15 hours. Then additional BnBr (700 μL, 5.885 mmol) and K.sub.2CO.sub.3 (1.5 g, 10.85 mmol) were added and the solution was stirred for 24 hours. Then a solution of sat. NH.sub.4Cl was added and the aqueous phase was extracted with EtOAc. After evaporation of the organic phase, the residue was purified by MPLC: 12 g column, eluting with 0-20% EtOAc in Hexanes to give two products S8 as a white solid (1.02 g, 46%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J=2.3 Hz, 1H), 7.40 (d, J=7.5 Hz, 2H), 7.37-7.23 (m, 5H), 7.14-6.98 (m, 3H), 5.15 (s, 2H), 2.26 (d, J=1.9 Hz, 3H) LCMS m/z 412.24 [M+H].sup.+

Preparation of S9

7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-2-oxido-isoquinolin-2-ium (S9)

[0378] ##STR00437##

Step 1. Synthesis of 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-2-oxido-isoquinolin-2-ium (S9)

[0379] A suspension of S4 (14.635 g, 39.314 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (8.960 g, 58.202 mmol) and an aqueous solution of Na.sub.2CO.sub.3 (40 mL of 2M, 80.000 mmol) in DMSO (130 mL) was heated to 100° C. and sparged with nitrogen for 15 min. PdCl.sub.2(dppf)⋅dichloromethane (1.652 g, 2.0229 mmol) was added and the reaction was sparged with N.sub.2 for 2 min. The reaction was stirred at 100° C. for 15 h. The reaction mixture was cooled to room temperature, cooled to 0° C., water (200 mL) was added, stirred at 0° C. for 20 minutes and the suspension was filtered and washed with water. The residue was then dissolved with dichloromethane (through filter paper). The filtrate was decanted, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on an ISCO CombiFlash Companion loaded with dichloromethane (300 g SiO.sub.2, dichloromethane/EtOAc 100:0 to 30:70). The mixed fractions were combined and purified by flash chromatography on a ISCO CombiFlash Companion loaded with dichloromethane (120 g SiO.sub.2, dichloromethane/EtOAc 100:0 to 30:70). All fractions containing the clean product were combined and the solvents were removed by rotary evaporation. The product was dried under reduced pressure to yield S9 (14.2 g, 90%) as a tan powder. .sup.1H NMR (300MHz, Chloroform-d): δ 8.70 (s, 1H), 7.50-7.32 (m, 5H), 7.21-6.98 (m, 6H), 5.17 (s, 2H), 3.21 (br. s., 1H), 2.37 (d, J=1.8 Hz, 3H), 1.41 (d, J=5.9 Hz, 6H). .sup.19F NMR (282MHz, Chloroform-d): δ −117.7 (s, 1F). LCMS m/z 402.2 [M+H].sup.+

Preparation of S10

1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-isoquinoline (S10)

[0380] ##STR00438##

Step 1. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-isoquinoline (S10)

[0381] To a solution of S9 (2 g, 4.872 mmol) and DABCO (2.73 g, 24.34 mmol) in dichloromethane (45 mL) was added TFAA (2.0 mL, 14.39 mmol) at 0° C. The reaction was stirred for 1 hour and was concentrated to a crude residue, which was purified via reverse phase chromatography (ISCO, 50 g C18 column, 0-95% MeCN in H.sub.2O gradient with TFA modifier) to provide the desired product S10 (as a white solid (mono trifluoroacetate salt) (2.4 g, 80%). LCMS m/z 496.38 [M+H].sup.+

Preparation of S11

7-benzyloxy-4-bromo-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (S11)

[0382] ##STR00439##

Step 1. Synthesis of 5-benzyloxy-2-(2-tetrahydropyran-4-ylethynyl)benzaldehyde (C26)

[0383] In a sealed tube, a solution of C14 (5.693 g, 19.554 mmol) in dioxane (20 mL) and triethylamine (20 mL) was degassed by bubbling N.sub.2 for 15 min. 4-Ethynyltetrahydropyran (3.765 g, 74.9% w/w, 25.600 mmol) in dioxane (10 mL), PdCl.sub.2(PPh.sub.3).sub.2 (271 mg, 0.3850 mmol) and CuI (139 mg, 0.7299 mmol) were added under N.sub.2 and the reaction were further inserted for 2 min. The reaction turned from yellow to dark brown. The vial was sealed and the reaction was stirred at 50° C. for 2 hours, cooled to RT, diluted with EtOAc (100 mL), washed with 1 M aq. HCl (2×50 mL), water (30 ml) and brine (30 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated in MeCN, filtered, washed with a minimal amount of ACN and dried under reduced pressure to yield C26 (4.598 g, 73%) as an off-white solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 1.71-1.86 (m, 2H), 1.88-2.01 (m, 2H), 2.92 (tt, J=8.6, 4.3 Hz, 1H), 3.58 (ddd, J=11.4, 8.5, 2.9 Hz, 2H), 3.90-4.02 (m, 2H), 5.12 (s, 2H), 7.17 (dd, J=8.7, 2.8 Hz, 1H), 7.31-7.51 (m, 7H), 10.50 (s, 1H). LCMS m/z 321.1 [M+H].sup.+

Step 2. Synthesis of 5-benzyloxy-2-(2-tetrahydropyran-4-ylethynyl)benzaldehyde oxime (C27)

[0384] To a solution of hydroxylamine hydrochloride (12.637 g, 181.85 mmol) was added acetonitrile (210 mL). The reaction was warmed to 50° C. and a solution of C26 (19.135 g, 59.726 mmol) in DCE (125 mL) was added. The reaction was stirred 2 hours at 50° C., cooled to RT and diluted with EtOAc (300 mL). The organic layer was washed with 1 M aq. HCl (5×150 mL), water (100 mL), brine (100 mL), dried over Na.sub.2 SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated in acetonitrile, filtered and dried under reduced pressure to yield C27 (18.463 g, 92%) as a pale orange solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 1.70-1.86 (m, 2H), 1.88-2.02 (m, 2H), 2.89 (tt, J=8.6, 4.2 Hz, 1H), 3.58 (ddd, J=11.6, 8.7, 2.9 Hz, 2H), 3.97 (ddd, J=11.7, 5.4, 3.8 Hz, 2H), 5.09 (s, 2H), 6.95 (dd, J=8.5, 2.6 Hz, 1H), 7.30-7.48 (m, 6H), 7.56 (s, 1H), 8.59 (s, 1H). LCMS m/z 336.2 [M+H].sup.+

Step 3. Synthesis of 7-benzyloxy-4-bromo-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (S11)

[0385] CuBr (20.78 g, 93.036 mmol) was added to a solution of C27 (12.45 g, 37.120 mmol) in N,N-dimethylacetamide (100 mL) and the resulting mixture was heated at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, then cooled to 0° C. and with vigorous stirring, an aqueous solution of ammonium hydroxide and water (2:1, 75 mL) was slowly added and stirred at 0° C. for 45 minutes. Then, the suspended solids were filtered and washed with water to give a tan solid. The solid was dissolved through filter paper with dichloromethane, decanted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated in methyl tert-butylether, filtered and washed with heptanes, then triturated in acetonitrile (50 mL) to S11 (11.129 g, 72%) as beige solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 1.54 (d, J=12.3 Hz, 2H), 2.86-3.32 (m, 2H), 3.59 (t, J=11.7 Hz, 2H), 3.87-4.24 (m, 3H), 5.20 (s, 2H), 6.97 (d, J=2.3 Hz, 1H), 7.30-7.60 (m, 6H), 8.08 (d, J=9.4 Hz, 1H), 8.64 (br.s., 1H). LCMS m/z 414.1 [M+H].sup.+

Preparation of S12

1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-tetrahydropyran-4-yl-isoquinoline (S12)

[0386] ##STR00440##

Step 1. Synthesis of 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C28)

[0387] A solution of S11 (7.66 g, 18.489 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (4.26 g, 27.672 mmol) and Na.sub.2CO.sub.3 (19 mL of 2 M in water, 38.000 mmol) in DMSO (80 mL) was heated to 100° C. and sparged with N.sub.2 for 15 minutes. PdCl.sub.2(dppf)⋅dichloromethane (789 mg, 0.9662 mmol) was added and the reaction was sparged for 2 minutes. The reaction was stirred at 100° C. for 4 hours, cooled to room temperature, diluted with EtOAc (300 mL), washed with a pH7 0.1M potassium phosphate buffer (2×150 mL). A solid precipitated and was filtered off, dissolved in dichloromethane, filtered over Celite®, washed with dichloromethane and concentrated under reduced pressure to yield C28 (2.314 g, 28%) as a tan solid. The organic layer was further washed with water (3×100 mL), brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on an ISCO CombiFlash Companion loaded with dichloromethane (220 g SiO.sub.2, dichloromethane/MeOH 100:0 to 95:5). The fractions containing the product were combined and recrystallized in ACN (about 250 mL), filtered and dried under reduced pressure to yield C28 (3.7 g, 45%) as tan crystals. Both batches were combined to yield C28 (6.014 g, 71%) as a grey solid. 41 NMR (300 MHz, Chloroform-d) δ 1.41 (d, J=11.7 Hz, 2H), 2.38 (d, J=1.5 Hz, 3H), 2.51-2.96 (m, 2H), 3.28 (t, J=11.3 Hz, 3H), 3.97 (dd, J=11.0, 3.4 Hz, 2H), 5.18 (s, 2H), 6.93-7.22 (m, 6H), 7.31-7.52 (m, 5H), 8.73 (s, 1H). 19F NMR (282 MHz, Chloroform-d) δ −117.1 (s, 1F). LCMS m/z 444.2 [M+H].sup.+

Step 2. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-tetrahydropyran-4-yl-isoquinoline (S12)

[0388] To a solution of C28 (1.4 g, 3.068 mmol) and DABCO (1.72 g, 15.33 mmol) in dichloromethane (30.7 mL) was added TFAA (1.27 mL, 9.137 mmol) at 0° C. and the reaction was stirred for another hour before being allowed to warm to room temperature and stirred for another 3 hours. Then, the reaction mixture was concentrated in vacuo and the crude residue purified by ISCO reverse phase flash chromatography (5-95% MeCN in H.sub.2O with 0.1% TFA modifier, 150 gram C18 column) to provide S12 (mono trifluoroacetate salt) as a white powder(1.52 g, 71%) LCMS m/z 538.36 [M+H].sup.+

Preparation of S13

1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S13)

[0389] ##STR00441##

Step 1. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C29)

[0390] A suspension of S11 (2 g, 4.8275 mmol), (4-fluorophenyl)boronic acid (1.02 g, 7.2899 mmol) and Na.sub.2CO.sub.3 (4.80 mL of 2 M in water, 9.6000 mmol) in DMSO (20 mL) was heated to 100° C. and sparged with N.sub.2 for 15 minutes. PdCl.sub.2(dppf)⋅dichloromethane (204 mg, 0.2498 mmol) was added and the reaction was sparged for 2 min. The reaction was stirred at 100° C. for 3 hours, cooled to room temperature, diluted with EtOAc (150 mL), washed with a pH7 0.1M potassium phosphate buffer (2×75 mL), water (3×75 mL), brine (75 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered on a pad of Celite. The filtrate was concentrated under reduced pressure and the residue was triturated in acetonitrile (±30 mL) to give C29 (1.196 g, 56%) as a grey solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 1.41 (d, J=11.7 Hz, 2H), 2.36-2.92 (m, 2H), 3.16-3.38 (m, 3H), 3.96 (dd, J=11.3, 3.7 Hz, 2H), 5.18 (s, 2H), 6.98-7.09 (m, 2H), 7.09-7.17 (m, 1H), 7.19-7.30 (m, 5H), 7.31-7.57 (m, 4H), 8.75 (s, 1H). .sup.19F NMR (282 MHz, Chloroform-d) δ −112.8-112.4 (m, 1F). LCMS m/z 430.2 [M+H].sup.+

Step 2. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S13)

[0391] To a solution of C29 (2.955 g, 6.550 mmol) and DABCO (3.67 g, 32.72 mmol) in dichloromethane (70 mL) was added TFAA (4.13 g, 19.66 mmol) at 0° C. The reaction was then stirred at 0° C. for 1 hour and then allowed to warm to room temperature and stirring was continued for an additional 3 hours. The reaction mixture was concentrated in vacuo to provide the desired S13 (tris-Trifluoroacetate salt) (10.5 g, 93%) LCMS m/z 525.11 [M+H].sup.+

Preparation of S14

1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-chlorophenyl)-3-isopropyl-isoquinoline (S14)

[0392] ##STR00442##

Step 1. Synthesis of 7-benzyloxy-4-(4-chlorophenyl)-3-isopropyl-2-oxido-isoquinolin-2-ium (C30)

[0393] A suspension of S4 (27 g, 72.53 mmol), (4-chlorophenyl)boronic acid (14 g, 100.1 mmol) and Na.sub.2CO.sub.3 (25 g, 235.9 mmol in 70 mL of water) in DMSO (400 mL) was heated to 100° C. and sparged with N.sub.2 for 5 min. PdCl.sub.2(dppf)⋅dichloromethane (2.5 g, 3.061 mmol) was added and the reaction was sparged for 5 minutes. The resulting reaction mixture was warmed to 100° C., stirred at this temperature for 2 hours at which time TLC revealed consumption of the starting material. The reaction mixture was cooled to room temperature, partitioned between EtOAc (˜1 L) and ice/water (˜300 mL), the organic phase was separated, washed with water (˜60 mL), brine (˜100 mL), dried over MgSO.sub.4, filtered through a Florisil® bed and concentrated under reduced pressure. The residue was triturated with MTBE (˜1 L) to afford C30 (21.6 g, 74%) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.87 (s, 1H), 7.69-7.61 (m, 2H), 7.54-7.47 (m, 2H), 7.46-7.29 (m, 6H), 7.18 (dd, J=9.2, 2.6 Hz, 1H), 6.93 (d, J=9.2 Hz, 1H), 5.21 (s, 2H), 3.05 (d, J=18.8 Hz, 1H), 1.30 (d, J=7.0 Hz, 6H). LCMS m/z 404.41 [M+H].sup.+

Step 2. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-chlorophenyl)-3-isopropyl-isoquinoline (S14)

[0394] To a solution of C30 (5 g, 12.38 mmol) and DABCO (4 g, 35.66 mmol) in dichloromethane (120 mL) was added TFAA (4 mL, 28.78 mmol) at −10° C. The reaction was then stirred from −4° C. to 0° C. over 3 hours. The reaction mixture was concentrated in vacuo and triturated with Et.sub.2O (200 mL) to provide the desired S14 (9 g, 95%) (trifluoroacetate salt) as a tan solid. LCMS m/z 498.62 [M+H].sup.+

Preparation of S15

N,N-diethyl-2-[(4-fluorophenyl)methyl]-5-methoxy-benzamide (S15)

[0395] ##STR00443##

[0396] Intermediate S15 was prepared as described for the preparation of C13 in the synthetic route to intermediate S3 above.

Preparation of S16

1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(3,4-difluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S16)

[0397] ##STR00444##

Step 1. Synthesis of 7-benzyloxy-4-(3,4-difluorophenyl)-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C31)

[0398] A suspension of S11 (320 mg, 0.7692 mmol), (3,4-difluorophenyl)boronic acid (180 mg, 1.140 mmol) and aqueous solution of Na.sub.2CO.sub.3 (1.0 mL of 2 M, 2.0 mmol) in DMSO (5 mL) was sparged with N.sub.2 for 5 minutes. Pd(dppf)Cl.sub.2.dichloromethane (50 mg, 0.0612 mmol) was added and the reaction was sparged with N.sub.2 for another 5 minutes. The resulting mixture was heated to 100° C. and stirred for 4 h. The reaction mixture was cooled to room temperature, water (50 mL) was added, stirred at room temperature for 30 minutes, and the suspension was filtered and washed with water. The residue was then dissolved with dichloromethane. The filtrate was decanted, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give C31 (379 mg, 82%). LCMS m/z 448.51 [M+H].sup.+

Step 2. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(3,4-difluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S16)

[0399] A solution of C31 (379 mg, 0.6298 mmol) and DABCO (300 mg, 2.674 mmol) in dichloromethane (20 mL) was cooled to 0° C., and to this was added TFAA (300 μL, 2.158 mmol). The resulting mixture was allowed to warm to room temperature and stirred for another 1 hours and then concentrated to dryness. The residue was dissolved in minimum of DMSO and purified by reverse phase chromatography (C18, eluting with 10% to 100% CH.sub.3CN in water with 0.1% TFA modifier) to give S16 bis trifluoroacetate salt (440 mg, 90%). LCMS m/z 542.32 [M+H].sup.+

Preparation of S17

1,3-dichloro-4-iodo-7-methoxy-isoquinoline (S17)

[0400] ##STR00445##

[0401] Compound S17 (equivalent to C23) was prepared as described for the C23 in the preparation of S8.

Preparation of S18

4-chloro-3-isopropenyl-7-methoxy-quinoline (S18)

[0402] ##STR00446##

Synthesis of 4-chloro-3-isopropenyl-7-methoxy-quinoline (S18)

[0403] A suspension of C32 (2.97 g, 10.90 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.0 mL, 10.64 mmol), K.sub.2CO.sub.3 (6.34 g, 45.87 mmol) in 1,4-dioxane (35 mL) and water (3 mL) was sparged with N.sub.2 for 2 minutes. Pd(dppf)Cl.sub.2.dichloromethane (431 mg, 0.5278 mmol) was added and the reaction was heated at 70° C. and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 40% EtOAc in heptane to give S18 (1.78 g, 63%) as a colorless oil. .sup.1H NMR (300 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.09 (dd, J=9.3, 0.4 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 7.22 (dd, J=9.2, 2.6 Hz, 1H), 5.35 (p, J=1.6 Hz, 1H), 5.08-4.98 (m, 1H), 2.13 (dd, J=1.6, 0.9 Hz, 3H). LCMS m/z 233.72 [M+H].sup.+

Preparation of S19

1,3-dichloro-7-(methoxymethoxy)isoquinoline (S19)

[0404] ##STR00447##

Step 1. Synthesis of 1,3-dichloroisoquinolin-7-ol (C33)

[0405] A solution of BBr.sub.3 (150 mL of 1 M in dichloromethane, 150.0 mmol) was added dropwise to a solution of C22 (10 g, 43.85 mmol) at 0° C. The resulting mixture was allowed to warm up to room temperature and stirred for 18 hours. After completion of reaction, the mixture was cooled down to 0° C., quenched with ice, and concentrated to remove dichloromethane. Water was added and the mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated to give C33 (9.1 g, 87%), which was used in the next step without further purification. LCMS m/z 214.06 [M+H].sup.+

Step 2. Synthesis of 1,3-dichloro-7-(methoxymethoxy)isoquinoline (S19)

[0406] To a solution of C33 (3.0 g, 14.02 mmol) in dichloromethane (100 mL) was added DIPEA (15 mL, 86.12 mmol) and chloro(methoxy)methane (8 mL, 105.3 mmol). The reaction was stirred at room temperature for 1 hours. After complete conversion, the mixture was evaporated and purified by silica gel chromatography, eluting with 0% to 100% EtOAc in heptane to give S19 (2.93 g, 72%). LCMS m/z 258.05 [M+H].sup.+

Preparation of S20

1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-isoquinoline (S20)

[0407] ##STR00448##

Step 1. Synthesis of 7-benzyloxy-4-(2-methyl-4-pyridyl)-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C34)

[0408] A suspension of S11 (2.97 g, 7.169 mmol), (2-methyl-4-pyridyl)boronic acid (1.83 g, 13.36 mmol) and aqueous solution of Na.sub.2CO.sub.3 (7 mL of 2M, 14.0 mmol) in DMSO (60 mL) was sparged with N.sub.2 for 5 min. Pd(dppf)Cl2.dichloromethane (400 mg, 0.4898 mmol) was added and the reaction was sparged with N.sub.2 for another 5 minutes. The resulting mixture was heated at 100° C. and stirred for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give C34 (2.6 g, 85%) as a tan solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.92 (s, 1H), 8.65 (dd, J=5.0, 0.8 Hz, 1H), 7.54-7.33 (m, 6H), 7.31-7.26 (m, 1H), 7.24-7.17 (m, 2H), 6.92 (d, J=9.2 Hz, 1H), 5.22 (s, 2H), 3.82 (dd, J=11.1, 3.7 Hz, 2H), 3.06 (t, J=11.5 Hz, 3H), 2.82-2.59 (m, 2H), 2.57 (s, 3H), 1.42-1.27 (m, 2H). LCMS m/z 427.3 [M+H].sup.+

Step 2. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-isoquinoline (S20)

[0409] A solution of C34 (513 mg, 1.203 mmol) and DABCO (500 mg, 4.457 mmol) in dichloromethane (10 mL) was cooled to 0° C., and to this was added TFAA (450 μL, 3.237 mmol). The resulting mixture was allowed to warm to room temperature and stirred for another 1 h and then concentrated to dryness. The residue was dissolved in minimum of DMSO and purified by reverse phase chromatography (C18, eluting from 10% to 100% CH.sub.3CN in water with 0.1% TFA modifier) to give S20 bistrifluoroacetate salt (930 mg, 99%) as an off-white solid. LCMS m/z 521.35 [M+H].sup.+

Preparation of S21

7-benzyloxy-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline (S21)

[0410] ##STR00449## ##STR00450##

Step 1. Synthesis of 4-benzyloxy-2-nitro-benzonitrile (C36)

[0411] CuCN (4.6507 g, 51.926 mmol) was added to a stirred solution of C35 (8.0 g, 25.963 mmol) in DMF (100 mL). The resulting mixture was heated at 150° C. and stirred for 3 hours. After completion of reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to give a crude C36 (6 g, 91%) as a light grey solid, which was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.1 (d,J=8.6 Hz, 1H), 7.97 (d,J=2.44,1H), 7.61 (dd, J=2.48,8.68 Hz, 1H), 7.49 (d,J=7.04 Hz, 2H), 7.44-7.35 (m, 3H), 5.34 (s, 2H).

Step 2. Synthesis of 2-amino-4-benzyloxy-benzonitrile (C37)

[0412] A solution of C36 (3 g, 11.800 mmol) in acetic acid (13 mL) was cooled 0° C., and to this Fe powder (13.179 g, 236.00 mmol) was added. The reaction was allowed to warm up to room temperature and stirred for 2 hours. After completion of reaction, the reaction mixture was filtered through celite. The residue was diluted with Na.sub.2CO.sub.3 solution and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give crude C37 (2.3 g, 87%) as a white solid, which was used in the next step without further purification. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.37-7.25 (m, 6H), 6.38 (dd, J=8.7, 2.2 Hz, 1H), 6.27 (d, J=2.3 Hz, 1H), 5.04 (s, 2H), 4.37 (s, 2H).

Step 3. Synthesis of (2-amino-4-benzyloxy-phenyl)-(4-fluorophenyl)methanone (C38)

[0413] To a stirred solution of C37 (16 g, 71.346 mmol) and (4-fluorophenyl)boronic acid (19.965 g, 142.69 mmol) in 2-MeTHF (160 mL) and water (80 mL) was added 5,5′-Dimethyl-2,2′-dipyridyl (1.3145 g, 7.1346 mmol), Pd(TFA).sub.2 (1.1860 g, 3.5673 mmol) and methanesulfonic acid (46.298 mL, 713.46 mmol) under N.sub.2 at room temperature. The resulting mixture was heated at 80° C. and stirred for 30 hours. After completion of reaction, the reaction mixture was quenched with Na.sub.2CO.sub.3 solution and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified with silica gel chromatography, eluting with 0% to 10% EtOAc in heptane to give C38 (18.375 g, 80%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.61-7.52 (m, 2H), 7.48-7.36 (m, 4H), 7.39-7.26 (m, 6H), 7.25-7.17 (m, 1H), 5.75 (s, 1H), 5.10 (s, 2H).

Step 4. Synthesis of N-[5-benzyloxy-2-(4-fluorobenzoyl)phenyl]-2-tetrahydropyran-4-yl-acetamide (C39)

[0414] A catalytic amount of DMF was added to a mixture of SOCl.sub.2 (4.6649 g, 2.8601 mL, 39.210 mmol) and 2-tetrahydropyran-4-ylacetic acid (3.3917 g, 23.526 mmol). The resulting mixture was refluxed for 1 hours. After complete formation of acid chloride, the reaction mixture was evaporated and then dissolved in dichloromethane (30 mL). This suspension was added to the mixture of C38 (6.3 g, 19.605 mmol) and pyridine (7.7538 g, 7.9282 mL, 98.025 mmol) in dichloromethane (147 ml) at 0° C. The reaction mixture was stirred at room temperature for 1 hours. The reaction was quenched with 1 N HCl and extracted with dichloromethane (100 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness. The residue was purified by silica gel chromatography, eluting 0% to 20% EtOAc in heptane to give C39 (7.4 g, 84%) as a light yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) δ 11.50 (s, 1H), 8.53 (d, J=2.6 Hz, 1H), 7.70-7.61 (m, 2H), 7.53-7.30 (m, 6H), 7.20-7.10 (m, 2H), 6.64 (dd, J=8.8, 2.6 Hz, 1H), 5.16 (s, 2H), 4.00-3.91 (m, 2H), 3.43 (td, J=11.8, 2.1 Hz, 2H), 2.39 (d, J=7.1 Hz, 2H), 2.17 (dp, J=11.6, 4.0 Hz, 1H), 1.75-1.67 (m, 2H), 1.44 (dd, J=12.2, 4.4 Hz, 1H), 1.43-1.34 (m, 1H). LCMS m/z 448.3 [M+H].sup.+

Step 5. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinolin-2-ol (C40)

[0415] To a stirred solution of C39 (6 g, 13.408 mmol) in toluene (125 mL) was added NaOtBu (3.8657 g, 40.224 mmol). The reaction mixture was refluxed for 16 hours. After completion of the reaction, the reaction mixture was evaporated. The residue was diluted with dichloromethane (300 mL) and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 30% EtOAc in hexane to give C40 (3.2 g, 49%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 7.45-7.27 (m, 8H), 6.92 (d, J=2.28 Hz, 1H), 6.73 (dd, J=9, 2.4 Hz, 1H), 6.65 (d, J=8.92 Hz, 1H), 5.12 (s, 2H), 3.78 (d, J=9.64 Hz, 2H), 2.99 (t, J=11.24 Hz,2H), 2.50 (d, J=21.4, 3H)1.22 (d, J=8.68 Hz, 2H). LCMS m/z 430.0 [M+H].sup.+

Step 6. Synthesis of 7-benzyloxy-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline (S21)

[0416] A solution of C40 (300 mg, 0.6985 mmol) in toluene (1.5 mL) was cooled to 0° C., and to this was added SOCl.sub.2 (831.01 mg, 0.5095 mL, 6.9850 mmol) followed by a catalytic amount of DMF. The resulting mixture was heated to 80° C. and stirred for 3 hours. After completion of the reaction, the reaction mixture was evaporated. The residue was diluted with dichloromethane (20 mL) and washed with sat. NaHCO.sub.3 solution (10 mL) and water (10 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel chromatography, eluting with 20% EtOAc in hexane to obtain S21 (300 mg, 89%) as a light yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ 7.49-7.33 (m, 10H), 7.26-7.23 (m, 1H), 7.03 (d, J=9.4 Hz, 1H), 5.76 (s, 1H), 5.30 (s, 2H), 3.85 (d, J=10.8 Hz, 2H), 3.62 (d, J=12.6 Hz, 1H), 3.07 (s, 4H), 1.44 (d, J=13.1 Hz, 2H). LCMS m/z 448.0 [M+H].sup.+

Preparation of S22

Synthesis of 2-chloro-4-(4-fluorophenyl)-3-isopropyl-7-methoxy-quinoline (S22)

[0417] ##STR00451##

Step 1. Synthesis of 4-(4-fluorophenyl)-3-isopropenyl-7-methoxy-quinoline (C41)

[0418] A suspension of S18 (3 g, 12.581 mmol), (4-fluorophenyl)boronic acid (2.1124 g, 15.097 mmol), K.sub.2CO.sub.3 (3.4775 g, 25.162 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was sparged with N.sub.2 for 30 minutes. PCy.sub.3 (352.81 mg, 1.2581 mmol) and Pd(PPh.sub.3).sub.4 (1.0177 g, 0.8807 mmol) were added under N.sub.2 and the reaction was heated at 100° C. and stirred for 18 hours. After completion of the reaction, the reaction mixture was filtered through celite, washed with EtOAc (80 mL) and concentrated. The residue was purified by silica gel chromatography, eluting with 0% to 100% EtOAc in hexane to afford C41 (4 g, 95%) as an off-white solid. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.76 (s, 1H), 7.52-7.43 (m, 2H), 7.35-7.25 (m, 2H), 7.19-7.13 (m, 2H), 7.12-7.08 (m, 1H), 5.20-5.14 (m, 1H), 5.05-4.96 (m, 1H), 3.95 (s, 3H), 1.63(s,3H). LCMS m/z 294.0 [M+H].sup.+

Step 2. Synthesis of 4-(4-fluorophenyl)-3-isopropyl-7-methoxy-quinoline (C42)

[0419] Pd (50 mg, 0.4698 mmol) was added to a solution of S18 (1.3 g, 4.432 mmol) in EtOH (20 mL) under N.sub.2. The resulting mixture was stirred at room temperature under a H.sub.2 balloon for 18 hours. The reaction mixture was filtered through a plug of Celite and concentrated under reduced pressure to give C42(1.26 g, 92%) LCMS m/z 295.32 [M+H].sup.+

Step 3. Synthesis of 4-(4-fluorophenyl)-3-isopropyl-7-methoxy-1-oxido-quinolin-1-ium (C43)

[0420] To a solution of C42 (1.36 g, 4.370 mmol) in dichloromethane (10 mL) was added m-CPBA (1.54 g, 8.924 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and washed with sat. NaHCO.sub.3 solution. The organic layer was dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 20% MeOH in dichloromethane to give C43 (1.05 g, 69%) .sup.1H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 8.04 (d, J=2.6 Hz, 1H), 7.19-7.13 (m, 5H), 7.06 (dd, J=9.2, 2.7 Hz, 1H), 3.94 (s, 3H), 2.80 (hept, J=7.0 Hz, 1H), 1.13 (d, J=7.0 Hz, 6H). .sup.19F NMR (376 MHz, Chloroform-d) δ −113.33. LCMS m/z 312.49 [M+H].sup.+

Step 4. Synthesis of 2-chloro-4-(4-fluorophenyl)-3-isopropyl-7-methoxy-quinoline (S22)

[0421] POCl.sub.3 (600 μL, 6.437 mmol) and DMF (150 μL, 1.937 mmol) were successively added in a dropwise manner to a solution of C43 (0.731 g, 2.113 mmol) in dichloromethane (10 mL) at 0° C. The resulting mixture was allowed to warm up to room temperature and stirred for 18 hours. The reaction mixture was diluted with aqueous solution of Na.sub.2CO.sub.3 and extracted with dichloromethane. The organic layer was dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give S22 (695.4 mg, 85%) as an off-white solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.28 (dd, J=2.3, 0.8 Hz, 1H), 7.17-7.08 (m, 4H), 6.99-6.94 (m, 2H), 3.85 (s, 3H), 3.22-2.98 (m, 1H), 1.25 (d, J=7.2 Hz, 6H). 19 F NMR (282 MHz, Chloroform-d) δ −113.52. LCMS m/z 329.66 [M+H].sup.+

Preparation of S23

7-benzyloxy-2-chloro-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-quinoline (S23)

[0422] ##STR00452## ##STR00453##

Step 1. Synthesis of 4-(4-fluoro-3-methyl-phenyl)-3-isopropenyl-7-methoxy-quinolin (C44)

[0423] A suspension of S18 (3.22 g, 13.78 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (5.3 g, 34.43 mmol, and Na.sub.2CO.sub.3 (5.9 g, 55.67 mmol) in DMF (30 mL) was sparged with N.sub.2 for 2 minutes. Pd(PPh.sub.3).sub.4 (811 mg, 0.7018 mmol) was added and the resulting mixture was heated at 120° C. and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (200 mL) and washed with water (200 mL) and brine (200 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% to 90% EtOAc in hexane to give C44 (3.6 g, 66%). LCMS m/z 307.34 [M+H].sup.+

Step 2. Synthesis of 4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-7-methoxy-quinoline (C45)

[0424] Pd (131.57 mg, 1.2363 mmol) was added to a stirred solution of C44 (380 mg, 1.2363 mmol) in EtOH (7 mL) under N.sub.2. The resulting mixture was stirred at room temperature under a H.sub.2 balloon for 12 hours. The reaction mixture was filtered through celite, washed with EtOH and concentrated under reduced pressure to give C45 (380 mg, 99%), which was used in the next step without further purification. LCMS m/z 310.2 [M+H].sup.+

Step 3. Synthesis of 4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-quinolin-7-ol (C46)

[0425] A solution of BBr.sub.3 (56.566 mL of 1M in dichloromethane, 56.566 mmol) was added dropwise to a solution of C45 (2.5 g, 8.0808 mmol) in dichloromethane (25 mL) at 0° C. The resulting mixture was heated at 60° C. for 4 hours. The reaction mixture was concentrated, neutralized with sat. NaHCO.sub.3 solution and extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 70% EtOAc in hexane to give C46 (1.8 g, 63%). LCMS m/z 296.1 [M+H].sup.+

Step 4. Synthesis of 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-quinoline (C47)

[0426] To a stirred solution of C46 (2 g, 6.7716 mmol) in DMF (10 mL) was added K.sub.2CO.sub.3 (2.3397 g, 16.929 mmol) followed by benzyl chloride (1.0286 g, 0.9351 mL, 8.1259 mmol) at room temperature. The resulting mixture was stirred for 18 h at room temperature. The mixture was quenched with sat. NaHCO.sub.3 solution (10 ml) and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluting with 0% to 20% EtOAc in hexane to give C47 (1.65 g, 62%) as a white solid. LCMS m/z 387.6 [M+H].sup.+

Step 5. Synthesis of 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-1-oxido-quinolin-1-ium (C48)

[0427] To a solution of C47 (650 mg, 1.6862 mmol) in dichloromethane (15 mL) was added m-CPBA (581.96 mg, 3.3724 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and washed with a sat. NaHCO.sub.3 solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was then triturated with 10% dichloromethane in pentane and concentrated to afford C48 (550 mg, 69%) as an off-white solid. LCMS m/z 386.2 [M+H].sup.+

Step 6. Synthesis of 7-benzyloxy-2-chloro-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-quinoline (S23)

[0428] POCl.sub.3 (840.25 mg, 0.5108 mL, 5.4800 mmol) and DMF (100.14 mg, 0.1061 mL, 1.3700 mmol) were successively added in a dropwise manner to a solution of C48 (550 mg, 1.3700 mmol) in dichloromethane (6 mL) at 0° C. The resulting mixture was allowed to warm up to room temperature and stirred at this temperature for 18 hours. After completion of the reaction, solvent was evaporated under reduced pressure and the residue was washed with sat. Na.sub.2CO.sub.3 solution (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 5% to 10% EtOAc in hexane to afford S23 (500 mg, 81%) as an off-white solid. LCMS m/z 420.49 [M+H].sup.+

Preparation of S24

4-chloro-3-isopropyl-2-methyl-quinolin-7-ol (S24)

[0429] ##STR00454##

Step 1. Synthesis of 4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-7-methoxy-1-oxido-quinolin-1-ium (C49)

[0430] To a solution of C42 (85 mg, 0.2747 mmol) in dichloromethane (5 mL) was added m-CPBA (185 mg, 0.8255 mmol). The resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with sat. NaHCO.sub.3 solution and extracted with dichloromethane. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 0% to 10% MeOH in dichloromethane to give C49 (85 mg, 95%). .sup.1H NMR (300 MHz, Chloroform-d) δ 8.61 (s, 1H), 8.12 (d, J=2.6 Hz, 1H), 7.28 (d, J=9.2 Hz, 1H), 7.22-6.99 (m, 4H), 4.02 (s, 3H), 2.90 (p, J=6.9 Hz, 1H), 2.37 (d, J=2.0 Hz, 3H), 1.21 (dd, J=6.9, 3.8 Hz, 6H) ppm. LCMS m/z 326.59 [M+H].sup.+

Step 2. Synthesis of 2-chloro-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-7-methoxy-quinoline (S24)

[0431] A mixture of C49 (80 mg, 0.2459 mmol) and POCl.sub.3 (1120 μL, 1.287 mmol) in CHCl.sub.3 (1.5 mL) was microwaved at 80° C. for 3 hours. After completion of the reaction, the reaction mixture was quenched with water. Then sat. NaHCO.sub.3 aqueous solution was added and the mixture was extracted with dichloromethane (2×10 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to give S24 (70 mg, 83%). .sup.1H NMR (300 MHz, Chloroform-d) δ 7.40 (d, J=2.4 Hz, 1H), 7.23-6.97 (m, 5H), 3.95 (s, 3H), 3.22 (s, 1H), 2.38 (d, J=2.0 Hz, 3H), 1.45-1.29 (m, 6H) ppm. LCMS m/z 344.55 [M+H].sup.+

Preparation of S25

4-chloro-3-isopropyl-2-methylquinolin-7-ol (S25)

[0432] ##STR00455##

Step 1. Synthesis of 4-chloro-3-isopropyl-7-methoxy-2-methyl-quinoline (C51)

[0433] A mixture of C50 (1.0 g, 4.324 mmol) and SOCl.sub.2 (10 mL, 137.1 mmol) in DMF (500 μL, 6.457 mmol) was microwaved at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was concentrated. The residue was diluted with cold water and sat. NaHCO.sub.3 solution until precipitate formed. The solid was filtered, washed with water, and dried to afford C51 (1.0 g, 93%) .sup.1H NMR (300 MHz, Chloroform-d) δ 8.12 (d, J=9.3 Hz, 1H), 7.32 (d, J=2.6 Hz, 1H), 7.21 (dd, J=9.2, 2.6 Hz, 1H), 3.96 (s, 3H), 2.82 (s, 3H), 1.50 (d, J=7.2 Hz, 6H) ppm. LCMS m/z 250.23 [M+H].sup.+

Step 2. Synthesis of 4-chloro-3-isopropyl-2-methyl-quinolin-7-ol (S25)

[0434] A solution of BBr.sub.3 (15 mL of 1 M in dichloromethane, 15.00 mmol) was added in a dropwise manner to a solution of C51 (900 mg, 3.604 mmol) in anhydrous dichloromethane (50 mL) at 0° C. under N.sub.2. The resulting mixture was allowed to warm up to room temperature and stirred for 60 hours. After completion of the reaction, the mixture was cooled down to 0° C., quenched with cold water and evaporated to remove dichloromethane. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated to give S25 (650 mg, 75%). .sup.1H NMR (300 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.29 (d, J=9.3 Hz, 1H), 7.57-7.31 (m, 2H), 3.69 (s, 1H), 2.92 (s, 3H), 1.45 (d, J=7.2 Hz, 6H) ppm. LCMS m/z 236.19 [M+H].sup.+

Preparation of S26

7-benzyloxy-2-chloro-4-(4-fluorophenyl)-3-(2-methoxy-1-methyl-ethyl)quinoline (S26)

[0435] ##STR00456## ##STR00457##

Step 1. Synthesis of 5-[(3-benzyloxyanilino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (C53)

[0436] To a suspension of C52 (30 g, 150.57 mmol) and Meldrum's acid (25.607 g, 177.67 mmol) in EtOH (30 mL) was added trimethyl orthoformate (18.854 g, 177.67 mmol). The resulting mixture was heated to reflux for 1 hour. The reaction mixture was cooled down to room temperature and stirring was continued for another 2 hours. The suspension was filtered, and the solid residue was stirred in anhydrous EtOH (150mL) for 2 hours. The solid residue was collected by filtration and dried in vacuo to give C53 (50 g, 92%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.21 (d, J=14.4 Hz, 1H), 8.61 (d, J=14.5 Hz, 1H), 7.47 (d, J=7.4 Hz, 2H), 7.40 (t, J=7.4 Hz, 2H), 7.37-7.29 (m, 3H), 7.12 (dd, J=8.2, 2.1 Hz, 1H), 6.91 (dd, J=8.2, 2.4 Hz, 1H), 5.16 (s, 2H), 1.68 (s, 6H). LCMS m/z 354.0 [M+H].sup.+

Step 2. Synthesis of 7-benzyloxy-1H-quinolin-4-one (C54)

[0437] A stirred mixture of C53 (50 g, 141.50 mmol) and Dowtherm A (100 mL) was heated at 220° C. for 30 min. The reaction mixture was cooled to RT and diluted with hexane (50 mL) until precipitation formed. The solid residue was collected by filtration and washed with hexane to give C54 (30 g, 79%) as a white solid. LCMS m/z 252.0 [M+H].sup.+

Step 3. Synthesis of 7-benzyloxy-3-bromo-1H-quinolin-4-one (C55)

[0438] To a suspension of C54 (1 g, 3.9796 mmol) in anhydrous DMF (4 mL) was added pyridine (978 mg, 1.00 mL, 12.364 mmol). The mixture was cooled to −16° C. and pyridinium tribromide (905 mg, 2.8297 mmol) was added within 5 minutes. After stirring for 1 hour, at which the temperature rose from −16° C. to −8° C., more pyridinium tribromide (249 mg, 0.7786 mmol) was added. After another 1 hour, more pyridinium tribromide (220 mg, 0.6879 mmol) was added again when the temperature rose from −8° C. to −6° C. The resulting mixture was stirred for another 1 hour. NaOAc (1.35 g, 16.457 mmol) was added followed by water (40 mL). The mixture was stirred for 10 min at 0° C., and then the solid was filtered, washed with water (5×10 mL) and dried under vacuum to afford C55 (1.3 g, 96%) as yellow solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 5.21 (s, 2H), 7.01-7.11 (m, 2H), 7.30-7.45 (m, 3H), 7.46-7.53 (m, 2H), 8.00-8.07 (m, 1H), 8.38 (d, J=6.1Hz, 1H), 12.01-12.12 (m, 1H); LCMS m/z 330.0 [M+H].sup.+

Step 4. Synthesis of 7-benzyloxy-3-bromo-4-chloro-quinoline (C56)

[0439] To a suspension of C55 (11.59 g, 33.347 mmol) in SOCl.sub.2 (97.860 g, 60 mL, 822.55 mmol) was added DMF (28.320 mg, 0.03 mL, 0.3874 mmol). The mixture was heated to 70° C. and stirred for 1.5 hours. After completion of the reaction, SOCl.sub.2 was co-evaporated with addition of toluene (2×75 ml). The residue was diluted with sat. NaHCO.sub.3 solution (3×150 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was triturated in CH.sub.3CN (50 mL) at stirred at room temperature for 3 hours. The residue was filtered off, washed with MTBE (2×5 mL) and dried in vacuo to afford C56 (10.91 g, 91%) as beige solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 5.33 (s, 2H), 7.31-7.46 (m, 3H), 7.47-7.55 (m, 3H), 7.56-7.63 m, 1H), 8.15 (d, J=9.2Hz, 1H), 8.98 (s, 1H); LCMS m/z 348.0 [M+H].sup.+

Step 5

Synthesis of 7-benzyloxy-4-chloro-3-isopropenyl-quinoline (C57)

[0440] A suspension of C56 (6 g, 15.490 mmol), potassium trifluoro(isopropenyl)borate (2.5214 g, 17.039 mmol), K.sub.2CO.sub.3 (6.4224 g, 46.470 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was sparged with N.sub.2 for 30 minutes. Pd(dppf)Cl.sub.2.dichloromethane (1.2650 g, 1.5490 mmol) was added and the reaction was heated at 100° C. for 18 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, washed with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 10% EtOAc in hexane to give C57 (4.3 g, 84%) as a white solid. LCMS m/z 310.0 [M+H].sup.+

Step 6. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-3-isopropenyl-quinoline (C58)

[0441] A mixture of C57 (6 g, 19.368 mmol), (4-fluorophenyl)boronic acid (3.2520 g, 23.242 mmol), and K.sub.2CO.sub.3 (5.3535 g, 38.736 mmol) in 1,4-dioxane (60 mL) and H.sub.2O (10 mL) was sparged with N.sub.2 for 10 minutes. Pd(PPh.sub.3).sub.4 (1.5667 g, 1.3558 mmol) and PCy.sub.3 (543.13 mg, 1.9368 mmol) were successively added under N.sub.2 and the reaction was heated at 90° C. for 18 hours. The reaction mixture was cooled to room temperature, filtered through celite, washed with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 20% EtOAc in hexane to give C58 (6 g, 79%) as a white solid. LCMS m/z 370.3 [M+H].sup.+

Step 7. Synthesis of 2-[7-benzyloxy-4-(4-fluorophenyl)-3-quinolyl]propan-1-ol (C59)

[0442] 9-BBN (54.192 mL of 0.5M, 27.096 mmol) was added dropwise to a solution of C58 (4.4 g, 7.7416 mmol) in THF (44.000 mL) at 0° C. After 1 hours, more 9-BBN (23.224 mL of 0.5M, 11.612 mmol) was added in a dropwise manner at 0° C. Stirring was continued for another 1 hours at room temperature, at which another lot of 9-BBN (30.966 mL of 0.5 M, 15.483 mmol) was added at 0° C. The resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was cooled to 0° C. An aqueous solution of NaOH (10.529 mL of 1 M, 10.529 mmol) and H.sub.2O.sub.2 (26.333 g, 23.723 mL, 232.25 mmol) were successively added in a dropwise manner. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with EtOAc (100 mL), washed with water (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. This residue was purified by silica gel chromatography, eluting with 60% EtOAc in hexane to afford C59 (2.8 g, 90%) as sticky light-yellow gum. LCMS m/z 388.0 [M+H].sup.+

Step 8. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-3-(2-methoxy-1-methyl-ethyl)quinoline (C60)

[0443] NaH (891.91 mg, 60% w/w, 22.300 mmol) was added to a stirred solution of C59 (1.8 g, 4.4600 mmol) in THF (40 mL) at 0° C. The resulting mixture was stirred at this temperature for 30 min and then CH.sub.3I (2.5322 g, 1.1106 mL, 17.840 mmol) was added. The resulting mixture was stirred at RT for 2 hours. After completion, the mixture was diluted with sat. NH.sub.4Cl solution (10 mL) and extracted with dichloromethane (20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 30% EtOAc in hexane to obtain pure C60 (1.1 g, 61%) as sticky yellow gum. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.91 (s, 1H), 7.54-7.47 (m, 3H), 7.37 (dt, J=27.9, 7.4 Hz, 7H), 7.23 (dd, J=9.4, 2.5 Hz, 1H), 7.15 (d, J=9.2 Hz, 1H), 5.29 (s, 2H), 3.54 (t, J=8.5 Hz, 1H), 3.45 (dd, J=9.5, 6.7 Hz, 1H), 3.12 (s, 3H),1.18 (d, J=6.9 Hz, 3H). LCMS m/z 402.0 [M+H].sup.+

Step 9. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-3-(2-methoxy-1-methyl-ethyl)-1-oxido-quinolin-1-ium (C61)

[0444] To a solution of C60 (1.1 g, 2.7399 mmol) in dichloromethane (30 mL) was added m-CPBA (709.21 mg, 4.1098 mmol) at 0° C. The resulting mixture was stirred at RT for 3 h. The reaction mixture was diluted with dichloromethane (10 mL), washed with sat. Na.sub.2CO.sub.3 solution (25 mL), water (25 mL) and brine (25 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give C61 (1 g, 83%), which was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.71 (s, 1H), 8.07 (d, J=2.7 Hz, 1H), 7.51 (d, J=7.1 Hz, 2H), 7.45-7.37 (m, 4H), 7.41-7.31 (m, 4H), 7.23 (d, J=9.2 Hz, 1H), 5.33 (s, 2H), 3.52 (dd, J=9.6, 7.7 Hz, 1H), 3.41 (dd, J=9.6, 6.3 Hz, 1H), 3.13 (s, 3H), 1.14 (d, J=7.0 Hz, 3H). LCMS m/z 418.0 [M+H].sup.+

Step 10. Synthesis of 7-benzyloxy-2-chloro-4-(4-fluorophenyl)-3-(2-methoxy-1-methyl-ethyl)quinoline (S26)

[0445] POCl.sub.3 (293.81 mg, 0.1786 mL, 1.9162 mmol) and catalytic amount of DMF were successively added in a dropwise manner to a stirred solution of C61 (400 mg, 0.9581 mmol) in toluene (4 mL). The resulting mixture was heated at 80° C. and stirred for 2 hours.

[0446] After completion of the reaction, reaction mixture was evaporated, diluted with EtOAc (50 mL) and washed with sat. NaHCO.sub.3 (20 mL) solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by column chromatography, eluting with 10% EtOAc in hexane to give S26 (350 mg, 82%) as a yellow gum. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.53-7.30 (m, 10H), 7.25 (dd, J=9.3, 2.6 Hz, 1H), 7.03 (d, J=9.3 Hz, 1H), 5.30 (s, 2H), 3.78 (s, 1H), 3.51 (s, 1H), 3.10 (s, 3H), 1.23 (s, 3H). LCMS m/z 436.0 [M+H].sup.+

Preparation of S27

4-(4-fluoro-3-methyl-phenyl)-7-methoxy-2-methyl-quinoline (S27)

[0447] ##STR00458##

[0448] To a solution of C62 (150 mg, 0.5950 mmol) and (4-fluoro-3-methyl-phenyl)boronic acid (140 mg, 0.9094 mmol) in DMF (3 mL), Pd(dppf)Cl.sub.2 (25 mg, 0.03061 mmol) was added under nitrogen. Then, an aqueous solution of Na.sub.2CO.sub.3 (600 μL of 2M, 1.2 mmol) was added and the reaction was heated in a microwave reactor at 110° C. for 30 minutes. The reaction mixture was diluted with water (30 mL) and filtered. Purification by silica gel chromatography (10-60% EtOAc in heptane) afforded S27 (149 mg, 88%) .sup.1H NMR (300 MHz, Chloroform-d) δ 7.73 (d, J=9.2 Hz, 1H), 7.44 (d, J=2.6 Hz, 1H), 7.34-7.29 (m, 1H), 7.28-7.24 (m, 1H), 7.20-7.05 (m, 3H), 3.98 (s, 3H), 2.75 (s, 3H), 2.39 (d, J=2.0 Hz, 3H). LCMS m/z 281.93 [M+H].sup.+

Preparation of S28

2-[7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-1-oxido-quinolin-1-ium-3-yl]propan-1-ol (S28)

[0449] ##STR00459##

Step 1. 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropenyl-quinoline (C63)

[0450] To a solution of C57 (3.5 g, 9.3209 mmol) in 1,4-dioxane (50 mL) were added (4-fluoro-3-methyl-phenyl)boronic acid (1.7219 g, 11.185 mmol) and a solution of K.sub.2CO.sub.3 (2.5764 g, 18.642 mmol) in water (10 mL). The reaction mixture was degassed with argon for 30 minutes, and PCy.sub.3 (261.39 mg, 0.9321 mmol) and Pd(PPh.sub.3).sub.4 (754.00 mg, 0.6525 mmol) were added. The reaction was heated at 100° C. for 18 hours. The mixture was filtered through a Celite plug, washed with EtOAc (150 mL) and concentrated. Purification by silica gel chromatography (15% EtOAc in hexanes) afforded C63 (2.9 g, 68%) as an off white solid. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.56-7.44 (m, 4H), 7.44-7.29 (m, 3H), 7.21-7.12 (m, 1H), 7.16-7.03 (m, 2H), 5.22 (s,2H), 5.16 (s, 1H), 4.98 (s, 1H), 2.33 (s, 3H), 1.65 (s, 3H). LCMS m/z 384.0 [M+H].sup.+

Step 2. 2-[7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-quinolyl]propan-1-ol (C64)

[0451] To a solution of C68 (2.9 g, 6.383 mmol) in dry THF (30 mL), a solution of 9-BBN (44.680 mL of 0.5M, 22.34 mmol) in THF was added drop wise at 0° C. The reaction mixture was stirred at room temperature for 1 hour, followed by drop wise addition of another amount of a solution of 9-BBN (19.149 mL of 0.5M, 9.5745 mmol) in THF at 0° C. The reaction mixture was stirred at room temperature for 1 hour more, and another portion of a solution of 9-BBN (25.532 mL of 0.5 M, 12.766 mmol) in THF was added at 0° C. The reaction was stirred at room temperature for additional 18 hours. The reaction mixture was cooled to 0° C. and an aqueous solution of NaOH (8.7 mL of 1M, 8.7000 mmol) was added drop wise, followed by drop wise addition of H.sub.2O.sub.2 (5.8442 g, 17.55 mL, 51.544 mmol). The reaction mixture was stirred at 0° C. for 45 minutes, warmed to room temperature and stirred for 1 hour more. The mixture was diluted with EtOAc (100 mL), washed successively with water (100 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (60% EtOAc in hexanes) afforded C64 (4 g, 94%) as a light yellow solid. LCMS m/z 402.0 [M+H].sup.+

Step 3. 2-[7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-1-oxido-quinolin-1-ium-3-yl]propan-1-ol (S28)

[0452] To a solution of C64 (4 g, 5.9780 mmol) in dichloromethane (100 mL) was added m-CPBA (1.4737 g, 6.5758 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (50 ml), washed successively with an aqueous saturated solution of NaHCO.sub.3 (40 ml), water (40 ml) and brine (40 ml). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to afford S28 (2.2 g, 84%) as a light brown solid which was advanced without further purification. 1H NMR (400 MHz, DMSO-d.sub.6) δ 8.65 (s, 1H), 8.06 (d, J=2.7 Hz, 1H), 7.92-7.86 (m, 1H), 7.59-7.47 (m, 2H), 7.45-7.12 (m, 8H), 5.32 (s, 2H), 4.73-4.68 (m, 1H),3.57-3.40 (m, 1H), 2.80-2.71 (m, 1H), 2.31 (s, 3H), 1.21-1.09 (m, 3H). LCMS m/z 418.0 [M+H].sup.+

Preparation of S29

7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-1-oxido-3-tetrahydropyran-4-yl-quinolin-1-ium (S29)

[0453] ##STR00460##

Step 1. 7-benzyloxy-4-chloro-3-(3,6-dihydro-2H-pyran-4-yl)quinoline (C65)

[0454] To a solution of K.sub.3PO.sub.4 (9.74 g, 45.886 mmol) in water (9 mL), was added toluene (100 mL) and the mixture was degassed with nitrogen for 15 minutes. Then, C56 (8 g, 22.259 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.5 g, 26.181 mmol), PCy.sub.3 (1.26 g, 4.4931 mmol) and Pd(OAc).sub.2 (575 mg, 2.5612 mmol) were successively added. The reaction was heated at 95° C. for 18 hours. The mixture was cooled to room temperature, diluted with EtOAc (600 mL), washed successively with an aqueous solution of 5% NaHCO.sub.3 (150 mL×3) and brine (150 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was triturated with heptane (50 mL) and acetonitrile (30 mL), filtered and dried. Purification by silica gel chromatography (0-50% EtOAc in dichloromethane) afforded C65 (5.7 g, 73%) as a beige solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 2.45-2.62 (m, 2H), 3.98 (t, J=5.2 Hz, 2H), 4.37 (q, J=2.6 Hz, 2H), 5.22 (s, 2H), 5.85-5.94 (m, 1H), 7.29-7.58 (m, 7H), 8.18 (d, J=9.2 Hz, 1H), 8.60 (s, 1H). LCMS m/z 352.1 [M+H].sup.+

Step 2. 7-benzyloxy-3-(3,6-dihydro-2H-pyran-4-yl)-4-(4-fluoro-3-methyl-phenyl)quinoline (C66)

[0455] A suspension of C65 (2.9 g, 8.2427 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (1.5227 g, 9.8912 mmol), K.sub.2CO.sub.3 (2.2783 g, 16.485 mmol), PCy.sub.3 (231.16 mg, 0.8243 mmol) in 1,4-dioxane (26 mL) and water (3.7 mL) was degassed with nitrogen for 10 minutes. Then, Pd(PPh.sub.3).sub.4 (666.76 mg, 0.5770 mmol) was added and the reaction mixture was heated at 100° C. for 12 hours. The mixture was filtered through a Celite® plug and washed with EtOAc. The solution was concentrated and purification by silica gel chromatography (20-30% EtOAc in hexanes) afforded C66 (2.5 g, 68%) as a white solid. LCMS m/z 426.0 [M+H].sup.+

Step 3. 4-(4-fluoro-3-methyl-phenyl)-3-tetrahydropyran-4-yl-quinolin-7-ol (C67)

[0456] A solution of C66 (1 g, 2.3502 mmol) in EtOH (20 mL) was degassed with nitrogen for 5 minutes and 10% palladium on carbon (2 g, 50% w/w, 9.396 mmol) was added. The container was purged with hydrogen and the reaction mixture stirred at room temperature for 2 hours. The mixture was filtered through a Celite® plug, washed with methanol (150 mL) and concentrated to afford C67 (600 mg, 72%) as a yellow solid. LCMS m/z 337.9 [M+H].sup.+

Step 4. 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-tetrahydropyran-4-yl-quinoline (C68)

[0457] To a solution of C67 (3.4 g, 10.08 mmol) in DMF (45 mL), K.sub.2CO.sub.3 (3.4818 g, 25.193 mmol) was added. Then, the mixture was cooled to 0° C. and benzyl chloride (1.531 g, 1.39 mL, 12.09 mmol) was added drop wise. The reaction was stirred at room temperature for 12 hours. An additional 1 equiv. of benzyl chloride and 2.5 equiv. of K.sub.2CO.sub.3 were added at 0° C., and the reaction was warmed to room temperature for another 12 h. The mixture was diluted with EtOAc (250 mL), washed with ice cold water (30 mL×4), dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (50% EtOAc in hexanes) afforded C68 (2.5 g, 51%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.92 (s, 1H), 7.50 (dd, J=5.0, 2.3 Hz, 3H), 7.40 (dd, J=8.2, 6.5 Hz, 2H), 7.33 (td, J=9.5, 8.4, 3.9 Hz, 2H), 7.23 (dt, J=9.3, 2.6 Hz, 2H), 7.16 (d, J=9.1 Hz, 2H), 5.29 (s, 2H), 3.88 (t, J=5.8 Hz, 2H), 3.16 (t, J=11.5 Hz, 2H), 2.67-2.61 (m, 1H), 2.31 (s, 3H), 2.01-1.84 (m, 2H), 1.56 (d, J=13.0 Hz, 2H). LCMS m/z 427.9 [M+H].sup.+

Step 5. 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-1-oxido-3-tetrahydropyran-4-yl-quinolin-1-ium (S29)

[0458] To a solution of C68 (2.7 g, 6.315 mmol) in dichloromethane (25 mL) was added m-CPBA (1.35 g, 7.831 mmol) at 0° C. The reaction was stirred at room temperature for 12 hours. The mixture was diluted with dichloromethane (200 mL), washed with an aqueous saturated solution of NaHCO.sub.3 (30 mL) and concentrated. Purification by silica gel chromatography (5% MeOH in dichloromethane) afforded S29 (2.6 g, 84%) as a yellow solid. LCMS m/z 444.1 [M+H].sup.+

Preparation of S30

7-benzyloxy-2-chloro-4-(4-fluoro-3-methyl-phenyl)-3-tetrahydropyran-4-yl-quinoline (S30)

[0459] ##STR00461##

[0460] To a solution of S29 (2.7 g, 6.089 mmol) in dichloromethane (25 mL), POCl.sub.3 (3.7338 g, 2.27 mL, 24.351 mmol) was added dropwise while in an ice bath, followed by DMF (472.0 mg, 0.5 mL, 6.457 mmol). The reaction was stirred at room temperature for 18 hours. The solvent was evaporated and a saturated aqueous solution of Na.sub.2CO.sub.3 (30 mL) was added. The mixture was extracted with EtOAc (100 mL×2), the organic phases were combined, dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (15% EtOAc in hexanes) afforded S30 (2.5 g, 89%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.50-7.30 (m, 8H), 7.25 (dd, J=9.2, 2.7 Hz, 2H), 7.06 (d, J=9.2 Hz, 1H), 5.76 (s,1H), 5.29 (s, 2H), 4.03 (q, J=7.0 Hz, 1H), 3.85 (d, J=10.9 Hz, 2H), 3.07 (s, 4H), 2.32 (d, J=2.0 Hz, 4H), 1.99 (s, 1H), 1.44 (d, J=12.6 Hz, 2H), 1.26-1.13 (m, 1H). LCMS m/z 462.1 [M+H].sup.+

Preparation of S31

7-benzyloxy-4-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-1-oxido-quinolin-1-ium (S31)

[0461] ##STR00462##

[0462] To a solution of C65 (1 g, 2.8423 mmol) in dichloromethane (15 mL) was added m-CPBA (589 mg, 3.410 mmol), and the mixture was stirred at RT for 6 h. An aqueous saturated solution of Na.sub.2CO.sub.3 (20 mL) was added. The mixture was extracted with dichloromethane (30 mL×2), the organic phases were combined, dried over Na.sub.2SO.sub.4 and concentrated. The crude compound was washed with 20% EtOAc in hexanes to afford S31 (810 mg, 72%) as a white solid. LCMS m/z 368.0 [M+H].sup.+

Preparation of S32

7-benzyloxy-4-(4-fluorophenyl)-3-isopropenyl-1-oxido-quinolin-1-ium (S32)

[0463] ##STR00463##

Step 1. 7-benzyloxy-4-(4-fluorophenyl)-3-isopropenyl-quinoline (C69)

[0464] C57 (6.0 g, 19.368 mmol), (4-fluorophenyl)boronic acid (3.252 g, 23.242 mmol), and K.sub.2CO.sub.3 (5.354 g, 38.736 mmol) were suspended in a mixture of 1,4-dioxane (60 mL) and water (10 mL). The suspension was degassed for 10 minutes and Pd(PPh.sub.3).sub.4 (1.567 g, 1.3558 mmol) and PCy.sub.3 (543 mg, 1.9368 mmol) were added. The reaction was heated at 90° C. for 18 hours. The mixture was filtered through a plug of Celite, washed with EtOAc and concentrated. Purification by silica gel chromatography (10-20% EtOAc in hexanes) afforded C69 as white solid. LCMS m/z 370.3 [M+H].sup.+

Step 2. 7-benzyloxy-4-(4-fluorophenyl)-3-isopropenyl-1-oxido-quinolin-1-ium (S32)

[0465] To a solution of C69 (6.0 g, 16.241 mmol) in dichloromethane (80 mL), m-CPBA (3.3631 g, 19.489 mmol) was added and the reaction was stirred at room temperature for 6 hours. The mixture was concentrated and a saturated aqueous solution of NaHCO.sub.3 was added. The resulting suspension was stirred for 15 minutes, the solids were filtered and dried to afford S32 (5.2 g, 83%). LCMS m/z 386.3 [M+H].sup.+

Preparation of S33

8-benzyloxy-1-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S33)

[0466] ##STR00464## ##STR00465##

Step 1. trimethyl(2-tetrahydropyran-4-ylethynyl)silane (C71)

[0467] To a mixture of ethylmagnesium bromide (120 mL of 3M, 360.0 mmol) solution in Et.sub.2O and THF (200 mL), ethynyltrimethylsilane (50 mL, 353.8 mmol) was added dropwise and while in an ice bath. The reaction was heated to reflux for 1 hour. The mixture was cooled to room temperature and NMP (300 mL), 4-iodotetrahydropyran (C70) (50 g of 97% w/w, 228.7 mmol), and FeBr.sub.2 (5 g, 23.19 mmol) were added successively. The mixture was placed under nitrogen and stirred at 30° C. for 4 hours. MTBE and aqueous saturated ammonium chloride (1:1, 800 mL) were added to the reaction mixture. The mixture was extracted with MTBE (20 mL×2), the organic phases were combined, dried over Na.sub.2SO.sub.4, filtered through a silica gel plug and rinse with MTBE to afford C71 (29.5 g, 70%) as an amber oil. .sup.1H NMR (300 MHz, Chloroform-d) δ 3.88 (m, 2H), 3.48 (m, 2H), 2.64 (tt, J=8.4, 4.1 Hz, 1H), 1.87-1.74 (m, 2H), 1.72-1.57 (m, 2H), 0.15 (s, 9H).

Step 2. 2-benzyloxy-6-bromo-benzaldehyde (C73)

[0468] To a solution of C72 (5.25 g, 26.12 mmol) and bromomethylbenzene (3.2 mL, 26.90 mmol) in DMF (50 mL), K.sub.2CO.sub.3 (4.97 g, 35.96 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction was diluted with EtOAc, washed successively with water (3×) and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give C73 (7.35 g, 97%) as an off-white solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 10.50 (s, 1H), 7.54-7.23 (m, 7H), 7.02 (dd, J=7.5, 2.0 Hz, 1H), 5.21 (s, 2H). LCMS m/z 290.8 [M+H].sup.+

Step 3. 2-benzyloxy-6-(2-tetrahydropyran-4-ylethynyl)benzaldehyde (C74)

[0469] To a mixture of C71 (25 g, 85.87 mmol) and C73 (25 g, 137.1 mmol) in 1,4-dioxane (170 mL), N-isopropylpropan-2-amine (75 mL, 535.1 mmol), CuI (840 mg, 4.411 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (2.5 g, 3.562 mmol) and TBAF dihydrate (40 g, 126.8 mmol) were added successively. The reaction was heated at 50° C. for 2 hours. The mixture was cooled to room temperature, poured into a mixture of water (50 mL), a saturated aqueous NH4Cl solution (100 mL) and ethyl acetate (500 mL), and stirred for 10 minutes. The organic phase was washed successively with an aqueous solution of HCl 1 M (100 mL×2) and brine (100 mL), dried over MgSO.sub.4, filtered and concentrated. Purification by silica gel chromatography (0-70% EtOAc in heptane) afforded C74 (25 g, 91%) as a yellow viscous oil. .sup.1H NMR (300 MHz, Chloroform-d) δ 10.65 (s, 1H), 7.50-7.30 (m, 6H), 7.11 (dd, J=7.7, 0.9 Hz, 1H), 6.96 (dd, J=8.5, 0.9 Hz, 1H), 5.20 (s, 2H), 3.97 (ddd, J=11.6, 5.9, 3.6 Hz, 2H), 3.58 (ddd, J=11.5, 8.2, 3.1 Hz, 2H), 2.94 (dt, J=8.3, 4.1 Hz, 1H), 2.02-1.87 (m, 2H), 1.80 (dtd, J=13.5, 8.2, 3.6 Hz, 2H). LCMS m/z 321.25 [M+H].sup.+.

Step 4. (1E)-2-benzyloxy-6-(2-tetrahydropyran-4-ylethynyl)benzaldehyde oxime (C75)

[0470] A mixture of hydroxylamine chlorohydrate (35 g, 503.7 mmol) in pyridine (130 mL, 1.607 mol) was stirred for 30 minutes at room temperature and a solution of C74 (50 g, 156.1 mmol) in acetonitrile (500 mL) was added over 20 minutes. The suspension was stirred at room temperature for 2 hours. The reaction was concentrated, and dichloromethane (600 mL) and a cold aqueous solution of HCl 1M (100 mL) were added to the residue. The mixture was stirred for 20 minutes and the organic layer was separated, washed successively with an aqueous solution of HCl 1 M (100 mL×2), water (100 mL), brine (100 mL), dried over MgSO.sub.4, filtered and concentrated. The residue was triturated with MTBE (200 mL) and dried to afford C75 (40 g, 76%) as a white solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 9.21 (s, 1H), 8.63 (s, 1H), 7.48-7.28 (m, 5H), 7.22-7.11 (m, 1H), 7.08 (dd, J=7.7, 1.2 Hz, 1H), 6.88 (dd, J=8.2, 1.2 Hz, 1H), 5.22 (s, 2H), 3.95 (ddd, J=11.6, 6.0, 3.6 Hz, 2H), 3.56 (ddd, J=11.4, 8.1, 3.1 Hz, 2H), 2.91 (dq, J=8.3, 4.1 Hz, 1H), 2.00-1.85 (m, 2H), 1.85-1.67 (m, 2H). LCMS m/z 336.08 [M+H].sup.+

Step 5. 8-benzyloxy-4-bromo-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C76)

[0471] To a solution of C75 (6.53 g, 19.470 mmol) in DMA (50 mL), CuBr (10.86 g, 48.622 mmol) was added and the mixture was heated at 60° C. for 1 hour. The reaction was cooled to 0° C., and a mixture of an aqueous solution of NH.sub.4OH and water (2:1, 50 mL) were slowly added in 5 minutes. The suspension was stirred at room temperature for 30 minutes, the solids were filtered and washed with water. The solid was dissolved in dichloromethane, dried over Na.sub.2SO.sub.4, filtered, concentrated and dried. The residue was triturated with MTBE (35 mL), filtered, washed with heptane and dried to afford C76 (5.8 g, 69%) as tan solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.84 (s, 1H), 7.69-7.62 (m, 2H), 7.60-7.50 (m, 2H), 7.49-7.33 (m, 3H), 7.32-7.22 (m, 1H), 5.36 (s, 2H), 4.08-3.83 (m, 3H), 3.43 (t, J=11.2 Hz, 2H), 3.07-2.78 (m, 2H), 1.43 (d, J=12.3 Hz, 2H). LCMS m/z 414.1 [M+H].sup.+

Step 6. 8-benzyloxy-4-(4-fluorophenyl)-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C77)

[0472] To a solution of C76 (2.0 g, 4.828 mmol) and (4-fluorophenyl)boronic acid (1.008 g, 7.204 mmol) in DMSO (20 mL), an aqueous solution of Na.sub.2CO.sub.3 (7.25 mL of 2M, 14.50 mmol) was added and the suspension was degassed with nitrogen for 5 minutes. Then, Pd(dppf)Cl.sub.2.dichloromethane (150 mg, 0.2460 mmol) was added and the solution was degassed again with nitrogen for 5 min. The mixture was heated to 100° C. for 3 hours. Water was added to the reaction, and the mixture was extracted with EtOAc (150mL×3). The product precipitated in EtOAc, the organic phase was filtered and washed with cold EtOAc to afford C77 (1.552 g, 64%). .sup.1H NMR (300 MHz, Chloroform-d) δ 9.30 (s, 1H), 7.52-7.37 (m, 8H), 7.32 (d, J=8.1 Hz, 1H), 7.27-7.23 (m, 5H), 6.92 (d, J=7.6 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 5.27 (s, 2H), 3.98 (dd, J=11.0, 4.0 Hz, 3H), 3.28 (t, J=10.8 Hz, 1H), 1.43 (dd, J=11.4, 2.6 Hz, 1H). LCMS m/z 430.56 [M+H].sup.+

Step 7. 8-benzyloxy-1-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S33)

[0473] To a solution of C77 (1.2 g, 2.403 mmol) and DIEA (1.45 mL, 8.325 mmol) in dichloromethane (14 mL), and oxalyl chloride (2.7 mL of 2M, 5.4 mmol) was added drop wise while at −78° C. The reaction was stirred for 4 hours and was allowed to warm to 0° C. MeOH (6 mL) was added and the mixture was stirred for 10 minutes. The suspension was concentrated, MeOH (5 mL) were added and the mixture was cooled down to 0° C. for 1 h. The solids were filtered and washed with cold MeOH to afford S33 (639 mg, 58%) as a white solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.60 (d, J=7.4 Hz, 2H), 7.48-7.32 (m, 4H), 7.25-7.19 (m, 4H), 7.00 (d, J=7.9 Hz, 1H), 6.85 (dd, J=8.5, 0.9 Hz, 1H), 5.32 (s, 2H), 4.00 (dd, J=11.4, 4.3 Hz, 2H), 3.30 (t, J=12.1 Hz, 2H), 2.80-2.65 (m, 1H), 2.25 (qd, J=12.5, 4.4 Hz, 2H), 1.49 (d, J=13.4 Hz, 2H). LCMS m/z 448.47 [M+H].sup.+

Preparation of S34

8-benzyloxy-4-(3,4-difluorophenyl)-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (S34)

[0474] ##STR00466##

[0475] To a suspension of C76 (5.0 g, 11.83 mmol) and (3,4-difluorophenyl)boronic acid (2.47 g, 15.64 mmol) in DMSO (62 mL), water (11.0 mL) and Na.sub.2CO.sub.3 (3.76 g, 35.48 mmol) were added. The mixture was degassed with of nitrogen for 5 minutes, and Pd(dppf)Cl.sub.2 was added (386.4 mg, 0.473 mmol). The suspension was degassed again with nitrogen for 5 minutes. The reaction was heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and poured into ice-cold brine and was extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried, filtered, and concentrated. The solid was triturated with MTBE and filtered to provide S34 (4.62 g, 78%) as a brown solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 9.28 (d, J=0.9 Hz, 1H), 7.50-7.27 (m, 8H), 7.10 (ddd, J=10.4, 7.4, 2.1 Hz, 1H), 7.00 (ddd, J=8.6, 4.3, 1.8 Hz, 1H), 6.91 (dd, J=7.9, 0.7 Hz, 1H), 6.64 (dt, J=8.5, 0.9 Hz, 1H), 5.25 (s, 2H), 4.06-3.91 (m, 2H), 3.29 (q, J=11.4, 10.4 Hz, 3H), 2.67 (d, J=31.8 Hz, 1H), 1.44 (s, 2H), 1.31-1.22 (m, 1H). LCMS m/z 448.42 [M+H].sup.+

Preparation of S35

8-benzyloxy-1-chloro-4-(3,4-difluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S35)

[0476] ##STR00467##

[0477] To a solution of S34 (599 mg, 1.34 mmol) and DIPEA (725 4.162 mmol) in dry dichloromethane (7 mL), oxalyl dichloride (1.42 mL of 2M, 2.84 mmol) was added while at −78° C. The reaction was allowed to warm to 0° C. for 2 hours. Then, MeOH (2 mL) was added and the mixture was stirred for 10 minutes. The reaction was concentrated, MeOH was added (5 mL), the solids were filtered, washed with cold MeOH and dried to afford S35 (335 mg, 54%) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.60 (ddt, J=7.5, 1.3, 0.7 Hz, 2H), 7.49-7.41 (m, 3H), 7.41-7.31 (m, 2H), 7.09 (ddd, J=10.5, 7.5, 2.1 Hz, 1H), 7.05-6.96 (m, 2H), 6.84 (dd, J=8.5, 0.9 Hz, 1H), 4.08-3.96 (m, 2H), 3.40-3.27 (m, 2H), 2.72 (tt, J=11.7, 3.8 Hz, 1H), 2.35-2.19 (m, 2H), 1.49 (dd, J=12.7, 3.5 Hz, 2H). LCMS m/z 466.38 [M+H].sup.+

Preparation of S36

8-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropenyl-1-oxido-quinolin-1-ium (S36)

[0478] ##STR00468## ##STR00469##

Step 1. 5-[(2-benzyloxyanilino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (C79)

[0479] To a solution of C78 (25.0 g, 22.9 mL, 119.2 mmol) in EtOH (150 mL), 2,2-dimethyl-1,3-dioxane-4,6-dione (20.616 g, 143.04 mmol) and trimethyl orthoformate (20.492 g, 21.17 mL, 193.10 mmol) were added. The reaction was heated at 100° C. for 2 hours. The mixture was stirred at room temperature for 1 hour, the solids were filtered, washed with EtOH and dried to give C79 (39.0 g, 88%) as an off-white solid. LCMS m/z 354.0 [M+H].sup.+

Step 2: 8-benzyloxy-1H-quinolin-4-one (C80)

[0480] Dowtherm A (150 mL) was heated at 220° C. for 10 minutes and C79 (35.0 g, 99.047 mmol) was added portion wise. The mixture was stirred for 30 min. The reaction was cooled to room temperature and stirred for 20 minutes. Then, hexanes were added, the solids were filtered, washed with hexanes and dried to afford C80 (22 g, 78%) as a brown solid. LCMS m/z 252.0 [M+H].sup.+

Step 3. 8-benzyloxy-3-bromo-1H-quinolin-4-one (C81)

[0481] To a solution of C80 (18.8 g, 65.839 mmol) in DMF (150.40 mL), NBS (12.890 g, 72.423 mmol) was added while in an ice bath. The reaction was stirred for 3 hours at room temperature. Cold water was added to the mixture; the solids were filtered, washed with water and dried to afford C81 (20 g, 88%) as brown solid. LCMS m/z 331.0 [M+H].sup.+

Step 4. 8-benzyloxy-3-bromo-4-chloro-quinoline (C82)

[0482] To a solution of C81 (20 g, 60.574 mmol) in toluene (150 mL), thionyl chloride (72.065 g, 44.212 mL, 605.74 mmol) was added and the reaction was refluxed for 2 hours. The mixture was concentrated, and dichloromethane and an aqueous solution of NaHCO.sub.3 were added. The mixture was extracted with dichloromethane, the organic phases were combined, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (10-50% EtOAc in hexanes) afforded C82 (19 g, 85%). LCMS m/z 349.0 [M+H].sup.+

Step 5. 8-benzyloxy-4-chloro-3-isopropenyl-quinoline (C83)

[0483] To a solution of C82 (14 g, 40.158 mmol) in 1,4-dioxane (120 mL) and water (30 mL), potassium isopropenyltrifluoroborate (5.9424 g, 40.158 mmol) and K.sub.2CO.sub.3 (16.650 g, 120.47 mmol) were added. The mixture was degassed under nitrogen and Pd(dppf)Cl.sub.2.dichloromethane (3.3199 g, 4.0158 mmol) was added. The reaction was heated at 90° C. for 16 hours. The reaction mixture was diluted with EtOAc and water was added. The mixture was extracted with dichloromethane, the organic phases were combined, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (0-50% EtOAc in hexanes) afforded C83 (8.5 g, 65%) as a brown solid. LCMS m/z 310.0 [M+H].sup.+

Step 6. 8-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropenyl-quinoline (C84)

[0484] To a solution of C83 (4.35 g, 10.856 mmol) in 1,4-dioxane (40 mL) and water (8.70 mL), (4-fluoro-3-methyl-phenyl)boronic acid (2.5069 g, 16.284 mmol) and K.sub.2CO.sub.3 (4.5011 g, 32.568 mmol) were added. Then, the mixture was degassed under N.sub.2 and Pd(PPh.sub.3).sub.4 (1.25 g, 1.08 mmol), PCy.sub.3 (304.43 mg, 1.0856 mmol) were added. The reaction was heated at 90° C. for 16 hours. The reaction mixture was diluted with EtOAc and water was added. The mixture was extracted with dichloromethane, the organic phases were combined, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (10-50% EtOAc in hexanes) afforded C84 (4.1 g, 90%). LCMS m/z 384.0 [M+H].sup.+

Step 7. 8-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropenyl-1-oxido-quinolin-1-ium (S36)

[0485] To a solution of C84 (2.5 g, 6.52 mmol) in dichloromethane (25 mL), m-CPBA (1.91 g, 11.08 mmol) was added. The mixture was stirred at room temperature for 7 hours. An aqueous saturated solution of Na.sub.2CO.sub.3 (10 mL) was added. The mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined and concentrated. Purification by trituration with hexanes afforded S36 (1.5 g, 51%) as a light yellow solid. LCMS m/z 400.0 [M+H].sup.+

Compound 1

(2S)-2-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]propanoic acid (1)

[0486] ##STR00470##

Step 1. Synthesis of benzyl (2S)-2-[[7-benzyloxy-4-(4-fluorophenyl)-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]propanoate (C85)

[0487] To a solution of S1 (120 mg, 0.2746 mmol) and benzyl (2R)-2-(p-tolylsulfonyloxy)propanoate (140 mg, 0.4187 mmol) in DMF (2 mL) was added CsF (200 mg, 1.317 mmol) and the resulting solution was stirred at 50° C. for 15 hours. The mixture was extracted with EtOAc and the organic layer was washed with NaHCO.sub.3 solution, dried. After evaporation, purification by silica gel chromatography (Gradient: 0-50% EtOAc in heptane) yielded the product as a colorless oil. benzyl (2S)-2-[[7-benzyloxy-4-(4-fluorophenyl)-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]propanoate (50.2 mg, 31%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J=2.7 Hz, 1H), 7.46-7.36 (m, 2H), 7.36-7.30 (m, 2H), 7.30-7.26 (m, 1H), 7.26-7.18 (m, 6H), 7.18-7.12 (m, 2H), 7.12-6.99 (m, 3H), 6.84 (d, J=9.3 Hz, 1H), 5.47 (q, J=7.0 Hz, 1H), 5.24-5.03 (m, 5H), 3.35 (d, J=8.7 Hz, 1H), 3.08 (d, J=2.1 Hz, 4H), 1.70 (d, J=7.0 Hz, 3H), 1.03 (s, 3H), 0.97 (s, 3H). LCMS m/z 594.4 [M+H].sup.+

Step 2. Synthesis of (2S)-2-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]propanoic acid (1)

[0488] To a solution of C85 (50 mg, 0.084 mmol) in MeOH (2 mL) and EtOAc (1 mL) was added Pd/C (8.9 mg, 0.08363 mmol) and a 1 atm balloon of H.sub.2. The reaction mixture was stirred for 1 hour and filtered through a pad of Celite®, the clear solution was concentrated give 1 as a white solid (33.2 mg, 95%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.37-6.90 (m, 6H), 6.82-6.69 (m, 1H), 6.63 (d, J=9.5 Hz, 1H), 5.28 (q, J=6.8 Hz, 1H), 3.48-3.29 (m, 2H), 3.22 (s, 3H), 1.58 (d, J=6.4 Hz, 3H), 1.00 (d, J=8.8 Hz, 6H). ESI-MS m/z calc. 413.16385, found 414.27 (M+1).sup.+; Retention time: 0.49 minutes

Compounds 2 and 3

(2S)-2-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]propanoic acid (2) and 4-(4-fluorophenyl)-7-hydroxy-3-(1-hydroxy-2-methylpropan-2-yl)isoquinolin-1(2H)-one (3)

[0489] ##STR00471##

[0490] To a solution of 1 (16 mg, 0.03870 mmol) in dichloromethane (0.5 mL) was added BBr.sub.3 (80 μL of 1 M, 0.08000 mmol) in dichloromethane at 0° C. and the resulting solution was allowed to warm to room temperature. After stirring for 2 hour, additional BBr.sub.3 (80 μL of 1 M, 0.08000 mmol) was added and the reaction was stirred for 12 hours and quenched with ice and extracted with dichloromethane (3×2 mL).The combined organic phase was concentrated and purified by HPLC: 0-70% ACN in Water (FA modifier) to give 2 (8 mg, 52%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.97 (d, J=2.8 Hz, 1H), 8.69-8.52 (m, 5H), 8.42 (dd, J=8.9, 2.8 Hz, 1H), 8.08 (d, J=8.9 Hz, 1H), 4.64 (p, J=1.6 Hz, 2H), 3.34 (p, J=2.5 Hz, 1H), 2.36 (s, 6H). LCMS m/z 400.36 [M+H].sup.+ and 3 (4.7 mg, 34%) .sup.1H NMR (400 MHz, Methanol-d.sub.4/acetonitrile-d.sub.3) δ 8.97 (d, J=2.8 Hz, 1H), 8.69-8.52 (m, 5H), 8.42 (dd, J=8.9, 2.8 Hz, 1H), 8.08 (d, J=8.9 Hz, 1H), 4.64 (p, J=1.6 Hz, 2H), 3.34 (p, J=2.5 Hz, 1H), 2.36 (s, 6H). LCMS m/z 328.1 [M+H].sup.+

Compounds 4 and 5

3-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (4) and 3-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (5)

[0491] ##STR00472##

Step 1. Synthesis of benzyl 3-[[7-benzyloxy-4-(4-fluorophenyl)-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylate (C86)

[0492] To a solution of S1 (120 mg, 0.2746 mmol) and benzyl 3-(p-tolylsulfonyloxy)cyclobutanecarboxylate (150 mg, 0.4129 mmol) in DMF (2 mL) was added CsF (200 mg, 1.317 mmol) and the reaction mixture was stirred at 50° C. for 15 hours. The mixture was extracted with EtOAc and the organic layer was washed with NaHCO.sub.3 solution, dried. After evaporation, purification by silica gel chromatography (Gradient: 0-50% EtOAc in heptane) yielded C86 as a colorless oil. (56 mg, 33%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.50 (d, J=2.6 Hz, 1H), 7.40 (ddd, J=8.1, 4.1, 1.4 Hz, 2H), 7.36-7.20 (m, 9H), 7.21-7.13 (m, 2H), 7.10-7.00 (m, 3H), 6.82 (dd, J=9.2, 4.0 Hz, 1H), 5.57 (ttd, J=7.4, 6.4, 1.1 Hz, 1H), 5.31 (tt, J=8.2, 7.0 Hz, 0H), 5.14 (s, 2H), 5.09 (d, J=1.5 Hz, 2H), 3.28 (s, 2H), 3.27-3.16 (m, 1H), 3.10 (d, J=4.7 Hz, 3H), 2.85 (dddd, J=11.5, 7.3, 4.4, 2.3 Hz, 2H), 2.62-2.47 (m, 2H), 1.04 (s, 5H). LCMS m/z 642.38 [M+H].sup.+

Step 2. Synthesis of 3-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (4) and 3-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (5)

[0493] To a solution of C86 (55 mg, 0.08834 mmol) in MeOH (1 μL) and EtOAc (3 mL) was added Pd/C (10 mg of 10% w/w, 0.009397 mmol) and a 1 atm H.sub.2 balloon (50 mg, 24.80 mmol) for 1 hour. The reaction mixture was stirred for 1 hour and filtered through a pad of Celite®, the clear solution was concentrated give a white solid which was purified by reverse phase chromatography 40-85% acetonitrile (0.1% TFA) on C18 to give 4 (36 mg, 91%) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.52 (s, 1H), 7.26 (dd, J=5.8, 2.6 Hz, 2H), 7.18 (t, J=8.6 Hz, 2H), 7.11 (dd, J=9.2, 2.6 Hz, 1H), 6.88 (d, J=9.1 Hz, 1H), 5.61 (q, J=6.7 Hz, 1H), 3.56 (s, 2H), 3.46 (s, 3H), 3.34 (t, J=10.0 Hz, 1H), 2.97 (t, J=5.5 Hz, 2H), 2.72 (q, J=12.2, 10.4 Hz, 2H), 1.13 (s, 6H). LCMS m/z 440.19 [M+H].sup.+ and 5 (3.3 mg, 8%) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.48 (d, J=2.6 Hz, 1H), 7.28-7.21 (m, 2H), 7.17 (t, J=8.6 Hz, 2H), 7.07 (dd, J=9.1, 2.6 Hz, 1H), 6.84 (d, J=9.2 Hz, 1H), 5.39 (q, J=6.9 Hz, 1H), 3.53 (s, 2H), 3.43 (s, 3H), 2.99 (dt, J=22.8, 8.4 Hz, 3H), 2.61 (t, J=9.7 Hz, 2H), 1.14 (s, 6H). LCMS m/z 440.24 [M+H].sup.+

Compound 6

3-[[4-(4-(4-fluorophenyl)-7-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (6)

[0494] ##STR00473##

Step 1. Synthesis of 3-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (6)

[0495] To a solution of 4 (11 mg, 0.02444 mmol) in dichloromethane (0.5 mL) was added BBr.sub.3 (50 μL of 1 M, 0.05 mmol) at 0° C. in a dropwise fashion. The reaction was warmed to room temperature and additional BBr.sub.3 (50 μL of 1 M, 0.05 mmol) was added at room temperature and stirred for another 2 hours. The reaction was quenched with ice and the mixture was evaporated to dryness. The residue was purified by reverse phase MPLC 0-70% ACN in Water (0.2% Formic Acid modifier) to give 6 (6.5 mg, 63%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.53-7.44 (m, 1H), 7.27 (t, J=6.8 Hz, 2H), 7.19 (t, J=8.5 Hz, 2H), 7.07 (dt, J=9.2, 1.9 Hz, 1H), 6.85 (d, J=9.1 Hz, 1H), 5.57 (p, J=6.8 Hz, 1H), 3.71 (s, 2H), 3.23 (dq, J=9.7, 4.8, 4.3 Hz, 1H), 2.96-2.81 (m, 2H), 2.62 (td, J=12.8, 11.6, 7.7 Hz, 2H), 1.07 (s, 6H). LCMS m/z 426.19 [M+H].sup.+

Compound 7

Synthesis of (2S)-2-[[8-fluoro-4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-1-isoquinolyl]oxy]propanoic acid (7)

[0496] ##STR00474##

Step 1: Synthesis of (2S)-2-[[8-fluoro-4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-1-isoquinolyl]oxy]propanoic acid (7)

[0497] To a solution of S2 (45 mg, 0.06 mmol) in DMF (2 mL) was added NaH (30 mg, 0.75 mmol) at room temperature. The reaction was stirred for 15 hours at room temperature and was quenched by addition of MeOH (4 mL). At this point, Pd/C (10 mg, 0.0094 mmol) was added and a balloon of H.sub.2 (1 atm) was fitted to the reaction mixture. The reaction was stirred for 2 hours and filtered through a pad of Celite® and the residue was purified by reverse MPLC: 40 g C18 column, eluting with 10-100% ACN in water with 0.1% FA to provide 7 (11.6 mg, 44%) .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.22 (d, J=7.2 Hz, 4H), 6.83 (dd, J=9.1, 1.5 Hz, 1H), 5.35 (q, J=7.0 Hz, 1H), 2.76 (p, J=6.7 Hz, 1H), 1.71 (d, J=7.0 Hz, 3H), 1.14 (dd, J=20.3, 6.7 Hz, 6H). LCMS m/z 388.2 [M+H].sup.+

Compounds 8-18

[0498] Compounds 8-18 (Table 1) were prepared from intermediate S2 according to the method described for 7. Any modifications to methods are noted in Table 1 and accompanying footnotes.

TABLE-US-00002 TABLE 1 Method of preparation, structure and physicochemical data for compounds 8-18 Compound Method/Product Alcohol .sup.1HNMR; LCMS m/z [M + H].sup.+ 8 Compound 7.sup.1 from S2 [00475] [00476] 1H NMR (400 MHz, Methanol- d.sub.4) δ 7.26-7.15 (m, 5H), 6.82 (dd, J = 9.1, 1.5 Hz, 1H), 5.42- 5.30 (m, 1H), 3.02-2.82 (m, 3H), 2.86-2.73 (m, 1H), 2.51- 2.39 (m, 2H), 1.17 (d, J = 6.7 Hz, 6H). LCMS m/z 414.49 [M + H].sup.+ 9 Compound 7.sup.1 from S2 [00477] [00478] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.26-7.15 (m, 5H), 6.82 (dd, J = 9.1, 1.4 Hz, IH), 5.60 (p, J = 6.9 Hz, 1H), 3.27-3.14 (m, 1H), 2.86 (dddd, J = 11.1, 7.3, 3.6, 2.4 Hz, 2H), 2.78 (p, J = 6.7 Hz, IH), 2.64-2.51 (m, 2H), 1.16 (d, J = 6.7 Hz, 6H). LCMS m/z 414.49 [M + H].sup.+ 10 Compound 7.sup.2 from S2 [00479] [00480] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.26-7.15 (m, 5H), 6.82 (dd, J = 9.1, 1.4 Hz, IH), 5.48 (p, J = 7.0 Hz, IH), 3.15-3.05 (m, 2H), 2.78 (p, J = 6.7 Hz, 1H), 2.25-2.15 (m, 2H), 1.50 (s, 3H), 1.15 (d, J = 6.7 Hz, 6H). LCMS m/z 428.49 [M + H].sup.+ 11 Compound 7.sup.2 from S2 [00481] [00482] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.26-7.14(m, 5H), 6.82 (dd, J = 9.1, 1.5 Hz, 1H), 5.47 (p, J = 7.3 Hz, 1H), 2.79 (p, J = 6.7 Hz, 1H), 2.73-2.63 (m, 2H), 2.62-2.51 (m, 2H), 1.53 (s, 3H), 1.17 (d, J = 6.7 Hz, 6H). LCMS m/z 428.49 [M + H].sup.+ 12 Compound 7 from S2 [00483] [00484] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.27-7.14 (m, 5H), 6.82 (dd, J = 9.1, 1.5 Hz, IH), 4.80 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 6.5 Hz, 2H), 2.80 (h, J = 6.9 Hz, 1H), 1.19 (d, J = 6.7 Hz, 6H). LCMS m/z 388.16 [M + H].sup.+ 13 Compound 7 from S2 [00485] [00486] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.21 (dd, J = 10.0, 7.5 Hz, 5H), 6.83 (dd, J = 9.1, 1.5 Hz, 1H), 5.35 (q, J = 7.0 Hz, IH), 2.76 (hept, J = 6.7 Hz, IH), 1.71 (d, J = 7.0 Hz, 3H), 1.14 (dd, J = 20.4, 6.7 Hz, 6H). LCMS m/z 388.2 [M + H].sup.+ 14 Compound 7 from S2 [00487] [00488] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.23 (d, J = 7.2 Hz, 3H), 7.19-7.02 (m, 1H), 6.82 (dd, J = 9.1, 1.5 Hz, 1H), 5.84-5.75 (m, 1H), 3.19-3.09 (m, 1H), 2.86-2.74 (m, 1H), 2.40-2.15 (m, 4H), 2.10-1.90 (m, 3H), 1.18 (dt, J = 6.8, 1.5 Hz, 6H). LCMS m/z 428.18 [M + H].sup.+ 15 Compound 7 from S2 [00489] [00490] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.27-7.21 (m, 3H), 7.17 (dd, J = 9.1, 8.0 Hz, 1H), 6.81 (dd, J = 9.0, 1.4 Hz, 1H), 5.72- 5.64 (m, 1H), 2.98-2.87 (m, 1H), 2.79 (p, J = 6.7 Hz, 1H), 2.55 (ddd, J = 14.8, 9.3, 6.3 Hz, 1H), 2.29-1.97 (m, 6H), 1.18 (dd, J = 6.7, 2.7 Hz, 6H). LCMS m/z 428.22 [M + H].sup.+ 16 Compound 7 from S2 [00491] [00492] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.71 (dd, J = 17.0, 2.5 Hz, 1H), 8.29 (d, J = 8.6 Hz, IH), 7.96 (ddd, J = 17.1, 8.6, 2.6 Hz, IH), 7.38-7.15 (m, 5H), 6.96 (dd, J = 9.1, 1.4 Hz, IH), 2.78 (dq, J = 13.4, 6.9 Hz, IH), 1.01 (dd, J = 9.4, 6.7 Hz, 6H). LCMS m/z 437.18 [M + H].sup.+ 17 Compound 7from S2 [00493] [00494] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.21 (dd, J = 16.9, 7.6 Hz, 5H), 6.83 (dd, J = 9.1, 1.4 Hz, IH), 6.10-5.99 (m, IH), 4.85 (d, J = 3.3 Hz, 1H), 2.80 (h, J = 6.6 Hz, 1H), 2.14 (s, 3H), 1.55 (d, J = 6.4 Hz, 3H), 1.19 (dd, J = 6.7, 2.0 Hz, 6H). LCMS m/z 459.23 [M + H].sup.+ 18 Compound 7from S2 [00495] [00496] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.30-7.23 (m, 4H), 6.88 (dd, J = 9.1, 1.4 Hz, 1H), 5.83 (q, J = 7.3 Hz, 1H), 2.79 (p, J = 6.7 Hz, 1H), 1.15 (dd, J = 23.1, 6.7 Hz, 6H). LCMS m/z 442.17 [M + H].sup.+

Compound 19

2-[2-[[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-1-isoquinolyl]oxy]-6-azaspiro[3.4]octan-6-yl]acetic acid (19)

[0499] ##STR00497## ##STR00498##

Step 1: Synthesis of tert-butyl 2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-1-isoquinolyl]oxy]-6-azaspiro[3.4]octane-6-carboxylate (C87)

[0500] To a mixture of S7 isoquinoline (200 mg, 0.4927 mmol) and tert-butyl 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (672 mg, 2.956 mmol) in dry DMF (12.00 mL) was slowly added NaH (130 mg of 60% w/w, 3.250 mmol) at room temperature. The reaction mixture was microwaved at 85° C. under N.sub.2 for 2 hours. The reaction mixture was quenched with water (1 mL) and HCl (1 M; ˜3 mL/pH=6). The desired product was extracted with EtOAc, washed with water, sat. NaCl and dried over sodium sulfate. Purification by silica gel chromatography led to C87 (116 mg, 39%) LCMS m/z 597.37 [M+H].sup.+

Step 2: Synthesis of 1-(6-azaspiro[3.4]octan-2-yloxy)-7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (C88)

[0501] To a solution of C87 (116 mg, 0.1944 mmol) in dichloromethane (2 mL) was added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred for 18 hours at room temperature and the excess solvent was removed to give C88 (Trifluoroacetate salt) (110 mg, 93%) which was used without further purification; LCMS m/z 497.12 [M+H].sup.+

Step 3. Synthesis of ethyl 2-[2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-1-isoquinolyl]oxy]-6-azaspiro[3.4]octan-6-yl]acetate (C89)

[0502] To a solution of C88 (110 mg, 0.1801 mmol), ethyl 2-oxoacetate (220.7 mg of 50% w/w, 1.081 mmol) and acetic acid (10.25 μL, 0.1802 mmol) in dichloromethane (4 mL) was added triacetoxy-hydrido-boron (Sodium salt) (305.4 mg, 1.441 mmol). The resulting mixture was stirred for 6 hours. The reaction was diluted with dichloromethane and slowly quenched with MeOH and sat. NaHCO.sub.3 (50 mL). After separation, the organic layer was washed with water, sat. NaCl and dried over sodium sulfate. Evaporation led to C89 (100 mg, 95%) which was used without further purification; LCMS m/z 583.47 [M+H].sup.+

Step 4. Synthesis of ethyl 2-[2-[[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-1-isoquinolyl]oxy]-6-azaspiro[3.4]octan-6-y]acetate (C90)

[0503] A solution of palladium (30 mg of 10% w/w, 0.02819 mmol) and C89 (100 mg, 0.1716 mmol) in MeOH (20 mL) and EtOAc (40 mL) was stirred under H.sub.2 (1 atm) at room temperature for 18 hours. The mixture was filtered through a pad of Celite® and concentrated to dryness. The residue was purified by silica gel chromatography 0-10% of MeOH in dichloromethane) to give C90 (84 mg, 99%). LCMS m/z 493.52 [M+H].sup.+.

Step 5. Synthesis of 2-[2-[[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-1-isoquinolyl]oxy]-6-azaspiro[3.4]octan-6-y]acetic acid (19)

[0504] A solution of C90 (84 mg, 0.1705 mmol) and LiOH.H.sub.2O (63 mg, 1.501 mmol) in water (1.5 mL) and THF (1.5 mL) was stirred at room temperature for 3 hours after which the reaction mixture was treated with HCl (1 N) until pH=7. The excess solvent was removed HPLC purification gave 19 (43 mg, 52%) .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.53 (dd, J=2.5, 0.6 Hz, 1H), 7.35-6.93 (m, 6H), 5.54 (p, J=6.8 Hz, 1H), 4.24-4.02 (m, 2H), 4.02-3.77 (m, 2H), 3.30 (d, J=12.2 Hz, 2H), 3.00-2.70 (m, 3H), 2.65-2.20 (m, 4H), 1.18 (d, J=6.7 Hz, 6H). LCMS m/z 465.19 [M+H].sup.+

Compounds 20-30

[0505] Compounds 20-30 (Table 2) were prepared from intermediate C91 and C92 according to the method described in Table 2. Any modifications to methods are noted in Table 2 and accompanying footnotes.

##STR00499##

Step 1. Synthesis of ethyl 2-[2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-1-isoquinolyl]oxy]-5-oxo-6-azaspiro[3.4]octan-6-yl]acetate (C91) and ethyl 2-[2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-1-isoquinolyl]oxy]-7-oxo-6-azaspiro[3.4]octan-6-yl]acetate (C92)

[0506] To a solution of C89 (200 mg, 0.3432 mmol) and NaHCO.sub.3 (3.75 mL of 1 M, 3.750 mmol) in THF (13 mL) was added I.sub.2 (140 μL, 2.719 mmol). The reaction mixture was stirred for 6 hours and quenched by the addition of sat. NaHCO.sub.3 and sat. sodium thiosulfate (10 mL). After extraction of the aqueous phase with EtOAc, the organic phase was dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel chromatography (0-25-50% of EtOAc in heptane) to give C91 (135 mg, 66%) LCMS m/z 597.57 [M+H].sup.+ and C92 (45 mg, 22%) LCMS m/z 597.57 [M+H].sup.+

TABLE-US-00003 TABLE 2 Method of preparation, structure and physicochemical data for compounds 20-30 .sup.1H NMR; LCMS m/z Compound Method/Product Alcohol [M + H].sup.+ 20 [00500] [00501] .sup.1H NMR (300 MHz, Chloroform-d and Methanol-d.sub.4) δ 7.54 (td, J = 2.4, 0.9 Hz, 1H), 7.30- 7.02 (m, 6H), 5.69-5.49 (m, 1H), 4.20 (dd, J = 7.1, 4.0 Hz, 2H), 4.10 (d, J = 0.9 Hz, 2H), 3.49 (dt, J = 13.4, 6.8 Hz, 2H), 3.14- 2.99 (m, 1H), 2.82 (h, J = 6.6 Hz, 1H), 2.75-2.56 (m, 2H), 2.47-2.25 (m, 3H), 1.31 (dt, J = 7.2, 3.6 Hz, 3H), 1.15 (dd, J = 6.7, 4.8 Hz, 6H). LCMS m/z 507.45 [M + H].sup.+ 21 [00502] [00503] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.98 (s, 1H), 7.44 (d, J = 2.5 Hz, 1H), 7.40-7.24 (m, 4H), 7.16 (dd, J = 9.0, 2.6 Hz, 1H), 7.00 (d, J = 9.0 Hz, 1H), 5.48 (dt, J = 9.5, 7.2 Hz, 1H), 3.94 (d, J = 3.2 Hz, 2H), 2.93-2.65 (m, 2H), 2.62-2.52 (m, 1H), 2.49- 2.36 (m, 2H), 2.35-2.09 (m, 4H), 1.16-1.06 (m, 6H). LCMS m/z 479.47 [M + H].sup.+ 22 [00504] [00505] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.55 (dd, J = 2.3, 0.9 Hz, 1H), 7.33- 6.95 (m, 6H), 5.69-5.53 (m, 1H), 4.08 (s, 2H), 3.48 (t, J = 6.9 Hz, 2H), 3.06 (ddd, J = 10.4, 7.3, 2.5 Hz, 2H), 2.81 (p, J = 6.6 Hz, 1H), 2.34 (qd, J = 6.4, 3.1 Hz, 4H), 1.14 (d, J = 6.7 Hz, 6H). LCMS m/z 479.0 [M + H].sup.+ 23 [00506] [00507] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.54 (dd, J = 2.3, 0.9 Hz, 1H), 7.35- 6.88 (m, 6H), 5.57 (p, J = 7.7 Hz, 1H), 4.07 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.83 (p, J = 6.6 Hz, IH), 2.77-2.49 (m, 4H), 2.41 (t, J = 6.8 Hz, 2H), 1.15 (d, J = 6.7 Hz, 6H). LCMS m/z 479.17 [M + H].sup.+ 24 [00508] [00509] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.55 (ddd, J = 5.6, 2.5, 0.7 Hz, 1H), 7.34-6.97 (m, 6H), 5.55 (dq, J = 21.1, 6.8 Hz, 1H), 4.08 (d, J = 9.1 Hz, 2H), 3.69 (d, J = 19.5 Hz, 2H), 2.84 (dddd, J = 14.8, 10.3, 8.3, 4.8 Hz, 3H), 2.68 (d, J = 16.3 Hz, 2H), 2.49-2.33 (m, 2H), 1.18 (dd, J = 6.8, 2.6 Hz, 6H). LCMS m/z 479.17 [M + H].sup.+ 25 [00510] [00511] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.63-7.53 (m, 1H), 7.30-7.01 (m, 6H), 5.75 (s, 1H), 4.10 (s, 2H), 3.65 (s, 4H), 2.87 (p, J = 6.6 Hz, 1H), 2.47 (s, 4H), 1.16 (d, J = 6.7 Hz, 6H). LCMS m/z 439.42 [M + H].sup.+ 26 [00512] [00513] .sup.1H NMR (300 MHz, Chloroform-d and Methanol-d.sub.4) δ 7.50 (d, J = 2.2 Hz, 1H), 7.30-6.95 (m, 6H), 5.32 (p, J = 6.9 Hz, 1H), 4.22 (dd, J = 13.5, 6.4 Hz, 2H), 3.57 (s, 2H), 3.49 (s, 2H), 3.34(s, 2H), 2.95-2.71 (m, 3H), 2.51-2.33 (m, 2H), 1.31 (d, J = 7.1 Hz, 3H), 1.15 (d, J = 6.7 Hz, 6H). LCMS m/z 479.47 [M + H].sup.+ 27 [00514] [00515] 1H NMR (300 MHz, Chloroform-d and Methanol-d.sub.4) δ 7.50-7.46 (m, 1H), 7.33-7.00 (m, 6H), 5.42 (q, J = 6.6 Hz, 1H), 4.46 (s, 2H), 4.38- 4.17 (m, 2H), 4.11 (s, 2H), 3.21-2.79 (m, 3H), 2.76- 2.47 (m, 2H), 1.17 (dd, J = 6.7, 1.3 Hz, 6H). LCMS m/z 451.18 [M + H].sup.+ 28 [00516] [00517] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.54 (t, J = 1.7 Hz, 1H), 7.26-7.02 (m, 5H), 5.39 (s, 1H), 5.10 (d, J = 37.1 Hz, 1H), 4.19 (m, 2H), 3.36 (d, J = 14.8 Hz, 1H), 2.99 (s, 1H), 2.81 (p, J = 6.6 Hz, 1H), 2.45- 2.22 (m, 1H), 2.06-1.71 (m, 2H), 1.51 (s, 9H), 1.13 (t, J = 7.0 Hz, 6H). ESI- MS m/z calc. 524.23224, found 525.45 [M + H] 29 [00518] [00519] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.59 (dd, J = 2.4, 0.8 Hz, 1H), 7.20 (s, 2H), 7.18 (d, J = 1.4 Hz, 2H), 7.13-7.08 (m, 2H), 6.11 (s, 1H), 5.49 (dqd, J = 13.2, 6.6, 5.9, 3.9 Hz, 2H), 4.05-3.90 (m, 2H), 2.87 (h, J = 6.7 Hz, 1H), 1.51 (d, J = 6.5 Hz, 3H), 1.19 (dd, J = 7.7, 6.8 Hz, 6H) ppm. LCMS m/z 356.6 [M + H].sup.+ 30 [00520] [00521] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.55 (dd, J = 2.6, 0.6 Hz, 1H), 7.25- 7.17 (m, 4H), 7.13 (dd, J = 9.1, 2.6 Hz, 1H), 7.06 (dd, J = 9.0, 0.5 Hz, 1H), 4.72 (dd, J = 12.1, 2.0 Hz, 1H), 4.57 (dd, J = 12.1, 7.0 Hz, 1H), 4.45 (pd, J = 6.5, 1.9 Hz, 1H), 2.90 (p, J = 6.8 Hz, 1H), 1.40 (d, J = 6.5 Hz, 3H), 1.22 (dd, J = 6.8, 2.8 Hz, 6H). LCMS m/z 356.17 [M + H].sup.+

Compounds 31-33

[0507] ##STR00522##

Step 1: Synthesis of ethyl 2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-1-isoquinolyl]oxy]acetate (C93)

[0508] To a solution of S5 (744 mg, 1.920 mmol) in DMF (8 mL) was added Cs.sub.2CO.sub.3 (1.30 g, 3.990 mmol) followed by ethyl 2-bromoacetate (385 μL, 3.472 mmol). The reaction was held at 90° C. for 90 minutes. The solvent was removed by rotary evaporation. The resulting crude material was purified by silica gel chromatography (0-60% EtOAc in heptane) to afford C93 (644 mg, 69%) LCMS m/z 473.17 [M+H].sup.+, which was used directly in the next step.

[0509] Step 2: To a solution of 4-(4-fluorophenyl)-3-isopropyl-7-methoxy-1-[(3S)-pyrrolidin-3-yl]oxy-isoquinoline (Trifluoroacetate salt) (50 mg, 0.1011 mmol) and 2-cyanoacetic acid (12 mg, 0.1411 mmol) in DMF (1 mL) was added TEA (50 μL, 0.3587 mmol) followed by HATU (58 mg, 0.1525 mmol). The reaction was stirred at room temperature for 3 hours and was quenched by addition of water. The aqueous phase was extracted with EtOAc (3×5 mL). The combined organic fractions were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 0-10% MeOH in dichloromethane to provide the desired product as white solid C94 (34 mg, 75%) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.42 (d, J=2.3 Hz, 1H), 7.24-7.10 (m, 6H), 5.94 (dtt, J=11.3, 4.6, 2.1 Hz, 1H), 4.09-3.99 (m, 1H), 3.93 (s, 3H), 3.91-3.70 (m, 3H), 3.53 (s, 1H), 3.46 (s, 1H), 2.87 (h, J=6.7 Hz, 1H), 2.67-2.27 (m, 2H), 1.17 (dt, J=6.7, 1.8 Hz, 6H). LCMS m/z 448.25 [M+H].sup.+

[0510] 44: .sup.1H NMR (400 MHz, Chloroform-d) δ 7.44 (dt, J=4.6, 1.6 Hz, 1H), 7.18-7.08 (m, 4H), 7.06 (dd, J=4.8, 1.5 Hz, 2H), 5.87 (dd, J=28.9, 24.0 Hz, 2H), 4.15-3.89 (m, 2H), 3.87-3.70 (m, 2H), 2.86-2.72 (m, 1H), 2.55-2.16 (m, 2H), 1.12-1.05 (m, 6H). LCMS m/z 434.3 [M+H].sup.+

Compounds 31-42

[0511] Compounds 31-42 (Table 3) were prepared from intermediates indicated in Table 3.

TABLE-US-00004 TABLE 3 Method of preparation, structure, physicochemical data for compounds 31-42 .sup.1H NMR; LCMS m/z Compound Method/Product Intermediate [M + H].sup.+ 31 [00523] N/A .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.95 (s, 1H), 9.89 (s, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.37- 7.22 (m, 3H), 7.06 (dd, J = 8.9, 2.7 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 2.67-2.54 (m, 1H), 1.15 (d, J = 7.0 Hz, 6H). ESI- MS m/z calc. 297.11652, found 298.22 (M + 1).sup.+ 32 [00524] N/A .sup.1H NMR (400 MHz, Acetone-d.sub.6) δ 8.91 (s, 1H), 7.63 (dd, J = 2.7, 0.6 Hz, 1H), 7.35-7.27 (m, 4H), 7.24 (dd, J = 9.1, 2.6 Hz, 1H), 7.12 (dd, J = 9.0, 0.6 Hz, 1H), 5.09 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 2.83 (p, J = 6.7 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.13 (d, J = 6.7 Hz, 6H). ESI-MS m/z calc. 383.1533, found 384.27 (M + 1).sup.+ 33 [00525] N/A .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.84 (s, 1H), 10.05 (s, 1H), 7.46 (t, J = 2.5 Hz, 1H), 7.40- 7.25 (m, 4H), 7.19 (dd, J = 9.1, 2.6 Hz, 1H), 7.03 (d, J = 9.1 Hz, 1H), 5.00 (s, 2H), 2.73 (p, J = 6.6 Hz, 1H), 1.09 (d, J = 6.6 Hz, 6H). ESI-MS m/z calc. 355.12198, found 356.22 (M + 1).sup.+ 34 [00526] [00527] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.62 (dd, J = 2.0, 1.2 Hz, 1H), 7.27-7.12 (m, 6H), 5.49 (q, J = 6.9 Hz, 1H), 2.89 (p, J = 6.8 Hz, 1H), 1.81 (d, J = 6.9 Hz, 3H), 1.20 (d, J = 6.7 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H). .sup.19F NMR (282 MHz, Chloroform-d ) δ −114.78. ESI-MS m/z calc. 369.13763, found 370.36 (M + 1).sup.+ 35 [00528] [00529] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.50 (dd, J = 2.2, 1.0 Hz, 1H), 7.18-7.07 (m, 6H), 2.81 (h, J = 6.8 Hz, 1H), 1.75 (s, 6H), 1.11 (d, J = 6.8 Hz, 6H). ESI-MS m/z calc. 383.1533, found 384.29 (M + 1).sup.+ 36 [00530] [00531] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.51 (dd, J = 2.4, 0.8 Hz, 1H), 7.17-7.02 (m, 6H), 5.38 (q, J = 7.0 Hz, 1H), 3.87 (s, 3H), 3.69 (s, 3H), 2.74 (hept, J = 6.7 Hz, 1H), 1.70 (d, J = 7.0 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 6.6 Hz, 3H). ESI-MS m/z calc. 397.16895, found 398.29 (M + 1).sup.+ 37 [00532] [00533] .sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) δ 7.53 (dd, J = 2.6, 0.6 Hz, 1H), 7.32-7.21 (m, 4H), 7.17 (dd, J = 9.1, 2.6 Hz, 1H), 7.10 (dd, J = 9.0, 0.6 Hz, 1H), 5.71-5.49 (m, 1H), 3.23 (ttd, J = 10.1, 4.0, 1.1 Hz, 1H), 2.92-2.79 (m, 3H), 2.64-2.52 (m, 2H), 1.17 (d, J = 6.7 Hz, 9H). ESI-MS m/z calc. 395.1533, found 396.21 (M + 1).sup.+ 38 [00534] [00535] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.62 (dd, J = 2.2, 1.0 Hz, 1H), 7.27-7.12 (m, 6H), 5.50 (q, J = 6.8 Hz, 1H), 2.89 (h, J = 6.8 Hz, 1H), 1.82 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 6.7 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H). ESI- MS m/z calc. 369.13763, found 370.15 (M + 1)+ 39 [00536] [00537] 1H NMR (400 MHz, Chloroform-d) δ 7.55 (s, 1H), 7.24-7.07 (m, 6H), 5.41 (q, J = 7.2 Hz, 1H), 2.96 (q, J = 9.0 Hz, 3H), 2.83 (p, J = 6.7 Hz, 1H), 2.68-2.51 (m, 2H), 1.15 (d, J = 6.7 Hz, 6H). ESI- MS m/z calc. 395.1533, found 396.21 (M + 1).sup.+ 40 [00538] [00539] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.50 (s, 2H), 7.49 (d, J = 2.5 Hz, 1H), 7.30-7.20 (m, 4H), 7.14 (dd, J = 9.1, 2.5 Hz, 1H), 7.08 (d, J = 8.9 Hz, 1H), 5.93 (t, J = 2.4 Hz, 1H), 3.82-3.67 (m, 2H), 3.68-3.49 (m, 2H), 2.86 (p, J = 6.7 Hz, 1H), 2.61- 2.45 (m, 2H), 1.20 (d, J = 6.7 Hz, 6H). ESI-MS m/z calc. 366.17435, found 367.18 (M + 1)+ 41 [00540] MeI .sup.1H NMR (400 MHz, Acetone-d.sub.6) δ 8.83 (s, 1H), 7.57 (dd, J = 2.6, 0.6 Hz, 1H), 7.35-7.27 (m, 4H), 7.21 (dd, J = 9.0, 2.6 Hz, 1H), 7.09 (dd, J = 9.0, 0.6 Hz, 1H), 4.13 (s, 3H), 2.86 (p, J = 6.7 Hz, 1H), 1.20 (d, J = 6.7 Hz, 6H). ESI-MS m/z calc. 311.13217, found 312.61 (M + 1).sup.+ 42 [00541] [00542] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.51 (dd, J = 2.5, 0.8 Hz, 1H), 7.16-6.99 (m, 6H), 5.96 (s, 1H), 5.43 (d, J = 8.9 Hz, 1H), 5.38 (qd, J = 6.7, 3.0 Hz, 1H), 3.87 (d, J = 7.4 Hz, 2H), 2.79 (hept, J = 6.7 Hz, 1H), 1.42 (d, J = 6.5 Hz, 3H), 1.10 (dd, J = 11.6, 6.8 Hz, 6H). ESI-MS m/z calc. 355.1584, found 355.99 (M + 1).sup.+

Compounds 43 and 44

[0512] ##STR00543##

2-Step procedure: Synthesis of ethyl 2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-1-isoquinolyl]oxy]acetate (C94)

[0513] Step 1: To a solution tert-butyl (3S)-3-[[4-(4-fluorophenyl)-3-isopropyl-7-methoxy-1-isoquinolyl]oxy]pyrrolidine-1-carboxylate (146 mg, 0.3034 mmol) in DCM (1 mL) was added TFA (250 μL, 3.245 mmol) at room temperature and the solution was stirred for 1 hour. Evaporation of the crude reaction mixture led to the isolation of a white solid ESI-MS m/z calc. 380.19, found 381.22 (M+1).sup.+; Retention time: 0.45 minutes, which was used directly in the next step.

[0514] Step 2: To a solution of 4-(4-fluorophenyl)-3-isopropyl-7-methoxy-1-[(3S)-pyrrolidin-3-yl]oxy-isoquinoline (Trifluoroacetate salt) (50 mg, 0.1011 mmol) and 2-cyanoacetic acid (12 mg, 0.1411 mmol) in DMF (1 mL) was added TEA (50 μL, 0.3587 mmol) followed by HATU (58 mg, 0.1525 mmol). The reaction was stirred at room temperature for 3 hours and was quenched by addition of water. The aqueous phase was extracted with EtOAc (3×5 mL). The combined organic fractions were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 0-10% MeOH in dichloromethane to provide the desired product as white solid C94 (34 mg, 75%) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.42 (d, J=2.3 Hz, 1H), 7.24-7.10 (m, 6H), 5.94 (dtt, J=11.3, 4.6, 2.1 Hz, 1H), 4.09-3.99 (m, 1H), 3.93 (s, 3H), 3.91-3.70 (m, 3H), 3.53 (s, 1H), 3.46 (s, 1H), 2.87 (h, J=6.7 Hz, 1H), 2.67-2.27 (m, 2H), 1.17 (dt, J=6.7, 1.8 Hz, 6H). LCMS m/z 448.25 [M+H].sup.+ 1).sup.+

[0515] Compounds 43 and 44 were isolated following general procedure 2 (GP2) using BBr.sub.3 as Lewis acid.

[0516] 43: .sup.1H NMR (400 MHz, Chloroform-d) δ 7.45 (d, J=3.1 Hz, 1H), 7.26-7.01 (m, 6H), 5.93 (d, J=10.1 Hz, 1H), 4.21-3.65 (m, 4H), 3.44-3.22 (m, 2H), 2.92-2.75 (m, 1H), 2.48 (d, J=14.5 Hz, 1H), 2.34 (ddt, J=35.9, 9.4, 4.7 Hz, 1H), 1.17 (d, J=6.7 Hz, 6H). ESI-MS m/z calc. 451.19073, found 452.26 (M+1).sup.+; Retention time: 0.44 minutes

[0517] 44: .sup.1H NMR (400 MHz, Chloroform-d) δ 7.44 (dt, J=4.6, 1.6 Hz, 1H), 7.18-7.08 (m, 4H), 7.06 (dd, J=4.8, 1.5 Hz, 2H), 5.87 (dd, J=28.9, 24.0 Hz, 2H), 4.15-3.89 (m, 2H), 3.87-3.70 (m, 2H), 2.86-2.72 (m, 1H), 2.55-2.16 (m, 2H), 1.12-1.05 (m, 6H). LCMS m/z 434.3 [M+H].sup.+

Compound 45

3-((4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)oxy)-1-methylcyclobutane-1-carboxylic acid (45)

[0518] ##STR00544##

[0519] Step 1: To a solution of S10 (Trifluoroacetate salt) (60 mg, 0.098 mmol) and methyl 3-hydroxy-1-methyl-cyclobutanecarboxylate (35.4 mg, 0.245 mmol) in DMF (1 mL) was added NaH (7.8 mg, 0.196 mmol) at 0° C., the solution was stirred at this temperature for 1 hours and then 4 hours at room temperature. After this time, LCMS shows complete consumption of starting material. This reaction mixture was directly carried forward to the next step.

[0520] Step 2: To the previous reaction mixture was added MeOH (1 mL) and the reaction mixture was filtered through a Celite® plug to remove precipitates. To this solution was added dihydroxypalladium (6.9 mg, 0.01 mmol) and the solution was placed in a Parr vessel. The vessel was brought to 25 psi under hydrogen atmosphere and was stirred for 4 hours by which time the reaction mixture was filtered through a 0.2 micron filter, and then concentrated in vacuo to remove MeOH. The crude mixture in DMF was carried directly in the next step.

[0521] Step 3: To the previous DMF mixture was added KOH (98 μL of 10M solution) at RT and the reaction mixture was stirred for 6 h and then diluted with H.sub.2O (3 mL) and flash frozen in a dry ice/acetone bath. The frozen solution was concentrated via lyophilization and the crude residue filtered through a Celite® pad adding DMF to a final volume of 2 mL. The sample was purified by automated reverse phase HPLC purification (CAPER, formic acid modifier) to provide 45. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.44 (d, J=2.6 Hz, 1H), 7.33-7.04 (m, 4H), 7.01 (d, J=9.0 Hz, 1H), 5.38 (p, J=7.0 Hz, 1H), 3.05-2.98 (m, 2H), 2.75 (td, J=12.7, 12.1, 6.1 Hz, 1H), 2.37-2.25 (m, 3H), 2.20-2.03 (m, 2H), 1.43 (s, 3H), 1.20-0.89 (m, 6H). LCMS m/z 424.24 [M+H].sup.+.

Compounds 46-59

[0522] Compounds 46-59 (Table 4) were prepared from intermediates indicated in Table 4.

TABLE-US-00005 TABLE 4 Method of preparation, structure and physicochemical data for compounds 46-59 .sup.1H NMR; LCMS m/z Compound Method/Product Alcohol [M + H].sup.+ 46 [00545] [00546] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.39 (d, J = 2.5 Hz, 1H), 7.27 (dd, J = 9.8, 8.3 Hz, 1H), 7.24- 7.17 (m, 2H), 7.16-7.08 (m, 1H), 7.05 (d, J = 9.1 Hz, 1H), 3.03 (d, J = 22.1 Hz, 5H), 2.77 (p, J = 6.6 Hz, 1H), 2.34-2.25 (m, 3H), 1.09 (dd, J = 6.7, 4.2 Hz, 6H). LCMS m/z 478.21 [M + H].sup.+ 47 [00547] [00548] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.43 (d, J = 2.6 Hz, 1H), 7.26 (dd, J = 9.8, 8.3 Hz, 1H), 7.21- 7.12 (m, 2H), 7.09 (td, J = 5.4, 2.6 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H), 5.50 (p, J = 7.2 Hz, 1H), 3.16-3.08 (m, 1H), 2.75 (qd, J = 7.9, 7.4, 4.5 Hz, 3H), 2.47 (d, J = 3.1 Hz, 2H), 2.36-2.20 (m, 3H), 1.11 (dd, J = 6.7, 4.4 Hz, 6H). LCMS m/z 410.23 [M + H].sup.+ 48 [00549] [00550] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.41 (d, J = 2.6 Hz, 1H), 7.26 (dd, J = 9.8, 8.3 Hz, 1H), 7.22- 7.05 (m, 3H), 7.01 (d, J = 9.0 Hz, 1H), 5.66 (dt, J = 5.9, 3.0 Hz, 1H), 3.05- 2.99 (m, 1H), 2.78 (p, J = 6.6 Hz, 1H), 2.30 (d, J = 1.9 Hz, 3H), 2.16 (dtd, J = 44.1, 13.2, 12.6, 8.0 Hz, 4H), 1.87 (tq, J = 15.0, 8.3, 7.5 Hz, 2H), 1.14 (ddd, J = 6.4, 4.4, 1.6 Hz, 6H). LCMS m/z 424.24 [M + H].sup.+ 49 [00551] [00552] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.48 (d, J = 2.5 Hz, 1H), 7.26 (dd, J = 9.8, 8.3 Hz, 1H), 7.22- 7.14 (m, 2H), 7.10 (ddd, J = 13.1, 8.2, 5.5 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H), 5.31 (t, J = 7.0 Hz, 1H), 2.83-2.67 (m, 3H), 2.30 (s, 3H), 2.28-2.21 (m, 1H), 1.26 (d, J = 4.7 Hz, 6H), 1.12 (td, J = 6.7, 4.8 Hz, 6H). LCMS m/z 438.25 [M + H].sup.+ 50 [00553] [00554] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.37 (d, J = 2.6 Hz, 1H), 7.27 (dd, J = 9.9, 8.3 Hz, 1H), 7.22- 7.12 (m, 2H), 7.12-7.05 (m, 1H), 7.01 (d, J = 9.0 Hz, 1H), 4.73 (s, 2H), 2.79 (p, J = 6.6 Hz, 1H), 2.45 (dd, J = 9.7, 6.9 Hz, 2H), 2.30 (d, J = 1.9 Hz, 3H), 2.12 (ddt, J = 24.3, 17.5, 8.9 Hz, 3H), 1.93 (dt, J = 10.1, 4.8 Hz, 1H), 1.28- 1.05 (m, 6H). LCMS m/z 424.24 [M + H].sup.+ 51 [00555] [00556] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.42 (d, J = 2.6 Hz, 1H), 7.26 (dd, J = 9.8, 8.3 Hz, 1H), 7.17 (td, J = 8.9, 2.4 Hz, 2H), 7.10 (td, J = 6.0, 5.4, 2.7 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H), 5.30 (p, J = 7.4 Hz, 1H), 2.90 (p, J = 8.8 Hz, 1H), 2.85-2.70 (m, 3H), 2.42-2.19 (m, 5H), 1.13 (dd, J = 6.7, 4.1 Hz, 6H). LCMS m/z 410.23 [M + H].sup.+ 52 [00557] [00558] LCMS m/z 424.24 [M + H].sup.+ 53 [00559] [00560] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.45 (d, J = 2.6 Hz, 1H), 7.28-7.07 (m, 4H), 7.00 (d, J = 9.0 Hz, 1H), 5.28-5.19 (m, 1H), 2.77 (q, J = 6.6 Hz, 1H), 2.66 (dd, J = 10.3, 7.7 Hz, 1H), 2.47 (s, 1H), 2.40- 2.28 (m, 4H), 1.43 (s, 3H), 1.14 (ddd, J = 9.9, 6.7, 4.5 Hz, 6H), 1.05 (s, 3H). LCMS m/z 438.25 [M + H].sup.+ 54 [00561] [00562] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.42 (d, J = 2.6 Hz, 1H), 7.26 (dd, J = 9.8, 8.3 Hz, 1H), 7.17 (ddd, J = 11.6, 8.3, 2.4 Hz, 2H), 7.09 (ddd, J = 7.8, 5.0, 2.2 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H), 5.42 (p, J = 1.2 Hz, 1H), 2.77 (p, J = 6.6 Hz, 1H), 2.58 (s, 2H), 2.47 (s, 2H), 2.35-2.26 (m, 3H), 1.45 (s, 3H), 1.12 (dd, J = 6.6, 4.3 Hz, 6H). LCMS m/z 424.24 [M + H].sup.+ 55 [00563] [00564] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.92 (s, 1H), 7.46 (s, 1H), 7.34-6.96 (m, 5H), 4.55 (s, 2H), 2.77 (s, 1H), 2.30 (s, 3H), 2.03 (d, J = 4.9 Hz, 6H), 1.12 (dd, J = 6.4, 3.4 Hz, 6H). LCMS m/z 436.41 [M + H].sup.+ 56 [00565] [00566] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88 (d, J = 2.2 Hz, 1H), 7.82 (dt, J = 6.9, 1.8 Hz, 1H), 7.58 (q, J = 3.4, 2.8 Hz, 3H), 7.31- 7.21 (m, 3H), 7.16-7.08 (m, 2H), 2.73 (p, J = 6.5 Hz, 1H), 2.31 (d, J = 1.9 Hz, 3H), 0.94 (dd, J = 6.1, 2.2 Hz, 6H). LCMS m/z 432.27 [M + H].sup.+ 57 [00567] [00568] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.70-7.62 (m, 2H), 7.57 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.30-7.22 (m, 2H), 7.20 (dd, J = 7.9, 2.0 Hz, 1H), 7.14-7.08 (m, 2H), 3.77 (s, 3H), 2.69 (dd, J = 14.1, 7.5 Hz, 1H), 2.30 (d, J = 1.8 Hz, 3H), 0.85 (dd, J = 6.7, 1.9 Hz, 6H). LCMS m/z 462.26 [M + H].sup.+ 58 [00569] [00570] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.76 (d, J = 2.7 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.96 (dd, J= 8.6, 2.7 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.34-7.25 (m, 2H), 7.22 (dd, J = 7.5, 2.1 Hz, 1H), 7.13 (dd, J = 9.6, 5.7 Hz, 2H), 2.75 (dt, J = 14.1, 7.0 Hz, 1H), 2.36- 2.26 (m, 3H), 0.96 (dd, J = 6.8, 2.3 Hz, 6H). LCMS m/z 433.28 [M + H].sup.+ 59 [00571] [00572] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.35 (s, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.35-7.20 (m, 4H), 7.15 (dd, J = 10.3, 5.1 Hz, 2H), 2.80 (p, J = 6.6 Hz, 1H), 2.36-2.25 (m, 3H), 1.17- 0.97 (m, 6H). LCMS m/z 422.91 [M + H] .sup.+

Compounds 60 and 61

2-((4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)oxy)-N-(methylsulfonyl)acetamide (60) and 2-((4-(4-fluoro-3-methylphenyl)-7-hydroxy isopropylisoquinolin-1-yl)oxy)acetic acid (61)

[0523] ##STR00573##

Compound 60

[0524] Step 1: To a solution of S8 (1.03 g, 2.477 mmol) and benzyl 2-hydroxyacetate (510 μL, 3.594 mmol) in THF (15.45 mL) was added KOtBu (3.6 mL of 1M, 3.600 mmol) in THF. The solution was stirred for 30 minutes and additional benzyl 2-hydroxyacetate (510 μL, 3.594 mmol) was added followed by the addition of KOtBu (3.6 mL of 1M, 3.60 mmol) in THF. The solution was stirred for another 30 minutes and was diluted with aq. NH.sub.4Cl and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using 0-50% EtOAc/heptanes gradient to afford C95 (1.03 g, 76%) LCMS m/z 542.32 [M+H].sup.+

[0525] Step 2: A solution of C95 (200 mg, 0.3638 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (127 mg, 0.7558 mmol) and Na.sub.2CO.sub.3 (570 μL of 2M, 1.140 mmol) in 1,4-dioxane (3 mL) and water (600 μL) was bubbled with N.sub.2 for 5 min. Then, Pd(OAc).sub.2 (5 mg, 0.02227 mmol) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (23 mg, 0.04825 mmol) were added and the solution was microwaved at 130° C. for 30 minutes. HCl (600 μL of 2M) was added to acidify the solution and EtOAc (10 mL) was added. After the extraction of aqueous phase with additional EtOAc (2×3 mL), the combined organic layer was washed with brine (2×2 mL) and dried over MgSO.sub.4, filtered and concentrated. The residue was purified by MPLC: 0-20% MeOH in dichloromethane to give C97 (96 mg, 48%) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.66 (d, J=2.6 Hz, 1H), 7.45-7.37 (m, 2H), 7.33 (ddt, J=8.7, 6.4, 1.1 Hz, 2H), 7.30-7.25 (m, 2H), 7.19 (dd, J=9.2, 2.6 Hz, 2H), 7.03-6.89 (m, 3H), 5.16 (s, 2H), 5.11 (s, 2H), 5.06 (s, 2H), 4.94 (p, J=1.6 Hz, 1H), 4.66 (dt, J=1.9, 0.9 Hz, 1H), 2.23 (d, J=2.0 Hz, 3H), 1.81 (dd, J=1.5, 0.9 Hz, 3H). LCMS m/z 548.36 [M+H].sup.+; and C96 (94 mg, 53%) LCMS m/z 458.29 [M+H].sup.+

[0526] Step 3: To a solution of C96 (95 mg, 0.1956 mmol), methanesulfonamide (22 mg, 0.2313 mmol), DMAP (30 mg, 0.2456 mmol) and TEA (55 μL, 0.3946 mmol) in dry dichloromethane (2 mL) cooled to 0° C. was added EDCI (52 mg, 0.2713 mmol). The reaction mixture was warmed to room temperature and stirred for 15 hours. The reaction mixture was then diluted with water, extracted with EtOAc, dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by MPLC: 12 g column, eluting with 0-50% EtOAc in dichloromethane to give C98 (60 mg, 56%) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J=2.6 Hz, 1H), 7.41 (d, J=7.5 Hz, 2H), 7.28 (ddt, J=33.7, 10.5, 7.7 Hz, 6H), 7.06-6.91 (m, 3H), 6.51 (d, J=8.3 Hz, 1H), 5.14 (s, 2H), 4.99 (d, J=5.1 Hz, 2H), 4.74 (s, 1H), 3.60 (s, 2H), 3.19 (s, 3H), 2.24 (d, J=2.0 Hz, 3H), 1.85 (s, 3H). LCMS m/z 535.3 [M+H].sup.+

[0527] Step 4: To a solution of C98 (60 mg, 0.1098 mmol) in MeOH (2 mL) was added Pd/C (10 mg of 10% w/w, 0.00939 mmol) and a hydrogen balloon (1 atm) was fitted to the reaction vial and the reaction mixture was stirred for 24 hours after which the solution was filtered through a Celite® pad and concentrated to dryness. The residue was purified by silica gel chromatography (12 g ISCO column) using 0-50% MeOH/dichloromethane gradient to afford 60 (14.2 mg, 28%) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.53 (d, J=2.1 Hz, 1H), 7.19 (s, 1H), 7.14-7.00 (m, 3H), 7.01-6.88 (m, 3H), 5.03 (s, 2H), 3.26 (s, 3H), 2.81 (p, J=6.7 Hz, 1H), 2.26 (s, 4H), 1.20 (q, J=6.4, 5.2 Hz, 6H). LCMS m/z 447.26 [M+H].sup.+;

Compound 61

[0528] To a solution of C97 (95 mg, 0.1710 mmol) in MeOH (2 mL) and EtOAc (2 mL) was added the wetted Pd/C (20 mg of 10% w/w, 0.01879 mmol) and a hydrogen balloon (1 atm) was fitted to the reaction vial and the reaction mixture was stirred for 48 hours by which time the reaction was incomplete. The solution was transferred into a Parr shaker and the hydrogen pressure was adjusted to 50 psi and the stirring was continued for 15 hours. The solution was then filtered and washed with MeOH (5 mL), then NaOH (500 μL of 1 M, 0.5000 mmol) was added and the solution was stirred for 1 hour at room temperature and 30 minutes at 50° C. The solution was then neutralized to pH 4, extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over MgSO.sub.4 and then concentrated to give 61 (60.2 mg, 95%) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.51 (s, 1H), 7.11-6.69 (m, 6H), 5.01 (s, 2H), 2.78 (hept, J=6.7 Hz, 1H), 2.24 (d, J=1.9 Hz, 3H), 1.30-1.10 (m, 3H), 0.88-0.74 (m, 3H). LCMS m/z 371.68 [M+H].sup.+;

Compounds 62 and 63

4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinoline-1-carboxylic acid (62) and 4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinoline-1-carboxamide (63)

[0529] ##STR00574##

[0530] To a solution of TMSCN (1.25 g, 12.60 mmol) and S9 (3000 mg, 7.345 mmol) in THF (60 mL) was added DBU (3.3 mL, 22.07 mmol) and the resulting solution was stirred at 50° C. for 15 hours. The solution was cooled to room temperature and then diluted with EtOAc and aqueous bicarbonate solution. The two phases were separated, and the organic phase was concentrated to dryness, triturated with MeOH and the solid was taken in acetonitrile and filtered. The solid was added to KOH/EtOAc (30 mL) and the solution was stirred at 70° C. for 1 hour, cooled down to room temperature, acidified to pH 2 and extracted with dichloromethane (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was taken into a solution of dichloromethane/MeOH/EtOAc (1:1:4, 30 mL) and Pd(OH).sub.2 (1 g, 1.424 mmol) was added. The solution was stirred for 15 hours and then filtered over a Celite® pad. After evaporation, the residue was purified by reverse phase flash chromatography (ISCO, C18 column, 30 g) eluting with CH.sub.3CN/water (0-100%, 0.1% TFA) to afford 62 (684 mg, 27%) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.61 (s, 1H), 7.27 (m, 1H), 7.17 (m, 1H), 7.07 (m, 2H), 6.97 (m, 1H), 2.92-2.73 (m, 1H), 2.32 (s, 3H), 1.12 (m, 6H) and 63 (2 mg, side product) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.16 (s, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.12 (s, 1H), 7.70 (s, 1H), 7.33-7.03 (m, 4H), 2.88 (m, 1H), 2.32 (m, 3H), 1.19 (m, 6H).

Compound 64

(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinoline-1-carbonyl)alanine (64)

[0531] ##STR00575##

[0532] To a solution of 62 (50 mg, 0.1473 mmol), ethyl 2-aminopropanoate (HCl salt) (35 mg, 0.2279 mmol) in DMF (2 mL) was added T3P (95 mg, 0.2986 mmol) and DIPEA (80 μL, 0.4593 mmol) at room temperature. The resulting solution was stirred for 15 hours and KOH (150 μL of 10 M, 1.500 mmol) was added and the solution was stirred further for 15 hours. The solution was then filtered with a syringe filter and submitted for prep-LCMS purification (C18 ACN/Water with HCl modifier) to yield 64 (16.1 mg, 25%). LCMS m/z 411.39 [M+H].sup.+.

Compounds 65-78

[0533] Compounds 65-78 (Table 5) were prepared from intermediates indicated in Table 5. Any modifications to methods are noted in Table 5 and accompanying footnotes.

TABLE-US-00006 TABLE 5 Method of preparation, structure and physicochemical data for compounds 65-78 .sup.1H NMR; LCMS m/z Compound Method/Product Amine [M + H].sup.+ 65 [00576] [00577] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.18 (s, 1H), 8.83 (d, J = 8.1 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.36-7.09 (m, 5H), 4.48 (h, J = 8.3 Hz, 1H), 3.00 (s, 1H), 2.98- 2.80 (m, 2H), 2.38- 2.25 (m, 6H), 1.20 (dd, J = 6.7, 4.8 Hz, 6H). LCMS m/z 437.18 [M + H].sup.+ 66 [00578] [00579] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.17 (s, 1H), 7.34-7.12 (m, 6H), 4.33 (d, J = 2.0 Hz, 1H), 4.08 (s, 1H), 2.88 (d, J = 8.5 Hz, 3H), 2.38- 2.19 (m, 4H), 1.19- 0.98 (m, 6H). LCMS m/z 411.39 [M + H].sup.+ 67 [00580] [00581] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.89 (s, 1H), 10.30 (s, 1H), 8.14 (d, J = 2.5 Hz, 1H), 8.01 (s, 4H), 7.42-7.10 (m, 5H), 3.03-2.87 (m, 2H), 2.40-2.27 (m, 3H), 1.24 (dd, J = 6.7, 4.7 Hz, 6H). LCMS m/z 459.14 [M + H].sup.+ 68 [00582] [00583] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.78 (s, 1H), 8.56 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.41- 7.13 (m, 5H), 2.94 (q, J = 6.7 Hz, 1H), 2.37- 2.31 (m, 3H), 1.25 (dd, J = 6.8, 4.8 Hz, 6H). LCMS m/z 459.14 [M + H].sup.+ 69 [00584] [00585] LCMS m/z 460.18 [M + H].sup.+ 70 [00586] [00587] LCMS m/z 465.24 [M + H].sup.+ 71 [00588] [00589] LCMS m/z 437.25 [M + H].sup.+ 72 [00590] [00591] LCMS m/z 451.20 [M + H].sup.+ 73 [00592] [00593] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.05 (s, 1H), 8.29 (d, J = 2.5 Hz, 1H), 7.33 (d, J = 8.9 Hz, 1H), 7.27-7.18 (m, 2H), 7.14 (dd, J = 8.5, 4.4 Hz, 2H), 2.88 (p, J = 6.8 Hz, 1H), 2.37-2.26 (m, 9H), 1.24-1.16 (m, 6H). LCMS m/z 449.26 [M + H].sup.+ 74 [00594] [00595] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.24 (s, 1H), 9.02 (d, J = 7.9 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H), 7.34 (t, J = 9.0 Hz, 1H), 7.26 (dd, J = 9.2, 2.6 Hz, 2H), 7.18 (d, J = 9.2 Hz, 2H), 4.57 (dt, J = 7.6, 3.7 Hz, 1H), 4.03- 3.81 (m, 2H), 2.94- 2.89 (m, 1H), 2.37- 2.27 (m, 3H), 1.21 (dd, J = 6.7, 4.9 Hz, 6H). LCMS m/z 427.18 [M + H].sup.+ 75 [00596] [00597] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.19 (s, 1H), 8.72 (m, 1H), 8.53 (d, J = 2.6 Hz, 1H), 7.33 (dd, J = 9.9, 8.3 Hz, 1H), 7.24 (dd, J = 9.2, 2.6 Hz, 2H), 7.15 (d, J = 9.2 Hz, 2H), 3.76-3.37 (m, 4H), 2.90 (p, J = 6.4 Hz, 1H), 2.33 (d, J = 1.9 Hz, 3H), 1.20 (m, 6H). LCMS m/z 383.38 [M + H].sup.+ 76 [00598] [00599] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.23 (s, 1H), 9.56 (s, 1H), 8.97 (t, J = 6.1 Hz, 1H), 8.58 (d, J = 2.5 Hz, 1H), 7.40- 7.11 (m, 5H), 3.76 (m, 2H), 3.37 (d, J = 5.7 Hz, 2H), 2.91 (d, J = 4.5 Hz, 7H), 2.33 (d, J = 1.9 Hz, 3H), 1.22 (m, 6H). LCMS m/z 383.38 [M + H].sup.+ 77 [00600] [00601] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.18 (s, 1H), 8.76 (t, J = 5.8 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H), 7.32 (t, J = 9.1 Hz, 1H), 7.25-7.21 (m, 2H), 7.19-7.12 (m, 2H), 3.45 (m, 6H), 2.88 (p, J = 6.7 Hz, 1H), 2.32 (d, J = 1.9 Hz, 3H), 2.22 (t, J = 8.0 Hz, 2H), 1.95 (p, J = 7.4 Hz, 2H), 1.28- 1.16 (m, 6H). LCMS m/z 450.39 [M + H].sup.+ 78 [00602] [00603] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.20 (s, 1H), 8.84 (m, 1H), 8.40 (d, J = 2.5 Hz, 1H), 7.32 (m, 1H), 7.24 (m, 2H), 7.18-7.09 (m, 2H), 3.23 (dd, J = 9.5, 6.4 Hz, 2H), 3.01 (s, 3H), 2.89 (p, J = 6.7 Hz, 1H), 2.33 (d, J = 1.9 Hz, 3H), 2.05 (t, J = 7.8 Hz, 2H), 1.21 (dd, J = 6.8, 4.9 Hz, 6H) LCMS m/z 459.35 [M + H].sup.+ .sup.aHATU was used instead of 3TP for the preparation if this compound.

Compound 79

3-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)propanoic acid (79)

[0534] ##STR00604## ##STR00605##

4-Step procedure: Synthesis of 3-[4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-3-isopropyl-1-isoquinolyl]propanoic acid (79)

[0535] Step 1: (COCl).sub.2 (2 mL of 2 M in dichloromethane, 4.000 mmol) was added to a solution of S9 (800 mg, 1.993 mmol) and DIEA (800 μL, 4.593 mmol) in dichloromethane (9 mL) at −78° C. The reaction was slowly warmed to 0° C. over 2 hours and was quenched by the addition of MeOH (2 mL) and after stirring for 10 minutes, the mixture was concentrated to dryness. MeOH (3 mL) was added and the resulting solid was filtered and washed with cold MeOH and dried under high vacuum to afford C99 (620 mg, 74%) .sup.1H NMR (300 MHz, Chloroform-d) δ 7.71-7.65 (m, 1H), 7.57-7.49 (m, 2H), 7.48-7.32 (m, 3H), 7.30 (d, J=2.4 Hz, 1H), 7.27 (d, J=0.7 Hz, 1H), 7.26-7.00 (m, 3H), 5.25 (s, 2H), 2.95 (p, J=6.8 Hz, 1H), 2.37 (d, J=2.0 Hz, 3H), 1.24 (dd, J=6.7, 3.8 Hz, 6H) ppm. LCMS m/z 419.94 [M+H].sup.+

[0536] Step 2: To a solution of C99 (350 mg, 0.8335 mmol) and Pd(PPh.sub.3).sub.4 (78 mg, 0.06750 mmol) in THF (7 mL) was slowly added bromo-(3-ethoxy-3-oxo-propyl)zinc (7 mL of 0.5M 3.500 mmol) under N.sub.2 atmosphere. The solution was then stirred at 80° C. for 8 hours. The solvent was evaporated, and the residue was dissolved in dichloromethane. The organic phase was washed with NaOH (0.5 M, 6 mL), water, brine and dried over sodium sulfate. After filtration and concentration to dryness, the residue was purified by silica gel chromatography (12 g ISCO column) using 0-50% EtOAc/heptanes gradient to afford C100 (310 mg, 77%) LCMS m/z 485.87 [M+H].sup.+;

[0537] Step 3: A suspension of Pd/C (100 mg of 10% w/w, 0.09397 mmol) and C100 (310 mg, 0.6384 mmol) in MeOH/EtOAc (1:1) (100 mL) was stirred under H.sub.2 (balloon, 1 atm) for 3 hour at room temperature. The suspension was then filtered through a Celite® pad the concentrated to dryness to afford C101 (250 mg, 99%) 1H NMR (300 MHz, Chloroform-d) δ 7.43 (d, J=2.5 Hz, 1H), 7.27-6.90 (m, 5H), 5.49 (s, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.59 (t, J=6.8 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H), 2.92 (p, J=6.7 Hz, 1H), 2.35 (d, J=1.9 Hz, 3H), 1.32 (t, J=7.1 Hz, 3H), 1.19 (dd, J=6.7, 3.8 Hz, 6H) ppm. LCMS m/z 396.24 [M+H].sup.+;

[0538] Step 4: A solution of C101 (240 mg, 0.6069 mmol) and LiOH.H.sub.2O (380 mg, 9.055 mmol) in THF/water (2:1) (15 mL) was stirred for 6 hours. The reaction mixture was then acidified with HCl (10 mL of 1M, 10.00 mmol) and extracted with EtOAc. The organic layer was washed with water, sat. NaCl, dried over sodium sulfate and concentrated to dryness to give 79 (hydrochloride salt) (215 mg, 83%) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.03 (s, 1H), 10.02 (s, 1H), 7.39 (d, J=2.3 Hz, 1H), 7.28 (dd, J=9.9, 8.3 Hz, 1H), 7.22-7.15 (m, 2H), 7.14-7.03 (m, 2H), 3.40 (dd, J=7.3, 5.8 Hz, 2H), 2.84 (dp, J=20.0, 6.7, 6.2 Hz, 3H), 2.30 (d, J=1.9 Hz, 3H), 1.14 (dd, J=6.7, 3.8 Hz, 6H) ppm. LCMS m/z 368.01 [M+H].sup.+.

Compounds 80-86

[0539] Compounds 80-86 (Table 6) were prepared from intermediates indicated in Table 6. Any modifications to methods are noted in Table 6 and accompanying footnotes.

TABLE-US-00007 TABLE 6 Method of preparation, structure and physicochemical data for compounds 80-86 Alkyl halide or .sup.1H NMR; LCMS m/z Compound Method/Product Zn reagent [M + H].sup.+ 80 [00606] [00607] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.38-7.29 (m, 1H), 7.26 (s, 1H), 7.20-6.96 (m, 3H), 3.61 (s, 2H), 3.04 (p, J = 7.0 Hz, 1H), 2.50 (d, J = 7.1 Hz, 2H), 2.36 (d, J = 1.8 Hz, 3H), 2.28 (d, J = 6.6 Hz, 2H), 1.41- 1.29 (m, 6H). LCMS m/z 382.09 [M + H].sup.+ 81 [00608] [00609] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.03 (s, 1H), 7.39 (s, 1H), 7.34-7.05 (m, 5H), 3.51 (d, J = 11.9 Hz, 1H), 3.19 (d, J = 14.9 Hz, 2H), 2.81 (s, 1H), 2.31 (s, 3H), 1.28 (d, J = 6.4 Hz, 3H), 1.15 (d, J = 9.8 Hz, 6H). LCMS m/z 382.41 [M + H].sup.+ 82 [00610] [00611] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.89 (s, 1H), 7.36 (d, J = 9.4 Hz, 1H), 7.27-6.86 (m, 4H), 3.65 (d, J = 58.9 Hz, 2H), 3.06 (p, J = 7.0 Hz, IH), 2.56 (s, 1H), 2.36 (dd, J = 3.6, 1.9 Hz, 3H), 2.13 (d, J = 21.9 Hz, 2H), 1.35 (d, J = 5.6 Hz, 6H), 1.17 (d, J = 6.6 Hz, 3H). LCMS m/z 396.36 [M + H].sup.+ 83 [00612] [00613] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.03 (s, 1H), 10.00 (s, 1H), 7.52-6.95 (m, 6H), 3.64-3.43 (m, 1H), 3.19 (d, J = 15.0 Hz, 2H), 2.94-2.70 (m, IH), 2.30 (s, 3H), 1.41-0.97 (m, 9H). LCMS m/z 381.96 [M + H].sup.+ 84 [00614] [00615] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.82 (s, 1H), 7.38 (dd, J = 9.3, 2.0 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H), 7.08 (t, J = 8.7 Hz, 1H), 6.95 (td, J = 8.6, 3.7 Hz, 2H), 4.66 (s, 1H), 3.44-3.24 (m, 1H), 3.04 (dd, J = 13.9, 6.8 Hz, 3H), 2.59 (s, 2H), 2.26 (d, J = 1.9 Hz, 3H), 1.37-1.28 (m, 6H). LCMS m/z 393.93 [M + H].sup.+ 85 [00616] [00617] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.46 (s, 1H), 7.24-6.95 (m, 5H), 4.72 (s, 1H), 3.40 (s, 1H), 3.03 (s, 5H), 2.46-2.23 (m, 3H), 1.40-1.27 (m, 6H). LCMS m/z 394.33 [M + H].sup.+ 86 [00618] [00619] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.53 (dd, J = 2.3, 0.7 Hz, 1H), 7.27- 6.98 (m, 5H), 3.32-3.16 (m, 2H), 2.96 (p, J = 6.8 Hz, 1H), 2.35 (d, J = 1.9 Hz, 3H), 2.16-1.99 (m, 2H), 1.22 (dd, J = 6.8, 3.2 Hz, 6H). LCMS m/z 410.04 [M + H].sup.+ .sup.aThe cyclopropyl group opened to the ethyl group during the hydrogenation step .sup.bThe Zn reagent was generated in-situ using ZnCu (3 eq. for 1 eq. of alkyl halide) in toluene/DMA at 85° C. in microwave (0.165 M). .sup.cThe cis and trans isomer were separated using SFC after the Negishi coupling step

Compounds 87 and 88

(E)-3-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)but-2-enoic acid (87) and 3-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)butanoic acid (88)

[0540] ##STR00620##

[0541] Step 1: To solution of C102 (100 mg, 0.2381 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (110 mg, 0.3616 mmol), Pd(PPh.sub.3).sub.4 (25 mg, 0.02163 mmol) in DMF (3.5 mL) was added Na.sub.2CO.sub.3 (550 μL of 2M, 1.100 mmol) under an atmosphere of N.sub.2. The reaction mixture was then microwaved at 130° C. for 1 hour. The reaction was then diluted with water and the aqueous phase was extracted with EtOAc. The organic layer was washed with water, brine and dried over sodium sulfate. After concentration to dryness, the residue was purified by silica gel chromatography (40 g ISCO column) using 0-60% EtOAc/heptanes gradient to afford C103 (127 mg, 95%) LCMS m/z 562.41 [M+H].sup.+

[0542] Step 2: A suspension of Pd/C (35 mg of 10% w/w, 0.03289 mmol) and C103 (100 mg, 0.2010 mmol) in MeOH/EtOAc (1:1) (34 mL) was stirred under H.sub.2 (balloon, 1 atm) for 3 hours at room temperature. The suspension was then filtered through a Celite® pad the concentrated to dryness to afford C104. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.46 (d, J=2.5 Hz, 1H), 7.32 (s, 1H), 7.21-7.02 (m, 4H), 6.14 (d, J=1.5 Hz, 1H), 5.57 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 3.00 (h, J=6.6 Hz, 1H), 2.75 (d, J=1.5 Hz, 3H), 2.38 (d, J=1.9 Hz, 3H), 1.36 (t, J=7.1 Hz, 3H), 1.23 (dd, J=6.7, 3.7 Hz, 6H). LCMS m/z 408.55 [M+H].sup.+

[0543] Step 3: A solution of C104 (48 mg, 0.1178 mmol) and LiOH.H.sub.2O (60 mg, 1.430 mmol) in THF/water (2:1) (3 mL) was stirred for 2 hours at room temperature. The reaction mixture was then acidified with HCl (1.5 mL of 1M, 1.5 mmol) and extracted with EtOAc. The organic layer was washed with water, sat. NaCl, dried over sodium sulfate and concentrated to dryness to give a residue which was purified by silica gel chromatography (4 g ISCO column) using 0-25% MeOH/dichloromethane gradient to afford 87 (45 mg, 92%) .sup.1H NMR (300 MHz, Chloroform-d and MeOH-d.sub.4) δ 7.39 (s, 1H), 7.32-7.00 (m, 5H), 6.11 (s, 1H), 3.36 (s, 2H), 3.11-2.91 (m, 1H), 2.68 (s, 3H), 2.36 (s, 3H), 1.22 (d, J=3.1 Hz, 6H). LCMS m/z 380.43 [M+H].sup.+

[0544] Step 4: A suspension of Pd/C (30 mg of 10% w/w, 0.02819 mmol) and 87 (45 mg, 0.1082 mmol) in MeOH/EtOAc (1:1) (16 mL) was stirred under H.sub.2 (balloon, 1 atm) for 3 hours at room temperature. The suspension was then filtered through a Celite® pad the concentrated to dryness to give a residue which was purified by silica gel chromatography (12 g ISCO column) using 0-25% MeOH/dichloromethane gradient to afford 88 (25 mg, 53%) .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.52 (t, J=3.4 Hz, 1H), 7.30 (s, 2H), 7.26-6.90 (m, 3H), 4.16 (dt, J=14.4, 7.4 Hz, 1H), 3.58-3.26 (m, 2H), 2.98 (d, J=16.4 Hz, 1H), 2.37 (s, 3H), 1.58 (d, J=7.2 Hz, 3H), 1.30 (dq, J=6.5, 3.3 Hz, 6H) ppm. LCMS m/z 382.05 [M+H].sup.+

Compound 89

3-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (89)

[0545] ##STR00621##

[0546] Step 1: MgSO.sub.4 (3.123 g, 25.945 mmol) was added to a solution of C15 (8.9 g, 27.179 mmol) and tert-butylamine (10.440 g, 15 mL, 142.75 mmol) in dichloromethane (70 mL). After 4 h, the reaction was monitored by .sup.1H NMR and showed complete conversion. The reaction mixture was filtered over Celite® and washed with dichloromethane. The filtrate was concentrated under reduced pressure to yield C105 (10.38 g, 97%) as an orange solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 1.03-1.46 (m, 15H), 2.83 (dt, J=13.7, 6.7 Hz, 1H), 5.12 (s, 2H), 6.83-7.02 (m, 1H), 7.29-7.54 (m, 6H), 7.65 (d, J=2.6 Hz, 1H), 8.78 (s, 1H).

[0547] Step 2: AgNO.sub.3 (1.063 g, 6.2576 mmol) and LiCO.sub.3 (2.540 g, 34.375 mmol) were added to a solution of C105 (10.387 g, 26.476 mmol) in dry DMA (130 mL). The reaction was stirred 2 minutes at room temperature and NBS (7.617 g, 42.796 mmol) was added. The reaction was stirred for 2 hours at room temperature and was filtered and the solid washed with EtOAc (50 mL). The filtrate was diluted with EtOAc (100 mL) and washed with a 10% aq. solution of Na.sub.2S.sub.2O.sub.3 (100 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with water (4×60 mL), brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (using 0-85% EtOAc/Heptane) to yield C106 (7.71 g, 82%) .sup.1H NMR (300 MHz, Chloroform-d) δ 1.36 (d, J=6.8 Hz, 6H), 3.84 (dquin, J=13.5, 6.7 Hz, 1H), 5.22 (s, 2H), 7.27-7.57 (m, 7H), 8.15 (d, J=9.4 Hz, 1H), 9.04 (s, 1H). LCMS m/z 356.1 [M+H].sup.+

[0548] Step 3: A solution of C106 (7.711 g, 21.645 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (4.60 g, 29.913 mmol) and Na.sub.2CO.sub.3 (21 mL of 2 M in water, 42.000 mmol) in DMSO (77 mL) was heated to 100° C. and sparged with N.sub.2 for 15 min. PdCl.sub.2(dppf)⋅dichloromethane (1.22 g, 1.4939 mmol) was added and the reaction was sparged for 2 min. The reaction was stirred at 100° C. for 4 hours and cooled to room temperature. An aqueous solution of pH 7 0.1M potassium phosphate buffer (150 mL) was added and the resulting precipitate was filtered and washed with water (2×200 mL). The solid was dissolved in dichloromethane (200 mL), dried over Na.sub.2SO.sub.4, filtered over Celite®, washed with dichloromethane and concentrated under reduced pressure. The crude product was purified by chromatography on a silica plug eluted with Heptane (100%) then Heptane/EtOAc (5:1) to yield C107 (7.71 g, 91%). .sup.1H NMR (300 MHz, Chloroform-d) δ 1.25 (m, 6H), 2.36 (s, 3H), 2.92-3.11 (m, 1H), 5.21 (s, 2H), 7.00-7.54 (m, 11H), 9.18 (s, 1H). .sup.19F NMR (282 MHz, Chloroform-d) δ −119.3 (s, 1F). LCMS m/z 386.2 [M+H].sup.+

[0549] Step 4: A clear vial was charged with C107 (50 mg, 0.1282 mmol), O3-(1,3-dioxoisoindolin-2-yl) O1-methyl bicyclo[1.1.1]pentane-1,3-dicarboxylate (66 mg, 0.1916 mmol), (Ir[dF(CF.sub.3)ppy].sub.2(dtbpy))PF.sub.6 (3 mg, 0.00267 mmol) and the vial was purged 3 times with N.sub.2. Then, DMA (1.5 mL) and TFA (20 μL, 0.259 mmol) and the mixture was stirred under argon and irradiated with two blue LED Kessil lamps. After 2 hours, the reaction was quenched with DIPEA (0.1 mL), diluted with water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc, dried with sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-25% EtOAc:Heptane gradient) to yield C108 (26 mg, 39%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.51 (dd, J=2.3, 0.8 Hz, 1H), 7.43-7.37 (m, 2H), 7.37-7.31 (m, 2H), 7.31-7.24 (m, 1H), 7.18 (d, J=0.8 Hz, 1H), 7.17-7.14 (m, 1H), 7.04 (dd, J=9.6, 8.2 Hz, 1H), 7.00-6.91 (m, 2H), 5.15 (s, 2H), 3.70 (s, 3H), 2.83 (h, J=6.7 Hz, 1H), 2.50 (d, J=8.5 Hz, 6H), 2.26 (d, J=1.9 Hz, 3H), 1.11 (dd, J=6.7, 5.1 Hz, 6H). LCMS m/z 510.26 [M+H].sup.+

[0550] Steps 5 and 6 were conducted in the same fashion as Steps 3 and 4 for compounds 87 and 88 to yield 89 (9 mg, 43%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.66 (d, J=2.3 Hz, 1H), 7.20-7.13 (m, 2H), 7.13-7.07 (m, 2H), 7.04 (ddd, J=7.8, 5.0, 2.2 Hz, 1H), 2.90 (p, J=6.7 Hz, 1H), 2.65 (s, 6H), 2.34 (d, J=2.0 Hz, 3H), 1.19 (dd, J=6.7, 3.5 Hz, 6H). LCMS m/z 406.35 [M+H].sup.+

Compound 90

4-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)benzoic acid (90)

[0551] ##STR00622##

[0552] Step 1: A solution of C102 (100 mg, 0.2381 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (110 mg, 0.3616 mmol) and Pd(PPh.sub.3).sub.4 (25 mg, 0.0216 mmol) and Na.sub.2CO.sub.3 (550 μL of 2 M, 1.100 mmol) in DMF (3.5 mL) was microwaved at 130° C. for 1 hour. The reaction was then diluted with water and the aqueous phase was extracted with EtOAc. The organic layer was washed with water, brine and dried over sodium sulfate. After concentration to dryness, the residue was purified by silica gel chromatography (12 g ISCO column) using 0-50% EtOAc/heptanes gradient to afford C109 (127 mg, 95%) LCMS m/z 562.41 [M+H].sup.+.

[0553] Step 2: The hydrogenation reaction (H.sub.2, Pd/C) was carried in the same fashion as for compound 89.

[0554] Step 3: To the product formed in Step 2 (105 mg, 0.2227 mmol) was added HCl (5 mL of 4M, 20.0 mmol) in dioxane. The reaction mixture was microwaved at 100° C. for 30 minutes. Concentration to dryness afforded 90 (hydrochloride salt) (95 mg, 85%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 10.13 (d, J=1.8 Hz, 1H), 8.36-6.86 (m, 10H), 2.94 (d, J=8.6 Hz, 1H), 2.34 (s, 3H), 1.21 (q, J=6.6, 4.5 Hz, 6H) ppm. LCMS m/z 416.38 [M+H].sup.+

Compound 91

(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-(tetrahydro-2H-pyran-4-yl)isoquinoline-1-carbonyl)serine (91)

[0555] ##STR00623##

[0556] Step 1: A solution of S11 (7.66 g, 18.489 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (4.26 g, 27.672 mmol) and Na.sub.2CO.sub.3 (19 mL of 2 M in water, 38.000 mmol) in DMSO (80 mL) was heated to 100° C. and sparged with N.sub.2 for 15 minutes. PdCl.sub.2(dppf)⋅dichloromethane (789 mg, 0.9662 mmol) was added and the reaction was sparged with N.sub.2 for 2 minutes. The reaction was stirred at 100° C. for 4 hours, cooled to room temperature, diluted with EtOAc (300 mL), washed with a pH 7 0.1 M potassium phosphate buffer (2×150 mL). A solid precipitated and was filtered off, dissolved in dichloromethane, filtered over Celite®, washed with dichloromethane and concentrated under reduced pressure to yield C110 (2.3 g, 28%) as a tan solid. The organic layer was further washed with water (3×100 mL), brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ISCO 220 g 0-5% MeOH/dichloromethane). The fractions containing the product were combined and recrystallized in ACN (about 250 mL), filtered and dried under reduced pressure to yield C110 (3.7 g, 45%) as tan crystals. Both batches were combined to yield C110 (6.0 g, 71%). .sup.1H NMR (300 MHz, Chloroform-d) δ 1.41 (d, J=11.7 Hz, 2H), 2.38 (d, J=1.5 Hz, 3H), 2.51-2.96 (m, 2H), 3.28 (t, J=11.3 Hz, 3H), 3.97 (dd, J=11.0, 3.4 Hz, 2H), 5.18 (s, 2H), 6.93-7.22 (m, 6H), 7.31-7.52 (m, 5H), 8.73 (s, 1H). .sup.19F NMR (282 MHz, Chloroform-d) δ −117.1 (s, 1F). LCMS m/z 444.2 [M+H].sup.+.

[0557] Steps 2 and 3: To a solution of C110 in ACN/THF (4:1) (125 mL) (100 mL) was added TMSCN (2.4 mL, 18.00 mmol) and TEA (2.2 mL, 15.78 mmol) under an atmosphere of N.sub.2. The solution was then heated to 40° C. for 3 days before concentration to dryness. The residue was purified by silica gel chromatography (220 g ISCO column) using 0-60% EtOAc/heptanes gradient to afford the cyano derivative (2.38 g, 95%) which was dissolved in EtOH and Pd(OH).sub.2 (778.0 mg, 1.108 mmol) was added and the solution was stirred under H.sub.2 (balloon, 1 atm) for 30 hours at room temperature. The suspension was then filtered through a Celite® pad the concentrated to dryness to give a residue which was diluted with dichloromethane/1N NaOH (1:1) (50 mL). The aqueous layer was acidified with 2 M HCl and was extracted with EtOAc and dried over sodium sulfate. Concentration to dryness afforded C111 (742 mg, 35%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.76 (s, 1H), 7.35-7.06 (m, 5H), 3.87 (m, 2H), 3.17 (s, 2H), 2.32 (m, 3H), 2.18-1.96 (m, 2H), 1.45 (d, J=12.9 Hz, 2H).

[0558] Step 4: To a solution of C111 (50 mg, 0.131 mmol), methyl 2-amino-3-hydroxy-propanoate (HCl salt) (33 mg, 0.196 mmol) in DMF (2 mL) was added T3P (83 mg, 0.262 mmol) and DIPEA (68 μL, 0.393 mmol) at room temperature. The resulting solution was stirred for 15 hours and KOH (150 μL of 10M, 1.500 mmol) was added and the solution was stirred further for 15 hours. The solution was then filtered with a syringe filter and submitted for prep-LCMS purification (C18 ACN/Water with HCl modifier) to yield 91 (12.8 mg, 17.8%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.29 (s, 1H), 8.95 (d, J=7.9 Hz, 1H), 8.74 (d, J=2.5 Hz, 1H), 7.34 (m, 1H), 7.27 (dd, J=9.1, 2.6 Hz, 2H), 7.18 (dd, J=9.3, 4.6 Hz, 2H), 4.56 (dd, J=7.9, 3.9 Hz, 1H), 4.03-3.79 (m, 4H), 3.21 (m, 2H), 2.87-2.69 (m, 1H), 2.33 (d, J=2.1 Hz, 3H), 2.07 (d, J=12.2 Hz, 3H), 1.54 (d, J=13.1 Hz, 2H). LCMS m/z 469.25 [M+H].sup.+;

Compounds 92-96

[0559] Compounds 92-96 (Table 7) were prepared from intermediates indicated in Table 7. When the amine coupling partner isn't an ester, the last step (KOH hydrolysis) isn't conducted. Any modifications to methods are noted in Table 7 and accompanying footnotes.

TABLE-US-00008 TABLE 7 Method of preparation, structure and physicochemical data for compounds 92-96 .sup.1H NMR; LCMS m/z Compound Method/Product Amine [M + H].sup.+ 92 [00624] [00625] LCMS m/z 479.19 [M + H].sup.+ 93 [00626] [00627] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.25 (s, 1H), 9.17 (s, 1H), 8.29 (d, J = 2.5 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 7.24 (dd, J = 9.3, 2.7 Hz, 2H), 7.15 (dd, J = 8.4, 4.8 Hz, 2H), 3.89 (d, J = 11.0 Hz, 2H), 3.19 (t, J = 12.0 Hz, 2H), 2.75 (t, J = 11.5 Hz, 1H), 2.41 (s, 6H), 2.33 (d, J = 1.9 Hz, 3H), 2.15 (dd, J = 15.8, 7.8 Hz, 2H), 1.45 (d, J = 12.8 Hz, 2H). LCMS m/z 491.25 [M + H].sup.+ 94 [00628] [00629] LCMS m/z 479.19 [M + H].sup.+ 95 [00630] [00631] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.22 (s, 1H), 8.87 (m, 1H), 8.42 (dd, J = 7.1, 2.5 Hz, 1H), 7.33 (m, 1H), 7.28-7.23 (m, 2H), 7.15 (d, J = 9.1 Hz, 2H), 3.97-3.82 (m, 2H), 3.60-3.49 (m, 2H), 3.22 (dt, J = 16.6, 9.8 Hz, 4H), 3.01 (d, J = 6.2 Hz, 3H), 2.75 (t, J = 12.3 Hz, 1H), 2.33 (d, J = 1.9 Hz, 3H), 2.11 (ddt, J = 50.0, 14.9, 7.3 Hz, 4H), 1.47 (d, J = 13.0 Hz, 2H). LCMS m/z 501.15 [M + H].sup.+ 96 [00632] [00633] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.22 (s, 1H), 8.72 (t, J = 5.9 Hz, 1H), 8.52 (d, J = 2.5 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 7.25 (dd, J = 9.3, 2.7 Hz, 2H), 7.16 (d, J = 9.2 Hz, 2H), 3.88 (dd, J = 11.4, 4.1 Hz, 2H), 3.61 (t, J = 6.1 Hz, 2H), 3.51- 3.47 (m, 2H), 3.20 (t, J = 11.9 Hz, 2H), 2.75 (td, J = 11.6, 11.1, 5.9 Hz, 1H), 2.33 (s, 3H), 2.11 (tt, J = 13.4, 8.7 Hz, 2H), 1.48 (d, J = 13.0 Hz, 2H). LCMS m/z 425.19 [M + H].sup.+ .sup.aThe hydrolysis step (KOH) was not conducted

Compound 97

4-((4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-1-yloxy)benzoic acid (97)

[0560] ##STR00634##

[0561] Step 1: To a solution of S12 (trifluoroacetate salt) (600 mg, 0.919 mmol) and methyl 4-hydroxybenzoate (416 mg, 2.734 mmol) in DMF (3.33 mL) was added K.sub.2CO.sub.3 (380 mg, 2.750 mmol) and the reaction was stirred at room temperature for 16 hours. After this time, LCMS showed complete consumption of starting material and the reaction mixture was directly carried forward to the next step.

[0562] Step 2: To the DMF reaction mixture was added MeOH (3.33 mL) and the resulting suspension was filtered through a Celite® pad to remove the excess K.sub.2CO.sub.3. To this solution was added Pd(OH).sub.2 (45 mg of 60% w/w, 0.1923 mmol). A H.sub.2 balloon (1 atm) was fitted to the reaction vessel and the reaction was stirred for 4 hours. The reaction mixture was filtered through a 0.2 micron filter, and then concentrated in vacuo to remove MeOH and the crude DMF reaction mixture was taken directly to the next step.

[0563] Step 3: To the DMF reaction mixture from the previous step was added KOH (920 μL of 10 M, 9.20 mmol) at room temperature and the reaction was stirred for 3 hours and diluted with water (3 mL) and flash frozen in a dry ice/acetone bath. The frozen solution was concentrated via lyophilization and the crude residue was purified by ISCO reverse phase flash chromatography (50 g C18, 5-95% MeCN in H.sub.2O with 0.1% formic acid modifier) to provide 97 (132.5 mg, 30%). .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.18-8.06 (m, 2H), 7.60 (dd, J=2.1, 1.0 Hz, 1H), 7.43-7.30 (m, 2H), 7.23-7.11 (m, 4H), 7.08 (ddd, J=7.9, 5.1, 2.2 Hz, 1H), 3.84 (dd, J=11.4, 4.0 Hz, 2H), 3.29-3.16 (m, 2H), 2.72 (tt, J=11.6, 3.8 Hz, 1H), 2.34 (d, J=1.9 Hz, 3H), 1.99-1.75 (m, 2H), 1.52-1.35 (m, 2H). LCMS m/z 474.25 [M+H].sup.+

Compounds 99-101

[0564] Compounds 98-101 (Table 8) were prepared from intermediates indicated in Table 8. Any modifications to methods are noted in Table 8 and accompanying footnotes.

TABLE-US-00009 TABLE 8 Method of preparation, structure and physicochemical data for compounds 98-101 .sup.1H NMR; LCMS m/z Compound Method/Product Alcohol [M + H].sup.+ 98 [00635] [00636] LCMS m/z 504.14 [M + H].sup.+ 99 [00637] [00638] LCMS m/z 474.15 [M + H].sup.+ 100 [00639] [00640] LCMS m/z 475.15 [M + H].sup.+ 101 [00641] [00642] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.53 (s, 1H), 7.30 (s, 1H), 7.17-6.94 (m, 4H), 5.62 (p, J = 6.8 Hz, 1H), 3.98 (d, J = 11.3 Hz, 2H), 3.40-3.19 (m, 3H), 2.93 (ddt, J = 11.8, 7.5, 4.0 Hz, 2H), 2.76-2.68 (m, 2H), 2.58 (ddt, J = 12.6, 9.4, 5.7 Hz, 2H), 2.34 (s, 3H), 2.16 (dd, J = 18.1, 8.2 Hz, 2H), 1.45 (d, J = 13.2 Hz, 2H). LCMS m/z 452.52 [M + H].sup.+ .sup.aFor step 1, NaH (21 equiv.) in DMSO (0.06 M) was used instead of K.sub.2CO.sub.3 in DMF. .sup.bHydrolysis step not conducted.

Compound 102

4-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-1-yl)butanoic acid (102)

[0565] ##STR00643##

Compounds 102-105

[0566] Compounds 102-105 (Table 9) were prepared from intermediates indicated in Table 9. Any modifications to methods are noted in Table 9 and accompanying footnotes.

TABLE-US-00010 TABLE 9 Method of preparation, structure, physicochemical data for compounds 102-105 Compound Product Zn reagent .sup.1H NMR; LCMS m/z [M + H].sup.+ 102 [00644] [00645] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.28-6.79 (m, 6H), 4.01 (d, J = 11.0 Hz, 2H), 3.61 (s, 2H), 3.32 (t, J = 11.7 Hz, 2H), 2.92 (s, 1H), 2.62 (s, 2H), 2.39-2.24 (m, 7H), 1.55 (d, J = 12.7 Hz, 2H). LCMS m/z 424.48 [M + H].sup.+ 103 [00646] [00647] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.07 (s, 1H), 10.04 (s, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.28 (dd, J = 9.9, 8.3 Hz, 1H), 7.24- 7.03 (m, 4H), 3.85 (d, J = 11.3 Hz, 2H), 3.53 (dd, J = 15.8, 6.6 Hz, 1H), 3.29-3.06 (m, 4H), 2.75-2.61 (m, 1H), 2.31 (d, J = 1.8 Hz, 3H), 2.09 (td, J = 12.3, 7.6 Hz, 2H), 1.40 (t, J = 12.0 Hz, 2H), 1.28 (d, J = 6.8 Hz, 3H). LCMS m/z 424.39 [M + H].sup.+ 104 [00648] [00649] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.08 (s, 1H), 10.04 (s, 1H), 7.40 (s, 1H), 7.35-7.03 (m, 5H), 3.85 (d, J = 10.9 Hz, 2H), 3.53 (d, J = 15.1 Hz, 1H), 3.19 (d, J = 13.4 Hz, 5H), 2.69 (d, J = 16.1 Hz, 1H), 2.31 (s, 3H), 2.09 (s, 2H), 1.51-1.17 (m, 5H). LCMS m/z 424.39 [M + H].sup.+ 105 [00650] .sup.aN/A 1H NMR (400 MHz, Methanol- d.sub.4) δ 7.74 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 9.2, 2.4 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.33- 7.27 (m, 2H), 7.22 (ddd, J = 7.9, 4.9, 2.2 Hz, 1H), 4.02 (dd, J = 11.6, 4.4 Hz, 2H), 3.91 (t, J = 7.1 Hz, 2H), 3.31 (tt, J = 4.1, 2.5 Hz, 3H), 3.09 (tt, J = 13.4, 4.2 Hz, 1H), 3.01 (t, J = 7.1 Hz, 2H), 2.38 (d, J = 2.0 Hz, 3H), 2.20 (dtd, J = 23.6, 11.9, 11.1, 6.8 Hz, 2H), 1.72 (dd, J = 13.8, 3.6 Hz, 2H). LCMS m/z 410.35 [M + H].sup.+ .sup.aCompound 105 was prepared from S8 using two successive Suzuki reactions (with ethyl (E)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate and 2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, respectively) followed by hydrogenation (H.sub.2, Pd/C).

Compound 106

4-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-1-yl)benzoic acid (106)

[0567] ##STR00651##

[0568] Compound 106 was prepared using the same procedure as for compound 90. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 10.10 (s, 1H), 8.28-8.06 (m, 2H), 7.90-7.76 (m, 2H), 7.42-7.12 (m, 6H), 3.86 (dd, J=11.3, 4.2 Hz, 2H), 3.75-3.63 (m, 1H), 3.55-3.42 (m, 1H), 2.81 (t, J=11.6 Hz, 1H), 2.34 (d, J=1.8 Hz, 3H), 2.07 (dt, J=12.4, 5.7 Hz, 2H), 1.52 (d, J=13.0 Hz, 2H). LCMS m/z 458.32 [M+H].sup.+

Compound 107

4-(4-fluoro-3-methylphenyl)-7-hydroxy-2-(3-hydroxypropyl)-3-isopropylisoquinolin-1(2H)-one (107)

[0569] ##STR00652##

[0570] Step 1: In a sealed tube, a suspension of C1 (3.05 g, 9.4966 mmol) in TEA (22 mL) was bubbled through with N.sub.2 for 10 minutes. Then, PdCl.sub.2(PPh.sub.3).sub.2 (657 mg, 0.9334 mmol) and CuI (56 mg, 0.2940 mmol) were added and bubbled through with N.sub.2 for another 2 min. 3-methylbut-1-yne (1.3986 g, 2.1 mL, 20.532 mmol) was added and the tube was sealed, stirred and heated at 70° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL). The organic layer was washed with 3MHCl (2×60 mL), water (60 mL), brine, dried over anhydrous sodium sulfate, filtered, loaded on silica gel and concentrated under reduced pressure. The residue was purified on silica gel chromatography, eluting from 0% to 20% ethyl acetate in heptanes to give C116 (2.7 g, 92%). .sup.1H NMR (300 MHz, Chloroform-d) δ 1.29 (d, J=6.8 Hz, 6H), 2.83 (spt, J=6.9 Hz, 1H), 3.93 (s, 3H), 5.09 (s, 2H), 7.04 (dd, J=8.7, 2.8 Hz, 1H), 7.31-7.47 (m, 6H), 7.50 (d, J=2.6 Hz, 1H). LCMS m/z 309.2 [M+H].sup.+

[0571] Step 2: To a solution of C116 (2 g, 6.4792 mmol) in anhydrous dichloromethane (40 mL) was added, at room temperature, a solution of 12 (1.88 g, 7.4071 mmol) in anhydrous dichloromethane (50 mL) over 30 minutes. The reaction mixture was stirred at room temperature for an additional 20 min then EtOAc (300 mL) was added. The organic phase was washed with a mixture of 5% aqueous NaHCO.sub.3 and brine (3×100 mL, 90/10 ratio) and brine (2×50 mL), dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with 20-70% dichloromethane in heptanes to afford C117 (2.32 g, 85%) as white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.20 (d, J=6.8 Hz, 6H), 3.49 (sept, J=6.8 Hz, 1H), 5.27 (s, 2H), 7.30-7.44 (m, 3H), 7.45-7.51 (m, 2H), 7.59 (dd, J=8.8, 2.8Hz, 1H), 7.64 (d, J=2.8Hz, 1H), 7.70 (d, J=8.8Hz, 1H). LCMS m/z 421.0 [M+H].sup.+

[0572] Step 3: In a sealed tube were added water (3.75 mL) and potassium phosphate (2.69 g, 12.673 mmol). The mixture was stirred for 10 minutes at room temperature then toluene (48 mL) was added. Nitrogen was bubbled through the mixture for 15 minutes and C117 (2.6 g, 6.1869 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (1.23 g, 7.9898 mmol) and XPhos Pd G2 (364.3 mg, 0.4630 mmol) were added. The tube was sealed then transferred to a pre-heated oil bath set to 70° C. and stirred at this temperature for 2 hours. The reaction mixture was cooled to room temperature, then diluted with EtOAc (350 mL). The organic phase was washed with 5% aqueous NaHCO.sub.3 (3×75 mL) and brine (2×75 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 30-90% dichloromethane in heptanes to afford C118 (2.33 g, 93%) as white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.12 (d, J=6.6 Hz, 6H), 2.29 (s, 3H), 2.54-2.67 (m, 1H), 5.25 (s, 2H), 6.84 (d, J=8.8 Hz, 1H), 7.13-7.21 (m, 1H), 7.23-7.51 (m, 8H), 7.70 (d, J=2.7Hz, 1H); .sup.19F NMR (282 MHz, DMSO-d.sub.6) δ −118.4-118.2 (m, 1F).

[0573] Step 4: A solution of C118 (500 mg, 1.241 mmol) and 3-aminopropan-1-ol (2000 μL, 26.18 mmol). was and heated to 180° C. for 90 minutes under microwave irradiation. The mixture was diluted with dichloromethane (60 mL) and water (30 mL) and then 1 MHCl was added (˜26 mL) to bring the pH to ˜1. At this time, the organic layer was removed and filtered over a phase separator and concentrated. The mixture was dissolved in dichloromethane (10 mL) and MsOH (20 μL, 0.3082 mmol) was added and the mixture was stirred at room temperature for 3.5 hours. The mixture was concentrated and then redissolved in minimal dichloromethane for purification by silica gel chromatography eluting with 0-5% MeOH in dichloromethane to yield 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-2-(3-hydroxypropyl)-3-isopropyl-isoquinolin-1-one (425 mg, 73%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J=2.8 Hz, 1H), 7.55-7.30 (m, 5H), 7.22-6.95 (m, 4H), 6.81 (s, 1H), 5.21 (s, 2H), 4.46 (s, 2H), 3.68 (s, 2H), 3.33 (p, J=7.3 Hz, 1H), 2.40-2.27 (m, 3H), 2.05 (d, J=21.2 Hz, 2H), 1.41-1.27 (m, 3H), 1.07 (s, 3H). LCMS m/z 460.35 [M+H].sup.+

[0574] Step 5: To a flask was added 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-2-(3-hydroxypropyl)-3-isopropyl-isoquinolin-1-one (250 mg, 0.5440 mmol), Pd/C (100 mg, 0.01879 mmol) and EtOAc (15 mL). The suspension was purged with N.sub.2 three times and then with H.sub.2 five times and then stirred under H.sub.2 (60 psi) for 2 hours, filtered through a pad of Celite® and concentrated to dryness to afford 107 (200 mg, 95%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.89 (s, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.25 (dd, J=9.8, 8.3 Hz, 1H), 7.18 (dd, J=7.7, 2.1 Hz, 1H), 7.10 (dt, J=8.4, 3.9 Hz, 1H), 7.03 (dd, J=8.8, 2.7 Hz, 1H), 6.61 (d, J=8.9 Hz, 1H), 4.68 (t, J=5.1 Hz, 1H), 4.16 (s, 2H), 3.60-3.49 (m, 2H), 3.17 (d, J=5.3 Hz, 1H), 2.29 (d, J=1.8 Hz, 3H), 1.83 (d, J=8.4 Hz, 2H), 1.23 (s, 6H). LCMS m/z 370.3 [M+H].sup.+

Compounds 108-111

[0575] Compounds 108-111 (Table 10) were prepared from intermediates indicated in Table 10. Any modifications to methods are noted in Table 10 and accompanying footnotes.

TABLE-US-00011 TABLE 10 Method of preparation, structure and physicochemical data for compounds 108-111 .sup.1H NMR; LCMS m/z Compound Method/Product amine [M + H].sup.+ 108 [00653] [00654] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.89 (s, 1H), 7.58 (d, J = 2.6 Hz, 1H), 7.24 (ddd, J = 10.0, 8.3, 2.4 Hz, 1H), 7.16 (dd, J = 7.8, 2.1 Hz, 1H), 7.08 (td, J = 6.3, 5.8, 3.0 Hz, 1H), 7.04 (dt, J = 8.9, 2.2 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 4.84 (d, J = 83.6 Hz, 2H), 4.35 (s, 1H), 4.11-3.86 (m, 2H), 3.44 (d, J = 1.8 Hz, 2H), 2.29 (t, J = 2.3 Hz, 3H), 1.17 (t, J = 7.1 Hz, 6H). LCMS m/z 386.37 [M + H].sup.+ 109 [00655] [00656] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.66-7.63 (m, 1H), 7.20-6.97 (m, 5H), 6.73 (d, J = 8.8 Hz, 1H), 4.38 (t, J = 6.8 Hz, 2H), 3.88 (t, J = 6.8 Hz, 2H), 3.33-3.32 (m, 0H), 2.33 (d, J = 2.0 Hz, 3H), 1.37-1.15 (m, 6H). LCMS m/z 356.35 [M + H].sup.+ 110 [00657] [00658] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.64 (s, 1H), 10.01 (s, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.28-7.16 (m, 2H), 7.14-7.01 (m, 2H), 6.58 (d, J = 9.0 Hz, 1H), 5.77 (s, 1H), 4.78 (s, 2H), 3.17 (s, 1H), 2.29 (d, J = 1.8 Hz, 3H), 1.11-0.93 (m, 6H). LCMS m/z 410.31 [M + H].sup.+ 111 [00659] [00660] LCMS m/z 408.9 [M + H].sup.+ .sup.ahydrolysis reacton (LiOH 10 equiv. in MeOH at 80 °C.) was performed after the hydrogenation step.

Compounds 112 and 113

3-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropyl-1-oxoisoquinolin-2(1H)-yl)propanoic acid (112) and 3-(4-(4-fluoro-3-methylphenyl)-3-isopropyl-1-oxoisoquinolin-2(1H)-yl)propanamide (113)

[0576] ##STR00661##

[0577] Step 1: To a suspension of C119 (coming from Step 4 of the synthesis of 107) (20 mg, 0.04352 mmol) and NaHCO.sub.3 (9 mg, 0.1071 mmol) in dichloromethane (0.5 mL) was added Dess-Martin periodinane (19 mg, 0.04480 mmol) and the reaction mixture was stirred at room temperature for 1 hour and additional Dess-Martin periodinane (19 mg, 0.04480 mmol) was added and the reaction was stirred for 1 hour. The reaction was quenched with a 1:1 mixture (5 mL) of sat. aq. sodium bicarbonate and sodium thiosulfate for 30 minutes. The product was extracted with dichloromethane and the organic phase was washed with brine, dried with sodium sulfate, filtered, and concentrated to give the aldehyde which was used in the next step with further purification.

[0578] Step 2: To a flask was added NaClO.sub.2 (20 mg, 0.2211 mmol), NaH.sub.2PO.sub.4 (55 mg, 0.4546 mmol), and water (2 mL), the mixture was stirred until the solids dissolved. In another flask, the crude aldehyde from the first step was dissolved in THF (1.3 mL) and t-BuOH (2 mL). 2-methylbut-2-ene (450 μL of 2M, 0.900 mmol) as a solution in THF was added and the resulting biphasic mixture was stirred for 1 hour. The mixture was diluted with EtOAc and water, the pH was adjusted with 1 MHCl to pH 2. The organic layer (containing C120) was concentrated and used in the next step without further purification.

[0579] Step 3: To a flask was added the solid from the previous step, Pd/C (10 mg, 0.001879 mmol), and EtOAc (2 mL). The suspension was purged with N.sub.2 three times and then with H.sub.2 five times and then stirred under H.sub.2 (60 psi) for 78 h (10:40). The material was filtered over a syringe filter and concentrated to yield 112 (5 mg, 20%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.64 (d, J=2.7 Hz, 1H), 7.19-7.00 (m, 5H), 6.75 (d, J=8.9 Hz, 1H), 4.54-4.40 (m, 2H), 2.84 (t, J=7.9 Hz, 2H), 2.33 (d, J=1.9 Hz, 3H), 2.27-2.15 (m, 1H), 1.29 (s, 6H). LCMS m/z 384.34 [M+H].sup.+

[0580] Step 4: The crude residue of a 100 mg scale reaction of step 3 (described above) was added DMF (4 mL), NH.sub.3 (2 mL of 0.5M, 1.000 mmol) in dioxane, DIPEA (100 μL, 0.5741 mmol) and HATU (100 mg, 0.2630 mmol) and the reaction mixture was stirred for 5 minutes. The mixture was diluted with water (50 mL) and EtOAc (50 mL), separated, and the organic mixture was washed with brine (2×50 mL). The organic layer was dried with magnesium sulfate, filtered, and concentrated. The crude solid was suspended in ˜2 mL dichloromethane and filtered to give 113 (35 mg, 42%) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.93 (s, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.47 (s, 1H), 7.26 (dd, J=9.8, 8.3 Hz, 1H), 7.21-7.14 (m, 1H), 7.09 (ddd, J=7.8, 4.9, 2.3 Hz, 1H), 7.04 (dd, J=8.8, 2.7 Hz, 1H), 6.97 (s, 1H), 6.62 (d, J=8.8 Hz, 1H), 4.27 (t, J=8.0 Hz, 2H), 3.25-3.11 (m, 1H), 2.56 (s, 2H), 2.29 (d, J=1.8 Hz, 3H), 1.21 (s, 6H). LCMS m/z 383.4 [M+H].sup.+

Compound 114

2-((4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-1-yl)oxy)acetic acid (114)

[0581] ##STR00662##

[0582] Compound 114 was prepared from S8 using the same reaction sequence as for compound 61 with the exception that 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used as the coupling partner in the Suzuki coupling step. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.47 (d, J=2.4 Hz, 1H), 7.09-7.03 (m, 1H), 7.03-6.97 (m, 3H), 6.96-6.90 (m, 1H), 4.93 (s, 2H), 3.88-3.78 (m, 2H), 3.17 (d, J=11.8 Hz, 3H), 2.71-2.53 (m, 1H), 2.22 (d, J=1.9 Hz, 2H), 2.14-1.96 (m, 2H), 1.40-1.31 (m, 2H). LCMS m/z 412.38 [M+H].sup.+

Compound 115

(1r,3r)-3-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-1-oxo-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-2(1H)-yl)cyclobutane-1-carboxylic acid (115)

[0583] ##STR00663##

[0584] Step 1: To a solution of C1 (5 g, 15.57 mmol) in DMF (31 mL) and TEA (15.8 g, 156.1 mmol) was added CuI (178 mg, 0.9346 mmol), TBAF (6.4 g, 20.28 mmol) and TMS-alkyne (3.7 g, 20.29 mmol). The solution was purged with N.sub.2 for 5 minutes and PdCl.sub.2(PPh.sub.3).sub.4 (328 mg, 0.4673 mmol) and the solution was purged for another 5 minutes and then heated at 80° C. for 15 hours. The solution was cooled down to room temperature and the TEA was removed in vacuo. Water (500 mL) was added followed by EtOAc (450 mL). The organic phase was washed with brine and concentrated. The residue was purified by silica gel chromatography (120 g ISCO column) using 0-40% EtOAc/heptanes gradient to afford C121 (2.0 g, 37%). .sup.1H NMR (300 MHz, Chloroform-d) δ 7.46-7.23 (m, 8H), 6.97 (dd, J=8.6, 2.8 Hz, 1H), 5.02 (s, 2H), 3.91 (ddd, J=11.5, 5.9, 3.6 Hz, 2H), 3.84 (s, 3H), 3.50 (ddd, J=11.4, 8.2, 3.1 Hz, 2H), 2.83 (tt, J=8.3, 4.1 Hz, 1H), 1.92-1.80 (m, 2H), 1.70 (dtd, J=13.5, 8.3, 3.6 Hz, 2H).

[0585] Step 2: To a solution of C121 (500 mg, 1.427 mmol) in THF (1.8 mL), methanol (600 μL) and H.sub.2O (600 μL) was added LiOH (205 mg, 8.560 mmol) at room temperature and the solution was stirred for 15 hours. The reaction was acidified with 1 MHCl and extracted with EtOAc (10 mL). The organic solution was concentrated and the product was triturated with heptane to give the corresponding acid (400 mg, 83%). .sup.1H NMR (300 MHz, Acetone-d.sub.6) δ 7.70 (d, J=2.7 Hz, 1H), 7.59-7.29 (m, 7H), 6.46 (d, J=0.8 Hz, 1H), 5.27 (s, 2H), 3.98 (ddd, J=11.6, 3.8, 1.9 Hz, 2H), 3.47 (td, J=11.7, 2.2 Hz, 2H), 2.73 (dt, J=11.8, 3.8 Hz, 1H), 1.90 (ddd, J=12.9, 4.1, 2.0 Hz, 2H), 1.72 (dtd, J=13.1, 11.8, 4.5 Hz, 2H).

[0586] Step 3: To a solution of the acid obtained above (50 mg, 0.1486 mmol) in acetone (3 mL) was added AgNO.sub.3 (7.57 mg, 0.04456 mmol). The reaction mixture was stirred in the dark for 24 hours at room temperature. The reaction was concentrated, and the residue was purified by silica gel chromatography (12 g ISCO column) using 0-40% EtOAc/heptanes gradient to afford C122 (33 mg, 66%). .sup.1H NMR (300 MHz, Chloroform-d) δ 7.70 (d, J=2.3 Hz, 1H), 7.46-7.15 (m, 8H), 6.14 (s, 1H), 5.08 (s, 2H), 4.01 (ddd, J=11.5, 4.2, 1.7 Hz, 2H), 3.42 (td, J=11.8, 2.2 Hz, 2H), 2.63 (tt, J=11.8, 3.8 Hz, 1H), 2.00-1.61 (m, 4H), 1.29-1.13 (m, 3H), 0.86-0.75 (m, 2H).

[0587] Step 4: To a suspension of C122 (102 mg, 0.3032 mmol), molecular sieves (400 mg), and methyl 3-aminocyclobutanecarboxylate (hydrochloride salt) (375 mg, 2.264 mmol) was added pyridine (2 mL). The suspension was then heated at 140° C. for 15 hours. The reaction was cooled to room temperature and diluted with dichloromethane. The reaction mixture was filtered through a Celite® pad and acidified with 1 M HCl. The organic phase was separated and concentrated. The product was purified by silica gel to afford the corresponding ester (78 mg, 57%). .sup.1H NMR (300 MHz, Chloroform-d) δ 7.88 (d, J=2.6 Hz, 1H), 7.54-7.30 (m, 7H), 6.34 (s, 1H), 5.20 (s, 3H), 4.14 (dt, J=11.7, 2.3 Hz, 2H), 3.78 (s, 3H), 3.74-3.47 (m, 5H), 2.93 (td, J=10.5, 5.5 Hz, 1H), 2.55 (ddd, J=12.5, 9.3, 3.8 Hz, 2H), 1.94-1.70 (m, 4H).

[0588] Step 5: To a solution of the above ester (114 mg, 0.2547 mmol) in THF (2 mL) was added NB S (59 mg, 0.3315 mmol) at 0° C. The reaction mixture was warmed to room temperature, stirred for 1 hours, quenched with aqueous sat. NaHCO.sub.3 and extracted with EtOAc. The organic phase was concentrated, and the residue was purified by silica gel chromatography (0 to 30% EtOAc in Heptane) to afford C123 (84 mg, 63%). .sup.1H NMR (300 MHz, Chloroform-d) δ 7.93 (d, J=9.0 Hz, 1H), 7.89 (d, J=2.7 Hz, 1H), 7.53-7.33 (m, 6H), 5.22 (s, 2H), 4.24-4.14 (m, 2H), 3.80 (s, 3H), 3.67-3.40 (m, 5H), 2.61 (t, J=8.9 Hz, 2H), 2.34 (d, J=10.8 Hz, 3H), 1.77 (d, J=13.0 Hz, 2H), 1.59 (s, 2H).

[0589] Step 6: In a 20 mL vial were added water (100 μL) and potassium phosphate (57 mg, 0.2685 mmol). The mixture was stirred for 10 minutes at room temperature then toluene (700 μL) was added. N.sub.2 was bubbled through the mixture for 15 minutes then C123 (40 mg, 0.07599 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (18 mg, 0.1169 mmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane;methanesulfonate;N-methyl-2-phenyl-aniline Pd (13 mg, 0.01529 mmol) were added. The tube was sealed then transferred to a pre-heated oil bath set to 70° C. and stirred at this temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc. The organic solution was dried with Na.sub.2SO.sub.4 and concentrated.

[0590] The product was purified by silica gel chromatography to afford the corresponding Suzuki product (35 mg, 67%) LCMS m/z 556.34 [M+H].sup.+.

[0591] Step 7: To a 20 mL vial was added Pd/C (1.6 mg, 0.001503 mmol) and the product from the previous step and MeOH (4 mL) was added via syringe. Then, H.sub.2 was bubbled for 5 min and the reaction was stirred at RT for 4 h, at which time complete reduction was observed. The reaction mixture was filtered, and product was purified by ISCO to afford the corresponding phenol. LCMS m/z 466.38 [M+H].sup.+.

[0592] Step 8: The product from the previous step was dissolved in THF/MeOH/H.sub.2O (3:1:1) (2 mL) and LiCl (10 mg, 0.2359 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with H.sub.2O and acidified with 1 N HCl. The product was extracted with EtOAc and the organic solution was dried with Na.sub.2SO.sub.4 and concentrated to give 115 (8 mg, 22%). .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.65 (d, J=2.6 Hz, 1H), 7.23-7.08 (m, 2H), 7.04 (dt, J=8.8, 3.3 Hz, 2H), 6.73 (d, J=8.8 Hz, 1H), 5.43 (p, J=8.7 Hz, 1H), 3.95 (dd, J=11.5, 4.4 Hz, 2H), 3.59 (q, J=10.1 Hz, 2H), 3.46-3.33 (m, 1H), 3.08 (dd, J=12.5, 10.0 Hz, 3H), 2.58 (ddd, J=12.4, 9.1, 3.6 Hz, 2H), 2.24-2.06 (m, 2H), 1.60 (d, J=13.1 Hz, 2H). LCMS m/z 452.38 [M+H].sup.+

Compound 116

(R)-2-((4-(4-fluorophenyl)-7-hydroxy-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-1-yl)oxy)propanoic acid (116)

[0593] ##STR00664##

[0594] Step 1: (2S)-2-[[7-benzyloxy-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]propanoic acid (C124)

[0595] Method A: DABCO-Catalyzed S.sub.NAr Reaction with Alcohols. To a mixture of S13 (170 mg, 0.1961 mmol) and (2S)-2-hydroxypropanoic acid (97 mg, 1.077 mmol) in dry DMF (4 mL) was added NaH (103 mg of 60% w/w, 2.575 mmol) under N.sub.2. The reaction mixture was stirred for 18 hours at room temperature. After completion, the reaction mixture was quenched with water and 1 M of HCl (5 mL). The residue was extracted with EtOAc, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was purified by silica gel chromatography eluting with 0-30% of MeOH in dichloromethane to afford C124 (65 mg, 66%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J=2.6 Hz, 1H), 7.55-7.49 (m, 2H), 7.46-7.41 (m, 2H), 7.38 (d, J=7.2 Hz, 1H), 7.28-7.14 (m, 6H), 5.45 (q, J=7.0 Hz, 1H), 5.22 (d, J=3.5 Hz, 2H), 4.10-3.89 (m, 2H), 3.33 (dddd, J=17.5, 13.2, 11.5, 2.1 Hz, 2H), 2.72 (tt, J=11.7, 3.7 Hz, 1H), 2.26 (qd, J=12.7, 4.5 Hz, 1H), 2.11-2.00 (m, 1H), 1.83 (d, J=7.1 Hz, 3H), 1.49 (d, J=7.0 Hz, 2H). LCMS m/z 501.93 [M+H].sup.+.

Step 2: (2S)-2-[[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]propanoic acid (116)

[0596] Method B: Pd Catalyzed Transfer Hydrogenation. Pd (16 mg of 10% w/w, 0.01503 mmol) was added to a solution of C124 (63 mg, 0.1256 mmol) in MeOH (10 mL) and EtOAc (10 mL). The resulting mixture was stirred at room temperature under a H.sub.2 balloon for 18 hours. The reaction mixture was filtered through a plug of celite and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20-30% MeOH in dichloromethane to give 116 (35 mg, 63%). .sup.1H NMR (400 MHz, Methanol-d4) δ 7.61 (dd, J=2.5, 0.6 Hz, 1H), 7.30-7.00 (m, 6H), 5.45 (q, J=7.0 Hz, 1H), 3.96 (ddd, J=20.5, 11.3, 4.3 Hz, 2H), 3.35-3.22 (m, 2H), 2.69 (tt, J=11.6, 3.7 Hz, 1H), 2.24 (qd, J=12.7, 4.6 Hz, 1H), 2.14-2.03 (m, 1H), 1.75 (d, J=7.0 Hz, 3H), 1.56-1.39 (m, 2H) ppm. LCMS m/z 412.29 [M+H].sup.+.

Compounds 117-142

[0597] Compounds 117-142 (Table 11) were prepared in two or three steps from intermediate S13 from the appropriate alcohols according to the method described for compound 116. Any modifications to methods are noted in Table 11 and accompanying footnotes.

TABLE-US-00012 TABLE 11 Method of preparation, structure, physicochemical data for compound 117-142 .sup.1H NMR; LCMS m/z Compound Method/Product Alcohols [M + H].sup.+ 117 [00665] [00666] .sup.1H NMR (300 MHz, Chloroform-d and Methanol-d.sub.4) δ 7.98 (s, 1H), 7.61 (dd, J = 2.5, 0.7 Hz, 1H), 7.25- 7.06 (m, 6H), 5.45 (q, J = 7.0 Hz, 1H), 3.95 (td, J = 11.6, 5.9 Hz, 2H), 2.69 (tt, J = 11.6, 3.7 Hz, 1H), 2.35-1.96 (m, 2H), 1.75 (d, J = 7.0 Hz, 3H), 1.47 (t, J = 14.2 Hz, 2H. LCMS m/z 412.38 118 [00667] [00668] .sup.1H NMR (300 MHz, Chloroform-d and Methanol-d.sub.4) δ 7.56 (dd, J = 2.4, 0.7 Hz, 1H), 7.29-7.01 (m, 6H), 5.62 (ttd, J = 7.3, 6.1, 1.1 Hz, 1H), 4.06- 3.89 (m, 2H), 3.36- 3.11 (m, 3H), 3.05- 2.83 (m, 2H), 2.78- 2.50 (m, 3H), 2.16 (qd, J = 12.7, 4.5 Hz, 2H), 1.62-1.37 (m, 2H). LCMS m/z 438.25 119 [00669] [00670] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.31 (s, 1H), 8.79 (d, J = 2.5 Hz, 1H), 8.22 (dd, J = 8.6, 2.5 Hz, 1H), 7.97 (dt, J = 8.6, 2.6 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.44-7.28 (m, 5H), 7.13 (dd, J = 9.2, 2.4 Hz, 1H), 3.75 (d, J = 11.0 Hz, 2H), 3.08 (t, J = 12.0 Hz, 2H), 2.66-2.58 (m, 1H), 1.64 (q, J = 12.8 Hz, 2H), 1.39 (d, J = 13.0 Hz, 2H). LCMS m/z 461.38 120 [00671] [00672] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.58 (t, J = 1.6 Hz, 1H), 7.27-7.06 (m, 5H), 5.51-5.35 (m, 1H), 4.04 (dd, J = 11.4, 4.3 Hz, 2H), 3.36 (t, J = 11.9 Hz, 2H), 2.96 (t, J = 6.2 Hz, 3H), 2.83-2.49 (m, 3H), 2.33-2.11 (m, 2H), 1.48 (d, J = 11.8 Hz, 2H). LCMS m/z 438.39 121 [00673] [00674] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.54 (dd, J = 2.5, 0.6 Hz, 1H), 7.29-7.24 (m, 3H), 7.20-7.09 (m, 2H), 5.93 (q, J = 7.4 Hz, 1H), 3.93 (td, J = 11.6, 4.4 Hz, 2H), 3.25 (dd, J = 4.2, 2.1 Hz, 2H), 2.72 (tt, J = 11.7, 3.7 Hz, 1H), 2.24-2.02 (m, 2H), 1.48 (dd, J = 22.4, 13.5 Hz, 2H). LCMS m/z 466.17 122 [00675] [00676] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.47 (dd, J = 2.5, 0.7 Hz, 1H), 7.31-7.19 (m, 4H), 7.14-7.01 (m, 2H), 4.57 (s, 2H), 3.96 (dd, J = 11.5, 4.4 Hz, 2H), 3.34 (d, J = 2.0 Hz, 1H), 3.28 (d, J = 2.0 Hz, 1H), 2.73 (tt, J = 11.6, 3.8 Hz, 1H), 2.22 (qd, J = 12.7, 4.5 Hz, 2H), 1.55-1.46 (m, 2H), 1.41 (s, 6H). LCMS m/z 440.24 123 [00677] [00678] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.43 (dd, J = 2.4, 0.7 Hz, 1H), 7.31-7.19 (m, 4H), 7.15-7.04 (m, 2H), 4.00-3.88 (m, 2H), 3.37-3.24 (m, 2H), 2.71 (tt, J = 11.5, 3.7 Hz, 1H), 2.16 (qd, J = 12.7, 4.5 Hz, 2H), 1.74-1.61 (m, 2H), 1.52-1.38 (m, 2H), 1.39-1.26 (m, 2H). LCMS m/z 424.17 124 [00679] [00680] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.90 (dd, J = 2.5, 0.7 Hz, 1H), 7.26-7.04 (m, 6H), 4.83-4.68 (m, 2H), 4.08-3.87 (m, 6H), 3.81 (s, 4H), 3.43- 3.25 (m, 2H), 2.73 (t, J = 5.8 Hz, 3H), 2.24 (qd, J = 12.8, 4.6 Hz, 2H), 1.56-1.37 (m, 2H). LCMS m/z 499.86 125 [00681] [00682] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.51 (d, J = 2.4 Hz, 1H), 7.33-7.19 (m, 4H), 7.13-7.01 (m, 2H), 4.74 (s, 2H), 3.95 (dd, J = 11.3, 4.3 Hz, 2H), 2.80-2.63 (m, 2H), 2.19 (qd, J = 12.7, 4.4 Hz, 3H), 1.49 (d, J = 12.9 Hz, 2H), 1.34 (q, J = 4.0 Hz, 2H), 1.13 (q, J = 4.0 Hz, 2H). LCMS m/z 438.3 126 [00683] [00684] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.47 (dd, J = 2.5, 0.7 Hz, 1H), 7.31-7.20 (m, 4H), 7.09 (qd, J = 9.1, 1.6 Hz, 2H), 5.04 (d, J = 6.2 Hz, 2H), 5.00 (s, 2H), 4.82 (d, J = 6.2 Hz, 2H), 3.96 (dd, J = 11.4, 4.4 Hz, 2H), 3.34 (d, J = 1.9 Hz, 2H), 2.75 (tt, J = 11.6, 3.8 Hz, 1H), 2.23 (qd, J = 12.8, 4.6 Hz, 2H), 1.52 (dd, J = 13.0, 3.6 Hz, 2H). LCMS m/z 454.28 127 [00685] [00686] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.53 (dd, J = 2.4, 0.7 Hz, 1H), 7.28-7.01 (m, 6H), 5.35 (p, J = 7.1 Hz, 1H), 4.00 (dd, J = 11.5, 4.1 Hz, 2H), 3.39 (d, J = 1.9 Hz, 1H), 3.34-3.26 (m, 1H), 3.11 (p, J = 8.6 Hz, 1H), 2.88-2.59 (m, 3H), 2.52-2.09 (m, 8H), 1.60-1.39 (m, 2H). LCMS m/z 478.29 128 [00687] [00688] .sup.1H NMR (400 MHz, Chloroform-d and Methanol-d.sub.4) δ 7.51- 7.43 (m, 1H), 7.18- 6.95 (m, 6H), 4.74- 4.59 (m, 2H), 4.50 (dt, J = 9.4, 4.8 Hz, 2H), 3.98-3.86 (m, 3H), 3.26-3.18 (m, 1H), 2.60 (dtd, J = 13.4, 9.6, 8.7, 4.8 Hz, 1H), 2.36-2.18 (m, 2H), 2.17-2.01 (m, 3H), 2.00-1.89 (m, 1H), 1.44-1.29 (m, 2H). LCMS m/z 467.99 129 [00689] [00690] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.06- 9.97 (m, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.33 (pd, J = 7.5, 6.4, 2.8 Hz, 4H), 7.17 (dt, J = 9.0, 2.6 Hz, 1H), 7.00 (dd, J = 9.0, 2.4 Hz, 1H), 5.25 (d, J = 4.6 Hz, 1H), 5.02-4.88 (m, 1H), 3.99 (d, J = 7.6 Hz, 1H), 3.86 (d, J = 10.3 Hz, 2H), 3.16 (t, J = 12.0 Hz, 2H), 2.98-2.86 (m, 2H), 2.04 (q, J = 16.3, 12.5 Hz, 4H), 1.43 (d, J = 12.9 Hz, 2H). LCMS m/z 410.18 130 [00691] [00692] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.58 (t, J = 1.6 Hz, 1H), 7.27-6.94 (m, 6H), 6.24 (s, 1H), 5.02 (dd, J = 8.0, 6.1 Hz, 2H), 4.90-4.67 (m, 4H), 4.02 (dd, J = 11.4, 4.4 Hz, 2H), 3.65 (tt, J = 8.0, 6.2 Hz, 1H), 3.45- 3.22 (m, 2H), 2.74 (tt, J = 11.6, 3.8 Hz, 1H), 2.24 (qd, J = 12.7, 4.5 Hz, 2H), 1.50 (dd, J = 13.4, 3.6 Hz, 2H). LCMS m/z 410.35 131 [00693] [00694] LCMS m/z 592.29 132 [00695] [00696] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.05- 9.98 (m, 1H), 7.54- 7.46 (m, 1H), 7.41- 7.25 (m, 4H), 7.17 (dt, J = 9.1, 2.8 Hz, 1H), 7.00 (dd, J = 8.9, 2.7 Hz, 1H), 5.04 (d, J = 4.6 Hz, 1H), 4.74 (s, 1H), 4.52 (dt, J = 10.8, 3.5 Hz, 1H), 4.46- 4.37 (m, 1H), 3.97 (s, 1H), 3.86 (d, J = 11.3 Hz, 2H), 3.57 (d, J = 5.6 Hz, 2H), 3.17 (t, J = 11.9 Hz, 2H), 2.61 (d, J = 13.6 Hz, 1H), 2.11-1.97 (m, 2H), 1.44 (d, J = 13.0 Hz, 2H). LCMS m/z 414.18 133 [00697] [00698] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.51 (dd, J = 2.6, 0.6 Hz, 1H), 7.31-7.18 (m, 4H), 7.16-7.02 (m, 2H), 5.77 (t, J = 8.3 Hz, 1H), 3.94 (dd, J = 10.2, 3.9 Hz, 2H), 3.60-3.44 (m, 2H), 3.32 (d, J = 2.8 Hz, 1H), 3.26 (d, J = 2.1 Hz, 1H), 2.99-2.88 (m, 1H), 2.73 (tt, J = 11.6, 3.7 Hz, 1H), 2.32-2.07 (m, 3H), 1.50 (d, J = 12.2 Hz, 2H). LCMS m/z 423.22 134 [00699] [00700] .sup.1H NMR (300 MHz, Chloroform-d and Methanol-d.sub.4) δ 7.57 (dd, J = 2.3, 0.9 Hz, 1H), 7.30-6.99 (m, 6H), 5.50 (p, J = 6.8 Hz, 1H), 3.98 (dd, J = 11.3, 4.3 Hz, 2H), 3.74 (d, J = 7.0 Hz, 2H), 3.39 (s, 1H), 3.33 (d, J = 10.8 Hz, 2H), 2.84-2.34 (m, 6H), 2.18 (qd, J = 12.8, 4.6 Hz, 2H), 1.48 (d, J = 12.5 Hz, 2H). LCMS m/z 424.22 135 [00701] [00702] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.53 (dd, J = 2.1, 1.1 Hz, 1H), 7.25-7.07 (m, 6H), 5.52 (s, 1H), 5.38- 5.24 (m, 1H), 4.87 (s, 2H), 4.77 (s, 2H), 4.02 (dd, J = 11.5, 4.4 Hz, 2H), 3.34 (t, J = 11.6 Hz, 2H), 2.98 (ddd, J = 10.5, 7.1, 3.0 Hz, 2H), 2.70 (ddt, J = 11.7, 7.6, 3.8 Hz, 1H), 2.56-2.41 (m, 2H), 2.19 (qd, J = 12.7, 4.5 Hz, 2H), 1.53-1.41 (m, 2H). LCMS m/z 436.36 136 [00703] [00704] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.53 (dt, J = 30.0, 2.6 Hz, 1H), 7.40-7.25 (m, 3H), 7.21-7.06 (m, 1H), 7.06-6.70 (m, 2H), 4.88 (d, J = 87.2 Hz, 1H), 4.65-4.44 (m, 2H), 4.08-3.89 (m, 1H), 3.89-3.78 (m, 2H), 3.68 (s, 1H), 3.52- 3.42 (m, 1H), 3.17 (t, J = 12.0 Hz, 1H), 3.11- 2.96 (m, 1H), 2.63 (s, 1H), 2.05 (d, J = 12.5 Hz, 2H), 1.54- 1.28 (m, 2H). LCMS m/z 444.19 137 [00705] [00706] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.53 (dd, J = 2.2, 1.1 Hz, 1H), 7.26-7.01 (m, 6H), 5.42 (s, 1H), 4.78 (d, J = 24.6 Hz, 4H), 4.49 (d, J = 6.5 Hz, 2H), 4.01 (dd, J = 11.4, 4.3 Hz, 2H), 3.35 (t, J = 11.9 Hz, 2H), 2.82-2.63 (m, 2H), 2.59-2.43 (m, 2H), 2.25 (td, J = 11.7, 4.9 Hz, 4H), 1.48 (d, J = 13.2 Hz, 2H). LCMS m/z 450.36 138 [00707] [00708] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.34 (d, J = 2.5 Hz, 1H), 7.29-7.16 (m, 4H), 7.04 (dd, J = 9.0, 2.5 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 4.70 (dd, J = 11.6, 5.5 Hz, 1H), 4.60 (dd, J = 11.6, 5.0 Hz, 1H), 4.39-4.22 (m, 3H), 3.95 (dd, J = 11.4, 4.3 Hz, 2H), 3.58-3.47 (m, 2H), 3.35 (s, 2H), 2.70 (ddt, J = 11.5, 7.5, 3.8 Hz, 1H), 2.26-2.11 (m, 2H), 1.54-1.45 (m, 2H). LCMS m/z 453.33 139 [00709] [00710] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.49 (dd, J = 2.5, 0.7 Hz, 1H), 7.31-7.19 (m, 4H), 7.11 (dd, J = 9.0, 2.5 Hz, 1H), 7.05 (dd, J = 9.1, 0.7 Hz, 1H), 4.72 (t, J = 6.2 Hz, 2H), 3.95 (dd, J = 11.3, 4.3 Hz, 2H), 3.40-3.32 (m, 4H), 2.73 (ddt, J = 11.5, 7.6, 3.8 Hz, 1H), 2.51- 2.38 (m, 2H), 2.29- 2.12 (m, 2H), 1.57- 1.44 (m, 2H). LCMS m/z 461.29 140 [00711] [00712] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.55 (dd, J = 2.4, 0.7 Hz, 1H), 7.26 (s, 2H), 7.24 (d, J = 1.4 Hz, 2H), 7.16-7.04 (m, 2H), 4.68 (t, J = 5.7 Hz, 2H), 3.95 (dd, J = 11.3, 4.4 Hz, 2H), 3.64 (t, J = 5.7 Hz, 2H), 3.37-3.24 (m, 2H), 3.00 (s, 3H), 2.74 (ddt, J = 11.6, 7.5, 3.9 Hz, 1H), 2.30-2.12 (m, 2H), 1.56-1.47 (m, 2H). LCMS m/z 461.25 141 [00713] [00714] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.58- 7.47 (m, 1H), 7.47- 7.26 (m, 4H), 7.18 (dt, J = 9.2, 2.4 Hz, 1H), 7.01 (dd, J = 9.1, 2.4 Hz, 1H), 6.40 (s, 1H), 5.05 (s, 2H), 4.67 (dd, J = 26.9, 11.7 Hz, 1H), 4.54-4.39 (m, 1H), 4.16 (s, 2H), 3.87 (d, J = 11.4 Hz, 2H), 3.76 (s, 1H), 3.17 (t, J = 12.0 Hz, 2H), 2.05 (d, J = 13.3 Hz, 2H), 1.45 (d, J = 13.1 Hz, 2H). LCMS m/z 472.14 142 [00715] [00716] .sup.1H NMR (300 MHz, Chloroform-d and Methanol-d.sub.4) δ 7.51 (d, J = 2.4 Hz, 1H), 7.31-6.92 (m, 6H), 5.53-5.19 (m, 1H), 4.24-3.94 (m, 5H), 2.93 (ddd, J = 14.0, 6.9, 3.3 Hz, 2H), 2.71 (dt, J = 16.6, 5.4 Hz, 1H), 2.59-2.35 (m, 2H), 2.28-2.08 (m, 2H), 1.89 (dd, J = 11.4, 3.9 Hz, 3H), 1.48 (d, J = 13.3 Hz, 2H), 1.33-1.07 (m, 3H). LCMS m/z 477.4 .sup.1Standard method D using KOH was carried out after standard method B using Pd(OH).sub.2. .sup.2Additional treatment with HCl to remove the acetal groups was carried out after standard method B using Pd(OH).sub.2. .sup.3TFA deprotection followed by standard method E using acetic anhydride and DIPEA were carried out before standard method B.

Compound 143

3-[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]propanoic acid (143)

[0598] ##STR00717##

Step 1: 7-benzyloxy-4-(4-fluorophenyl)-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C29)

[0599] Method C-1: Suzuki Coupling Method. A suspension of S11 (14.41 g, 34.782 mmol), (4-fluorophenyl)boronic acid (7.29 g, 52.101 mmol) and aq. solution of Na.sub.2CO.sub.3 (35 mL of 2 M in water, 70.000 mmol) in DMSO (140 mL) was purged with N.sub.2 for 30 minutes. Pd(dppf)Cl.sub.2.dichloromethane (1.42 g, 1.7388 mmol) was added and the reaction was purged with N.sub.2 for another 5 minutes. The reaction was heated to 100° C. for 2 hours, cooled to room temperature, cooled to 0° C., diluted with water (280 mL) and filtered. The residue was then dissolved with dichloromethane (through filter paper). The filtrate was decanted, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The brown solid was triturated in ACN (50 mL), filtered and washed with ACN. The residue was triturated again in a mixture of dichloromethane (10 mL) and ACN (25 mL), the solid was filtered and washed with minimum dichloromethane to give C29 (9.19 g, 59%) as tan solid. .sup.1H NMR (300 MHz, CDCl3) δ 1.40 (d, J=11.7 Hz, 2H), 2.67 (br. s., 2H), 3.11-3.37 (m, 3H), 3.95 (dd, J=11.0, 3.7 Hz, 2H), 5.17 (s, 2H), 6.94-7.18 (m, 3H), 7.19-7.29 (m, 4H), 7.31-7.51 (m, 5H), 8.73 (s, 1H). .sup.19F NMR (282 MHz, Chloroform-d) δ −113.2-112.2 (m, 1F). LCMS m/z calc. 430.2 [M+H].sup.+.

Step 1: 7-benzyloxy-1-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (C125)

[0600] Method C-2: Halogenation of Isoquinoline N-Oxide with Oxalyl Chloride. Oxalyl dichloride (6 mL of 2M in dichloromethane, 12.00 mmol) was added to a solution of C29 (3 g, 6.985 mmol) and DIPEA (3 mL, 17.22 mmol) in dry dichloromethane (25 mL) at −78° C. The reaction was allowed to warm to 0° C. over 2 hours, and the dark reaction was quenched by the addition of MeOH (2 mL). After stirring for 10 minutes, the mixture was concentrated in vacuo. MeOH (5 mL) was added and the resulting solid was filtered and washed with cold MeOH and dried under high vacuum to afford C125 (2.73 g, 87%) as a colorless solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.72-7.30 (m, 7H), 7.27-7.20 (m, 5H), 5.26 (s, 2H), 4.01 (dd, J=11.4, 4.4 Hz, 2H), 3.32 (t, J=11.4 Hz, 2H), 2.55-2.45 (m, 1H), 2.34-2.11 (m, 2H), 1.50 (m, 2H).

Steps 2-3: ethyl 3-[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]propanoate (C126)

[0601] The transformation of intermediate C125 to C127 was accomplished via standard Suzuki protocol using ethyl Pd(PPh.sub.3).sub.4 in DMF stirred at 130° C. for 2 hours, followed by standard hydrogenation using method B.

Step 4: 3-[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]propanoic acid (143)

[0602] Method D: Ester hydrolysis with LiOH. A solution of C127 (70 mg, 0.1653 mmol) dissolved in a mixture of THF (3 mL) and H.sub.2O (1.5 mL) was treated with LiOH(100 mg, 2.383 mmol), and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was acidified with HCl (2.5 mL of 1 M, 2.500 mmol) and extracted with EtOAc. Organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give 143 (65 mg, 87%). .sup.1H NMR (300 MHz, Chloroform-d) δ 7.58 (s, 1H), 7.28-7.13 (m, 7H), 4.06-3.98 (m, 2H), 3.68 (d, J=6.4 Hz, 2H), 3.31 (t, J=11.7 Hz, 2H), 3.08 (t, J=6.1 Hz, 2H), 2.85 (t, J=12.0 Hz, 1H), 2.32-2.18 (m, 2H), 1.60-1.49 (m, 2H). LCMS m/z 396.13 [M+H].sup.+.

Compound 144

1-[[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-isoquinoline-1-carbonyl]amino]cyclopropanecarboxylic acid (144)

[0603] ##STR00718##

Step 1: 7-benzyloxy-4-bromo-3-tetrahydropyran-4-yl-isoquinoline-1-carbonitrile (C128)

[0604] To a mixture of S11 (10 g, 23.73 mmol) in ACN (150 mL) and THF (100 mL) was added TEA (8.25 mL, 59.19 mmol) and TMSCN (10 mL, 75.00 mmol) under N.sub.2. The reaction was heated to 55° C. for 18 hours. More TMSCN (10 mL, 75.00 mmol) was added and the reaction was stirred for another 2 days. After completion of the reaction, the mixture was concentrated to dryness. MeOH (30 mL) was added and the solid was filtered off to yield C128 (1400 mg, 14%). .sup.1H NMR (300 MHz, Chloroform-d) δ 8.26 (d, J=10.0 Hz, 1H), 7.65-7.34 (m, 7H), 5.30 (s, 2H), 4.15 (dd, J=11.5, 4.3 Hz, 2H), 3.73-3.57 (m, 2H), 2.24-2.08 (m, 1H), 1.78 (d, J=13.4 Hz, 2H), 1.28(s, 1H). LCMS m/z 423.22 [M+H].sup.+.

Steps 2-4: 4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-isoquinoline-1-carboxylic acid (C129)

[0605] The transformation of intermediate C128 to C129 was accomplished via standard method C, standard method B using Pd(OH).sub.2 and standard method D using NaOH, respectively.

Step 5: 1-[[[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-isoquinoline-1-carbonyl]amino]methyl]cyclopropanecarboxylic acid (144)

[0606] Method E: Amide Coupling Method. To a mixture of C129 (40 mg, 0.1089 mmol) in DMF (2 mL) was added ethyl 1-(aminomethyl)cyclopropanecarboxylate (approximately 23.38 mg, 0.1634 mmol), T3P (approximately 138.6 μL of 50% w/v, 0.2178 mmol) and DIPEA (approximately 42.22 mg, 56.90 μL, 0.3267 mmol). The reaction was stirred at room temperature for 18 hours. After completion of reaction, the mixture was concentrated to dryness and dissolved in minimal amount of DMSO. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 micron). Gradient: MeCN in H.sub.2O with 5 mM HCl afforded 144 (HCl salt) (5.80 mg, 11%). LCMS m/z 465.19 [M+H].sup.+.

Compounds 145-155

[0607] Compounds 145-155 (Table 12) were prepared in five or six steps from intermediate S11 from the appropriate amines according to the method described for compound 144. Any modifications to methods are noted in Table 12 and accompanying footnotes.

TABLE-US-00013 TABLE 12 Method of preparation, structure, physicochemical data for compounds 145-155 .sup.1H NMR; LCMS m/z Compound Method/Product Amines [M + H].sup.+ 145 [00719] [00720] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.29 (s, 1H), 8.96 (m, 1H), 8.66 (d, J = 2.6 Hz, 1H), 7.39 (m, 4H), 7.26 (dd, J = 9.2, 2.5 Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H), 3.88 (dd, J = 11.0, 4.3 Hz, 2H), 3.62 (d, J = 6.4 Hz, 2H), 3.18 (m, 3H), 2.78-2.66 (m, 1H), 2.03 (m, 2H), 1.51 (d, J = 13.1 Hz, 2H), 1.11 (m, 2H), 1.02 (m, 2H). LCMS m/z 495.16 146 [00721] [00722] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.13 (s, 1H), 8.39 (d, J = 2.5 Hz, 1H), 7.45-7.32 (m, 4H), 7.25 (dd, J = 9.2, 2.6 Hz, 1H), 7.13 (d, J = 9.2 Hz, 1H), 3.88 (dd, J = 11.2, 4.3 Hz, 3H), 3.17 (t, J = 11.8 Hz, 3H), 2.70 (d, J = 12.1 Hz, 1H), 2.24-2.07 (m, 2H), 1.54-1.42 (m, 4H), 1.26 (q, J = 4.7 Hz, 2H). LCMS m/z 453.18 147 [00723] [00724] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.27 (s, 1H), 8.80 (t, J = 6.5 Hz, 1H), 8.66 (d, J = 2.5 Hz, 1H), 7.40 (dd, J = 7.4, 3.4 Hz, 4H), 7.26 (dd, J = 9.2, 2.5 Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H), 3.87 (dd, J = 11.0, 4.2 Hz, 2H), 3.54 (d, J = 6.4 Hz, 2H), 3.18 (t, J = 11.8 Hz, 2H), 2.80- 2.65 (m, 1H), 2.11-1.95 (m, 2H), 1.58-1.46 (m, 2H), 1.21 (s, 6H). LCMS m/z 467.21 148 [00725] [00726] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.30 (s, 1H), 9.11 (d, J = 9.1 Hz, 1H), 8.82 (d, J = 2.5 Hz, 1H), 7.47-7.35 (m, 3H), 7.33-7.26 (m, 1H), 7.16 (d, J = 9.2 Hz, 1H), 4.45 (d, J = 8.7 Hz, 1H), 3.96- 3.77 (m, 4H), 3.68-3.51 (m, 2H), 3.18 (t, J = 11.8 Hz, 2H), 3.01 (d, J = 5.1 Hz, 1H), 2.75 (m, 1H), 2.00 (m, 3H), 1.80 (d, J = 13.8 Hz, 1H), 1.53 (d, J = 12.9 Hz, 2H). LCMS m/z 495.23 149 [00727] [00728] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.25 (s, 1H), 8.88 (t, J = 6.1 Hz, 1H), 8.55 (d, J = 2.5 Hz, 1H), 7.44-7.34 (m, 4H), 7.25 (dd, J = 9.2, 2.5 Hz, 1H), 7.14 (d, J = 9.2 Hz, 1H), 3.88 (dd, J = 10.8, 4.2 Hz, 2H), 3.62 (t, J = 6.6 Hz, 2H), 3.18 (t, J = 11.8 Hz, 2H), 2.78-2.66 (m, 1H), 2.62 (d, J = 6.9 Hz, 1H), 2.19-2.00 (m, 2H), 1.51-1.43 (m, 2H). LCMS m/z 439.17 150 [00729] [00730] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.23 (s, 1H), 8.88 (d, J = 8.1 Hz, 1H), 8.16 (d, J = 2.5 Hz, 1H), 7.46-7.33 (m, 4H), 7.24 (dd, J = 9.2, 2.5 Hz, 1H), 7.13 (d, J = 9.2 Hz, 1H), 4.71 (h, J = 8.2 Hz, 1H), 3.97-3.84 (m, 2H), 3.18 (t, J = 11.8 Hz, 2H), 3.01 (dt, J = 9.5, 5.2 Hz, 1H), 2.78-2.67 (m, 1H), 2.60-2.41 (m, 3H), 2.24- 2.07 (m, 2H), 1.47 (d, J = 13.0 Hz, 2H). LCMS m/z 465.19 151 [00731] [00732] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.74 (t, J = 5.9 Hz, 1H), 8.58 (d, J = 2.5 Hz, 1H), 7.47-7.35 (m, 4H), 7.26 (dd, J = 9.2, 2.6 Hz, 1H), 7.14 (d, J = 9.2 Hz, 1H), 3.88 (dd, J = 11.5, 3.9 Hz, 2H), 3.71 (p, J = 5.7 Hz, 1H), 3.41- 3.33 (m, 2H), 3.18 (t, J = 11.8 Hz, 2H), 2.78-2.68 (m, 1H), 2.08 (dd, J = 17.6, 8.1 Hz, 2H), 1.55- 1.44 (m, 3H). LCMS m/z 441.19 152 [00733] [00734] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.06 (t, J = 6.0 Hz, 1H), 8.50 (d, J = 2.5 Hz, 1H), 7.44-7.32 (m, 3H), 7.30-7.24 (m, 2H), 7.15-7.09 (m, 2H), 4.00-3.75 (m, 4H), 3.17 (m, 3H), 3.00 (p, J = 6.3 Hz, 1H), 2.67 (s, 3H), 2.16 (q, J = 12.7 Hz, 2H), 1.45 (d, J = 13.1 Hz, 2H). LCMS m/z 457.15 153 [00735] [00736] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.72 (s, 1H), 10.84 (s, 1H), 10.55 (s, 1H), 8.87 (d, J = 2.5 Hz, 1H), 8.38 (d, J = 6.0 Hz, 1H), 7.42 (d, J = 7.4 Hz, 4H), 7.36-7.16 (m, 2H), 3.89 (dd, J = 11.0, 4.4 Hz, 2H), 3.20 (m, 2H), 2.78 (dd, J = 13.8, 10.1 Hz, 1H), 2.05 (tt, J = 13.1, 6.6 Hz, 2H), 1.63-1.51 (m, 2H). LCMS m/z 477.12 154 [00737] [00738] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.81 (t, J = 6.0 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H), 7.45-7.35 (m, 4H), 7.25 (dd, J = 9.2, 2.6 Hz, 1H), 7.14 (d, J = 9.2 Hz, 1H), 3.88 (dd, J = 11.3, 4.2 Hz, 2H) 3.60- 3.30 (m, 4H), 3.34-3.14 (m, 5H), 2.79-2.67 (m, 1H), 2.14 (qd, J = 12.6, 4.4 Hz, 2H), 1.52-1.41 (m, 3H). LCMS m/z 479.23 155 [00739] [00740] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.30 (s, 1H), 9.02 (d, J = 8.1 Hz, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.45-7.36 (m, 3H), 7.26 (dd, J = 9.2, 2.6 Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H), 4.87 (h, J = 8.1 Hz, 1H), 3.89 (dd, J = 11.3, 4.1 Hz, 3H), 3.36-3.16 (m, 4H), 2.83-2.67 (m, 1H), 2.42-2.30 (m, 1H), 2.14 (m, 2H), 1.47 (t, J = 8.3 Hz, 3H), 1.02-0.94 (m, 1H). LCMS m/z 485.33 .sup.1KOH was added before submitting for purification by reversed-phase HPLC. Method C: C18 Waters Sunfire column (30 × 150 mm, 5 micron). Gradient: 10-100% MeCN in H.sub.2O with 0.2% formic acid.

Compound 156

4-[[4-(4-fluorophenyl)-7-hydroxy-1-oxo-3-tetrahydropyran-4-yl-2-isoquinolyl]methyl]cyclohexanecarboxylic acid (156)

[0608] ##STR00741##

Step 1: methyl 5-benzyloxy-2-bromo-benzoate (C1)

[0609] Method F: S.sub.N2 reaction using Alkyl Bromide. To a solution of methyl 2-bromo-5-hydroxybenzoate (5.34 g, 23.113 mmol) in anhydrous DMF (60 mL) was added K.sub.2CO.sub.3 (6.45 g, 46.669 mmol) followed by benzyl bromide (4.6735 g, 3.25 mL, 27.325 mmol). The mixture was stirred at room temperature for 6 hours and then diluted with EtOAc (650 mL). The organic phase was washed with 5% aqueous NaHCO.sub.3 (5×100 mL) and brine (2×100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Column: 120 g Combiflash ISCO. Gradient: 0-20% EtOAc in heptane) to afford C1 (7.32 g, 98%) as white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 3.85 (s, 3H), 5.15 (s, 2H), 7.15 (dd, J=8.8, 3.1Hz, 1H), 7.26-7.50 (m, 6H), 7.53 (d, J=8.8 Hz, 1H). LCMS m/z 321.0 [M+H].sup.+.

Step 2: methyl 5-benzyloxy-2-(2-tetrahydropyran-4-ylethynyl)benzoate (C130)

[0610] Sonogashira Coupling Method. To a mixture of C1 (8 g, 24.91 mmol) and TEA (35 mL, 251.1 mmol) in DMF (50 mL) was added CuI (474 mg, 2.489 mmol), TBAF.3H.sub.2O (12 mL, 34.34 mmol), and TMS-alkyne (C71) (5.94 g, 32.58 mmol). The mixture was purged with N.sub.2 for 5 minutes, and then PdCl.sub.2(PPh.sub.3).sub.4 (873 mg, 1.244 mmol) was added. The mixture was purged again with N.sub.2 for 5 minutes and then heated to 80° C. for 18 hours. The reaction mixture was cooled down to room temperature, concentrated, diluted with water (500 mL), and extracted with EtOAc (450 mL). The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by silica gel chromatography (Column: 120 g Combiflash ISCO. Gradient: 0-40% EtOAc in heptane) to yield C130 (6 g, 69%). .sup.1H NMR (300 MHz, Chloroform-d) δ 7.56-7.31 (m, 7H), 7.06 (dd, J=8.6, 2.8 Hz, 1H), 5.11 (s, 2H), 4.00 (ddd, J=11.5, 5.9, 3.6 Hz, 2H), 3.93 (s, 3H), 3.59 (ddd, J=11.5, 8.2, 3.1 Hz, 2H), 2.93 (tt, J=8.3, 4.1 Hz, 1H), 1.95 (ddt, J=13.4, 6.5, 3.7 Hz, 2H), 1.88-1.73 (m, 2H).

Step 3: 7-benzyloxy-4-iodo-3-tetrahydropyran-4-yl-isochromen-1-one (C131)

[0611] Electrophilic Cyclization of Alkyne (12-promoted). To a solution of C130 (1.54 g, 4.390 mmol) in anhydrous dichloromethane (20 mL) was added slowly a solution of I.sub.2 (1.23 g, 4.846 mmol) in anhydrous dichloromethane (24 mL) over a course of 30 min at RT. The reaction mixture was stirred at room temperature for an additional 20 minutes, and then EtOAc (100 mL) was added. The organic phase was washed with a mixture of 5% aqueous NaHCO.sub.3, brine (3×100 mL, 90/10 ratio), followed with more brine (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure, in which a white precipitate formed. The precipitate was filtered off to afford C131 (1.76 g, 87%) as a white solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.79 (d, J=2.7 Hz, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.52-7.33 (m, 7H), 5.20 (s, 2H), 4.11 (dd, J=11.7, 4.3 Hz, 2H), 3.61-3.34 (m, 3H), 2.24-1.95 (m, 2H), 1.75 (dq, J=12.9, 1.9 Hz, 2H).

Steps 4-6: 4-[[4-(4-fluorophenyl)-7-hydroxy-1-oxo-3-tetrahydropyran-4-yl-2-isoquinolyl]methyl]cyclohexanecarboxylic acid (156)

[0612] The transformation of C131 to C133 was accomplished via standard method C using RuPhos Pd G4 and K.sub.3PO.sub.4 in toluene stirred at 70° C. for 2 hours, followed by standard method D using NaOH on C132. C133 was subjected to standard method E using HATU and DIPEA in DMF followed by MsOH-mediated cyclization in dichloromethane, and then standard method B and standard method D using LiCl, respectively to form 156. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.57 (d, J=2.7 Hz, 1H), 7.24-7.10 (m, 4H), 6.94 (dd, J=8.9, 2.7 Hz, 1H), 6.58 (d, J=9.0 Hz, 1H), 3.76 (d, J=11.5 Hz, 2H), 3.04 (s, 2H), 2.28-2.09 (m, 1H), 1.67 (dd, J=41.7, 31.8 Hz, 7H), 1.29-1.18 (m, 5H). LCMS m/z 480.47 [M+H].sup.+

Compounds 157-159

[0613] Compounds 157-159 (Table 13) were prepared four steps from intermediate C133 using appropriate amines according to the method described for compound 156. Any modifications to methods are noted in Table 13 and accompanying footnotes.

TABLE-US-00014 TABLE 13 Method of preparation, structure, physicochemical data for compounds 157-159 .sup.1H NMR; LCMS m/z Compound Method/Product Amines [M + H].sup.+ 157 [00742] [00743] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.20- 8.10 (m, 2H), 7.56 (d, J = 2.6 Hz, 1H), 7.44- 7.38 (m, 2H), 7.32- 7.24 (m, 2H), 7.23- 7.14 (m, 2H), 7.01 (dd, J = 8.9, 2.7 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 3.58-3.47 (m, 2H), 2.71-2.61 (m, 2H), 2.52 (t, J = 11.9 Hz, 1H), 1.44 (d, J = 12.8 Hz, 2H). LCMS m/z 460.39 158 [00744] [00745] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.68 (d, J = 2.6 Hz, 1H), 7.28 (d, J = 7.1 Hz, 5H), 7.06 (dd, J = 8.8, 2.7 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.33-5.21 (m, 1H), 3.97 (dd, J = 11.5, 4.4 Hz, 2H), 3.73 (d, J = 6.1 Hz, 2H), 3.42 (dd, J = 20.4, 10.1 Hz, 1H), 3.18-3.06 (m, 4H), 2.77 (s, 2H), 2.25-2.10 (m, 5H), 1.62 (d, J = 13.4 Hz, 2H). LCMS m/z 424.39 159 [00746] [00747] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.54 (d, J = 2.6 Hz, 1H), 7.16 (d, J = 7.1 Hz, 4H), 6.93 (dd, J = 8.8, 2.7 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 4.90 (p, J = 8.0 Hz, 1H), 3.86 (dd, J = 11.5, 4.4 Hz, 2H), 3.68-3.57 (m, 1H), 3.10-2.92 (m, 4H), 2.50-2.20 (m, 5H), 1.52 (d, J = 12.7 Hz, 2H). LCMS m/z 478.39

Compound 160

4-(4-fluorophenyl)-7-hydroxy-2-(3-hydroxypropyl)-3-tetrahydropyran-4-yl-isoquinolin-1-one (160)

[0614] ##STR00748##

[0615] Compound 160 was obtained directly from a reaction of C132 with 3-aminopropanol followed by MsOH-mediated cyclization and finally standard method B and standard method D. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.94 (s, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.40-7.24 (m, 4H), 7.03 (dd, J=8.8, 2.8 Hz, 1H), 6.56 (s, 1H), 4.73 (s, 1H), 4.23 (s, 2H), 3.56 (d, J=5.4 Hz, 2H), 1.85 (s, 2H), 1.56 (d, J=12.4 Hz, 2H). LCMS m/z found 398.38 [M+H].sup.+.

Compounds 161-165

[0616] Compounds 161-165 (Table 14) were prepared in three to five steps from intermediate C132 using appropriate amines according to the method described for compound 160. Any modifications to methods are noted in Table 14 and accompanying footnotes.

TABLE-US-00015 TABLE 14 Method of preparation, structure, physicochemical data for compounds 161-165 .sup.1H NMR; LCMS m/z Compound Method/Product Amines [M + H].sup.+ 161 [00749] [00750] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.62 (d, J = 2.7 Hz, 1H), 7.35- 7.18 (m, 4H), 7.03 (dd, J = 8.9, 2.7 Hz, 1H), 6.73- 6.61 (m, 1H), 4.98 (s, 2H), 3.80 (d, J = 11.0 Hz, 2H), 3.26 (q, J = 13.2, 10.8 Hz, 5H), 1.69- 1.55 (m, 3H), 1.24 (tdd, J = 10.7, 7.7, 3.6 Hz, 4H), 1.06-0.72 (m, 3H). LCMS m/z 438.34 162 [00751] [00752] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.66 (d, J = 2.6 Hz, 1H), 7.32- 7.20 (m, 5H), 7.04 (dd, J = 8.9, 2.7 Hz, 1H), 6.71 (d, J = 8.9 Hz, 1H), 4.62- 4.44 (m, 2H), 3.87 (d, J = 11.1 Hz, 3H), 3.26- 3.09 (m, 1H), 2.79- 2.66 (m, 3H), 1.63 (d, J = 12.3 Hz, 3H). 163 [00753] [00754] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.68- 7.61 (m, 1H), 7.26 (d, J = 7.9 Hz, 4H), 7.03 (dd, J = 8.9, 2.7 Hz, 1H), 6.71 (s, 1H), 4.28 (t, J = 8.2 Hz, 2H), 4.02 (s, 2H), 3.87 (s, 2H), 3.70 (t, J = 6.3 Hz, 2H), 3.34 (s, 2H), 3.08 (s, 3H), 2.20-2.05 (m, 1H), 2.11 (s, 2H), 1.61 (d, J = 12.0 Hz, 2H). 164 [00755] [00756] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.66 (d, J = 2.6 Hz, 1H), 7.25 (d, J = 7.1 Hz, 3H), 7.04 (dd, J = 8.8, 2.7 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 5.52-5.34 (m, 1H), 3.95 (dd, J = 11.3, 4.3 Hz, 2H), 3.72-3.51 (m, 2H), 3.39 (dd, J = 24.2, 3.7 Hz, 0H), 3.39 (s, 1H), 3.07 (td, J = 11.6, 2.3 Hz, 3H), 2.58 (s, 1H), 2.65-2.50 (m, 1H), 2.15 (qd, J = 12.5, 4.4 Hz, 2H), 1.66-1.55 (m, 2H). LCMS m/z 438.39 165 [00757] [00758] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.64 (d, J = 2.6 Hz, 1H), 7.34- 7.18 (m, 4H), 7.02 (dd, J = 8.9, 2.7 Hz, 1H), 6.65 (d, J = 8.9 Hz, 1H), 5.49 (s, 0H), 4.87 (s, 9H), 4.10 (q, J = 7.1 Hz, 1H), 3.79 (d, J = 11.2 Hz, 2H), 3.49 (s, 2H), 2.01 (s, 1H), 1.61 (d, J = 12.3 Hz, 2H), 1.24 (t, J = 7.1 Hz, 1H), 0.46 (s, 4H). LCMS m/z 424.39 .sup.1Oxidation to aldehyde was performed with Dess-Martin periodinane and NaHCO.sub.3. Further oxidation to carboxylic acid was achieved via treatment with NaClO.sub.2 and 2-methylbut-2-ene and Na.sub.3PO.sub.4. The product was obtained via standard method E using NH.sub.3, HATU, and DIPEA before continuing to standard method B. .sup.2Additional Mitsunobu reaction with the appropriate amine, PPh.sub.3, and ethyl N-ethoxycarbonyliminocarbamate was carried out before continuing to standard method B.

Compounds 166-167

[0617] Compounds 166-167 (Table 15) were prepared in two steps from intermediate S14 using appropriate alcohols according to the method described for compound 116. Any modifications to methods are noted in Table 15 and accompanying footnotes.

TABLE-US-00016 TABLE 15 Method of preparation, structure, physicochemical data for compounds 166-167 .sup.1H NMR; LCMS m/z Compound Method/Product Alcohols [M + H].sup.+ 166 [00759] [00760] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.54 (dd, J = 2.2, 0.9 Hz, 1H), 7.50-7.43 (m, 2H), 7.28-6.87 (m, 4H), 5.71-5.51 (m, 1H), 3.31-3.14 (m, 1H), 3.01- 2.72 (m, 3H), 2.70-2.48 (m, 2H), 1.14 (d, J = 6.7 Hz, 6H). LCMS m/z 412.13 167 [00761] [00762] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.61-7.54 (m, 2H), 7.50 (d, J = 2.5 Hz, 1H), 7.33-7.23 (m, 2H), 7.16 (dd, J = 9.0, 2.6 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 5.34 (q, J = 6.9 Hz, 1H), 2.69 (p, J = 6.6 Hz, 1H), 1.60 (d, J = 7.0 Hz, 3H), 1.08 (dd, J = 18.8, 6.7 Hz, 6H). LCMS m/z 386.14

Compound 168

[0618] Methyl (S)-2-((3-ethyl-4-(4-fluorophenyl)-7-hydroxyisoquinolin-1-yl)oxy)propanoate (168)

##STR00763##

Step 1: 3-ethyl-4-(4-fluorophenyl)-7-methoxy-2H-isoquinolin-1-one (C134)

[0619] Isoquinolinones formation using nitriles. LDA (300 μL of 2 M, 0.6000 mmol) was added dropwise to a solution of S15 (126 mg, 0.3995 mmol) in THF (3 mL) at 0° C. The clear colorless solution turned red and stirred at the same temperature for 1 hours until the temperature warmed up to 0° C. To this, propanenitrile (50 μL, 0.7008 mmol) was added dropwise and the reaction was allowed to warm up to room temperature and stirred for 18 hours. The reaction was quenched with 1N HCl (200 μL) and solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Column: 4 g Combiflash ISCO. Gradient: 10-100% EtOAc in hexane to yield C134 (34 mg, 29%) as an off-white solid. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J=2.8 Hz, 1H), 7.19-7.14 (m, 2H), 7.14-7.03 (m, 3H), 6.92 (d, J=8.9 Hz, 1H), 3.86 (s, 3H), 2.37 (q, J=7.6 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H). LCMS m/z 298.12 [M+H].sup.+.

Step 2: methyl (2S)-2-[[3-ethyl-4-(4-fluorophenyl)-7-methoxy-1-isoquinolyl]oxy]-propanoate (C135)

[0620] CsF-mediated substitution using tosylates. In a round bottom flask, CsF (60 mg, 0.3950 mmol) was heated at 200° C. in vacuo for 15 minutes. The flask was then cooled down to room temperature and purged with N.sub.2. To this flask was sequentially added C134 (35 mg, 0.1174 mmol) and DMF (1 mL). After the mixture was stirred for 5 minutes, methyl (2R)-2-(p-tolylsulfonyloxy)propanoate (33 mg, 0.1278 mmol) was added. The reaction mixture was heated at 50° C. and stirred for 12 hours. The mixture was quenched with ice-water and dried with air. The solid was purified by silica gel chromatography (Column: 4 g Combiflash ISCO. Gradient: 0-50% EtOAc in hexane) to yield as C135 (17 mg, 33%) a colorless clear oil. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.52 (t, J=1.6 Hz, 1H), 7.16-7.05 (m, 6H), 5.42 (q, J=7.0 Hz, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 2.47-2.31 (m, 2H), 1.69 (d, J=7.1 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H). LCMS m/z 714.03 [M+H].sup.+.

Step 3: (2S)-2-[[3-ethyl-4-(4-fluorophenyl)-7-hydroxy-1-isoquinolyl]oxy]propanoic acid (168)

[0621] Method G: Demethylation reaction. To a solution of C135 (17 mg, 0.04434 mmol) in EtSH (250 μL) was added AlBr.sub.3 (70 mg, 0.2625 mmol) at 0° C. The reaction was stirred for 1 hour. More AlBr.sub.3 (70 mg, 0.2625 mmol) were added to push the reaction to completion. After another 1 hour, the reaction was dried under air and the crude product was dissolved in minimal amount of ACN (0.5 mL). The residue was purified by reverse-phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 micron). Gradient: 0-70% MeCN in H.sub.2O with 0.2% formic acid to yield 168 (3 mg, 19%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.73-7.66 (m, 0H), 7.63-7.57 (m, 1H), 7.24-7.14 (m, 6H), 5.53-5.41 (m, 1H), 3.22 (q, J=7.1 Hz, 1H), 2.60-2.43 (m, 2H), 1.79 (dd, J=6.9, 5.6 Hz, 3H), 1.16 (td, J=7.5, 1.8 Hz, 3H). LCMS m/z 356.19 [M+H].sup.+.

Compounds 169-172

[0622] Compounds 169-172 (Table 16) were prepared in three steps from intermediate S15 using appropriate nitriles and alcohols according to the method described for compound 168. Any modifications to methods are noted in Table 16 and accompanying footnotes.

TABLE-US-00017 TABLE 16 Method of preparation, structure, physicochemical data for compounds 169-172 .sup.1H NMR; LCMS m/z Compound Method/Product P.sup.1 Q.sup.1 LG.sup.1 [M + H].sup.+ 169 [00764] [00765] H Br .sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) δ 7.58 (dd, J = 2.5, 0.7 Hz, 1H), 7.32-7.24 (m, 4H), 7.24-7.14 (m, 2H), 5.16 (s, 2H), 3.51- 3.39 (m, 1H), 2.50- 2.37 (m, 2H), 1.95 (s, 2H), 1.90-1.77 (m, 2H). LCMS m/z 368.3 170 [00766] CF.sub.3 CH.sub.3 Ts .sup.1H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 2.5 Hz, 1H), 7.18- 7.03 (m, 6H), 5.55 (q, J = 6.9 Hz, 1H), 1.74 (d, J = 7.0 Hz, 3H). LCMS m/z 396.08 171 [00767] CF.sub.3 CH.sub.3 Ts .sup.1H NMR (400 MHz, Chloroform-d) δ 7.57 (dd, J = 2.2, 1.0 Hz, 1H), 7.23-7.14 (m, 3H), 7.13-7.06 (m, 3H), 5.56 (q, J = 7.0 Hz, 1H), 3.91 (s, 3H), 1.76 (d, J = 7.0 Hz, 3H). LCMS m/z 410.17 172 [00768] [00769] CH.sub.3 Ts .sup.1H NMR (400 MHz, Chloroform-d) δ 7.69- 7.54 (m, 1H), 7.17- 6.98 (m, 7H), 5.47 (dd, J = 7.1, 4.5 Hz, 1H), 3.22- 2.94 (m, 2H), 2.80 (dp, J = 23.2, 12.0, 11.5 Hz, 1H), 2.55 (dtd, J = 16.4, 8.2, 7.2, 3.8 Hz, 2H), 1.77 (d, J = 7.1 Hz, 3H). LCMS m/z 418.14 173 [00770] [00771] — — .sup.1H NMR (400 MHz, Chloroform-d) δ 7.59 (d, J = 2.5 Hz, 1H), 7.24- 7.10 (m, 6H), 5.74- 5.61 (m, 1H), 3.34 (dp, J = 14.2, 4.6 Hz, 1H), 3.20 (pd, J = 8.4, 3.4 Hz, 1H), 3.09-2.86 (m, 4H), 2.74-2.52 (m, 4H). LCMS m/z 444.2 174 [00772] [00773] (CH.sub.3).sub.2 Br .sup.1H NMR (400 MHz, Chloroform-d) δ 7.45 (d, J = 2.6 Hz, 1H), 3.27 (dd, J = 3.3, 1.7 Hz, 2H), 2.58-2.42 (m, 3H), 2.42-2.30 (m, 1H), 2.00 (dtd, J = 23.7, 12.1, 6.1 Hz, 2H), 1.78 (d, J = 14.2 Hz, 2H), 1.70 (s, 6H). LCMS m/z 442.17 .sup.1benzyl 3-(p-tolylsulfonyloxy)cyclobutanecarboxylate was used as the reactant in the second step.

Compound 175

4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-isoquinoline-1-carbonitrile (175)

[0623] ##STR00774##

[0624] Step 1: 7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-isoquinoline-1-carbonitrile (C136)

[0625] DBU (85 μL, 0.5684 mmol) and TMSCN (42 μL, 0.3150 mmol) were added to a suspension of C21 (100 mg, 0.2581 mmol) in dry THF (1.5 mL) at room temperature. The mixture was heated at 50° C. and after stirring for 15 minutes, the mixture became homogeneous. After stirring for 3 hours, a precipitate formed, and the reaction mixture was diluted with EtOAc and washed with 1M HCl. The organic layer was washed with NH.sub.4OH and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (Column: 4 g Combiflash ISCO. Gradient: 0-20% EtOAc in heptane) to afford C136 (40 mg, 39%) as a colorless solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.63 (dd, J=2.3, 0.8 Hz, 1H), 7.58-7.49 (m, 2H), 7.49-7.31 (m, 5H), 7.25 (m, 4H), 5.29 (s, 2H), 3.00 (hept, J=6.8 Hz, 1H), 1.24 (d, J=6.7 Hz, 6H).

Step 2: 4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-isoquinoline-1-carbonitrile (175)

[0626] Compound C136 was subjected to standard method B to furnish 175. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.68 (dd, J=2.4, 0.7 Hz, 1H), 7.44-7.16 (m, 6H), 6.40 (s, 1H), 3.00 (h, J=6.7 Hz, 1H), 1.24 (d, J=6.8 Hz, 6H). LCMS m/z 307.58 [M+H].sup.+.

Compound 176

2-[[3-(dimethylamino)-4-(4-fluorophenyl)-7-methoxy-1-isoquinolyl]oxy]acetic acid (176)

[0627] ##STR00775##

Step 1: methyl 2-[(3-chloro-7-methoxy-1-isoquinolyl)oxy]acetate (C137)

[0628] Method H: Nucleophilic Substitution Using Alcohols. To a mixture of C22 (5.09 g, 22.32 mmol) and methyl 2-hydroxyacetate (1.8 mL, 23.32 mmol), in THF (100 mL) was added dropwise KOtBu (25 mL of 1 M, 25.00 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours. More methyl 2-hydroxyacetate (1.8 mL, 23.32 mmol) and KOtBu (25 mL of 1M, 25.00 mmol) were added to push the reaction to completion. sat. NH.sub.4Cl was added to the reaction mixture and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (1×50 mL), water (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (Column: 120 g gold Combiflash ISCO. Gradient: 0-100% EtOAc in heptane) to give C137 (3560 mg, 55%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.61-7.50 (m, 2H), 7.33 (dt, J=9.0, 1.9 Hz, 1H), 7.24 (s, 1H), 5.12 (d, J=1.4 Hz, 2H), 3.95 (d, J=1.4 Hz, 3H), 3.82 (d, J=1.4 Hz, 3H). LCMS m/z 282.18 [M+H].sup.+.

Step 2: methyl 2-[[3-(dimethylamino)-7-methoxy-1-isoquinolyl]oxy]acetate (C138)

[0629] Method I: Buchwald Coupling Method. A suspension of C137 (70 mg, 0.2401 mmol), N-methylmethanamine (HCl salt) (25 μL, 0.2876 mmol), Cs.sub.2CO.sub.3 (300 mg, 0.9208 mmol), and dioxane (3 mL) was purged under N.sub.2 for 5 minutes. To this, was added RuPhos Pd G2 (10 mg, 0.01287 mmol), and the mixture was purged again under N.sub.2 for another 5 minutes. The reaction mixture was heated to 80° C. and stirred for 2 hours. The reaction mixture was filtered and concentrated under reduce pressure. The residue was dissolved in minimal amount of DMSO (2 mL) and purified by reverse-phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 micron). Gradient: 2-98% MeCN in H.sub.2O with 0.2% formic acid to yield C138 (32 mg, 41%). LCMS m/z 290.91 [M+H].sup.+.

Step 3-5: 2-[[3-(dimethylamino)-4-(4-fluorophenyl)-7-methoxy-1-isoquinolyl]oxy]acetic acid (C139)

[0630] Compound C138 was then subjected to bromination with NBS in dichloromethane. Further transformation to C139 was accomplished according to standard method B using 4-fluorophenyl boronic acid followed by standard method D with NaOH.

Step 6: 2-[[3-(dimethylamino)-4-(4-fluorophenyl)-7-methoxy-1-isoquinolyl]oxy]acetic acid (176)

[0631] Compound 176 was obtained according to standard method G. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.09 (s, 2H), 7.54 (d, J=2.5 Hz, 1H), 7.41-7.34 (m, 2H), 7.30-7.23 (m, 2H), 7.20 (d, J=9.1 Hz, 1H), 7.13 (dd, J=9.1, 2.6 Hz, 1H), 5.04 (s, 2H), 2.80 (s, 6H). LCMS m/z 357.27 [M+H].sup.+.

Compounds 177-181

[0632] Compounds 177-181 (Table 17) were prepared in five steps from intermediate C137 using appropriate amines according to the method described for compound 176. Any modifications to methods are noted in Table 17 and accompanying footnotes.

TABLE-US-00018 TABLE 17 Method of preparation, structure, physicochemical data for compounds 177-181 Compound Method/Product Amines .sup.1H NMR; LCMS m/z [M + H].sup.+ 177 Compound 176 from C137   [00776] [00777] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.53 (d, J = 2.5 Hz, 1H), 7.41 (dd, J = 8.3, 5.5 Hz, 2H), 7.27 (q, J = 9.2, 8.5 Hz, 3H), 7.15 (dd, J = 9.1, 2.6 Hz, 1H), 5.05 (s, 2H), 3.62 (s, 4H), 3.14 (s, 4H). LCMS m/z 399.1 178 Compound 176 from C137.sup.1   [00778] [00779] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.56 (t, J = 1.6 Hz, 1H), 7.30-7.15 (m, 5H), 5.06 (s, 2H), 2.96 (s, 6H), 2.33 (d, J = 1.9 Hz, 3H). LCMS m/z 371.32 179 Compound 176 from C137.sup.1,2   [00780] [00781] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.65 (d, J = 2.5 Hz, 1H), 7.37-7.16 (m, 5H), 5.13 (s, 2H), 3.36-3.31 (m, 2H), 3.22 (d, J = 2.7 Hz, 3H), 3.13 (d, J = 3.3 Hz, 3H), 2.74 (d, J = 65.3 Hz, 2H), 2.39 (d, J = 1.9 Hz, 3H). LCMS m/z 415.21 180 Compound 176 from C137.sup.1   [00782] [00783] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.07 (d, J = 6.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.30 (d, J = 9.1 Hz, 1H), 7.28 -7.23 (m, 1H), 7.21-7.16 (m, 2H), 7.14 (dd, J = 9.2, 2.6 Hz, 1H), 5.04 (d, J = 1.0 Hz, 2H), 3.75 (d, J = 11.5 Hz, 1H), 3.56 (d, J = 11.4 Hz, 2H), 3.27-2.99 (m, 3H), 2.76 (s, 1H), 2.38-2.29 (m, 3H), 1.06 (d, J = 6.3 Hz, 3H). LCMS m/z 427.36 181 Compound 176 from C137.sup.1,3   [00784] [00785] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.40 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 9.2 Hz, 4H), 6.98 (dd, J = 9.2, 2.6 Hz, 1H), 4.96 (d, J = 2.4 Hz, 2H), 4.47 (s, 1H), 3.73-3.62 (m, 1H), 3.45 (d, J =12.5 Hz, 1H), 3.32 (s, 1H), 3.14 (s, 1H), 2.20 (qd, J = 8.4, 4.2 Hz, 1H), 2.01 (d, J = 0.9 Hz, 4H). LCMS m/z 475.3 .sup.1(4-fluoro-3-methyl-phenyl)boronic acid was used in the fourth step. .sup.2MOM deprotection was accomplished using HCl instead of standard method G. .sup.3The reaction with BBr.sub.3 resulted in F displacement to form the product.

Compounds 182-184

[0633] Compounds 182-184 (Table 18) were prepared in two or three steps from intermediate S16 using 3-hydroxycyclobutanecarboxylic acid according to the method described for compound 116. Any modifications to methods are noted in Table 18 and accompanying footnotes.

TABLE-US-00019 TABLE 18 Method of preparation, structure, physicochemical data for compounds 182-184 .sup.1H NMR; LCMS m/z Compound Product Method [M + H].sup.+ 182 [00786] Compound 116 from S16 .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.49 (d, J = 2.5 Hz, 1H), 7.40 (dt, J = 10.7, 8.4 Hz, 1H), 7.21-7.10 (m, 2H), 7.08- 7.01 (m, 2H), 5.68-5.54 (m, 1H), 3.96 (dt, J = 10.3, 4.2 Hz, 2H), 3.38- 3.27 (m, 2H), 3.21 (ttd, J = 10.2, 4.1, 1.1 Hz, 1H), 2.88 (dddd, J = 11.3, 7.3, 4.1, 2.7 Hz, 2H), 2.69 (tt, J = 11.6, 3.7 Hz, 1H), 2.58 (tdd, J = 10.1, 6.6, 2.8 Hz, 2H), 2.16 (qt, J = 12.7, 4.6 Hz, 2H), 1.55- 1.44 (m, 2H). LCMS m/z 456.22 183 [00787] Compound 116 from S16.sup.1 .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.49 (d, J = 2.5 Hz, 1H), 7.40 (dt, J = 10.8, 8.4 Hz, 1H), 7.22-7.10 (m, 2H), 7.08- 7.00 (m, 2H), 5.65-5.54 (m, 1H), 4.01-3.90 (m, 2H), 3.76 (s, 3H), 3.39- 3.21 (m, 4H), 2.94-2.82 (m, 2H), 2.69 (tt, J = 11.7, 3.8 Hz, 1H), 2.64-2.53 (m, 2H), 2.15 (qt, J = 12.7, 4.6 Hz, 2H), 1.56- 1.42 (m, 2H). LCMS m/z 470.22 184 [00788] Compound 116 from S16.sup.2 .sup.1H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J = 2.5 Hz, 1H), 7.32 (d, J = 1.2 Hz, 1H), 7.31-7.24 (m, 1H), 7.14 (dd, J = 9.0, 2.5 Hz, 1H), 7.11-7.02 (m, 2H), 6.98 (d, J = 4.1 Hz, 1H), 5.54 (p, J = 6.5 Hz, 1H), 3.98 (dd, J = 10.7, 5.0 Hz, 2H), 3.44- 3.28 (m, 2H), 3.23 (dt, J = 9.9, 4.9 Hz, 1H), 2.90 (ddd, J = 14.6, 7.2, 4.6 Hz, 2H), 2.72-2.52 (m, 3H), 2.25-2.07 (m, 2H), 1.44 (d, J = 13.9 Hz, 2H). LCMS m/z 455.03 .sup.1Pd-Catalyzed transfer hydrogenation reaction of compound 182 in MeOH also resulted in the formation of compound 179. .sup.2Compound 184 was synthesized from further treatment of compound 182 with NH.sub.4Cl, HATU, and DIPEA according to standard method E.

Compound 185

3-[[7-hydroxy-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (185)

[0634] ##STR00789##

Step 1: 7-benzyloxy-4-(2-methyl-4-pyridyl)-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C34)

[0635] C34 was synthesized according to standard method C.

Step 2: 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-isoquinoline (S20)

[0636] Method J: Amination of N-oxide using TFAA and DABCO. A solution of C34 (513 mg, 1.203 mmol) and DABCO in dichloromethane (10 mL) was cooled to 0° C., and to it was added TFAA (450 μL, 3.237 mmol). The mixture was allowed to warm to room temperature and then stirred for 1 hour. The reaction mixture was concentrated, dissolved in minimal amount of DMSO, and purified by reverse-phase HPLC. (C18, 10-100% MeCN in H.sub.2O with 0.1% trifluoroacetic acid) to yield S20 (Trifluoroacetic Acid salt) as an off-white solid (930 mg, 99%). LCMS m/z 521.35 [M+H].sup.+.

Steps 3 & 4: 3-[[7-hydroxy-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (185)

[0637] S20 was then subjected to standard method A followed by standard method B to form 185. .sup.1H NMR (300 MHz, Chloroform-d and Methanol-d.sub.4) δ 8.54 (dd, J=5.2, 0.8 Hz, 1H), 7.57 (dd, J=2.6, 0.5 Hz, 1H), 7.20-6.98 (m, 4H), 5.71-5.56 (m, 1H), 3.99 (d, J=11.1 Hz, 2H), 3.35-3.09 (m, 2H), 3.00-2.86 (m, 2H), 2.73-2.49 (m, 6H), 2.36-1.97 (m, 3H), 1.48 (d, J=13.0 Hz, 2H). LCMS m/z 435.37 [M+H].sup.+.

Compounds 186-190

[0638] Compounds 186-190 (Table 19) were prepared in four or five steps from intermediate S11 using appropriate boronic acids or esters according to the method described for compound 185. Any modifications to methods are noted in Table 19 and accompanying footnotes.

TABLE-US-00020 TABLE 19 Method of preparation, structure, physicochemical data for compounds 186-190 Boronic acids Compound Method/Product or esters .sup.1H NMR; LCMS m/z [M + H].sup.+ 186 Compound 185 from S11   [00790] [00791] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.80 (d, J = 9.1 Hz, 1H), 7.45 (d, J = 2.6 Hz, 1H), 7.25 (dd, J = 9.1, 2.7 Hz, 1H), 5.53 (p, J = 6.9 Hz, 1H), 4.05 (dd, J = 11.1, 4.3 Hz, 2H), 3.71-3.54 (m, 2H), 3.31- 3.10 (m, 2H), 2.84 (ddd, J = 13.6, 7.0, 3.5 Hz, 2H), 2.52 (dtd, J = 10.7, 7.4, 7.0, 3.4 Hz, 2H), 2.46 (s, 3H), 2.13 (qd, J = 12.6, 4.5 Hz, 2H), 1.67- 1.51 (m, 2H). LCMS m/z 358.22 187 Compound 185 from S11   [00792] .sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) δ 7.60 (dd, J = 9.0, 0.6 Hz, 1H), 7.48 (dd, J = 2.7, 0.5 Hz, 1H), 7.27 (dd, J = 9.0, 2.6 Hz, 1H), 5.62-5.55 (m, 1H), 5.54 (s, 1H), 4.00 (td, J = 10.9, 4.4 Hz, 2H), 3.54- 3.37 (m, 2H), 3.28-3.15 (m, 1H), 3.01 (tt, J = 11.6, 3.7 Hz, 1H), 2.89-2.72 (m, 4H), 2.62- 2.37 (m, 4H), 2.35-2.08 (m, 4H), 1.57-1.42 (m, 2H). LCMS m/z 460.22 188 Compound 185 from S11   [00793] [00794] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.49 (d, J = 2.5 Hz, 1H), 7.42-7.34 (m, 2H), 7.20 (ddd, J = 8.4, 4.6, 2.2 Hz, 1H), 7.14 (dd, J = 9.0, 2.6 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 5.66-5.55 (m, 1H), 3.96 (dt, J = 10.3, 4.5 Hz, 2H), 3.39- 3.32 (m, 2H), 3.26-3.16 (m, 1H), 2.94-2.84 (m, 2H), 2.74- 2.65 (m, 1H), 2.64-2.53 (m, 2H), 2.17 (ddt, J = 16.3, 12.8, 6.3 Hz, 2H), 1.50 (d, J = 13.2 Hz, 2H). LCMS m/z 472.1 189 Compound 185 from S11   [00795] [00796] LCMS m/z 472.2 190 Compound 185 from S11   [00797] [00798] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.69 (dd, J = 9.2, 8.4 Hz, 1H), 7.55-7.46 (m, 1H), 7.31 (dd, J = 8.3, 3.8 Hz, 1H), 7.14 (dd, J = 9.0, 2.6 Hz, 1H), 6.99 (dd, J = 9.0, 0.5 Hz, 1H), 5.69-5.57 (m, 1H), 3.95 (dd, J = 11.6, 4.2 Hz, 2H), 3.31 (p, J = 1.7 Hz, 2H), 3.26-3.16 (m, 1H), 2.89 (dddd, J = 11.3, 7.3, 4.1, 2.7 Hz, 2H), 2.64-2.48 (m, 6H), 2.25-2.08 (m, 2H), 1.64- 1.46 (m, 2H). LCMS m/z 453.14

Compound 191

3-[(4-cyclopropyl-7-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl)oxy]cyclobutanecarboxylic acid (191)

[0639] ##STR00799##

Steps 1 & 2: 3-[(7-benzyloxy-4-bromo-3-tetrahydropyran-4-yl-1-isoquinolyl)oxy]cyclobutanecarboxylic acid (C142)

[0640] C142 was synthesized according to standard method J with S11 followed by standard method A on C141.

Step 3: 3-[(7-benzyloxy-4-cyclopropyl-3-tetrahydropyran-4-yl-1-isoquinolyl)oxy]cyclobutanecarboxylic acid (C143)

[0641] Negishi Coupling Method. A suspension of C142 (20 mg, 0.03751 mmol), bromo(cyclopropyl)zinc (400 μL of 0.5M, 0.200 mmol), and THF (1 mL) was purged under N.sub.2 for 5 minutes. To this was added Cphos Pd G3 (10 mg, 0.0124 mmol) and DavePhos (5 mg, 0.01271 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC. (100 g C18, 10-100% MeCN in H.sub.2O with 0.1% trifluoroacetic acid) to yield C143 (10 mg, 55%). LCMS m/z 474.31 [M+H].sup.+.

Step 4: 3-[(4-cyclopropyl-7-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl)oxy]cyclobutanecarboxylic acid (191)

[0642] Compound 191 was synthesized according to standard method B. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.24 (d, J=9.1 Hz, 1H), 7.43 (d, J=2.6 Hz, 1H), 7.23 (dd, J=9.1, 2.7 Hz, 1H), 5.58-5.46 (m, 1H), 4.06 (dd, J=11.4, 4.3 Hz, 2H), 3.76 (tt, J=11.6, 3.7 Hz, 1H), 3.61 (ddd, J=13.1, 11.4, 1.9 Hz, 2H), 3.24-3.11 (m, 1H), 2.84 (dddd, J=11.4, 7.3, 4.1, 2.5 Hz, 2H), 2.52 (dtd, J=13.5, 6.6, 2.8 Hz, 2H), 2.16 (qd, J=12.8, 4.5 Hz, 2H), 1.88 (tt, J=8.3, 5.6 Hz, 1H), 1.53 (ddd, J=12.9, 3.9, 1.8 Hz, 2H), 1.25-1.15 (m, 2H), 0.53 (td, J=5.9, 4.1 Hz, 2H). LCMS m/z 384.24 [M+H].sup.+.

Compounds 192-194

[0643] Compounds 192-194 (Table 20) were prepared in three or four steps from intermediate S11 using appropriate alkyl zinc reagent or amines according to the method described for compound 191 or. Any modifications to methods are noted in Table 20 and accompanying footnotes.

TABLE-US-00021 TABLE 20 Method of preparation, structure, physicochemical data for compounds 192-194 Alkyl ZnBr .sup.1H NMR; LCMS m/z Compound Method/Product or amines [M + H].sup.+ 192 Compound 191 from S11   [00800] [00801] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.00 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7.19 (dd, J = 9.2, 2.7 Hz, 1H), 5.58-5.46 (m, 1H), 4.25 (p, J = 9.2 Hz, 1H), 4.09-4.00 (m, 2H), 3.59 (ddd, J = 13.1, 11.3, 1.9 Hz, 2H), 3.30 (s, 2H), 3.30- 3.12 (m, 1H), 2.85 (ddt, J = 14.1, 7.3, 3.3 Hz, 2H), 2.68- 2.39 (m, 5H), 2.26-2.09 (m, 3H), 2.01 (dd, J = 11.1, 8.5 Hz, 1H), 1.55 (d, J = 13.3 Hz, 2H). LCMS m/z 398.24 193 Compound 191 from S11.sup.1   [00802] [00803] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.97 (d, J = 9.1 Hz, 1H), 7.47 (d, J = 2.5 Hz, 1H), 7.28 (dd, J = 9.1, 2.6 Hz, 1H), 5.57-5.47 (m, 1H), 4.41 (t, J = 12.8 Hz, 4H), 4.07 (dd, J = 11.5, 4.3 Hz, 2H), 3.63 (ddd, J = 13.1, 11.4, 1.9 Hz, 2H), 3.55 (tt, J = 11.7, 3.7 Hz, 1H), 3.23- 3.11 (m, 1H), 2.84 (dddd, J = 11.3, 7.3, 4.0, 2.5 Hz, 2H), 2.52 (dtd, J = 13.5, 6.5, 2.8 Hz, 2H), 2.13 (qd, J = 12.7, 4.5 Hz, 2H), 1.56 (ddd, J = 13.1,4.0, 1.8 Hz, 2H). LCMS m/z 435.2 194 Compound 191 from S11   [00804] N/A .sup.1H NMR(400 MHz, Methanol-d.sub.4) δ 7.99 (d, J = 9.1 Hz, 1H), 7.45 (d, J = 2.5 Hz, 1H), 7.32 (dd, J = 9.1, 2.6 Hz, 1H), 5.60-5.48 (m, 1H), 4.11-4.02 (m, 2H), 3.67-3.52 (m, 3H), 3.25- 3.13 (m, 1H), 2.85 (dddd, J = 11.3, 7.3, 4.0, 2.5 Hz, 2H), 2.55 (dtd, J = 13.4, 6.6, 2.8 Hz, 2H), 2.15-2.04 (m, 2H), 1.68 (ddd, J = 13.0, 4.0, 1.9 Hz, 2H). LCMS m/z 1Coupling of the amine was performed according to standard method I using tBuXPhos Pd G1 and NaOtBu.

Compound 195

2-[[3-chloro-4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-1-isoquinolyl]oxy]acetic acid (195)

[0644] ##STR00805##

Step 1: 1,3-dichloro-4-(4-fluoro-3-methyl-phenyl)-7-methoxy-isoquinoline (C24)

[0645] Compound C24 was synthesized according to standard method C. .sup.1H MR (400 MHz, Chloroform-d) δ 7.57 (d, J=2.5 Hz, 1H), 7.42 (dd, J=9.3, 0.5 Hz, 1H), 7.33 (dd, J=9.2, 2.6 Hz, 1H), 7.21-7.09 (m, 3H), 4.02 (s, 3H), 2.38 (d, J=1.9 Hz, 3H). LCMS m/z 336.1 [M+H].sup.+.

Step 2: 2-[[3-chloro-4-(4-fluoro-3-methyl-phenyl)-7-methoxy-1-isoquinolyl]oxy]acetic acid (C144)

[0646] Compound C144 was synthesized according to standard method H using NaH. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.63-7.58 (m, 1H), 7.27 (dd, J=9.3, 0.6 Hz, 1H), 7.21 (dd, J=9.2, 2.6 Hz, 1H), 7.17-7.06 (m, 3H), 5.16 (s, 2H), 3.94 (s, 3H), 2.39-2.27 (m, 3H). LCMS m/z 376.21 [M+H].sup.+.

Step 3: 2-[[3-chloro-4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-1-isoquinolyl]oxy]acetic acid (195)

[0647] Compound 195 was synthesized according to standard method G using BBr.sub.3. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.45 (dd, J=2.0, 1.2 Hz, 1H), 7.12-7.07 (m, 2H), 7.07-7.01 (m, 2H), 6.98 (ddd, J=8.0, 5.1, 1.9 Hz, 1H), 4.97 (s, 2H), 2.22 (d, J=2.0 Hz, 3H). LCMS m/z 362.17 [M+H].sup.+.

Compound 196

2-[[4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-3-(2-hydroxy-1-methyl-ethyl)-1-isoquinolyl]oxy]acetic acid (196)

[0648] ##STR00806## ##STR00807##

Step 1: benzyl 2-[[7-benzyloxy-3-chloro-4-(4-fluoro-3-methyl-phenyl)-1-isoquinolyl]oxy]acetate (C95)

[0649] S8 was subjected to standard method H to form C95. LCMS m/z 542.32 [M+H].sup.+.

Step 2: benzyl 2-[[7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropenyl-1-isoquinolyl]oxy]acetate (C97)

[0650] C97 was synthesized according to standard method B using Pd(OAc).sub.2 and XPhos.

Step 3: benzyl 2-[[7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-(2-hydroxy-1-methyl-ethyl)-1-isoquinolyl]oxy]acetate (C145)

[0651] To a suspension of C97 (100 mg, 0.1826 mmol) in THF (2 mL) was added BH.sub.3 (100 of 1M in THF, 0.1000 mmol) at 0° C. The reaction was allowed to stir at room temperature for 2 hours and then cooled back to 0° C. To this was added NaBO.sub.3.4H.sub.2O (30 mg, 0.1950 mmol) in water (2 mL), and the reaction mixture was stirred for 18 hours. The reaction was quenched with 1 MNaS.sub.2O.sub.3 solution (5 mL) and stirred for 30 minutes. The solution was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4 and concentrated. The crude product was purified by silica gel chromatography (Column: 4 g Combiflash ISCO. Gradient: 0-70% EtOAc in hexane) to give C145 (25 mg, 21%) as a light yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J=2.6 Hz, 1H), 7.46-7.38 (m, 2H), 7.37-7.24 (m, 9H), 7.23-7.17 (m, 2H), 7.13 (dd, J=9.2, 2.0 Hz, 1H), 7.06-6.89 (m, 3H), 5.19 (d, J=0.8 Hz, 2H), 5.11 (d, J=8.2 Hz, 2H), 5.08-4.92 (m, 2H), 3.74 (dt, J=10.6, 7.2 Hz, 1H), 3.59 (dt, J=10.6, 3.9 Hz, 1H), 2.89 (tdd, J=7.1, 4.4, 2.7 Hz, 1H), 2.26 (d, J=1.8 Hz, 3H), 2.14 (d, J=27.4 Hz, 1H), 1.23-1.15 (m, 3H). LCMS m/z 566.31 [M+H].sup.+.

Step 4: 2-[[4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-3-(2-hydroxy-1-methyl-ethyl)-1-isoquinolyl]oxy]acetic acid (196)

[0652] C145 was then subjected to standard to standard method B to form 196. .sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) δ 7.42 (dt, J=2.5, 0.7 Hz, 1H), 7.14-6.97 (m, 5H), 5.01-4.85 (m, 2H), 3.73-3.61 (m, 1H), 3.42 (ddd, J=10.3, 5.9, 4.2 Hz, 1H), 2.75 (dddd, J=7.8, 6.8, 5.9, 0.9 Hz, 1H), 2.24 (d, J=2.0 Hz, 3H), 0.97 (dd, J=6.8, 2.9 Hz, 3H). LCMS m/z 386.18 [M+H].sup.+.

Compounds 197-199

[0653] Compounds 197-199 (Table 21) were prepared in three to four steps from intermediate S8 using appropriate boronic acids or esters according to the method described for compound 196. Any modifications to methods are noted in Table 21 and accompanying footnotes.

TABLE-US-00022 TABLE 21 Method of preparation, structure, physicochemical data for compounds 197-199 Boronic acids .sup.1H NMR; LCMS m/z Compound Method/Product or esters [M + H].sup.+ 197 Compound 196 from S8.sup.1   [00808] [00809] .sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) δ 7.57 (s, 1H), 7.35 (d, J = 1.7 Hz, 1H), 7.30-7.15 (m, 4H), 7.15- 7.02 (m, 2H), 6.31 (d, J = 1.8 Hz, 1H), 5.10 (s, 2H), 2.34 (d, J = 2.0 Hz, 3H). LCMS m/z 394.23 198 Compound 196 from S8.sup.1   [00810] [00811] .sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) δ 7.50 (d, J = 2.4 Hz, 1H), 7.20-6.96 (m, 6H), 4.98 (s, 2H), 2.29 (d, J = 2.0 Hz, 3H), 2.28-2.13 (m, 1H), 1.74 (d, J = 33.6 Hz, 6H), 1.58-1.39 (m, 3H). LCMS m/z 396.26 199 Compound 196 from S8.sup.1   [00812] [00813] .sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) δ 7.86-7.58 (m, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.25-7.16 (m, 4H), 7.16-7.01 (m, 1H), 5.04 (s, 2H), 3.95 (td, J = 8.9, 8.4, 5.9 Hz, 1H), 3.88 (t, J = 7.8 Hz, 1H), 3.79 (tt, J = 7.6, 3.9 Hz, 1H), 3.71 (q, J = 8.1 Hz, 1H), 3.27 (p, J = 8.3 Hz, 1H), 2.34 (q, J = 3.3, 2.3 Hz, 4H), 2.30- 2.16 (m, 1H), 1.97 (dt, J = 5.1, 2.7 Hz, 2H). LCMS m/z 398.33 .sup.1Hydroboration step was skipped.

Compound 200

4-((7-hydroxy-3-isopropyl-4-(2-methylpyrimidin-5-yl)isoquinolin-1-yl)oxy)benzoic acid (200)

[0654] ##STR00814##

[0655] S4 was subjected to standard method C-1 and then standard method H followed by standard method A and finally standard method B to form 200. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.96 (s, 1H), 10.28 (s, 1H), 8.70 (s, 2H), 8.14-7.98 (m, 2H), 7.59 (t, J=2.7 Hz, 1H), 7.48-7.38 (m, 2H), 7.31 (dt, J=9.0, 2.1 Hz, 1H), 7.16 (d, J=9.1 Hz, 1H), 2.75 (s, 3H), 2.63 (p, J=6.7 Hz, 1H), 0.97 (d, J=6.6 Hz, 6H). LCMS m/z 416.34 [M+H].sup.+.

Compounds 201-203

[0656] Compounds 201-203 (Table 22) were prepared in five steps from intermediate S4 using appropriate boronic acids or esters according to the method described for compound 200. Any modifications to methods are noted in Table 22 and accompanying footnotes.

TABLE-US-00023 TABLE 22 Method of preparation, structure, physicochemical data for compounds 201-203 Boronic acids or .sup.1H NMR; LCMS m/z Compound Method/Product esters [M + H].sup.+ 201 Compound 200 from S4   [00815] [00816] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.99 (s, 1H), 10.32 (s, 1H), 8.78 (d, J = 5.5 Hz, 1H), 8.10-8.02 (m, 2H), 7.67-7.48 (m, 3H), 7.45-7.39 (m, 2H), 7.31 (dd, J = 9.2, 2.5 Hz, 1H), 7.14 (d, J = 9.1 Hz, 1H), 2.68 (s, 3H), 2.66-2.56 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H). LCMS m/z 415.35 202 Compound 200 from S4   [00817] [00818] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.62 (d, J = 2.7 Hz, 1H), 8.35 (s, 1H), 8.14-8.08 (m, 2H), 7.68 (ddd, J = 9.1, 2.8, 1.6 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.42-7.33 (m, 2H), 7.25 (dd, J = 9.1, 2.5 Hz, 1H), 7.13 (d, J = 9.1 Hz, 1H), 2.70 (hept, J = 6.6 Hz, 1H), 1.04 (dd, J = 6.7, 4.8 Hz, 6H). LCMS m/z 419.35 203 Compound 200 from S4.sup.1   [00819] [00820] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.51 (dd, J = 9.0, 0.6 Hz, 1H), 7.46 (dd, J = 2.5, 0.6 Hz, 1H), 7.16 (dd, J = 9.0, 2.5 Hz, 1H), 7.01- 6.93 (m, 2H), 6.80-6.70 (m, 2H), 5.65-5.51 (m, 1H), 3.25-3.14 (m, 1H), 2.91-2.79 (m, 2H), 2.57 (ddd, J = 13.3, 10.1, 6.6 Hz, 2H), 1.16 (d, J = 6.8 Hz, 6H). .sup.1Ether linkage was synthesized using CuI, 2-(dimethylamino)acetic acid, and Cs.sub.2CO.sub.3 in the first step.

Compounds 204-205

[0657] Compounds 204-205 (Table 23) were prepared in five steps from intermediate S4 using appropriate alcohol according to the method described for compound 200. Any modifications to methods are noted in Table 23 and accompanying footnotes.

TABLE-US-00024 TABLE 23 Method of preparation, structure, physicochemical data for compounds 204-205 .sup.1H NMR; LCMS m/z Compound Method/Product Alcohols [M + H].sup.+ 204 Compound 200 from S4   [00821] None .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.57 (d, J = 8.8 Hz, 1H), 7.41 (dt, J = 2.6, 0.7 Hz, 1H), 7.19 (dd, J = 8.8, 2.5 Hz, 1H), 6.96 (s, 1H), 5.62-5.49 (m, 1H), 3.18 (ttd, J = 10.0, 4.0, 1.1 Hz, 1H), 2.99-2.87 (m, 1H), 2.91- 2.77 (m, 2H), 2.60- 2.46 (m, 2H), 1.29 (d, J = 6.8 Hz, 6H). LCMS m/z 302.13 205 Compound 200 from S4   [00822] [00823] .sup.1H NMR (300 MHz, Chloroform-d and Methanol-d.sub.4) δ 8.51 (dd, J = 5.1, 0.8 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.22- 6.91 (m, 4H), 5.79-5.54 (m, 1H), 3.30-3.14 (m, 1H), 2.92 (dddd, J = 11.7, 7.4, 4.5, 2.7 Hz, 2H), 2.74 (p, J = 6.6 Hz, 1H), 2.67- 2.39 (m, 5H), 1.16 (dd, J = 6.6, 3.3 Hz, 6H) ppm. LCMS m/z 393.3

Compounds 206-211

[0658] Compounds 206-211 (Table 24) were prepared in three to four steps from intermediate S20 using appropriate alcohol according to the method described for compound 116. Any modifications to methods are noted in Table 24 and accompanying footnotes.

TABLE-US-00025 TABLE 24 Method of preparation, structure, physicochemical data for compounds 206-211 .sup.1H NMR; LCMS Compound Method/Product Alcohols m/z [M + H].sup.+ 206 Compound 116 From S20.sup.1   [00824] [00825] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.54 (dd, J = 5.1, 0.8 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.30-7.22 (m, 1H), 7.21-7.13 (m, 2H), 7.11-7.00 (m, 1H), 5.02 (s, 2H), 3.94 (dd, J = 11.4, 4.4 Hz, 2H), 3.31 (p, J = 1.7 Hz, 2H), 2.71- 2.66 (m, 1H), 2.62 (s, 3H), 2.21 (ddq, J = 19.0, 12.5, 6.6, 5.7 Hz, 2H), 1.50 (d, J = 13.4 Hz, 2H). LCMS m/z 394.23 207 Compound 116 from S20.sup.2   [00826] [00827] LCMS m/z 406.25 208 Compound 116 from S20   [00828] [00829] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.81 (d, J = 5.7 Hz, 1H), 7.91 (s, 1H), 7.84 (d, J = 5.4 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.20 (dd, J = 8.9, 2.6 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 5.05 (p, J = 7.3 Hz, 1H), 4.20- 4.05 (m, 1H), 3.96 (dd, J = 11.2, 4.3 Hz, 2H), 3.50 (d, J = 3.5 Hz, 1H), 3.38 (d, J = 11.9 Hz, 2H), 3.06 (dddt, J = 9.2, 6.8, 5.4, 2.3 Hz, 2H), 2.89 (s, 3H), 2.62 (tq, J = 17.2, 5.9, 5.0 Hz, 1H), 2.31-2.10 (m, 5H), 1.55 (dt, J = 16.5, 8.3 Hz, 2H). LCMS m/z 407.24 209 Compound 116 from S20.sup.2   [00830] [00831] LCMS m/z 411.22 210 Compound 116 from S20   [00832] [00833] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.55 (dd, J = 5.2, 0.8 Hz, 1H), 8.09 (s, 2H), 7.51 (dd, J = 4.7, 2.5 Hz, 1H), 7.34-7.27 (m, 1H), 7.21 (dd, J = 5.3, 1.6 Hz, 1H), 7.14 (ddd, J = 9.1, 5.1, 2.6 Hz, 1H), 7.03 (dd, J = 9.0, 4.0 Hz, 1H), 5.74-5.57 (m, 1H), 4.63-4.47 (m, 1H), 3.95 (dd, J = 11.5, 4.2 Hz, 2H), 3.33 (d, J = 11.0 Hz, 2H), 2.82-2.67 (m, 1H), 2.64 (s, 3H), 2.59-2.53 (m, 3H), 2.31-1.99 (m, 2H), 1.58-1.44 (m, 2H). LCMS m/z 407.17 211 Compound 116 from S20.sup.3   [00834] [00835] .sup.1H NMR (300 MHz, Chloroform-d and Methanol-d.sub.4) δ 8.55 (dd, J = 5.1, 0.9 Hz, 1H), 7.59 (ddd, J = 7.7, 2.6, 0.5 Hz, 1H), 7.23- 6.95 (m, 4H), 5.42 (p, J = 4.7 Hz, 1H), 4.72-4.57 (m, 1H), 4.19 (t, J = 5.3 Hz, 1H), 4.10 (d, J = 4.9 Hz, 1H), 4.04-3.89 (m, 4H), 3.79 (qd, J = 11.5, 5.3 Hz, 1H), 2.65 (s, 4H), 2.19 (tt, J = 12.1, 5.7 Hz, 2H), 1.51 (d, J = 13.3 Hz, 2H). LCMS m/z 411.39 .sup.1Standard method E was carried out using NH.sub.4Cl, HATU, and DIPEA before continuing to standard method B. .sup.2Additional treatment with HCl was carried out at the last step. .sup.3Additional treatment with HCl was carried out before continuing to standard method B.

Compound 212

2-hydroxy-1-(3-((7-hydroxy-4-(2-methylpyridin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-1-yl)oxy)azetidin-1-yl)ethan-1-one (212)

[0659] ##STR00836##

[0660] C149 was synthesized according to the method described for compound 206-211. C149 was then treated with HCl to form C150 which underwent further reaction with 2-hydroxyacetic acid according to standard method E using HATU and DIPEA to form 212. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.80 (dd, J=6.1, 0.7 Hz, 1H), 7.90 (t, J=2.1 Hz, 1H), 7.82 (dt, J=5.8, 2.2 Hz, 1H), 7.58 (dd, J=2.6, 0.5 Hz, 1H), 7.24 (dd, J=9.1, 2.6 Hz, 1H), 7.12 (dd, J=9.0, 0.5 Hz, 1H), 5.68 (tt, J=6.7, 4.2 Hz, 1H), 4.89-4.84 (m, 1H), 4.68-4.59 (m, 1H), 4.46 (ddd, J=10.4, 4.5, 1.3 Hz, 1H), 4.26-4.13 (m, 3H), 3.96 (d, J=9.7 Hz, 2H), 3.42-3.32 (m, 2H), 2.87 (s, 3H), 2.69-2.56 (m, 1H), 2.27-2.07 (m, 2H), 1.56 (d, J=13.0 Hz, 2H). LCMS m/z 450.28

Compounds 213-215

[0661] Compounds 213-215 (Table 25) were prepared according to the method described for compound 212 from either intermediate C149 or compound 207 with appropriate alcohols. Any modifications to methods are noted in Table 25 and accompanying footnotes.

TABLE-US-00026 TABLE 25 Method of preparation, structure, physicochemical data for compounds 213-215 .sup.1H NMR; LCMS m/z Compound Method/Product Alcohols [M + H].sup.+ 213 Compound 212 from C149   [00837] [00838] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.79 (d, J = 6.0 Hz, 1H), 7.89 (s, 1H), 7.81 (d, J = 6.0 Hz, 1H), 7.58 (d, J = 2.5 Hz, 1H), 7.24 (dd, J = 9.1, 2.6 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 5.67 (d, J = 7.4 Hz, 1H), 4.98 (t, J = 8.8 Hz, 1H), 4.71-4.47 (m, 2H), 4.34 (q, J = 6.9 Hz, 1H), 4.18 (d, J = 9.4 Hz, 1H), 4.06-3.88 (m, 2H), 3.36 (d, J =12.1 Hz, 2H), 2.86 (s, 3H), 2.71-2.56 (m, 1H), 2.17 (s, 2H), 1.56 (d, J = 13.3 Hz, 2H), 1.37 (d, J = 6.7 Hz, 3H). LCMS m/z 464.18 214 Compound 212 from 207   [00839] [00840] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.81 (d, J = 6.0 Hz, 1H), 7.92 (d, J = 3.7 Hz, 1H), 7.84 (t, J = 5.0 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.21 (dd, J = 9.1, 2.6 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.05-5.87 (m, 1H), 4.31-4.15 (m, 2H), 4.03-3.65 (m, 6H), 3.36 (t, J = 12.2 Hz, 2H), 2.88 (s, 3H), 2.73-2.59 (m, 1H), 2.54-2.33 (m, 2H), 2.32-2.15 (m, 2H), 1.68-1.52 (m, 2H). LCMS m/z 464.18 215 Compound 212 from 207   [00841] [00842] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.72 (d, J = 5.7 Hz, 1H), 8.07 (s, 1H), 7.74-7.59 (m, 2H), 7.48 (q, J = 2.7 Hz, 1H), 7.19 (ddd, J = 9.1, 2.6, 1.0 Hz, 1H), 7.15-7.05 (m, 1H), 5.93 (dd, J = 26.8, 4.2 Hz, 1H), 4.60-4.40 (m, 1H), 4.18-3.64 (m, 6H), 3.41- 3.33 (m, 2H), 2.79 (d, J = 1.6 Hz, 3H), 2.72-2.61 (m, 1H), 2.55-2.34 (m, 2H), 2.23 (td, J = 8.3, 4.1 Hz, 2H), 1.62-1.52 (m, 2H), 1.40-1.29 (m, 3H) LCMS m/z 478.22

Compound 216

3-[[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-2-quinolyl]oxy]cyclobutanecarboxylic acid (216)

[0662] ##STR00843## ##STR00844##

Step 1: 7-benzyloxy-3-(3,6-dihydro-2H-pyran-4-yl)-4-(4-fluorophenyl)quinoline (C151)

[0663] C65 was subjected to standard method C using XPhos Pd G2 to form C151. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.72 (s, 1H), 7.46-7.57 (m, 3H), 7.23-7.45 (m, 9H), 5.73-5.81 (m, 1H), 5.30 (s, 2H), 4.02-4.12 (m, 2H), 3.52 (t, J=5.2Hz, 2H), 1.76-1.88 (m, 2H). .sup.19F NMR (282 MHz, DMSO-d.sub.6) δ −113.9-113.7 (m, 1F). LCMS m/z 412.2 [M+H].sup.+.

Step 2: 7-benzyloxy-3-(3,6-dihydro-2H-pyran-4-yl)-4-(4-fluorophenyl)-1-oxido-quinolin-1-ium (C152)

[0664] Method K: m-CPBA Oxidation to form N-oxide. To a solution of C151 (50 mg, 0.1215 mmol) in dichloromethane (1.5 mL) was added m-CPBA (32 mg, 0.1428 mmol) at 0° C. The mixture was stirred from 0° C. to room temperature over 5 hours then at room temperature for another 3 days. EtOAc (25 mL) was added then the organic layer was washed with 5% aq. solution of NaHCO.sub.3 (3×20 mL) and brine (2×20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to give the crude C152 (50 mg).

Step 3: methyl 3-[[7-benzyloxy-3-(3,6-dihydro-2H-pyran-4-yl)-4-(4-fluorophenyl)-2-quinolyl]oxy]cyclobutanecarboxylate (C153)

[0665] To a stirred solution of C152 (200 mg, 0.4679 mmol) in THF (1 mL) was added methyl 3-hydroxycyclobutanecarboxylate (913.40 mg, 7.0185 mmol) and MsCl (535.99 mg, 0.3622 mL, 4.6790 mmol). The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was quenched with water (5 mL) and extracted with EtOAc (20 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The crude product was purified by silica gel chromatography (Gradient: 0-20% EtOAc in hexane) to give C153 (65 mg, 25%) as colorless gum. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.49 (d, J=7.1 Hz, 2H), 7.41 (t, J=7.4 Hz, 2H), 7.37 — 7.26 (m, 6H), 7.15 (d, J=9.4 Hz, 1H), 7.07 (d, J=9.3 Hz, 1H), 5.29 (d, J=25.5 Hz, 3H), 3.87 (s, 2H), 3.69-3.59 (m, 5H), 2.97-2.67 (m, 4H), 2.24 (d, J=9.2 Hz, 2H), 2.16 (s, 2H). LCMS m/z 540.0 [M+H].sup.+.

Step 4-5: 3-[[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-2-quinolyl]oxy]cyclobutanecarboxylic acid (216)

[0666] C153 was subjected to standard method B to afford C154 and D to afford 216. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.95 (s, 1H), 7.40-7.28 (m, 4H), 7.00 (s, 1H), 6.84 (d, J=3.4 Hz, 2H), 5.35-5.31 (m, 1H), 3.85-3.83 (m, 2H), 3.04-2.99 (m, 2H), 2.90-2.86 (m, 1H), 2.77-2.76 (m, 2H), 2.32-2.23 (m, 4H), 1.35-1.32 (m, 2H), 1.24-1.20 (m, 1H). LCMS m/z 438.0 [M+H].sup.+.

Compound 217

4-[[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-2-quinolyl]oxy]benzoic acid (217)

[0667] ##STR00845##

[0668] Compound 217 was synthesized according to standard method H using Cs.sub.2CO.sub.3 to afford C155 followed by standard method B to get to C156 and finally standard method D. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.91 (s, 1H), 10.08 (s, 1H), 8.05 (d, J=8.3 Hz, 2H), 7.44-7.32(m, 6H), 6.97-6.90 (m, 2H), 6.85 (s, 1H), 3.84 (d, J=11.1 Hz, 2H), 3.06 (t, J=11.7 Hz, 2H), 2.74-2.66 (m, 1H), 2.38-2.32 (m, 2H), 1.50 (d, J=12.8 Hz, 2H). LCMS m/z 460.0 [M+H].sup.+.

Compounds 218-221

[0669] Compounds 218-221 (Table 26) were prepared in two to three steps from intermediate S21 using appropriate alcohols according to the method described for compound 217. Any modifications to methods are noted in Table 26 and accompanying footnotes.

TABLE-US-00027 TABLE 26 Method of preparation, structure, physicochemical data for compounds 218-221 Alcohols or Amines or Alkyl .sup.1H NMR; LCMS m/z Compound Method/Product halides [M + H].sup.+ 218 Compound 217 from S21.sup.1   [00846] [00847] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.33 (s, 1H), 9.96 (s, 1H), 7.39- 7.35 (m, 2H), 7.30-7.27 (m, 2H), 7.04 (s, 1H), 6.86-6.81 (m, 2H), 4.67 (s, 2H), 3.78-3.75 (m, 2H), 2.98 (t, J = 11.6 Hz, 2H), 2.54 (s, 1H), 2.49-2.39 (m, 2H), 2.22-1.90 (m, 6H), 1.29-1.23 (m, 2H). LCMS m/z 452 219 Compound 217 from S21.sup.1   [00848] [00849] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.96 (s, 1H), 7.38 (t, J = 8.7 Hz, 2H), 7.29 (dd, J = 8.3, 5.6 Hz, 2H), 7.02 (s, 1H), 6.84 (d, J = 2.9 Hz, 2H), 4.60 (t, J = 5.6 Hz, 2H), 3.80 (d, J = 9.1 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H), 3.52 (t, J = 7.0 Hz, 2H), 3.02 (t, J = 11.7 Hz, 2H), 2.29-2.19 (m, 4H), 1.98-1.90 (m, 2H), 1.34-1.26 (m, 2H). LCMS m/z 451.0 220 Compound 217 from S21   [00850] [00851] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.92 (s, 1H), 7.38 (t, J = 8.7 Hz, 2H), 7.30 (dd, J = 8.5, 5.6 Hz, 2H), 7.02 (d, J = 2.2 Hz, 1H), 6.88-6.78 (m, 2H), 4.55 (t, J = 7.5 Hz, 2H), 4.45 (s, 1H), 3.82 (d, J = 8.4 Hz, 2H), 3.01 (t, J = 11.6 Hz, 2H), 2.60 (d, J = 12.7 Hz, 1H), 2.40-2.33 (m, 1H), 1.97 (t, J = 7.6 Hz, 2H), 1.31 (d, J= 12.5 Hz, 2H), 1.23 (s, 221 Compound 217 from S21.sup.1   [00852] [00853] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.93 (s, 1H), 7.38 (t, J = 8.7 Hz, 2H), 7.31-7.27 (m, 2H), 7.01 (d, J = 2.2 Hz, 1H), 6.86- 6.80 (m, 2H), 4.49 (t, J = 5.2 Hz, 2H), 3.86-3.78 (m, 4H), 3.02 (t, J = 11.6 Hz, 2H), 2.66-2.57 (m, 1H), 2.45 - 2.37 (m, 2H), 1.30 (d, J = 13.2 Hz, 2H). LCMS 384.0 .sup.1Standard method H was carried out using NaH.

Compound 222

3-[[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-2-quinolyl]amino]bicyclo[1.1.1]pentane-1-carboxylic acid (222)

[0670] ##STR00854## ##STR00855##

Steps 1-3: 7-benzyloxy-4-(4-fluorophenyl)-1-oxido-3-tetrahydropyran-4-yl-quinolin-1-ium (C159)

[0671] Compound C159 was synthesized according to standard method B followed by standard method F and standard method K (via the intermediates C157 and C158). .sup.1H NMR (300 MHz, Chloroform-d) δ 8.63 (s, 1H), 8.22 (s, 1H), 7.46-7.54 (m, 2H), 7.31-7.45 (m, 3H), 7.13-7.30 (m, 6H), 5.27 (s, 2H), 3.99 (dd, J=11.4, 3.7Hz, 2H), 3.26 (t, J=11.5Hz, 2H), 2.70 (tt, J=12.1, 3.5Hz, 1H), 1.85 (qd, J=12.4, 4.1Hz, 2H), 1.60 (br d, J=12.4 Hz, 2H); .sup.19F NMR (282 MHz, Chloroform-d) δ −112.6 (s, 1F). LCMS m/z 430.2 [M+H].sup.+.

Step 4: methyl 3-[[7-benzyloxy-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-2-quinolyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (C160)

[0672] A mixture of C159 (150.9 mg, 0.3510 mmol), methyl 3-aminobicyclo[1.1.1]-pentane-1-carboxylate (HCl salt) (116.8 mg, 0.6576 mmol), PyBroP (497.3 mg, 1.067 mmol) and DIPEA (200 μL, 1.148 mmol) in DCE (3 mL) was stirred at 60° C. for 18 hours. The mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with water, dried over MgSO.sub.4, filtered, and evaporated. The residue was purified by silica gel chromatography (Column: 4 g Combiflash ISCO. Gradient: 0-70% EtOAc in heptane) to give C160 (135.7 mg, 65%) as a white solid. LCMS m/z 553.4 [M+H].sup.+.

Steps 5-6: 3-[[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-2-quinolyl]amino]bicyclo[1.1.1]pentane-1-carboxylic acid (222)

[0673] C160 was then subjected to standard method B to give C161 which was subjected to standard method D to form 222. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.38 (s, 1H), 9.65 (s, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.24 (dd, J=8.5, 5.7 Hz, 2H), 6.87 (s, 1H), 6.63-6.56 (m, 2H), 5.76 (s, 1H), 3.74 (d, J=9.6 Hz, 2H), 3.19 (d, J=11.4 Hz, 2H), 2.88 (s, 1H), 2.44 (s, 6H), 1.68 (s, 2H), 1.35 (d, J=13.0 Hz, 2H). LCMS m/z 449.32 (M+H).sup.+.

Compounds 223-230

[0674] Compounds 223-230 (Table 27) were prepared in six steps from intermediate C151 using appropriate alcohols according to the method described for compound 222. Any modifications to methods are noted in Table 27 and accompanying footnotes.

TABLE-US-00028 TABLE 27 Method of preparation, structure, physicochemical data for compounds 223-230 Alcohols or Amines or Alkyl .sup.1H NMR; LCMS m/z Compound Method/Product halides [M + H].sup.+ 223 Compound 222 from C151   [00856] [00857] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.20 (s, 1H), 10.75 (s, 1H), 7.47- 7.38 (m, 2H), 7.38-7.32 (m, 2H), 7.16 (s, 1H), 6.83 (s, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.12-3.57 (m, 7H), 3.15 (s, 2H), 2.95 (s, 1H), 2.42 (q, J = 10.6, 9.9 Hz, 2H), 2.07-1.93 (m, 1H), 1.86 (s, 2H), 1.46 (d, J = 12.8 Hz, 2H). LCMS m/z 451.3 224 Compound 222 from C151   [00858] [00859] .sup.1H NMR (DMSO-d.sub.6) δ 12.5 (br, 1H), 9.63 (s, 1H), 7.34 (t, J = 8.8 Hz, 2H), 7.26 (t, J = 5.5 Hz, 2H), 6.83 (s, 1H), 6.62-6.56 (m, 2H), 6.14 (br, 1H), 3.81- 3.78 (m, 2H), 3.64-3.62 (m, 2H), 3.08-2.66 (m, 4H), 1.94-1.92 (m, 2H), 1.37-1.34 (m, 2H), 1.14 (d, J = 7.0 Hz, 3H). LCMS m/z 425 225 Compound 222 from C151   [00860] [00861] .sup.1H NMR (Methanol-d.sub.4) δ 7.37-7.29 (m, 5H), 6.92- 6.84 (m, 2H), 4.73-4.69 (m, 1H), 3.92-3.89 (m, 2H), 3.30-3.21 (m, 2H), 3.06-2.99 (m, 1H), 2.95- 2.84 (m, 2H), 2.02-1.99 (m, 2H), 1.53-1.47 (m, 5H). LCMS m/z 425 226 Compound 222 from C151   [00862] [00863] .sup.1H NMR (DMSO-d.sub.6) δ 12.5 (br, 1H), 10.8 (br, 1H), 7.42 (t, J = 8.8 Hz, 2H), 7.34-7.31 (m, 3H), 6.80-6.72 (m, 2H), 3.91- 3.90 (m, 2H), 3.79-3.77 (m, 2H), 3.16-3.14 (m, 2H), 2.90-2.88 (m, 1H), 2.77-2.66 (m, 2H), 1.74 (br, 2H), 1.39-1.36 (m, 2H). LCMS m/z 411 227 Compound 222 from C151   [00864] [00865] .sup.1H NMR (DMSO-d.sub.6) δ 13.9 (br, 1H), 9.75 (s, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.28 (d, J = 7.0 Hz, 1H), 6.85 (s, 1H), 6.65-6.59 (m, 2H), 6.22 (br, 1H), 3.83- 3.75 (m, 4H), 3.06-3.04 (m, 2H), 2.80-2.78 (m, 1H), 2.0 (br, 2H), 1.40- 1.37 (m, 2H), 1.10-1.07 (m, 4H). LCMS m/z 437 228 Compound 222 from C151   [00866] [00867] .sup.1H NMR (DMSO-d.sub.6) δ 12.4 (br, 1H), 9.64 (s, 1H), 7.34 (t, J = 8.8 Hz, 2H), 7.26 (t, J = 2.8 Hz, 2H), 6.83 (s, 1H), 6.62-6.59 (m, 2H), 5.88 (br, 1H), 4.75- 4.71 (m, 1H), 3.80-3.77 (m, 2H), 3.09-3.07 (m, 2H), 2.80-2.65 (m, 3H), 1.89-1.78 (m, 2H), 1.41- 1.36 (m, 2H), 1.30 (d, J = 6.56 Hz, 3H). LCMS m/z 425 229 Compound 222 from C151.sup.1   [00868] [00869] .sup.1H NMR (DMSO-d.sub.6) δ 9.6 (br, 1H), 7.35 (t, J = 8.4 Hz, 2H), 7.28-7.25 (m, 2H), 6.82 (s, 1H), 6.64-6.58 (m, 2H), 6.12 (br, 1H), 4.6 (br, 1H), 3.82 (d, J = 7.76 Hz, 2H), 3.11 (br, 2H), 2.89- 2.87 (m, 2H), 2.08 (br, 2H), 1.48 (br, J = 6.95, 3H), 1.43-1.40 (m, 2H). LCMS m/z 411 230 Compound 222 from C151.sup.2   [00870] [00871] .sup.1H NMR (DMSO-d.sub.6) δ 12.5 (br, 1H), 9.6 (br, 1H), ), 7.35 (t, J = 8.4 Hz, 2H), 7.27-7.25 (m, 2H), 6.82 (d, J = 1.76 Hz, 1H), 6.64- 6.58 (m, 2H), 5.99 (br, 1H), 4.76-4.69 (m, 1H), 3.82-3.80 (m, 2H), 3.12- 2.86 (m, 3H), 1.90 (br, 2H), 1.50 (d, J = 7.08 Hz, 3H), 1.40 (d, J = 12.8 Hz, 2H). LCMS m/z 411 .sup.1HCl was used in standard method D .sup.2TFA was used in standard method D

Compound 231

(3R)-1-[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-2-quinolyl]pyrrolidine-3-carboxylic acid (231)

[0675] ##STR00872##

Step 1: methyl-(3R)-1-[7-benzyloxy-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-2-quinolyl]pyrrolidine-3-carboxylate (C162)

[0676] A mixture of S21 (300 mg, 0.6698 mmol), methyl-(3R)-pyrrolidine-3-carboxylate (HCl salt) (332.79 mg, 2.0094 mmol), K.sub.2CO.sub.3 (370.28 mg, 2.6792 mmol) and 1,4 dioxane (5 mL) was purged with N.sub.2 for 10 minutes and then P(t-Bu).sub.3 Pd G4 (85.226 mg, 0.1340 mmol) was added. The reaction mixture was heated to 85° C. and stirred for 48 hours. The reaction mixture was filtered through Celite, washed with 10% MeOH in dichloromethane and concentrated. This crude product was purified by silica gel chromatography (Eluent: % EtOAc in hexane) to afford C162 (200 mg, 38%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.46 (d, J=7.1 Hz, 2H), 7.43-7.28 (m, 6H), 7.21-7.12 (m, 2H), 7.10-7.03 (m, 1H), 6.91 (ddd, J=9.5, 7.0, 2.6 Hz, 1H), 6.75 (dd, J=18.5, 9.2 Hz, 1H), 5.23 (d, J=3.0 Hz, 2H), 4.13 (q, J=6.9 Hz, 1H), 3.77 (ddd, J=16.4, 12.1, 4.9 Hz, 3H), 3.67 (s, 3H), 3.66-3.54 (m, 2H), 3.45 (dd, J=9.9, 5.6 Hz, 1H), 3.28-3.16 (m, 5H), 2.22 (s,1H), 2.10 (dd, J=12.3, 7.5 Hz, 1H), 1.67 (d, J=15.4 Hz, 1H), 1.57 (s, 2H), 1.55-1.35 (m,3H), 1.32-1.13 (m, 1H). LCMS m/z 541.5 [M+H].sup.+.

Steps 2-3: (3R)-1-[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-2-quinolyl]pyrrolidine-3-carboxylic acid (231)

[0677] C162 was then subjected to standard method B to afford C163 and standard method D to form 231. .sup.1E NMR (DMSO-d.sub.6) δ 9.99 (brs,1H), 7.38-7.31 (m, 4H), 6.95 (d, J=2.28 Hz 1H), 6.74-6.71 (m, 1H,), 6.63 (d, J=9.04 Hz, 1H), 3.75-3.68 (m, 3H), 3.57-3.41 (m,3H), 3.46-3.18 (m,4H), 3.11(t, J=7.24,1H), 2.18-2.06(m,2H), 1.54-1.52 (m,3H), 1.40-1.37 (m,1H). LCMS m/z 437.2 (M+H).sup.+.

Compounds 232-234

[0678] Compounds 232-234 (Table 28) were prepared in six steps from intermediate S21 using appropriate alcohols according to the method described for compound 231. Any modifications to methods are noted in Table 28 and accompanying footnotes.

TABLE-US-00029 TABLE 28 Method of preparation, structure and physicochemical data for compounds 232-234 Alcohols or Amines or .sup.1H NMR; LCMS m/z Compound Method/Product Alkyl halides [M + H].sup.+ 232 Compound 222 from C151..sup.2   [00873] [00874] .sup.1H NMR (DMSO-d.sub.6) δ 9.99 (brs, 1H), 7.36- 7.26 (m, 4H), 6.93 (d, J = 2.16 Hz, 1H), 6.70- 6.62 (m, 1H), 6.61 (d, J = 9 Hz, 1H), 4.32-4.24 (m, 4H), 3.71 (d, J = 11 Hz, 2H), 3.52-3.45 (m, 1H), 3.22-3.17 (m, 2H), 2.96 (brs, 1H), 1.44 (brs, 4H). LCMS m/z 423.2 233 Compound 216 from S21   [00875] [00876] .sup.1H (DMSO-d.sub.6) δ 9.99 (brs, 1H), 7.37-7.29 (m, 4H), 7.29 (brs, 1H), 6.95 (d, J = 2.16 Hz, 1H), 6.72-6.70 (m, 1H), 6.63 (d, J = 9.08 Hz, 1H), 4.67-4.59 (m, 2H), 4.34-4.27 (m, 2H), 3.71-3.68 (m, 2H), 3.33-3.26 (m, 2H), 2.92 (brs, 1H), 1.45-1.42 (m, 4H). LCMS m/z 441.2 234 Compound 216 from S21   [00877] [00878] .sup.1H (DMSO-d.sub.6) δ 7.38- 7.31 (m, 4H), 6.95 (d, J = 2.28 Hz, 1H), 6.74- 6.71 (m, 1H), 6.63 (d, J = 9.04 Hz, 1H), 3.75- 3.68 (m, 3H), 3.57- 3.52 (m, 3H), 3.57- 3.52 (m, 2H), 3.46- 3.41 (m, 1H), 3.21- 3.14 (m, 3H), 3.13- 3.09 (t, J = 7.28 Hz, 1H), 2.18-2.06 (m, 2H), 1.54-1.49 (m, 3H), 1.40-1.37 (m, 1H). LCMS m/z 437.2

Compound 235

3-((4-(4-fluorophenyl)-7-hydroxy-2-oxo-3-(tetrahydro-2H-pyran-4-yl)quinolin-1(2H)-yl)methyl)cyclobutane-1-carboxylic acid (235)

[0679] ##STR00879##

[0680] Compound 235 was synthesized according to standard method F using Cs.sub.2CO.sub.3 on C164 (coming from S21) to afford C165 followed by standard method B and finally standard method D (via C166). .sup.1H (DMSO-d.sub.6) δ 12.0 (bs, 1H), 10.21 (bs, 1H), 7.36 (t, J=8.7 Hz, 2H), 7.29 (dd, J=8.4, 5.1 Hz, 2H), 6.83 (d, J=2.9 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 6.57 (d, J=8.9 Hz, 1H), 4.41-4.24 (m, 1H), 3.79 (d, J=10.9 Hz, 2H), 2.93 (m, 2H), 2.78 (s, 1H), 2.44 (s, 3H), 2.20-2.08 (m, 5H), 1.20 (bs, 2H). LCMS m/z 452 (M+H).sup.+.

Compound 236

3-(4-(4-fluorophenyl)-7-hydroxy-2-oxo-3-(tetrahydro-2H-pyran-4-yl)quinolin-1(2H)-yl)cyclobutane-1-carboxylic acid (236)

[0681] Compound 236 (Table 29) was prepared in three steps from intermediate C164 using appropriate alcohol according to the method described for compound 235. Any modifications to methods are noted in Table 29 and accompanying footnotes.

TABLE-US-00030 TABLE 29 Method of preparation, structure and physicochemical data for compound 236 Alcohols or Amines or Alkyl .sup.1H NMR; LCMS m/z Compound Method/Product halides [M + H].sup.+ 236 [00880] [00881] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.33 (bs, 1H), 9.93 (s, 1H), 7.40- 7.28 (m, 4H), 6.99 (d, J = 2.1 Hz, 1H), 6.84 − 6.83 (m, 2H), 5.52 (t, J = 6.9 Hz, 1H), 3.85 − 3.83 (m, 2H), 3.15 − 2.99 (m, 4H), 2.74 − 2.70 (m, 2H), 2.61 − 2.58 (m, 1H), 2.43 − 2.38 (m, 3H), 1.35 (d, J = 12.6 Hz, 2H). LCMS m/z 438 .sup.1. K.sub.2CO.sub.3 was used in the first step.

Compound 237

4-(4-fluorophenyl)-3-isopropyl-2-methyl-quinolin-7-ol (237)

[0682] ##STR00882##

Step 1: 4-(4-fluorophenyl)-3-isopropyl-7-methoxy-2-methyl-quinoline (C167)

[0683] To a solution of C51 (100 mg, 0.4004 mmol), (4-fluorophenyl)boronic acid (123 mg, 0.879 mmol) and Pd(dppf)Cl.sub.2 (18 mg, 0.022 mmol) in DMF (3 mL), an aqueous solution of Na.sub.2CO.sub.3 (610 μL of 2M, 1.22 mmol) was added under N.sub.2 and reaction was heated in a microwave reactor at 130° C. for 4 hours. Water was added, the mixture was extracted with EtOAc, the organic phases combined and concentrated. Purification by reverse-phase HPLC (Method: C18 Waters Sunfire column, 30×150 mm, 5 micron. Gradient: MeCN in H.sub.2O with 0.1% trifluoroacetic acid) afforded C167 (20 mg, 16%) 1H NMR (300 MHz, Chloroform-d) δ 8.41 (s, 1H), 7.30 (d, J=10.0 Hz, 3H), 7.21 (d, J=9.7 Hz, 3H), 4.08 (s, 3H), 3.30 (s, 3H), 1.27 (d, J=7.0 Hz, 6H). LCMS m/z 310.24 [M+H].sup.+

Step 2: 4-(4-fluorophenyl)-3-isopropyl-2-methyl-quinolin-7-ol (237)

[0684] To a solution of C167 (20 mg, 0.06465 mmol) in dry dichloromethane (1 mL), a solution of BBr.sub.3 (500 μL of 1M, 0.500 mmol) in dichloromethane was added and the reaction was stirred under nitrogen for 60 hours. Water and ice were added, the mixture was stirred for 1 hours, extracted with dichloromethane. Purification by silica gel chromatography (0-10% of MeOH in dichloromethane) afforded 237 (11 mg, 55%). .sup.1H NMR (300 MHz, Chloroform-d) δ 7.55 (s, 1H), 7.26 — 7.06 (m, 4H), 6.85 (d, J=9.1 Hz, 1H), 6.75 (d, J=9.1 Hz, 1H), 3.16 (h, J=7.2 Hz, 1H), 2.87 (s, 3H), 1.23 (d, J=7.3 Hz, 6H). LCMS m/z 296.24 [M+H].sup.+

Compound 238

4-[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-2-quinolyl]butanoic acid (238)

[0685] ##STR00883##

Step 1: methyl 4-[4-(4-fluorophenyl)-3-isopropyl-7-methoxy-2-quinolyl]butanoate (C168)

[0686] To a mixture of Zn—Cu couple (390.9 mg, 3.032 mmol) in toluene (4 mL) and DMA (1 mL), methyl 4-iodobutanoate (414.8 mg, 1.82 mmol) was added under argon. The reaction was heated at 85° C. for 150 minutes and cooled to room temperature. Then, S22 (100 mg, 0.303 mmol) and Pd(PPh.sub.3).sub.4 (70 mg, 0.061 mmol) were added and the reaction was heated at 85° C. for 16 hours. The mixture was diluted with EtOAc and filtered. The organic phase was washed successively with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. Purification by silica gel chromatography (0-20% EtOAc in hexanes) afforded C168 (60 mg, 35%). LCMS m/z 396.1 [M+H].sup.+

Step 2: 4-[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-2-quinolyl]butanoic acid (238)

[0687] To a solution of C168 (60 mg, 0.1517 mmol) in dichloromethane (2 mL), a solution of BBr.sub.3 (1M in dichloromethane) (0.7585 mL of 1M, 0.7585 mmol) was added at −20° C. The reaction was stirred for 8 hours at 25° C. The reaction was concentrated and purified by reverse phase HPLC (Method: C18 YMC Triart Actus column, 20×250 mm, 5 micron. Gradient: acetonitrile in water with 20 mM Ammonium Bicarbonate) to afford 238 (5.5 mg, 10%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.08 (s, 1H), 9.98 (s, 1H), 7.38-7.27 (m, 4H), 7.15 (bs, 1H), 6.95 (d, J=9.08 Hz, 1H), 6.86 (d, J=9.04, 1H), 3.48 (t, J=4.84 Hz, 1H), 3.41 (t, J=5.04 Hz, 1H), 3.08 (bs, 1H), 2.99 (t, J=7.52 Hz, 1H), 2.42 (t, J=7.2 Hz, 2H), 2.02 (t, J=7.44 Hz, 2H), 1.11 (d, J=6.04 Hz, 6H). LCMS m/z 368 [M+H+]

Compounds 239-243

[0688] Compounds 239-243 (Table 30) were prepared in two steps from intermediate S22 and the appropriate alkyl iodide or alkyl zincate according to the method described for compound 238. Any modifications to methods are noted in Table 30 and accompanying footnotes.

TABLE-US-00031 TABLE 30 Method of preparation, structure, physicochemical data for compounds 239-243 Alkyl iodide or .sup.1H NMR; LCMS m/z Compound Method/Product zincate [M + H].sup.+ 239 [00884] [00885] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.70 (s, 2H), 7.37 (t, J = 8.8 Hz, 2H), 7.29 (ddd, J = 8.5, 5.4, 2.5 Hz, 2H), 7.18 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 9.1,2.5 Hz, 1H), 6.85 (d, J = 9.1 Hz, 1H), 3.25 (t, J = 7.0 Hz, 2H), 3.16 (s, 1H), 2.85 (t, J = 7.0 Hz, 2H), 1.17 (d, J = 7.1 Hz, 6H). LCMS m/z 354.17 [M + H+] 240 [00886] [00887] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.38 (t, J = 8.68 Hz, 2H), 7.30 (t, J = 5.64 Hz, 2H), 7.13 (d, J = 2.32 Hz, 1H), 6.94 − 6.92 (m, 1H), 6.85 (d, J = 9.04 Hz, 1H), 3.38 (m, 2H), 3.14 (bs, 1H), 3.07 − 3.03 (m, 1H), 1.23 (d, J = 6.72 Hz, 3H), 1.15 (s, 6H). LCMS m/z 368 [M + H+] 241 [00888] [00889] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.38 (t, J = 8.68 Hz, 2H), 7.30 (t, J = 5.64 Hz, 2H), 7.13 (d, J = 2.32 Hz, 1H), 6.94 − 6.92 (m, 1H), 6.85 (d, J = 9.04 Hz, 1H), 3.38 (m, 2H), 3.14 (bs, 1H), 3.07 − 3.03 (m, 1H), 1.23 (d, J = 6.72 Hz, 3H), 1.15 (s, 6H). LCMS m/z 368.1 [M + H+] 242 [00890] [00891] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.38 − 7.28 (m, 4H), 7.14 (d, J = 2.36 Hz, 1H), 6.94 (dd, J1 = 2.39 Hz, J2 = 9.12 Hz, 1H), 6.86 (d, J = 9.04 Hz, 1H), 3.41 − 3.36 (m, 1H), 3.14 (bs, 1H), 2.22 − 2.17 (m, 1H), 2.15 − 1.91 (m, 3H), 1.28 (d, J = 6.48 Hz, 3H), 1.18 (d, J = 5.28 Hz, 6H). LCMS m/z 382.4 [M + H+] 243 [00892] [00893] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.21 (s, 1H), 9.98 (s, 1H), 7.36 (t, J = 8.7 Hz, 2H), 7.29 (t, J = 6.8 Hz, 2H), 7.15 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 9.0, 2.5 Hz, 1H), 6.85 (d, J = 9.1 Hz, 1H), 3.10 (s, 1H), 3.04 − 2.93 (m, 1H), 2.61 − 2.52 (m, 1H), 1.95 (s, 1H), 1.18 (d, J = 7.0 Hz, 3H), 1.15 (s, 5H). LCMS m/z 382 [M + H+] .sup.1. The reaction was started with the zincate, no treatment with ZnCu couple was necessary. THF was used as solvent for the Negishi coupling.

Compound 244

3-[[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-2-quinolyl]amino]-2-methyl-propanoic acid (244)

[0689] ##STR00894##

Step 1: methyl 3-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropenyl-2-quinolyl]amino]-2-methyl-propanoate (C169)

[0690] To a solution of S32 (600 mg, 1.55 mmol), methyl 3-amino-2-methylpropanoate hydrochloride (478.24 mg, 3.11 mmol) in dichloromethane (10 mL), DIEA (1.006 g, 1.39 mL, 7.7835 mmol) was added followed by PyBrop (2.18 g, 4.67 mmol) and the reaction was heated at 45° C. for 18 h. The mixture was diluted with dichloromethane, washed successively with an aqueous solution NaHCO.sub.3 (5 mL) and water (10 mL), the organic phase was dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (10% EtOAc in hexanes) afforded C169 (350 mg, 43%). LCMS m/z 485.3 [M+H].sup.+

Step 2: methyl 3-[[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-2-quinolyl]amino]-2-methyl-propanoate (C170)

[0691] To a solution of C169 (300 mg, 0.6191 mmol) in EtOH (20 mL), Pd/C (250 mg, 2.3492 mmol) was added under argon. The reaction was purged with hydrogen and stirred at room temperature for 18 h. The mixture was filtered and concentrated to afford C170 (190 mg, 62%). LCMS m/z 397.0 [M+H].sup.+

Step 3: 3-[[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-2-quinolyl]amino]-2-methyl-propanoic acid (244)

[0692] To a solution of C170 (200 mg, 0.5045 mmol) in THF (2 mL), Methanol (0.5 mL) and water (0.2 mL), LiOH (60 mg, 2.52 mmol) was added and the reaction stirred at room temperature for 18 hours. The mixture was concentrated, diluted with water (5 mL), acidified with a saturated aqueous solution of citric acid and extracted with EtOAc (2 mL×2). The organic phases were combined, dried over Na.sub.2SO.sub.4 and concentrated. Purification by reverse-phase HPLC (Method: C18 YMC Triart Actus column, 20×250 mm, 5 micron. Gradient: acetonitrile in water with 20 mM Ammonium Bicarbonate) afforded 244 (65 mg, 34%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.59 (s, 1H), 7.35-7.31 (t, 2H J=8.76 Hz), 7.26-7.22 (q, 2H), 6.83 (d, 1H J=2.16), 6.61-6.55 (m, 2H,), 5.95 (s, 1H), 3.68-3.60 (m, 2H), 2.96-2.89 (m, 2H), 1.17-1.13 (m, 9H). LCMS m/z 383.2 [M+H+]

Compounds 245-252

[0693] Compounds 245-252 (Table 31) were prepared in three steps from intermediate S32 and the appropriate amine according to the method described for compound 244. Any modifications to methods are noted in Table 31 and accompanying footnotes.

TABLE-US-00032 TABLE 31 Method of preparation, structure, physicochemical data for compounds 244-252 .sup.1H NMR; LCMS m/z Compound Method/Product Amine [M + H].sup.+ 245 [00895] [00896] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.25 (brs, 1H), 9.59 (s, 1H), 7.35 − 7.33 (t, 2H J = 8.76 Hz), 7.26 − 7.24 (m, 2H), 6.82 − 6.82 (d, 1H, J = 2.04 Hz), 6.61 − 6.54 (m, 2H,), 5.75 (s, 1H), 4.76 − 4.73 (t, 1H, J = 6.88 Hz), 2.94 − 2.69 (m, 1H), 2.69 − 2.63 (m, 2H), 1.30 − 1.28 (d, 3H, J = 6.52 Hz), 1.18 − 1.13 (t, 6H, J = 8.08 Hz). LCMS m/z 383 [M + H.sup.+] 246 [00897] [00898] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.86 (bs, 1H), 9.64 (s, 1H), 7.35 (t, J = 8.86 Hz, 2H), 7.26 (t, J = 6.7 Hz, 2H), 6.82 (bs, 1H), 6.65 − 6.58 (m, 2H), 5.86 (bs, 1H), 4.73 (q, 1H), 3.05 − 2.95 (m, 1H), 1.5 (s, 3H), 1.19 (bs, 6H). LCMS m/z 369 [M + H.sup.+] 247 [00899] [00900] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.82 (bs, 1H), 9.64 (s, 1H), 7.35 (t, J = 8.8 Hz, 2H), 7.26 (t, J = 6.9 Hz, 2H), 6.82 (s, 1H), 6.64-6.58 (m, 2H), 5.83 (bs, 1H), 4.73 (q, 1H), 3.05 − 2.95 (m, 1H), 1.5 (s, 3H), 1.19 (bs, 6H). LCMS m/z 369 (M + H+] 248 [00901] [00902] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.45 (brs, 1H), 9.60 (s, 1H), 7.34 − 7.32 (d, 2H J = 8.08 Hz), 7.24 (s, 2H), 6.80 (s, 1H), 6.61 − 6.58 (d, 2H, J = 10.96), 6.19 (s, 1H), 4.12 (s, 2H), 3.17 (s, 1H), 2.94 (s, 1H), 1.20 (s, 6H). LCMS m/z 355.42 [M + H.sup.+] 249 [00903] [00904] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.72 (s, 1H), 7.37 − 7.33 (t, 2H J = 8.88 Hz), 7.28 − 7.25 (t, 2H, J = 6.68), 6.85 (s, 1H), 6.66 − 6.59 (t, 2H, J = 4.76), 6.05 (s, 1H), 3.78 (d, 2H, J = 5.72), 2.96-2.92 (t, 2H, J − 7.68), 1.23 − 1.05 (m, 10H). LCMS m/z 395 [M + H.sup.+] 250 [00905] [00906] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (s, 1H), 7.38 − 7.33 (t, 2H J = 8.88 Hz), 7.26 (s, 2H), 6.80 (s, 1H), 6.66 − 6.59 (q, 2H, J = 10.96), 5.95 (s, 1H), 4.73 (s, 1H), 3.95 − 3.88 (t, 2H), 2.96 (s, 1H), 1.24 (t, 6H, J = 6.44). LCMS m/z 385 [M + H.sup.+] 251 [00907] [00908] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (s, 1H), 7.38 − 7.33 (t, 2H J = 8.88 Hz), 7.26 (s, 2H), 6.80 (s, 1H), 6.66 − 6.59 (q, 2H, J = 10.96), 5.95 (s, 1H), 4.73 (s, 1H), 3.95 − 3.88 (t, 2H), 2.96 (s, 1H), 1.24 (t, 6H, J = 6.44). LCMS m/z 385 [M + H.sup.+] 252 [00909] [00910] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.45 (brs, 1H), 9.58 (s, 1H), 7.36 − 7.31 (t, 2H, J = 8.88 Hz), 7.25 − 7.24 (t, 2H, J = 3.08), 6.83 (s, 1H), 6.62 − 6.56 (q, 2H), 5.78 (s, 1H), 4.77 − 4.74 (t, 1H, J = 6.76), 2.95 − 2.91 (t, 1H, J = 7.32), 2.67 − 2.61 (q, 2H), 1.11 − 1.29 (d, 3H, J = 6.56), 1.17 − 1.13 (t, 6H, J = 8.32). LCMS m/z 383 [M + H.sup.+] .sup.1. PyBrop amination was performed at room temperature. .sup.2. The order of steps was changed; ester hydrolysis was performed before the hydrogenation/benzyl ether deprotection. .sup.3. t-Butyl hydrolysis was performed with HCl in dioxane. .sup.4. The order of steps was changed; ester hydrolysis was performed before the hydrogenation/benzyl ether deprotection. The ester hydrolysis was performed using NaOH in a mixture of MeOH and water. The then hydrogenation hydrogenation/benzyl ether deprotection was performed with Pt sulfide. .sup.5. Benzyl ester was cleaved during the hydrogenation/benzyl ether deprotection procedure

Compound 253

1-[[[4-(3,4-difluorophenyl)-7-hydroxy-3-isopropyl-2-quinolyl]amino]methyl]cyclopropanecarboxylic acid (253)

[0694] ##STR00911## ##STR00912##

Step 1: 7-benzyloxy-4-(3,4-difluorophenyl)-3-isopropenyl-quinoline (C171)

[0695] To a solution of C57 (5 g, 16.140 mmol) in dioxane (25 mL) and water (3 mL), (3,4-difluorophenyl)boronic acid (5.0974 g, 32.280 mmol) and K.sub.3PO.sub.4 (10.278 g, 48.420 mmol) were added. The reaction was purged with nitrogen, Pd(dppf)Cl.sub.2 (1.0519 g, 1.614 mmol) was added and the mixture was heated at 90° C. for 16 hours. EtOAc (50 mL) was added and the mixture was stirred for 10 minutes, filtered through Celite plug, washed with EtOAc (50 mL) and concentrated. Purification by silica gel chromatography (30-40% EtOAc in hexanes) afforded C171 (5 g, 69%) as an off white solid. LCMS m/z 388.0 [M+H].sup.+

Step 2: 7-benzyloxy-4-(3,4-difluorophenyl)-3-isopropenyl-1-oxido-quinolin-1-ium (C172)

[0696] To a solution of C171 (3 g, 7.7435 mmol), m-CPBA (1.6035 g, 9.2922 mmol) was added at 0° C. and under argon atmosphere. The reaction was stirred for 5 h. Water (50 mL) was added, the mixture was extracted with EtOAc (100 mL), washed successively with brine and an aqueous saturated solution of NaHCO.sub.3, dried over MgSO.sub.4 and concentrated. Purification by silica gel chromatography (30-40% EtOAc in hexanes) afforded C172 (2.5 g, 64%) as a yellow oil. LCMS m/z 404.0 [M+H].sup.+

Step 3: methyl 1-[[[7-benzyloxy-4-(3,4-difluorophenyl)-3-isopropenyl-2-quinolyl]amino]methyl]cyclopropanecarboxylate (C173)

[0697] To a solution of C172 (335 mg, 0.8304 mmol), methyl 1-(aminomethyl)cyclopropanecarboxylate hydrochloride (412.6 mg, 2.49 mmol) in dichloromethane (10 mL), DIEA (536.6 mg, 0.75 mL, 4.152 mmol) and PyBrop (1.1614 g, 2.4912 mmol) were added. The reaction was heated at 50° C. for 2 days. The mixture was diluted with dichloromethane (20 mL), washed successively with an aqueous solution of NaHCO.sub.3 (10 mL) and water (10 mL), dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (30-50% EtOAc in hexane) to afford C173 (70 mg, 9%). LCMS m/z 515.0 [M+H].sup.+

Step 4: methyl 1-[[[4-(3,4-difluorophenyl)-7-hydroxy-3-isopropyl-2-quinolyl]amino]methyl]cyclopropanecarboxylate (C174)

[0698] To a solution of C173 (65 mg, 0.126 mmol) in EtOH (10 mL), Pd/C (100 mg, 0.939 mmol) was added under an argon atmosphere. The reaction was purged with hydrogen and stirred at room temperature for 18 hours. The mixture was filtered through a Celite® plug, washed with EtOAc, and concentrated to afford C174 (30 mg, 31%). LCMS m/z 427.46 [M+H].sup.+

Step 5: 1-[[[4-(3,4-difluorophenyl)-7-hydroxy-3-isopropyl-2-quinolyl]amino]methyl]cyclopropanecarboxylic acid (253)

[0699] To a solution of C174 (25 mg, 0.058 mmol) in THF (2 mL), Methanol (1 mL) and Water (0.3 mL), LiOH (4.677 mg, 0.195 mmol) was added at 0° C. The reaction was stirred at room temperature for 18 hours. The mixture was concentrated, diluted with water (5 mL), acidified with a saturated aqueous solution of citric acid and extracted with EtOAc (10 mL×2). The organic phases were combined, dried over Na.sub.2SO.sub.4 and concentrated. Purification by reverse-phase HPLC (Method: C18 YMC Triart Actus column, 20×250 mm, 5 micron. Gradient: acetonitrile in water with 20 mM Ammonium Bicarbonate) afforded 253 (3.5 mg, 14%) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.95 (bs, 1H), 9.73 (bs, 1H), 7.61-7.54 (m, 1H), 7.42(t, J=8.8 Hz, 1H), 7.09 (bs, 1H), 6.84 (d, J=2.04 Hz, 1H), 6.65-6.59 (m, 2H), 6.07 (bs,1H), 3.75 (d, J=5.04 Hz, 2H), 2.94-2.89 (m, 1H), 1.33-1.17(m, 6H), 1.09-0.88 (m, 4H). LCMS m/z 413.4 [M+H].sup.+

Preparation of C176

7-benzyloxy-2-chloro-4-(4-fluorophenyl)-3-isopropyl-quinoline (C176)

[0700] ##STR00913##

Step 1: 2-chloro-4-(4-fluorophenyl)-3-isopropyl-quinolin-7-ol (C175)

[0701] To a solution of S22 (695 mg, 1.785 mmol) in dichloromethane (4 mL) at 0° C., a solution of BBr.sub.3 (4 mL of 1 M, 4.000 mmol) in dichloromethane was added dropwise and the reaction was stirred at room temperature for 3 hours. A cold aqueous solution of NaHCO.sub.3 was added, the mixture was extracted with dichloromethane, the organic phases were combined, dried over MgSO.sub.4, filtered and concentrated. Purification by silica gel chromatography (0 to 20% EtOAc in heptane) afforded C175 (250 mg, 41%) as a white solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.35 (dd, J=2.5, 0.6 Hz, 1H), 7.26-7.16 (m, 4H), 7.10 (dd, J=9.2, 0.6 Hz, 1H), 7.03 (dd, J=9.1, 2.5 Hz, 1H), 5.90 (s, 1H), 3.20 (s, 1H), 1.33 (d, J=7.2 Hz, 5H). LCMS m/z 315.67 [M+H].sup.+

Step 2: 7-benzyloxy-2-chloro-4-(4-fluorophenyl)-3-isopropyl-quinoline (C176)

[0702] To a solution of C175 (250 mg, 0.7917 mmol) in DMF (8 mL), K.sub.2CO.sub.3 (235.2 mg, 1.702 mmol) and BnCl (200 μL, 1.738 mmol) were added and the reaction was heated 60° C. for 1 h. Water was added and the mixture was extracted with dichloromethane. The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated. Purification by silica gel chromatography (0 to 50% EtOAc in heptane) afforded C176 (210.6 mg, 59%) as a white solid. .sup.1H NMR (300 MHz, Chloroform-d) δ 7.42-7.21 (m, 6H), 7.17-7.07 (m, 4H), 7.06-6.95 (m, 2H), 5.12 (s, 2H), 3.11 (s, 1H), 1.24 (d, J=7.2 Hz, 6H). LCMS m/z 406.2 [M+H].sup.+

Compound 254

1-[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-2-quinolyl]azetidine-3-carboxylic acid (254)

[0703] ##STR00914##

Step 1: methyl 1-[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-2-quinolyl]azetidine-3-carboxylate (C177)

[0704] To a solution of C176 (300 mg, 0.7391 mmol) in 1,4-dioxane (4 mL), methyl azetidine-3-carboxylate hydrochloride and K.sub.2CO.sub.3 (408.59 mg, 2.9564 mmol) were added. The reaction mixture was purged with nitrogen, methanesulfonato(tri-t-butylphosphino)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) (94.003 mg, 0.1478 mmol) was added and the reaction mixture was heated at 80° C. for 48 h. The mixture was filtered, washed with EtOAc and the organic phase concentrated. Purification by silica gel chromatography (10-20% EtOAc in hexanes) afforded C177 (40 mg, 10%) as a yellow oil. LCMS m/z 486.24 [M+H].sup.+

Step 2: methyl 1-[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-2-quinolyl]azetidine-3-carboxylate (C178)

[0705] To a solution of C177 (40 mg, 0.083 mmol) in EtOH (2 mL), Pd—C (40 mg, 10% w/w, 0.033 mmol) was added under argon. The reaction was purged with hydrogen and stirred at room temperature for 2 hours. The mixture was filtered through a celite plug, washed with EtOAc and concentrated to afford C178 (30 mg, 86%) as a yellow oil. LCMS m/z 395.13 [M+H].sup.+

Step 3: 1-[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-2-quinolyl]azetidine-3-carboxylic acid (254)

[0706] To a solution of C178 (50 mg, 0.1003 mmol) in a mixture of THF (1.5 mL) and MeOH (0.3 mL), an aqueous solution of aqueous LiOH 1M (0.1003 mL of 1M, 0.1003 mmol) was added and the reaction was stirred for at room temperature for 2 hours. The mixture was concentrated, an aqueous solution of citric acid (5 mL) was added and the mixture was extracted with EtOAc (2×5 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4 and concentrated. Purification by reverse-phase HPLC (Method: C18 YMC Triart Actus column, 20×250 mm, 5 micron. Gradient: acetonitrile in water with 10 mM AA) afforded 254 (10 mg, 34%) as off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.65 (bs, 1H), 9.77 (bs, 1H), 7.35-7.27 (m, 4H), 6.93 (s, 1H), 6.70-6.63 (m, 2H), 4.31-4.21 (m, 4H), 3.50-3.43 (m, 1H), 3.50-3.43 (m, 1H), 3.19-3.12 (m, 1H), 0.96 (d, J=7.08 Hz, 6H). LCMS m/z 381.05 [M+H.sup.+]

Compounds 255-258

[0707] Compounds 255-258 (Table 32) were prepared in three steps from intermediate C176 and the appropriate amine according to the method described for compound 254. Any modifications to methods are noted in Table 32 and accompanying footnotes.

TABLE-US-00033 TABLE 32 Method of preparation, structure, physicochemical data for compounds 255-258 .sup.1H NMR; LCMS m/z Compound Method/Product Amine [M + H].sup.+ 255 [00915] [00916] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.878 (Bs, 1H), 7.34 − 7.25 (m, 4H), 6.90 (s, 1H), 6.67 − 6.61 (m, 2H), 4.24 (t, J = 8.08 Hz, 2H), 3.86 (t, J = 7.2 Hz, 2H), 3.19 − 3.15 (m, 1H), 2.92 − 2.88 (m, 1H), 2.61 (d, J = 7.64 Hz, 1H), 0.94 (d, J = 7.12 Hz, 1H). LCMS m/z 395.11 [M + H.sup.+] 256 [00917] [00918] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.82 (bs, 1H), 7.35 − 7.31 (m, 4H), 7.24 (bs, 1H), 6.5 (s, 1H), 6.71 − 6.65 (m, 2H), 4.63 − 4.55 (m, 2H), 4.31 − 4.23 (m, 2H), 3.15 − 3.11 (m, 1H), 0.95 (d, J = 7.04 Hz, 6H). LCMS m/z 399.07 [M + H.sup.+] 257 [00919] [00920] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.83 (bs, 1H), 7.36 − 7.32 (m, 4H), 6.93 (s, 1H), 6.72 (d, J = 8.46 Hz, 2H), 6.72 (d, J = 8.46 Hz, 1H), 6.66 (d, J = 8.46 Hz, 1H), 3.69 − 3.61 (m, 1H), 3.59 − 3.49 (m, 2H), 3.44 − 3.37 (m, 2H), 3.12 − 3.08 (m, 1H), 2.16 − 2.07 (m, 2H), 0.99 (dd, J = 7.04, Hz, 6H). LCMS m/z 395.14 [M + H.sup.+] 258 [00921] [00922] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.85 (bs, 1H), 7.36 − 7.31 (m, 4H), 6.95 (s, 1H), 6.73 (d, J = 8.96 Hz, 2H), 6.66 (d, J = 8.46 Hz, 1H), 3.69 − 3.65 (m, 1H), 3.61 − 3.49 (m, 2H), 3.44 − 3.37 (m, 2H), 3.31 − 3.08 (m, 1H), 2.16 − 2.05 (m, 2H), 0.99 (dd, J = 7.04, Hz, 6H). LCMS m/z 395.13 [M + H.sup.+] .sup.1. 255-258: Buchwald coupling performed at 100° C.

Compound 259

3-[4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-3-isopropyl-2-quinolyl]bicyclo[1.1.1]pentane-1-carboxylic acid (259)

[0708] ##STR00923##

Step 1: methyl 3-[4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-7-methoxy-2-quinolyl]bicyclo[1.1.1]pentane-1-carboxylate (C179)

[0709] Under inert atmosphere, a suspension of C45, O3-(1,3-dioxoisoindolin-2-yl) O1-methyl bicyclo[1.1.1]pentane-1,3-dicarboxylate (78 mg, 0.2265 mmol), Ir[dF(CF3)ppy]2 (dtbpy))PF6, (4 mg, 0.00356 mmol) and TFA (25 μL, 0.3245 mmol) in DMA (1.5 mL) was stirred and irradiated with two blue LED Kessil lamps for 2 h. DIEA (0.1 mL) was added to the reaction and then diluted with 10 mL of water and 10 mL of EtOAc. The mixture was extracted with EtOAc (2×), dried with Na.sub.2SO.sub.4, filtered, and concentrated. Purification by silica gel chromatography (0-50% EtOAc in heptane) afforded C179 (35 mg, 51%) as a white solid.

Step 2: 3-[4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-3-isopropyl-2-quinolyl]bicyclo-[1.1.1]pentane-1-carboxylic acid (259)

[0710] To a solution of C179 (35 mg, 0.081 mmol) in dichloromethane (2 mL), a solution of BBr.sub.3 (200 μL of 1M, 0.20 mmol) in dichloromethane was added while at 0° C. The reaction was stirred at room temperature for 18 hours. Water was added and the organic phase was recovered, dried and concentrated. Purification by reverse phase chromatography (C18 column, 30-100% MeCN:Water, TFA modifier), afforded the desired acid product as well as the ester. Ester containing fractions were concentrated, dissolved in MeOH and LiOH was added and the mixture was heated to 50° C. for 3 hours. The mixture was neutralized with 1 M HCl, extracted with dichloromethane, concentrated, and combined with the isolated acid to afford 259 (7.9 mg, 24%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.31 (dd, J=1.8, 1.1 Hz, 1H), 7.19-7.02 (m, 4H), 6.93-6.86 (m, 2H), 3.87 (t, J=7.4 Hz, 1H), 2.52 (s, 6H), 2.34 (d, J=1.9 Hz, 3H), 1.02 (dd, J=7.2, 4.0 Hz, 6H). LCMS m/z 406.35 [M+H].sup.+

Compounds 260-262

[0711] Compounds 260-262 (Table 33) were prepared in two steps from intermediate S24 and the appropriate alkyl iodide zincate according to the method described for compound 238. Any modifications to methods are noted in Table 33 and accompanying footnotes.

TABLE-US-00034 TABLE 33 Method of preparation, structure, physicochemical data for compounds 260-262 Alkyl iodide Compound Method/Product or zincate .sup.1H NMR; LCMS m/z [M + H].sup.+ 260 [00924] [00925] .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 7.30 (t, J = 8.68 Hz, 2H), 7.17 (d, J = 6.96 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.07 (bs, 1H), 6.94 (dd, H = 2.28 Hz, J2 = 9.04, 1H) 6.88 (d, J = 9.08 Hz, 1H), 3.38 (m, 2H), 3.14 (bs, 1H), 3.07 − 3.03 (m, 1H), 2.30 (s, 3H) 1.23 (d, J = 6.72 Hz, 3H), 1.17 (s, 6H). LCMS m/z 382 [M + H.sup.+] 261 [00926] [00927] .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 7.30 (t, J = 8.68 Hz, 2H), 7.17 (d, J = 6.96 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.07 (bs, 1H), 6.94 (dd, J1 = 2.28 Hz, J2 = 9.04, lH)6.88(d, J = 9.08 Hz, 1H), 3.38 (m, 2H), 3.14 (bs, 1H), 3.07 − 3.03 (m, 1H), 2.30 (s, 3H) 1.23 (d, J = 6.72 Hz, 3H), 1.17 (s, 6H). LCMS m/z 382.2 [M + H.sup.+] 262 [00928] [00929] .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 12.22 (s, 1H), 9.97 (s, 1H), 7.30 (t, J = 8.7 Hz, 2H), 7.18 (t, J = 6.68 Hz, 2H), 7.08 (bs, 1H), 6.93 (bs, 1H), 6.89 (bs, 1H), 3.01 (bs, 1H), 2.99 (s, 2H), 2.32 (s, 3H) 2.01 (s, 1H), 1.95 (s, 1H), 1.16 (d, J = 7.0 Hz, 3H), 1.11 (s, 5H). LCMS m/z 396 [M + H.sup.+]

Compound 263

4-[4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-3-isopropyl-2-quinolyl]butanoic acid (263)

[0712] ##STR00930##

Step 1: methyl 4-[7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-2-quinolyl]butanoate (C180)

[0713] To a mixture of Zn—Cu couple (153.55 mg, 1.1910 mmol) in Toluene (2 mL) and DMA (0.5 mL), methyl 4-iodobutanoate (162.95 mg, 0.7146 mmol) was added under argon atmosphere and the reaction mixture was heated at 85° C. for 150 min. Then, S23 (50 mg, 0.1191 mmol) and Pd(PPh.sub.3).sub.4 (24.729 mg, 0.0214 mmol) were added and the reaction mixture was heated at 85° C. for 16 hours. The mixture was diluted with EtOAc, filtered, washed successively with water and brine, dried over Na.sub.2SO.sub.4 and concentrated to afford crude C180 (40 mg, 55%). LCMS m/z 486.0 [M+H].sup.+

Step 2: methyl 4-[4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-3-isopropyl-2-quinolyl]butanoate (C181)

[0714] To a solution of C180 (40 mg, 0.0824 mmol) in MeOH (3 mL), 10% Pd/C (20 mg, 0.1879 mmol) was added. The reaction was purged with hydrogen and stirred at room temperature for 1 hour. The mixture was filtered through a Celite plug, washed with MeOH and concentrated to afford C181 (20 mg, 55%). LCMS m/z 396.0 [M+H].sup.+

Step 3: 4-[4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-3-isopropyl-2-quinolyl]butanoic acid (263)

[0715] To a solution of C181 (20 mg, 0.0506 mmol) in THF (5 mL) and Water (1.5 mL), LiOH (2.4236 mg, 0.1012 mmol) was added and the reaction was stirred for 16 hours. The mixture was concentrated and purified by reverse-phase HPLC (Method: C18 YMC Triart Actus column, 20×250 mm, 5 micron. Gradient: acetonitrile in water with 20 mM Ammonium Bicarbonate) afforded 263 (6.9 mg, 36%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.28 (t, J=8.6 Hz, 1H), 7.18 (m, 1H), 7.14 (d, J=2.3 Hz, 1H), 7.09 (m, 1H), 6.93 (dd, J=9.1,2.3 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 3.01 (m, 1H), 2.99 (t, J=7.7 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 2.30 (s, 3H), 2.05 (m, 2H), 1.15 (d, J=6.7 Hz, 1H). LCMS m/z 382 [M+H.sup.+]

Compounds 264-270

[0716] Compounds 264-270 (Table 34) were prepared in three steps from intermediate S23 and the appropriate amine according to the method described for compound 254. Any modifications to methods are noted in Table 34 and accompanying footnotes.

TABLE-US-00035 TABLE 34 Method of preparation, structure, physicochemical data for compounds 264-270 .sup.1H NMR; LCMS m/z Compound Method/Product Amine [M + H].sup.+ 264 [00931] [00932] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.60 (bs, 1H), 9.75 (s, 1H), 7.25 (t, J = 8.24 Hz, 1H), 7.17 (d, J = 7.35 Hz, 1H), 7.10 (t, J = 6.56 Hz, 1H), 6.93 (s, 1H), 6.68 (d, J = 7.84 Hz, 2H), 4.3 (t, J = 8.44 Hz, 2H), 4.23 (t, J = 7.22 Hz, 2H), 3.5 − 3.46 (m, 1H), 3.17 − 3.13 (m, 1H), 2.3 (s, 3H), 0.96 (t, J = 6.56 Hz, 2H, 6H). LCMS m/z 395.4 [M + H.sup.+] 265 [00933] [00934] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.20 (bs, 1H), 9.71 (s, 1H), 7.22 (t, J = 7.42 Hz, 1H), 7.15 (d, J = 7.25 Hz, 1H), 7.06 (t, J = 6.24 Hz, 1H), 6.89 (s, 1H), 6.65 (bs, 2H), 4.24 (t, J = 7.84 Hz, 2H), 3.85 (t, J = 6.84 Hz,2H), 3.18 − 3.15 (m, 1H), 2.92 − 2.88 (m, 1H), 2.62 (bs, 2H), 2.29 (s, 3H), 0.95 (t, J = 6.56 Hz, 6H). LCMS m/z 409.43 [M + H.sup.+] 266 [00935] [00936] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.42 (bs, 1H), 9.79 (s, 1H), 7.28 − 7.19 (m, 2H), 7.10 (bs, 1H), 6.96 (bs, 1H), 6.72 (bs, 2H), 3.66 − 3.32 (m, 8H), 2.32 (s, 3H), 2.14-2.09 (bs, 2H), 1.23-0.96 (tt, 6H). LCMS m/z 409.37 [M + H] 267 [00937] [00938] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.35 (bs, 1H), 9.85 (s, 1H), 7.26 (t, J = 7.64 Hz, 1H), 7.20 (d, J = 6.84 Hz, 1H), 7.18 (t, J = 6.26 Hz, 1H), 6.93 (s, 1H), 6.68 (d, J = 7.24 Hz, 2H), 3.66 − 3.65 (M, 1H), 3.60 − 3.45 (M, 2H), 3.42 − 3.32 (M, 2H), 3.12 − 3.09 (M, 1H), 2.3 (s, 3H), 2.14 − 2.08 (m, 2H), 1.05 − 0.96 (tt, 6H). LCMS m/z 409.37 [M + H.sup.+] 268 [00939] [00940] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.85 (s, 1H), 7.28 − 7.09 (M, 4H), 6.94 (s, 1H), 6.7 (s, 1H), 4.62-4.54 (m, 2H), 4.31 − 4.23 (m, 2H), 3.14 − 3.11 (m, 1H), 2.29 (s, 3H), 0.97 (t, J = 6.26 Hz, 6H). LCMS m/z 413.46 [M + H.sup.+] 269 [00941] [00942] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.61 (s, 1H), 7.26 (t, J = 9.02 Hz, 1H), 7.11 (d, J = 7.08 Hz, 1H), 7.03 (t, J = 8.42 Hz, 1H), 6.87 (bs, 1H), 6.65 (d, J = 8.88 Hz, 1H), 6.59 (d, J = 8.72 Hz, 1H), 6.15 (bs, 1H), 3.98 − 3.96 (m, 2H), 3.51 (t, J = 6.36 Hz, 1H), 3.1 (s, 3H), 2.98 − 2.91 (m, 1H), 2.29 (s, 3H), 1.16 (d, J = 8.88 Hz, 1H). LCMS m/z 417.1 [M + H.sup.+] 270 [00943] [00944] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 7.26 (t, J = 9.16 Hz, 1H), 7.1 (d, J = 7.24 Hz, 1H), 7.02 (t, J = 5.62 Hz, 1H), 6.8 (bs, 1H), 6.63 (d, J = 8.84 Hz, 1H), 6.55 (d, J = 8.88 Hz, 1H), 5.93 (bs, 1H), 4.21 (t, J = 7.64 Hz, 2H), 3.7 (t, J = 8.32 Hz, 4H), 3.48 (t, J = 5.8 Hz, 2H), .95 − 2.92 (m, 1H), 2.3 (s, 3H), 1.14 (t, J = 6.84 Hz, 6H). LCMS m/z 424.53 [M + H.sup.+] .sup.1. Saponification was not necessary for these examples.

Compound 271

3-[[4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-3-isopropyl-2-quinolyl]amino]propanoic acid (271)

[0717] ##STR00945##

Step 1: methyl 3-[[4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-7-methoxy-2-quinolyl]amino]propanoate (C182)

[0718] To a mixture of C49 (250 mg, 0.7683 mmol), methyl 3-aminopropanoate (160 mg, 1.552 mmol) and PyBrop (1.12 g, 2.402 mmol) in dichloromethane (3 mL), DIPEA (400 μL, 2.296 mmol) was added and the reaction was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (5 mL), washed successively with water and brine, dried and concentrated. Purification by silica gel chromatography (10 to 90% EtOAc in hexanes) afforded C182 (162 mg, 49%). LCMS m/z 410.54 [M+H].sup.+

Step 2: 3-[[4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-3-isopropyl-2-quinolyl]amino]-propanoic acid (271)

[0719] To a solution of C182 (45 mg, 0.1096 mmol) in EtSH (1 mL), AlBr.sub.3 (102 mg, 0.3825 mmol) was added and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated and 2 ml of DMSO and water (3020 μL, 167.6 mmol) were added. The mixture was filtered, the filtrated was recovered and purified by C18 reverse-phase chromatography (10 to 90% acetonitrile in water, 0.1% formic acid as additive) to afford 271 (30 mg, 66%). .sup.1H NMR (400 MHz, Chloroform-d) δ 12.46 (s, 1H), 7.37 (s, 1H), 7.05 (t, J=8.8 Hz, 2H), 6.91-6.74 (m, 2H), 6.67 (q, J=9.1 Hz, 2H), 3.99 (s, 2H), 3.00 (p, J=7.3 Hz, 1H), 2.86 (s, 2H), 2.25 (s, 3H), 1.12 (d, J=7.3 Hz, 6H). LCMS m/z 383.25 [M+H].sup.+

Compounds 272-273

[0720] Compounds 272-273 (Table 35) were prepared in two steps from intermediate C49 and the appropriate amine according to the method described for compound 271. Any modifications to methods are noted in Table 35 and accompanying footnotes.

TABLE-US-00036 TABLE 35 Method of preparation, structure, physicochemical data for compounds 272-273 Compound Product Amine Method .sup.1H NMR; LCMS m/z [M + H].sup.+ 272 [00946] [00947] Compound 271 from C49 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.38 (s, 1H), 7.27 − 6.99 (m, 4H), 6.84 (d, J = 9.0 Hz, 1H), 6.72 (dd, J = 9.0, 2.4 Hz, 1H), 3.21 − 3.04 (m, 2H), 2.88 − 2.73 (m, 2H), 2.46 (tdd, J = 10.0, 7.5, 2.7 Hz, 2H), 2.35 (d, J = 1.9 Hz, 3H), 1.29 − 1.15 (m, 6H). LCMS m/z 409.21 [M + H.sup.+] 273 [00948] [00949] Compound 271 from C49 .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.20 (dd, J = 9.7, 8.3 Hz, 1H), 7.14 − 7.07 (m, 2H), 7.04 (ddd, J = 7.7, 4.9, 2.3 Hz, 1H), 6.81 (d, J = 8.9 Hz, 1H), 6.69 (dd, J = 9.0, 2.4 Hz, 1H), 4.68 (t, J = 7.8 Hz, 1H), 3.12 (p, J = 7.4 Hz, 1H), 2.97 − 2.78 (m, 3H), 2.39 − 2.22 (m, 5H), 1.28 − 1.18 (m, 6H). LCMS m/z 409.17 (M + H.sup.+]

Preparation of C183

7-(benzyloxy)-4-(4-fluoro-3-methylphenyl)-3-(prop-1-en-2-yl)quinoline 1-oxide (C183)

[0721] ##STR00950##

[0722] To a solution of C63 (6 g, 15.647 mmol) in dichloromethane (50 mL), m-CPBA (3.2401 g, 18.776 mmol) was added and the reaction was stirred at room temperature 12 h. Water and a saturated aqueous solution of NaHCO.sub.3 solution (10 mL) were added and the mixture was extracted with dichloromethane (20 mL). The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to afford C183 (5.8 g, 85%) as a as light brown solid. LCMS m/z 400.0 [M+H].sup.+

Compounds 274-288

[0723] Compounds 274-288 (Table 36) were prepared in three steps from intermediate C183 and the appropriate amine according to the method described for compound 244. Any modifications to methods are noted in Table 36 and accompanying footnotes.

TABLE-US-00037 TABLE 36 Method of preparation, structure, physicochemical data for compounds 274-288 .sup.1H NMR; LCMS m/z Compound Method/Product Amine [M + H].sup.+ 274 [00951] [00952] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.45 (bs, 1H), 9.51 (s, 1H), 7.22 (t, J = 9.04 Hz, 1H), 7.08 (d, J = 6.94 Hz, 1H), 7.03-7.01 (m, 1H), 6.80 (s, 1H), 6.60 (d, J = 8.84 Hz, 1H), 6.54 (d, J = 8.88 Hz, 1H), 5.8 (bs, 1H), 3.67 − 3.60 (m, 1H), 2.94 − 2.88 (m, 1H), 2.26 (s, 3H), 1.2 − 1.11 (m, 9H). LCMS m/z 397.2 [M + H.sup.+] 275 [00953] [00954] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.33 (bs, 1H), 9.58 (s, 1H), 7.26 (t, J = 9.06 Hz, 1H), 7.13 (bs, 1H), 7.05 (bs, 1H), 6.83 (s, 1H), 6.63 (d, J = 8.76 Hz, 1H), 6.57 (d, J = 9.04 Hz, 1H), 5.68 (bs, 1H), 2.97 − 2.93 (m, 1H), 2.69 − 2.61 (m, 2H), 2.28 (s, 3H), 1.3 (s, 3H), 1.16 (t, J = 8.14 Hz, 6H). LCMS m/z 397 [M + H.sup.+] 276 [00955] [00956] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.74 (bs, 1H), 9.65 (s, 1H), 7.25 (t, J = 9.06 Hz, 1H), 7.16 (t. J = 8.86 Hz, 1H), 7.03 − 7.02 (m, 1H), 6.80 (s, 1H), 6.61 (d, J = 8.64 Hz, 1H), 6.54 (d, J = 8.84 Hz, 1H), 6.35 (bs, 1H), 4.67 (q, 1H), 2.97 − 2.91 (m, 1H), 2.29 (s, 3H), 1.27 (s, 3H), 1.18 (t, J = 6.92 Hz, 6H). LCMS m/z 397 [M + H.sup.+] 277 [00957] [00958] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.13 (bs, 1H), 9.70 (bs, 1H), 7.27 (t, J = 9.04 Hz, 1H), 7.15 (d, J = 6.12 Hz, 1H), 7.08 − 7.05 (m, 1H), 6.84 (s, 1H), 6.65 (d, J = 8.92 Hz, 1H), 6.60 (d, J = 8.88 Hz, 1H), 6.08 (bs, 1H), 3.76 (d, J = 5.36 Hz, 1H), 2.96 (q, 1H), 2.31 (s, 3H), 1.19 (d, J = 1.48, 6H), 1.09 (s, 2H), 1.04 (s, 2H). LCMS m/z 409 [M + H.sup.+] 278 [00959] [00960] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (s, 1H), 7.28 (t, J = 8.98 Hz, 1H), 7.14 (t, J = 7.02 Hz, 1H), 7.06 − 7.04 (m, 1H), 6.79 (s, 1H), 6.67 (d, J = 8.88 Hz, 1H), 6.60 (d, J = 8.96 Hz, 1H), 5.88 (bs, 1H), 4.74 (bs, 1H), 3.95 − 3.85 (m, 2H), 3.0 − 2.97 (m, 1H), 2.3 (s, 3H), 1.23 (s, 6H). LCMS m/z 399 [M + H.sup.+] 279 [00961] [00962] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 7.25 (t, J = 9.04 Hz, 1H), 7.16 (t, J = 8.86 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 7.04 (bs, 1H), 6.78 (s, 1H), 6.60 (d, J = 8.84 Hz, 1H), 6.50 (d, J = 9.32 Hz, 1H), 4.2 (bs, 1H), 2.97 − 2.92 (m, 1H), 2.3(s, 3H), 1.4 (s, 3H), 1.21 (t, J = 5.42 Hz, 6H). LCMS m/z 383 [M + H.sup.+] 280 [00963] [00964] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.85 (bs, 1H), 9.65 (s, 1H), 7.27 (t, J = 9.06 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.06 − 7.03 (m, 1H), 6.82 (s, 1H), 6.66 (d, J = 8.88 Hz, 1H), 6.60 (d, J = 8.88 Hz, 1H), 5.8 (bs, 1H), 4.76 − 4.69 (m, 1H), 3.08 − 2.97 (m, 1H), 2.29 (s, 3H), 1.5(s, 3H), 1.18 (t, J = 6.92 Hz, 6H). LCMS m/z 383 [M + H.sup.+] 281 [00965] [00966] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.52 (bs, 1H), 9.58 (s, 1H), 7.27 (t, J = 8.8 Hz, 1H), 7.12 (d, J = 7.28 Hz, 1H), 7.04 (t, J = 5.56 Hz, 1H), 6.79 (s, 1H), 6.65 (d, J = 8.84 Hz, 1H), 6.58 (d, J = 8.88 Hz, 1H), 6.16 (bs, 1H), 2.98 − 2.94 (m, 1H), 2.23 (s,3H), 1.2 (d, J = 6.52 Hz, 6H). LCMS m/z 369.1 [M + H.sup.+] 282 [00967] [00968] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (s, 1H), 7.27 (t, J = 9.24 Hz, 1H), 7.14 (t, J = 6.68 Hz, 1H), 7.05 (brs, 1H), 6.79 (s, 1H), 6.68 (d, J = 8.95 Hz, 1H), 6.60 (d, J = 9.04 Hz, 1H), 5.89 (bs, 1H), 4.66 (bs, 1H), 3.94 − 3.83 (m, 2H), 3.0 − 2.96 (m, 1H), 2.3 (s, 3H), 1.24 (s,6H). LCMS m/z 399 [M + H.sup.+] 283 [00969] [00970] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.49 (s, 1H), 9.64 (s, 1H), 7.26 (dd, J = 9.9, 8.3 Hz, 1H), 7.17 − 7.08 (m, 1H), 7.08 − 6.97 (m, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 6.56 (dd, J = 8.9, 2.4 Hz, 1H), 6.00 (s, 1H), 3.64 (s, 2H), 3.03 − 2.80 (m, 2H), 2.29 (d, J = 1.9 Hz, 3H), 1.23 − 1.08 (m, 9H). LCMS m/z 397.19 [M + H.sup.+] 284 [00971] [00972] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.62 (s, 1H), 7.26 (dd, J = 9.9, 8.3 Hz, 1H), 7.12 (dd, J = 7.6, 2.1 Hz, 1H), 7.07 − 6.96 (m, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 6.56 (dd, J = 8.9, 2.4 Hz, 1H), 6.05 (s, 1H), 3.64 (s, 2H), 3.00 − 2.82 (m, 2H), 2.31 − 2.26(m, 3H), 1.25 − 1.02 (m, 9H). LCMS m/z 397.39 [M + H.sup.+] 285 [00973] [00974] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.54 (s, 1H), 7.25 (t, J = 8.88 Hz, 1H), 7.11 (d, J = 7.20 Hz, 1H), 7.02 (t, J = 6.6 Hz, 1H), 6.80 (bs, 1H), 6.61 (d, J = 8.84 Hz, 1H), 6.56 (d, J = 8.84 Hz, 1H), 5.4 (bs, 1H), 5.01 (d, J = 6.0 Hz, 1H), 4.22 − 4.16 (m, 1H), 3.96 − 3.91 (m, 1H), 3.01 − 2.96 (m, 1H), 2.74 − 2.67 (m, 2H), 2.29 (s,3H), 1.90 − 1.88 (m, 2H), 1.13 (d, J = 6.68 Hz, 6H). LCMS m/z 381.18 [M + H.sup.+] 286 [00975] [00976] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.54 (s, 1H), 7.25 (t, J = 8.86 Hz, 1H), 7.11 (d, J = 7.40 Hz, 1H), 7.02 (t, J = 6.2 Hz, 1H), 6.80 (bs, 1H), 6.61 (d, J = 8.86 Hz, 1H), 6.56 (d, J = 8.82 Hz, 1H), 5.56 (bs, 1H), 5.02 − 4.98 (m, 1H), 4.75 − 4.73 (m, 1H), 4.33 − 4.31 (m, 1H), 4.20 − 3.92 (m, 1H), 3.1 − 2.97 (m, 1H), 2.72 − 2.66 (m, 1H), 2.32 − 2.24 (m,5H), 1.90 − 1.87 (m, 1H), 1.13 (d, J = 6.68 Hz, 6H). LCMS m/z 381.18 [M + H.sup.+] 287 [00977] [00978] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.58 (s, 1H), 7.26 (t, J = 8.96 Hz, 1H), 7.11 (d, J = 6.64 Hz, 1H), 7.02 (t, J = 7.86 Hz, 1H), 6.80 (bs, 1H), 6.63 (d, J = 8.8 Hz, 1H), 6.56 (d, J = 8.76 Hz, 1H), 5.8 (bs, 1H), 5.14 (bs, 1H), 3.64 − 3.62 (m, 4H), 2.97 − 2.93 (m, 1H), 2.29 (s,3H), 1.16 (d, J = 6.6, Hz, 6H). LCMS m/z 355.18 [M + H.sup.+] 288 [00979] [00980] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.58 (s, 1H), 7.26 (t, J = 8.8 Hz, 1H), 7.11 (d, J = 6.58 Hz, 1H), 7.02 (t, J = 8.02 Hz, 1H), 6.98 (bs, 2H), 6.86 (bs, 1H), 6.64 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 9.0 Hz, 1H), 6.07 (bs, 1H), 3.97 − 3.95 (m, 2H), 3.38 (t, J = 6.2 Hz, 1H), 2.95 − 2.92 (m, 1H), 2.29 (s, 3H), 1.16 (d, J = 6.52, Hz, 6H). LCMS m/z 418.13 [M + H.sup.+] .sup.1. The order of steps was changed; hydrolysis of the ester was performed before hydrogenation/benzyl ether deprotection. .sup.2. The t-butyl ester was deprotected with HCI in dioxane. .sup.3. The benzyl ester was removed during hydrogenation/benzyl ether deprotection. .sup.4. 283 and 284 were obtained after SFC chiral separation, stereochemistry is unknown. .sup.5. 285 and 286 were obtained after C18 chromatography, stereochemistry is unknown. .sup.6. No saponification was necessary.

Compound 289

3-isopropyl-2-methyl-4-phenylquinolin-7-ol (289)

[0724] ##STR00981##

[0725] To a mixture of S25 (60 mg, 0.2495 mmol), phenylboronic acid (76 mg, 0.6233 mmol) and Pd(dppf)Cl.sub.2 (12 mg, 0.01469 mmol) in DMF (3 mL), an aqueous solution of Na.sub.2CO.sub.3 (400 μL of 2 M, 0.8000 mmol) was added under nitrogen and the reaction was heated in a microwave reactor at 130° C. for 4 hours. An aqueous solution of HCl (1 N; 0.5 mL) and water were added, the mixture was extracted with EtOAc and the combined organic phases were concentrated. Purification by silica gel chromatography (0 to 10% MeOH in dichloromethane) afforded crude product which was re-purified by reverse-phase HPLC (Method: C18 Waters Sunfire column, 30×150 mm, 5 micron. Gradient: MeCN in water) to afford 289 (Hydrochloride salt) (3.5 mg, 4%) 1H NMR (300 MHz, Chloroform-d and Methanol-d.sub.4) δ 7.70-7.49 (m, 4H), 7.21 (td, J=11.7, 9.9, 6.3 Hz, 4H), 3.28 (q, J=7.3 Hz, 1H), 3.13 (d, J=2.5 Hz, 3H), 1.27 (d, J=7.2 Hz, 6H). LCMS m/z 278.32 [M+H].sup.+

Compound 290

3-isopropyl-2-methyl-4-(2-methyl-4-pyridyl)quinolin-7-ol (290)

[0726] ##STR00982##

Step 1: 4-chloro-3-isopropyl-7-(methoxymethoxy)-2-methyl-quinoline (C184)

[0727] To a mixture of S25 (600 mg, 2.546 mmol) and DIEA (1.4 mL, 8.038 mmol) in dichloromethane (20 mL), chloro(methoxy)methane (400 μL, 5.266 mmol) was added. The reaction mixture was stirred for 18 hours at room temperature under N.sub.2. N′,N′-dimethylethane-1,2-diamine (1 mL, 9 mmol) and a saturate aqueous solution of NH.sub.4Cl were added. The mixture was extracted with dichloromethane (200 mL) and the organic phase was washed successively with water (100 mL) and brine, dried with Na.sub.2SO.sub.4 and concentrated to afford C184 (500 mg, 70%) .sup.1H NMR (300 MHz, Chloroform-d) δ 8.15 (d, J=9.2 Hz, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.28 (dd, J=9.2, 2.5 Hz, 2H), 5.33 (s, 2H), 3.76 (s, 1H), 3.52 (s, 3H), 2.81 (s, 3H), 1.49 (d, J=7.2 Hz, 6H). LCMS m/z 279.99 [M+H].sup.+

Step 2: 3-isopropyl-7-(methoxymethoxy)-2-methyl-4-(2-methyl-4-pyridyl)quinoline (C185)

[0728] To a mixture of C184 (50 mg, 0.1787 mmol), (2-methyl-4-pyridyl)boronic acid (49 mg, 0.3578 mmol) and PD(dppf)Cl.sub.2 (88 mg, 0.1078 mmol) in DMF (2 mL), an aqueous solution of Na.sub.2CO.sub.3 (360 μL of 2 M, 0.7200 mmol) was added under nitrogen and the reaction was heated in a microwave reactor at 125° C. for 4 hours. An aqueous solution of HCl (1 N; 0.5 mL) and water were added, the mixture was extracted with EtOAc and the combined organic phases were concentrated. Purification by silica gel chromatography (0 to 10% MeOH in dichloromethane) afforded crude product which was repurified by reverse-phase HPLC (Method: C18 Waters Sunfire column, 30×150 mm, 5 micron. Gradient: MeCN in water) to afford C185 (16 mg, 27%). LCMS m/z 337.24 [M+H].sup.+

Step 3: 3-isopropyl-2-methyl-4-(2-methyl-4-pyridyl)quinolin-7-ol (290)

[0729] To a solution of C185 (16 mg, 0.04756 mmol) in MeOH (0.5 mL), a solution of hydrogen chloride (500 μL of 6M, 3.000 mmol) in MeOH was added and the reaction was stirred at room temperature for 4 hours. The mixture was concentrated to afford 290 (14 mg, 78%). .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 9.02 (d, J=4.9 Hz, 1H), 7.81 (d, J=26.9 Hz, 3H), 7.30 (d, J=7.8 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 3.36 (s, 1H), 3.20 (s, 3H), 3.05 (s, 3H), 1.34 (d, J=6.2 Hz, 6H). LCMS m/z 293.31 [M+H].sup.+

Compounds 291-293

[0730] Compounds 291-293 (Table 37) were prepared in five steps from intermediate C57 and the appropriate boronic acid according to the method described for compound 253. Any modifications to methods are noted in Table 37 and accompanying footnotes.

TABLE-US-00038 TABLE 37 Method of preparation, structure, physicochemical data for compounds 291-293 Boronic .sup.1H NMR; LCMS m/z Compound Method/Product acid [M + H].sup.+ 291 [00983] [00984] .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.73 (bs, 1H), 7.55 (q, J = 7.16 Hz, 1H), 7.40 − 7.36 (m, 2H), 7.27 (t, J = 7.64 Hz, 1H), 6.85 (s, 1H), 6.62 (s, 2H), 6.07 (bs, 1H), 3.77 (bs, 2H), 2.91 (t, J = 7.36 Hz, 1H), 1.21 − 1.15 (m, 6H), 1.12 − 1.04 (m, 4H). LCMS m/z 395.15 [M + H.sup.+] 292 [00985] [00986] .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 8.56 (d, J = 5 Hz, 1H), 7.15 (s, 1H), 7.07 (d, J = 4..68 Hz, 1H), 6.81 (s, 1H), 6.57 (bs, 1H), 3.69 (s, 2H), 2.56 (s, 3H), 1.23 − 1.19 (m, 6H), 1.02 (bs, 2H), 0.88 (bs, 2H). LCMS m/z 392.49 [M + H.sup.+] 293 [00987] [00988] .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 13.94 (bs, 1H), 9.73 (s, 1H), 7.57 (q, J = 7.4 Hz, 1H), 7.31 (td, J = 8.7, 2.7 Hz, 1H), 7.14 (d, J = 9.36 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.85 (bs, 1H), 6.65 − 6.59 (m, 2H), 6.07 (bs, 1H), 3.77 (d, J = 5.5 Hz, 2H), 2.92 (p, J = 7.4 Hz, 1H), 1.19 (t, J =6.9 Hz, 6H), 1.11 (q, J = 3.8, 3.0 Hz, 2H), 1.05 (t, J = 3.0 Hz, 2H). LCMS m/z 395.1 [M + H.sup.+] .sup.1. The order of steps changed for the first three steps. The formation of the N-oxide was performed first, PyBrop amination at 45° C. was performed second and Suzuki coupling was performed third. The other steps proceeded as in the scheme.

Compound 294

(2S)-3-(7-(hydroxy)-4-(4-fluoro-3-methylphenyl)-3-(1-methoxypropan-2-yl)quinolin-2-yl)-2-methylpropanoic acid (294)

[0731] ##STR00989##

[0732] Compounds 294 was prepared in three steps from intermediate S26 and methyl (2R)-3-iodo-2-methyl-propanoate according to the method described for compound 263. .sup.1H NMR (400 MHz, DMSO-d.sub.6, 100° C.) δ 10.02 (s, 1H), 7.34-7.28 (m, 4H), 7.18 (s, 1H), 6.96-6.87 (m, 2H), 3.43-3.24 (m, 6H), 3.13 (s, 1H), 3.07-3.02 (m, 1H), 1.26 (d, J=6.1 Hz, 3H), 1.18-1.15 (m, 3H). LCMS m/z 398 [M+H.sup.+].

Compound 295

(4-(4-fluorophenyl)-7-hydroxy-3-(1-methoxypropan-2-yl)quinolin-2-yl)-L-alanine (295)

[0733] ##STR00990##

[0734] Compound 295 was prepared in two steps (via C188) from intermediate C61 and benzyl (2S)-2-aminopropanoate hydrochloride according to the method described for compound 251. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.63 (s, 1H), 7.35 (t, J=8.8 Hz, 2H), 7.26-7.25 (m, 2H), 6.84-6.80 (m, 1H), 6.63-6.57 (m, 2H), 4.64-4.62 (m, 1H), 3.50-3.48 (m, 2H), 3.24-3.22 (m, 3H), 3.02 (s, 1H), 1.45 (d, J=7.1 Hz, 3H), 1.20 (dd, J=7.4, 3.8 Hz, 3H). LCMS m/z 399 [M+H.sup.+]

Compound 296

4-(4-fluoro-3-methylphenyl)-2-methylquinolin-7-ol (296)

[0735] ##STR00991##

[0736] A mixture of S27 (144 mg, 0.5119 mmol) and pyridine (hydrochloride salt) (2.5 g, 21.63 mmol) was microwaved at 220° C. for 30 min. The mixture was cooled down to RT, 60 mL of water and 20 mL of a saturated aqueous solution of NH.sub.4Cl were added. The mixture was filtered and extracted with EtOAc, the organic phases were combined and concentrated. Purification by trituration with dichloromethane to give 296 (25 mg, 17%). .sup.1H NMR (300 MHz, Chloroform-d and Methanol-d.sub.4) δ 7.71 (d, J=9.1 Hz, 1H), 7.35-7.22 (m, 3H), 7.20-7.02 (m, 3H), 2.70 (s, 3H), 2.37 (d, J=2.0 Hz, 3H). LCMS m/z 268.2 [M+H].sup.+

Compounds 297-310

[0737] Compound 297-310 (Table 38) were prepared in three steps from intermediate S28 and the appropriate amine according to the method described for compound 244. Any modifications to methods are noted in Table 38 and accompanying footnotes.

TABLE-US-00039 TABLE 38 Method of preparation, structure, physicochemical data for compounds 297-310 .sup.1H NMR; LCMS m/z Compound Method/Product Amine [M + H].sup.+ 297 [00992] [00993] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.71 (bs, 1H), 7.34 (bs, 1H), 7.26 (t, J = 8.8 Hz, 1H), 7.12 (d, J = 7.0Hz, 1H), 7.04 − 7.03 (m, 1H), 6.84 (d, J = 2Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 6.57 (dd, J = 8.8 Hz,1.9Hz, 1H), 5.38 (bs, 1H), 3.81 (d, J = 12.6 Hz, 1H), 3.59 (m, 3H), 2.89 (m, 1H), 2.28 (s,3H), 1.22 − 0.97 (m, 7H). LCMS m/z 425 [M + H.sup.+] 298 [00994] [00995] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.57 (s, 1H), 7.25 (t, J = 8.8 Hz, 1H), 7.13 − 7.09 (m, 1H), 7.01 − 7.04 (m, 2H), 6.79 (d, J = 2 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), ), 6.53 (dd, J = 8.8 Hz, 2 Hz, 1H), 5.30 (bs, 1H), 5.10 (bs, 1H), 3.62 − 3.51 (m, 6H), 2.9 (m, 1H), 2.28 (s, 3H), 1.13 (d, J = 4.5 Hz, 3H). LCMS m/z 371 [M + H.sup.+] 299 [00996] [00997] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.7 (bs, 1H), 7.97 (bs, 1H), 7.25 (t, J = 9.0 Hz, 1H), 7.10 − 7.09 (m, 1H), 7.01 − 7.00 (m, 1H), 6.85 (s, 1H), 6.63 − 6.57 (m, 2H), 5.7 (bs, 1H), 3.56 − 3.54 (m, 2H), 2.86 (bs, 1H), 2.37 − 2.33 (m, 6H), 2.24 (s, 3H), 1.10 (t, J = 3 Hz, 3H). LCMS m/z 437 [M + H.sup.+] 300 [00998] [00999] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (bs, 1H), 7.52 (bs, 1H), 7.25 (t, J = 8.5 Hz, 1H), 7.10 (d, J = 7.1 Hz, 1H), 7.02 (m, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 6.56 (m, 1H), 5.57 (bs, 1H), 4.64 − 4.59 (m, 1H), 3.60 (m, 2H), 2.91 (m, 1H), 2.28 (s, 3H), 1.41 (d, J = 7.08 Hz, 3H), 1.19 (t, J = 3.6 Hz, 3H). LCMS m/z 399 [M + H.sup.+] 301 [01000] [01001] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (bs, 1H), 7.69 (bs, 1H), 7.25 (t, J = 8.12 Hz, 1H), 7.11 (m, 1H), 7.02 (m, 1H), 6.78 (d, J = 2.2 Hz, 1H), 6.64 (t, J = 5.72 Hz, 1H), 6.58 (m, 1H), 5.57 (bs, 1H), 4.54 (m, 1H), 3.62 (m, 2H), 2.91 (m, 1H), 2.28 (s, 3H), 1.43 (t, J = 3.72 Hz, 3H), 1.17 (t, J = 3.32 Hz, 3H). LCMS m/z 399 [M + H.sup.+] 302 [01002] [01003] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.6 (s, 1H), 7.25 (t, J = 8.6 Hz, 1H), 7.11 − 7.02 (m, 3H), 6.86 (d, J = 2.2 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 6.58 (dd, J = 8.82 Hz, 1H), 5.17 (bs, 1H), 3.92 − 3.85 (m, 2H), 3.59 − 3.47 (m, 4H), 3.07 (s, 3H), 2.92 − 2.87 (m, 1H), 2.29 (s, 3H), 1.10 (d, J = 5 Hz, 3H). LCMS m/z 433 [M + H.sup.+] 303 [01004] [01005] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.1 (bs, 1H), 9.63 (bs, 1H), 7.96 (bs, 1H), 7.26 (t, J = 8.6 Hz, 1.3H), 7.13 − 7.12 (m, 1H), 7.05 − 7.04 (m, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 9.2 Hz, 1H), 5.78 (bs, 1H), 3.62 (s, 2H). 2.90 − 2.87 (m, 1H), 2.28 (s, 3H), 1.56 (s, 3H), 1.52 (s, 3H), 1.17 (d, J = 3.4 Hz, 3H). LCMS m/z 413 [M + H.sup.+] 304 [01006] [01007] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.61 (bs, 1H), 7.8 (bs, 1H), 7.25 (t, J = 8.5 Hz, 1.3H), 7.10 − 7.08 (m, 1.3H), 7.02 − 7.01 (m, 1.3H), 6.82 (m, 1H), 6.63 − 6.61 (m, 1.3H), 6.56 − 6.53 (m, 1H), 5.76 (bs, 1H), 5.08 (d, J = 5.6 Hz, 1.3H). 4.55 − 4.54 (m, 0.3H), 4.55 − 4.54 (m, 0.3H), 4.11 − 4.05 (m, 1H), 3.96 − 3.91 (m, 1H), 3.61 (m, 2.6H), 2.89 (m, 1.3H), 2.72 − 2.53 (m, 2H), 2.28 (s, 3.9H), 2.17 − 2.07 (m, 1.3H), 1.79 − 1.72 (m, 2H), 1.12 (d, J = 3.6 Hz, 3.9H). LCMS m/z 397 [M + H.sup.+] 305 [01008] [01009] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.63 (bs, 1H), 7.53 (bs, 1H), 7.32 − 7.23 (m, 1H), 7.22 − 7.10 (m, 1H), 7.08 7.01 (m, 1H), 6.80 (s, 1H), 6.65 − 6.55 (m, 2H), 5.58 (bs, 1H), 4.68 − 4.59 (m, 1H), 3.65 − 3.59 (m, 2H), 2.98 − 2.92 (m, 1H), 2.29 (s, 3H), 1.43 (d, J = 4.96Hz, 3H), 1.20 − 1.15 (m, 3H). LCMS m/z 399 [M + H.sup.+] 306 [01010] [01011] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.7 (bs, 1H), 9.62 (s, 1H), 7.68 (bs, 1H), 7.26 (t, J = 8.32 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 7.05 − 7.01 (m, 1H), 6.79 (s, 1H), 6.68 − 6.54 (m, 2H), 5.6 (bs, 1H), 4.65 − 4.45 (m, 1H), 3.73 − 3.58 (m, 2H), 2.95 − 2.90 (m, 1H), 2.29 (s, 3H), 1.44 (d, J = 7.2Hz, 3H), 1.19 − 1.14 (m, 3H). LCMS m/z 399 [M + H.sup.+] 307 [01012] [01013] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.86 (bs, 1H), δ 7.30 − 7.16 (m, 2H), 7.28 − 7.08 (m, 1H), 7.03 (s, 1H), 6.86 − 6.79 (m, 1H), 6.74 (d, J = 9.0 Hz, 1H), 3.46 − 3.18 (m, 7H), 2.76 (s,3H), 2.30 (s,3H), 1.02 − 0.95 (m, 3H). LCMS m/z 413 [M + H.sup.+] 308 [01014] [01015] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 7.60 (bs, 1H), 7.25 (t, J = 9.1 Hz, 1H), 7.12 − 7.01 (m, 2H), 6.80 (d, J = 2.4 Hz, 1H), 6.60 (d, J = 8.9 Hz, 1H), 6.54 (d, J = 9.3 Hz, 1H), 5.63 (bs, 1H), 4.62 − 4.48 (m, 1H), 3.60 − 3.48 (m, 2H), 2.89 − 2.58 (m, 4H), 2.29 (s, 3H), 2.05 − 1.98 (m, 2H), 1.18 − 1.12 (m, 3H). LCMS m/z 425 [M + H.sup.+] 309 [01016] [01017] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 7.25 (t, J = 9.1 Hz, 1H), 7.10 (d, J = 7.4 Hz, 2H), 7.02 (bs, 1H), 6.83 (d, J = 2.3 Hz, 1H), 6.62 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 9.9 Hz, 1H), 5.27 (bs, 1H), 4.22 (t, J = 7.9 Hz, 2H), 3.73 − 3.58 (m, 6H), 3.45 (d, J = 6.1 Hz, 2H), 2.88 (d, J = 7.7 Hz, 1H), 2.29 (s, 3H), 1.33 − 1.21 (m, 3H). LCMS m/z 440 [M + H.sup.+] 310 [01018] [01019] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.59 (s, 1H), 7.25 (t, J = 8.72 Hz, 1H), 7.15 − 6.93 (m, 2H), 6.95 (s, 3H), 6.86 (s, 1H), 6.65 − 6.53 (m, 2H), 5.13 (bs, 1H), 3.87 (d, J = 5.24 Hz, 2H), 3.61 − 3.50 (m, 2H), 3.37 (t, J = 6.76 Hz, 2H), 2.91 − 2.82 (m, 1H), 2.28 (s, 3H), 1.14 − 1.07 (m, 3H). LCMS m/z 434 [M + H.sup.+] .sup.1. No ester saponification was necessary. .sup.2. t-Butyl ester deprotection was performed with HCI in dioxane. .sup.3. 300 and 301 are diastereomers with different stereochemistry at the C3 substituent, stereochemistry at this center is unknown. .sup.4. 305 and 306 are diastereomers with different stereochemistry at the C3 substituent, stereochemistry at this center is unknown.

Preparation of C189

7-(benzyloxy)-3-(3,6-dihydro-2H-pyran-4-yl)-4-(4-fluoro-3-methylphenyl)quinoline 1-oxide (C189)

[0738] ##STR01020##

[0739] To a solution of C66 (2.75 g, 6.4631 mmol) in dichloromethane (27.005 mL), m-CPBA (1.3830 g, 8.0142 mmol) was added while at 0° C. and the reaction was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (200 mL), washed with an aqueous saturated solution of NaHCO.sub.3 solution (˜20 mL) and concentrated. Purification by silica gel chromatography afforded (30 to 50% EtOAc in hexanes, followed by 2 to 5% MeOH in dichloromethane) afforded C189 (2.6 g, 86%). LCMS m/z 442.3 [M+H].sup.+.

Compounds 311-320

[0740] Compound 311-320 (Table 39) were prepared in three steps from intermediate C189 and the appropriate amine according to the method described for compound 244. Any modifications to methods are noted in Table 39 and accompanying footnotes.

TABLE-US-00040 TABLE 39 Method of preparation, structure and physicochemical data for compounds 311-320 .sup.1H NMR; LCMS m/z Compound Method/Product Amine [M + H].sup.+ 311 [01021] [01022] .sup.1H NMR (DMSO-d.sub.6) δ 13.9 (br, 1H), 9.74 (s, 1H), 7.27 (t, J = 9.1Hz, 1H), 7.16 (t, J = 6.4Hz, 1H), 7.09-7.06 (m, 1H), 6.84 (d, J = 2.0Hz, 1H), 6.68-6.59 (m, 2H), 6.22 (br, 1H), 3.84-3.74 (m, 4H), 3.31- 3.04 (m, 2H), 2.82-2.79 (m, 1H), 2.30 (s, 3H), 2.07- 2.04 (m, 2H), 1.40-1.37 (m, 2H), 1.10-1.06 (m, 4H). LCMS m/z 451.3 [M + H.sup.+] 312 [01023] [01024] .sup.1H NMR (DMSO-d.sub.6) δ 12.5 (br, 1H), 10.8 (br, 1H), 8.1 (br, 1H), 7.33 (t, J = 8.8 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.12-7.08 (m, 1H), 6.96-6.76 (m, 2H), 3.89-3.78 (m, 4H), 3.14- 3.12 (m, 2H), 2.91-2.88 (m, 1H), 1.75-1.74 (m, 2H), 2.31 (s, 3H), 1.88 (br, 2H), 1.39-1.36 (m, 2H). LCMS m/z 424.9 [M + H.sup.+] 313 [01025] [01026] .sup.1H NMR (DMSO-d.sub.6) δ 9.67 (s, 1H), 7.28 (t, J = 8.8 Hz, 1H), 7.15 (t, J = 5.8 Hz, 1H), 7.07-7.06 (m, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.69-6.67 (m, 1H), 6.61-6.59 (m, 1H), 6.1 (br, 1H), 4.66 (br, 1H), 3.90- 3.84 (m, 4H), 3.06-3.04 (m, 2H), 2.86-2.84 (m, 1H), 2.30 (s, 3H), 2.28 (br, 2H), 1.44-1.41 (m, 2H). LCMS m/z 441.4 [M + H.sup.+] 314 [01027] [01028] .sup.1H NMR (DMSO-d.sub.6) δ 9.66 (s, 1H), 7.28 (t, J = 8.8Hz, 1H), 7.15 (t, J = 7.68Hz, 1H), 7.09-7.07 (m, 1H), 6.80 (d, J = 2.1Hz, 1H), 6.69-6.67 (m, 1H), 6.62-6.59 (m, 1H), 5.95 (br, 1H), 4.76 (br, 1H), 3.94-3.84 (m, 3H), 3.09- 3.06 (m, 1H), 2.88-2.82 (m, 1H), 2.30 (s, 2H), 1.45-1.42 (m, 1H). LCMS m/z 441 [M + H.sup.+] 315 [01029] [01030] .sup.1H NMR (DMSO-d.sub.6) δ 12.5 (br, 1H), 9.66 (s, 1H), 7.27 (t, J = 8.8Hz, 1H), 7.16-7.06 (m, 2H), 6.81 (d, J = 1.88 Hz, 1H), 6.66-6.58 (m, 2H), 6.06 (br, 1H), 4.80 (br, 1H), 3.82 (d, J = 7.2 Hz, 2H), 3.14-3.12 (m, 2H), 2.89-2.87 (m, 1H), 2.32-2.30 (m, 3H), 1.90 (br, 2H), 1.50-1.41 (m, 5H). LCMS m/z 424.9 [M + H.sup.+] 316 [01031] [01032] .sup.1H NMR (DMSO-d.sub.6) δ 9.2 (br, 1H), 7.26 (t, J = 9.0 Hz, 1H), 7.13-7.05 (m, 2H), 6.84 (d, J = 1.84 Hz, 1H), 6.64-6.56 (m, 2H), 5.88 (br, 1H), 4.72-4.70 (m, 1H), 3.80-3.78 (m, 2H), 3.12-3.09 (m, 2H), 2.79- 2.69 (m, 1H), 2.67-2.64 (m, 2H), 2.29 (s, 3H), 1.95- 1.90 (m, 2H), 1.37-1.23 (m, 5H). LCMS m/z 439 [M + H.sup.+] 317 [01033] [01034] .sup.1H NMR (DMSO-d.sub.6) δ 12.5 (br, 1H), 9.7 (br, 1H), 7.26 (t, J = 8.7 Hz, 1H), 7.22-6.97 (m, 2H), 6.87 (br, 1H), 6.67-6.47 (m, 2H), 4.22 (br, 2H), 3.83-3.81 (m, 2H), 3.13-2.97 (m, 2H), 2.90-2.88 (m, 1H), 2.30 (s, 3H), 1.96-1.90 (m, 2H), 1.41-1.38 (m, 2H). LCMS m/z 411 [M + H.sup.+] 318 [01035] [01036] .sup.1H NMR (DMSO-d.sub.6) δ 12.5 (br, 1H), 9.6 (br, 1H), 7.26 (t, J = 8.7 Hz, 1H), 7.15-7.05 (m, 2H), 6.81 (d, J = 2.2 Hz, 1H), 6.66-6.58 (m, 2H), 6.05 (br, 1H), 4.68 (t, J = 6.7 Hz, 1H), 3.82 (d, J = 8 Hz, 1H), 3.12- 2.89 (m, 3H), 2.30 (s, 3H), 1.98 (br, 2H), 1.50-1.60 (m, 6H). LCMS m/z 425.2 [M + H.sup.+] 319 [01037] [01038] .sup.1H NMR (DMSO-d.sub.6) δ 12.4 (br, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.18-7.10 (m, 3H), 6.70 (brs, 2H), 4.76 (br, 1H), 3.79-3.78 (m, 2H), 3.14-3.13 (m, 2H), 2.88- 2.66 (m, 3H), 2.30 (s, 3H), 1.80-1.70 (m, 2H), 1.43- 1.36 (m, 2H), 1.35 (d, J = 5.5 Hz, 3H). LCMS m/z 439 [M + H.sup.+] 320 [01039] [01040] .sup.1H NMR (DMSO-d.sub.6) δ 12.5 (br, 1H), 9.6 (s, 1H), 7.26 (t, J = 8.8 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.05-7.04 (m, 1H), 6.83 (d, J = 2.12 Hz, 1H), 6.62 (d, J = 8.8 Hz, 1H), 6.57 (dd, J = 8.4, 2.1 Hz, 1H), 6.70 (brs, 2H), 3.81-3.80 (m, 2H), 3.79-3.63 (m, 2H), 3.12- 3.06 (m, 2H), 2.97-2.92 (m, 1H), 2.82-2.79 (m, 1H), 2.29 (s, 3H), 2.07-1.98 (m, 2H), 1.37-1.34 (m, 2H), 1.15 (d, J = 7.0 Hz, 3H). LCMS m/z 439 [M + H.sup.+] .sup.1Benzyl ester was removed during the hydrogenation/benzyl ether deprotection step. .sup.2t-Butyl ester deprotection was performed with HCl in EtOAc.

Compounds 321-324

[0741] Compounds 321-324 (Table 40) were prepared in three steps from intermediate S30 and the appropriate amine according to the method described for compound 254. Any modifications to methods are noted in Table 40 and accompanying footnotes.

TABLE-US-00041 TABLE 40 Method of preparation, structure, physicochemical data for compounds 321-324 .sup.1H NMR; LCMS m/z Compound Method/Product Amine [M + H].sup.+ 321 [01041] [01042] .sup.1H NMR (DMSO-d.sub.6) δ 9.82 (s, 1H), 7.28 (dd, J = 9.8, 8.3 Hz, 1H), 7.18 (dd, J = 7.7, 2.2 Hz, 1H), 7.09 (ddd, J = 7.8, 5.0, 2.2 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.69-6.63 (m, 2H), 4.35-4.22 (m, 4H), 3.77-3.69 (m, 2H), 3.57-3.45 (m, 1H), 3.32-3.22 (m, 3H), 2.96 (s, 1H), 2.31 (s, 3H), 1.50-1.45 (m, 4H). LCMS m/z 437.2 [M + H.sup.+] 322 [01043] [01044] .sup.1H NMR (DMSO-d.sub.6) δ 9.83 (bs, 1H), 7.3-7.25 (m, 1H), 7.2-7.19 (m 1H), 7.12-7.1 (m, 2H), 6.94 (d, J = 2.3 Hz, 1H), 6.71-6.63 (m, 2H), 4.66-4.58 (m, 2H), 4.32-4.24 (m, 2H), 3.72-3.69 (m, 2H), 3.31-3.25 (m, 2H), 2.97-2.89 (m, 1H), 2.32 (s, 3H), 1.55- 1.45 (m, 4H). LCMS m/z 455.1 [M + H.sup.+] 323 [01045] [01046] .sup.1H NMR (DMSO-d.sub.6) δ 7.28 (t, J = 9.0 Hz, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 9.1, 2.4 Hz, 1H), 6.66 (d, J = 9.0 Hz, 1H), 3.72 (s, 3H), 3.53 (dt, J = 10.5, 7.6 Hz, 2H), 3.44 (s, 1H), 3.30-3.18 (m, 3H), 3.10 (q, J = 7.2 Hz, 1H), 2.32 (s, 3H), 2.17-2.06 (m, 2H), 1.59-1.54 (m, 3H), 1.40-1.39 (m, 1H). LCMS m/z 451.2 [M + H.sup.+] 324 [01047] [01048] .sup.1H NMR (DMSO-d.sub.6) δ 9.87 (bs, 1H), 7.28 (t, J = 9.0 Hz, 1H), 7.19 (t, J = 5.5 Hz, 1H), 7.11 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 9.0, 2.4 Hz, 1H), 6.66 (d, J = 9.0 Hz, 1H), 3.74-3.71 (m, 3H), 3.56-3.48 (m, 2H), 3.44 (bs, 1H), 3.31-3.18 (m, 4H), 3.11-3.08 (m, 1H), 2.32 (s, 3H), 2.17-2.06 (m, 2H), 1.62-1.54 (m, 3H), 1.38 (d, J = 12.8 Hz, 1H). LCMS m/z 451.2 [M + H.sup.+]

Compounds 325-330

[0742] Compounds 325-330 (Table 41) were prepared in five steps from intermediate C65 and the appropriate boronic acid according to the method described for compound 253. Any modifications to methods are noted in Table 41 and accompanying footnotes.

TABLE-US-00042 TABLE 41 Method of preparation, structure, physicochemical data for compounds 325-330 Compound Method/Product Boronic acid .sup.1H NMR; LCMS m/z [M + H].sup.+ 325 [01049] [01050] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.9 (bs, 1H), 9.75 (bs, 1H), 7.59-7.54 (m, 1H), 7.33 (t, J = 8.04 Hz, 1H,), 7.16 (d, J = 9.04, 1H), 7.08 (d, J = 7.52 Hz, 1H,), 6.84 (d, J = 1.6 Hz 1H), 6.65- 6.59 (m, 2H), 6.24 (bs, 1H) 3.83 (d, J = 9.76 Hz, 2H), 3.75 (d, J = 3.96, 2H), 3.03 (bs, 1H), 2.77-2.66 (m, 1H), 2.07 (bs, 2H), 1.445-1.37 (m,2H), 0.88-0.86 (m, 4H). LCMS m/z 437.4 [M + H.sup.+] 326 [01051] [01052] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.95 (bs, 1H), 7.58 (dt, J = 10.8, 8.4 Hz, 3H), 7.45 (td, J = 9.1, 8.6, 4.2 Hz, 3H), 7.11 (t, J = 6.4 Hz, 3H), 6.84 (d, J = 2.3 Hz, 3H), 6.60-6.67 (m, 2H), 6.26 (s, 1H), 3.83 (d, J = 9.08 Hz, 2H), 3.74 (s, 2H), 3.09 (d, J = 10.28 Hz, 2H), 2.77 (s, 2H), 2.03 (bs, 2H), 1.33-1.46 (m, 2H), 1.03-1.08 (m, 2H), 1.08- 1.03 (m, 4H). LCMS m/z 455.6 [M + H.sup.+] 327 [01053] [01054] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.90 (bs, 1H), 7.40 (td, J = 9.6, 4.9 Hz, 2H), 7.08 (d, J = 5.80 Hz, 3H), 6.83 (d, J = 1.68 Hz, 2H), 6.62-6.66 (m, 2H), 3.85-3.83 (m, 2H), 3.71 (s, 2H), 3.09 (s, 2H), 2.74 (s, 1H), 2.05 (s, 1H), 1.44 (d, J = 11.36 Hz, 2H), 1.06 (s, 3H), 0.97 (s,2H). LCMS m/z 455.6 [M + H.sup.+] 328 [01055] [01056] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.61 (bs, 1H), 9.76 (bs, 1H), 7.49-7.47 (m, 1H), 7.39-7.36 (m, 1H), 7.27-7.26 (m, 1H), 6.86 (bs, 1H), 6.64 (bs, 2H), 6.25 (bs, 2H), 3.85-3.74 (m, 4H), 3.08 (bs, 2H), 2.77(bs, 2H), 1.40 (d, J = 12.9 Hz, 2H), 2.07 (bs, 2H), 1.42-1.39 (m, 2H), 1.23-1.06 (m, 4H). LCMS m/z 437.5 [M + H.sup.+] 329 [01057] [01058] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.66 (bs, 1H), 9.78 (bs, 1H), 7.49-7.44 (m, 1H), 7.41-7.35 (m, 1H), 7.29-7.23 (m, 1H), 6.85 (bs, 1H), 6.64 (bs, 2H), 6.28 (bs, 1H), 3.86-3.81 (m, 2H), 3.76 (s, 2H), 3.15-3.10 (m, 2H), 2.77 (s, 1H), 1.99 (bs, 2H), 1.41 (d, J = 8.48 Hz, 2H), 1.17-1.05 (m, 4H). LCMS m/z 455.47 [M + H.sup.+] 330 [01059] [01060] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.79 (bs, 1H), 7.64-7.58 (m, 1H), 7.41-7.36 (m, 1H), 7.15 (t, J = 6.52 Hz, 1H), 6.85 (s, 1H), 6.65 (s, 2H), 6.29 (s, 1H), 3.86- 3.71 (m, 4H), 3.76 (s, 2H), 3.15-3.06 (m, 2H), 2.79 (s, 1H), 2.04 (bs, 2H), 1.42 (d, J = 11.76 Hz, 2H), 1.10-1.06 (m, 4H). LCMS m/z 455.5 [M + H.sup.+]

Preparation of C198

7-benzyloxy-2-chloro-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-quinoline (C198)

[0743] ##STR01061## ##STR01062##

Step 1: 4-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-quinoline (C191)

[0744] To a suspension of C190 (20 g, 73.387 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16.959 g, 80.726 mmol) in 1,4-dioxane (200 mL) and water (20 mL) was added Pd(dppf)Cl.sub.2.dichloromethane (5.9931 g, 7.3387 mmol). The mixture was purged with argon and the reaction was heated for at 90° C. for 12 hours. The mixture was filtered through a Celite® plug, washed with EtOAc and concentrated. Purification by silica gel column chromatography with (40-50% EtOAc in hexane) afforded C191 (13 g, 64%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.68 (s, 1H), 8.14 (d, J=9.2 Hz, 1H), 7.46 (bs, 1H), 7.4 (d, J=9.2 Hz, 1H), 5.99 (bs, 1H), 4.26 (bs, 2H), 3.93 (s, 3H), 3.86 (t, J=5.32 Hz, 2H), 2.47 (bs, 2H). LCMS m/z 275.8 [M+H].sup.+

Step 2: 4-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-1-oxido-quinolin-1-ium (C192)

[0745] To a solution of C191 (1 g, 3.6267 mmol) in dichloromethane (25 mL), m-CPBA (813.60 mg, 4.7147 mmol) was added at 0° C. and stirred at room temperature for 3 hours. The reaction was concentrated, the residue was washed with aqueous NaHCO.sub.3 solution (25 mL), extracted with EtOAc (2×30 mL), and the organic phases combined, dried with MgSO.sub.4 and concentrated. Purification by silica gel column chromatography (40-60% EtOAc in hexane) afforded C192 (850 mg, 69%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.54 (s, 1H), 8.18 (d, J 9.26 Hz, 1H), 7.93 (bs, 1H), 7.51 (d, J=7.68 Hz, 1H), 6.04 (bs, 1H), 4.23 (bs, 2H), 3.97 (s, 3H), 3.83 (t, J=5.2 Hz, 1H), 2.44 (bs, 2H). LCMS m/z 292.11 [M+H].sup.+

Step 3: 4-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-quinolin-2-ol (C193)

[0746] To a solution of C192 (6 g, 20.567 mmol) in water (50 mL) and THF (10 mL), methanesulfonyl chloride (4.7120 g, 3.1838 mL, 41.134 mmol) was added and the reaction was stirred at room temperature for 15 minutes. The mixture was diluted with EtOAc (30 mL), washed successively with water (2×20 mL) and brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel column chromatography (50-60% EtOAc and hexane) afforded C193 (5 g, 77%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.95 (s, 1H), 7.79 (d, J=9.0 Hz, 1H), 6.91 (dd, J=9.0, 2.5 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 5.71 (d, J=2.9 Hz, 1H), 4.19 (q, J=2.8 Hz, 2H), 3.80 (t, J=5.4 Hz, 2H), 3.33 (s, 2H), 2.27-2.20 (m, 2H). LCMS m/z 292.0 [M+H].sup.+

Step 4: 3-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-4-(2-methyl-4-pyridyl)quinolin-2-ol (C194)

[0747] To a solution of (2-methyl-4-pyridyl)boronic acid (3.5206 g, 25.708 mmol) and C193 (5 g, 17.139 mmol) in 1,4 dioxane (10 mL) and water (2 mL) was added K.sub.2CO.sub.3 (5.9217 g, 42.847 mmol). Then, under inert atmosphere, Pd(PPh.sub.3).sub.4 was added and the reaction was heated at 90° C. for 12 hours. The mixture was filtered through celite plug, washed with 10% MeOH in dichloromethane and concentrated. Purification by silica gel column chromatography (50-60% EtOAc and hexane) afforded C194 (5 g, 80%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.87 (s, 1H), 8.52 (d, J=5.0 Hz, 1H), 7.16 (s, 1H), 7.12-7.06 (m, 1H), 6.87 (d, J=2.5 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 6.72 (dd, J=9.0, 2.5 Hz, 1H), 5.29 (s, 1H), 3.80 (d, J=6.0 Hz, 5H), 3.58-3.51 (m, 2H), 2.14 (s, 2H). LCMS m/z 349.2 [M+H].sup.+

Step 5: 7-methoxy-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-quinolin-2-ol (C195)

[0748] To a stirred solution of C194 (3 g, 8.6109 mmol) in AcOH (10 mL) and MeOH (20 mL), Pd (4.5819 g, 10% w/w, 4.3055 mmol) was added at room temperature. The reaction was purged with hydrogen gas, kept at 45 psi and stirred at room temperature for 12 hours. The mixture was filtered through a Celite® plug, washed with EtOH and concentrated to afford C195 (2.5 g, 52%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.76 (s, 1H), 8.61 (d, J=5.0 Hz, 1H), 7.18 (s, 1H), 7.11 (d, J=5.1 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 6.71-6.64 (m, 1H), 6.62 (d, J=9.0 Hz, 1H), 3.79 (d, J=10.0 Hz, 5H), 3.00 (t, J=11.7 Hz, 2H), 2.55 (s, 3H), 2.38 (d, J=11.1 Hz, 1H), 1.70 (s, 5H), 1.25 (d, J=11.6 Hz, 2H), 1.09 (t, J=7.1 Hz, 1H). LCMS m/z 351.0 [M+H].sup.+

Step 6: 2-chloro-7-methoxy-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-quinoline (C196)

[0749] To a solution of C195 (4 g, 11.415 mmol) in POCl.sub.3 (20 mL) was added DMF (1.6687 g, 1.7677 mL, 22.830 mmol), and the reaction was heated at 100° C. for 4 h. The mixture was concentrated, diluted with EtOAc (100 mL) and washed with a saturated aqueous solution of NaHCO.sub.3 solution (˜20 mL), and the organic phase was dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel column chromatography (60% EtOAc in hexane) afforded C196 (3.5 g, 77%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.65 (d, J=5.0 Hz, 1H), 7.40 (d, J=2.6 Hz, 1H), 7.29 (s, 1H), 7.24-7.15 (m, 2H), 6.99 (d, J=9.3 Hz, 1H), 3.91 (s, 3H), 3.89-3.81 (m, 2H), 3.08 (s, 2H), 2.89 (s, 1H), 2.57 (s, 3H), 2.54 (s, 1H), 1.47 (d, J=12.5 Hz, 2H). LCMS m/z 93.02 [M+H].sup.+

Step 7: 2-chloro-4-(3-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-quinolin-7-ol (C197)

[0750] To a mixture of AlCl.sub.3 (2.1691 g, 16.267 mmol) in dichloromethane (10 mL), 1-dodecanethiol (1.37 g, 1.63 mL, 6.78 mmol) was added at 0° C. and the mixture was stirred for 30 min. Then, a solution of C196 (1 g, 2.7111 mmol) in dichloromethane (10 mL) was added at 0° C. and the mixture was stirred at RT for 12 h. The mixture was poured into ice water, an aqueous solution of NaHCO.sub.3 1M (˜16 mL) was added and extracted with dichloromethane (150 mL). The combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel column chromatography (20% MeOH in dichloromethane) afforded C197 (750 mg, 68%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.47 (s, 1H), 8.65 (d, J=5.0 Hz, 1H), 7.29 (s, 1H), 7.20 (dd, J=14.9, 3.9 Hz, 2H), 7.10 (dd, J=9.2, 2.5 Hz, 1H), 6.94 (d, J=9.1 Hz, 1H), 3.85 (d, J=10.4 Hz, 2H), 3.56 (q, J=7.2 Hz, 1H), 3.08 (qd, J=7.2, 4.6 Hz, 7H), 2.57 (s, 3H), 1.45 (d, J=12.5 Hz, 2H), 1.34 (s, 1H), 1.22 (dt, J=29.3, 7.2 Hz, 13H). LCMS m/z 355.0 [M+H].sup.+

Step 8: 7-benzyloxy-2-chloro-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-quinoline (C198)

[0751] To a stirred solution of C197 (1 g, 2.81 mmol) in dry DMF (10 mL), NaH (225.44 mg, 60% w/w, 5.637 mmol) was added at 0° C., and the mixture was stirred at room temperature for 10 minutes. Then, benzyl chloride (678 mg, 0.616 mL, 5.355 mmol) was added and the reaction was stirred at room temperature for 4 hours. The mixture was concentrated, diluted with water, extracted with EtOAc (10×2 mL), the organic phases were combined, washed sequentially with water (10 mL) and brine (10 mL), dried over MgSO.sub.4 and concentrated. Purification by silica gel column chromatography (50% EtOAc in dichloromethane) afforded C198 (1 g, 76%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.65 (d, J=4.9 Hz, 1H), 7.52-7.46 (m, 3H), 7.40 (dd, J=8.3, 6.5 Hz, 2H), 7.34 (dd, J=8.5, 5.9 Hz, 1H), 7.30-7.23 (m, 2H), 7.23-7.18 (m, 1H), 7.00 (d, J=9.3 Hz, 1H), 5.30 (s, 2H), 3.85 (d, J=10.5 Hz, 2H), 3.07 (s, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.57 (s, 3H), 1.47 (d, J=12.4 Hz, 2H). LCMS m/z 445.0 [M+H].sup.+

Compounds 331-332

[0752] Compounds 331-332 (Table 42) were prepared in two steps from intermediate C198 and the appropriate amine according to the method described for compound 254 without performing the final saponification step. Any modifications to methods are noted in Table 42 and accompanying footnotes.

TABLE-US-00043 TABLE 42 Method of preparation, structure, physicochemical data for compounds 331-332 .sup.1H NMR; LCMS m/z Compound Method/Product Amine [M + H].sup.+ 331 [01063] [01064] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.71 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H), 7.17 (s, 1H), 7.10 (d, J = 5.0 Hz, 1H), 6.89 (s, 1H), 6.66-6.55 (m, 2H), 6.38 (s, 1H), 3.96 (d, J = 6.0 Hz, 2H), 3.81 (d, J = 11.0 Hz, 2H), 3.51 (t, J = 6.7 Hz, 2H), 3.09 (s, 3H), 2.74 (s, 1H), 2.55 (s, 3H), 1.99 (s, 3H), 1.36 (d, J = 12.8 Hz, 2H). LCMS m/z 442 [M + H.sup.+] 332 [01065] [01066] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 7.15 (s, 1H), 7.08 (d, J = 5.0 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.62-6.52 (m, 2H), 6.27 (s, 1H), 4.21 (t, J = 7.9 Hz, 2H), 3.80 (d, J = 10.3 Hz, 3H), 3.70 (t, J = 7.7 Hz, 4H), 3.47 (t, J = 6.1 Hz, 2H), 3.12 (s, 3H), 2.75 (s, 1H), 2.54 (s, 3H), 1.92 (s, 2H), 1.35 (d, J = 12.8 Hz, 2H). LCMS m/z 449 [M + H.sup.+] .sup.1Saponification was not necessary for these compounds.

Compound 333

(2S)-2-[[4-(4-fluorophenyl)-7-hydroxy-3-isopropenyl-2-quinolyl]amino]propanoic acid (333)

[0753] ##STR01067##

Step 1: tert-butyl (2S)-2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropenyl-2-quinolyl]amino]propanoate (C199)

[0754] To a solution of S32 (150 mg, 0.3892 mmol) and L-alanine tert-butyl ester hydrochloride (212.11 mg, 1.1676 mmol) in dichloromethane (6 mL), DIEA (251.51 mg, 0.3493 mL, 1.9460 mmol) and PyBrop (544.31 mg, 1.1676 mmol) were added and the reaction was heated at 45° C. for 18 hours. The mixture was diluted with dichloromethane (5 mL), washed successively with an aqueous solution of NaHCO.sub.3 (5 mL) and water (10 mL), dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (10% EtOAc in hexanes) afforded C199 (115 mg, 51%). LCMS m/z 513.4 [M+H].sup.+

Step 2: tert-butyl (2S)-2-[[4-(4-fluorophenyl)-7-hydroxy-3-isopropenyl-2-quinolyl]amino]propanoate (C200)

[0755] To a solution of C199 (620 mg, 1.21 mmol) in MeOH (3 mL), 10% Pd/C (128.7 mg, 50% w/w, 0.726 mmol) was added under nitrogen. The reaction was purged with hydrogen and stirred at room temperature for 1 hours. The mixture was filtered through a Celite® plug, washed with MeOH (˜15 mL) and concentrated to afford C200 (470 mg, 64%). LCMS m/z 423.0 [M+H].sup.+

Step 3: (2S)-2-[[4-(4-fluorophenyl)-7-hydroxy-3-isopropenyl-2-quinolyl]amino]propanoic acid (333)

[0756] Through a solution of C200 (370 mg, 0.6130 mmol) in 1,4-Dioxane (10 mL), dry HCl(gas) (using NaCl+conc. H.sub.2SO.sub.4) was purged for 15 minutes at 0° C. and then stirred at room temperature for 1.5 hours. The mixture was concentrated and purified by reverse-phase HPLC (Method: C18 YMC Triart Actus column, 20×250 mm, 5 micron. Gradient: acetonitrile in water with 20 mM Ammonium Bicarbonate) to afford 333 (132 mg, 58%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.98 (bs, 1H), 7.29-7.27 (m, 4H), 6.86-6.83 (m, 2H), 6.65-6.63 (m, 1H), 5.94 (bs, 1H), 5.27 (s, 1H), 4.94 (s, 1H), 4.60-4.59 (m, 1H), 1.67 (s, 3H), 1.44 (d, J=7.04, 3H). LCMS m/z 367.09 [M+H].sup.+

Compound 334

3-[[4-(4-fluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]benzoic acid (334)

[0757] ##STR01068##

Step 1: 3-[[8-benzyloxy-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]-benzoic acid (C201)

[0758] A mixture of S33 (240 mg, 0.5358 mmol), 3-hydroxybenzoic acid (240 mg, 1.738 mmol) and Cs.sub.2CO.sub.3 (900 mg, 2.762 mmol) in DMSO (5.3 mL) was stirred and heated at 140° C. under nitrogen for 1 week. The mixture filtered, concentrated. Purification by reverse phase C18 chromatography (water: acetonitrile with 0.1% TFA modifier) afforded C201 (111 mg, 30%). .sup.1H NMR (300 MHz, Chloroform-d) δ 8.00 (s, 1H), 7.91 (dd, J=6.5, 2.2 Hz, 1H), 7.56-7.51 (m, 3H), 7.49-7.24 (m, 6H), 7.21-7.15 (m, 5H), 6.96 (d, J=8.0 Hz, 1H), 6.80 (dd, J=8.4, 0.9 Hz, 1H), 5.26 (s, 2H), 3.83 (dd, J=11.4, 4.1 Hz, 3H), 3.18 (t, J=11.7 Hz, 3H), 2.66-2.54 (m, 1H), 1.85 (tt, J=12.5, 6.4 Hz, 2H), 1.35 (d, J=13.2 Hz, 2H). LCMS m/z 550.4 [M+H].sup.+

Step 2: 3-[[4-(4-fluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]benzoic acid (334)

[0759] A solution of C201 (111 mg, 0.160 mmol) in MeOH (8 mL) was added under nitrogen to palladium on carbon (85 mg of 10% w/w, 0.079 mmol). The reaction was purged with hydrogen and stirred at room temperature for 2 hours. The mixture was filtered through a Celite plug and concentrated. Purification by reverse phase HPLC (Method: C18 Waters Sunfire column, 30×150 mm, 5 micron. Gradient: MeCN in water with 0.2% formic acid) afforded 334 (63.3 mg, 77%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 13.10 (s, OH), 10.07 (s, 1H), 7.85-7.76 (m, 2H), 7.59 (t, J=7.8 Hz, 1H), 7.54-7.43 (m, 2H), 7.39-7.28 (m, 4H), 7.00 (dd, J=7.9, 1.0 Hz, 1H), 6.58 (dd, J=8.4, 1.0 Hz, 1H), 3.69 (dd, J=11.3, 4.1 Hz, 2H), 3.04 (t, J=11.4 Hz, 2H), 2.56 (s, 0H), 1.59 (dd, J=12.3, 4.2 Hz, 1H), 1.33 (d, J=12.8 Hz, 2H). LCMS m/z 460.48 [M+H].sup.+

Compounds 335-336

[0760] Compounds 335-336 (Table 43) were prepared in two steps from intermediate S33 and the appropriate phenol according to the method described for 334. Any modifications to methods are noted in Table 43 and accompanying footnotes.

TABLE-US-00044 TABLE 43 Method of preparation, structure, physicochemical data for compounds 335-336 .sup.1H NMR; LCMS m/z Compound Method/Product Phenol [M + H].sup.+ 335 [01069] [01070] .sup.1H NMR (300 MHz, DMSO- d.sub.6) δ 12.92 (s, 1H), 10.15 (s, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.47 (t, J = 8.1 Hz, 1H), 7.41-7.26 (m, 6H), 6.98 (d, J = 7.8 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 3.73 (d, J = 10.9 Hz, 2H), 3.06 (t, J = 11.7 Hz, 2H), 2.55 (m, 1H), 1.71- 1.52 (m, 2H), 1.35 (d, J = 13.1 Hz, 2H). LCMS m/z 460.48 [M + H.sup.+] 336 [01071] [01072] .sup.1H NMR (300 MHz, Chloroform-d and Methanol- d.sub.4) δ 8.06-7.90 (m, 2H), 7.50 (ddd, J = 13.5, 8.4, 7.6 Hz, 2H), 7.22 (d, J = 7.1 Hz, 4H), 7.05 (dd, J = 7.8, 1.0 Hz, 1H), 6.77 (dd, J = 8.4, 1.0 Hz, 1H), 3.93-3.73 (m, 2H), 3.31-3.10 (m, 2H), 2.63 (ddd, J = 11.5, 7.8, 3.3 Hz, 1H), 1.74 (qd, J = 12.3, 11.9, 4.2 Hz, 2H), 1.37 (d, J = 13.3 Hz, 2H). LCMS m/z 477.93 [M + H.sup.+] .sup.1Nucleophilic aromatic substitution was performed in DMF. The conditions allowed for one pot hydrolysis of ester. .sup.21.0 equivalent of acetic acid was used during the benzyl ether deprotection.

Preparation of C202

1-(8-(benzyloxy)-4-(3,4-difluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-1-yl)-1,4-diazabicyclo[2.2.2]octan-1-ium (C202)

[0761] ##STR01073##

[0762] To a solution of S34 (1.82 g, 4.067 mmol) and 1,4-diazabicyclo[2.2.2]octane (2.4 g, 21.40 mmol) in dichloromethane (40 mL), TFAA (2.4 mL, 17.27 mmol) was added at 0° C. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated and purified by reverse phase C18 chromatography (10 to 100% acetonitrile in water, 0.1% TFA modifier) to afford C202 (2620 mg, 82%) LCMS m/z 542.37 [M+H].sup.+

Compound 337

3-[[4-(3,4-difluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (337)

[0763] ##STR01074##

Step 1: 3-[[8-benzyloxy-4-(3,4-difluorophenyl)-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]-cyclobutanecarboxylic acid (C203)

[0764] To a solution of 3-hydroxycyclobutanecarboxylic acid (180 mg, 1.55 mmol) in anhydrous DMSO (5 mL), heptane prewashed NaH (120 mg, 3.000 mmol) was added and the reaction was stirred at room temperature for 10 minutes. Then, C202 was added (400 mg, 0.519 mmol) and the reaction was stirred at room temperature for 2 hours. TFA (250 μL, 3.245 mmol) was added and the mixture was purified by C18 reverse phase chromatography (10-100% acetonitrile in water with 0.1% TFA) to afford C203 (140 mg, 48%). LCMS m/z 546.24 [M+H].sup.+

Step 2: 3-[[4-(3,4-difluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]-cyclobutanecarboxylic acid (337)

[0765] To a solution of C203 (60 mg, 0.105 mmol) in EtOH (5 mL), 10% palladium on carbon (50 mg, 0.047 mmol) was added. The reaction was purged with hydrogen and stirred at room temperature for 2 hours. The mixture was filtered and concentrated. Purification by C18 reverse phase chromatography (10-100% acetonitrile in water with 0.1% formic acid) afforded 337 (26.1 mg, 52%). .sup.1H NMR (300 MHz, Chloroform-d) δ 9.15 (s, 1H), 7.43 (t, J=8.1 Hz, 1H), 7.39-7.25 (m, 1H), 7.07 (ddd, J=10.4, 7.7, 2.0 Hz, 1H), 7.03-6.89 (m, 2H), 6.66 (dd, J=8.3, 1.0 Hz, 1H), 5.87-5.69 (m, 1H), 4.05 (d, J=11.1 Hz, 2H), 3.35 (h, J=6.8 Hz, 3H), 3.07 (ddt, J=11.6, 7.3, 4.3 Hz, 2H), 2.83-2.59 (m, 3H), 2.16 (q, J=12.2 Hz, 2H), 1.47 (d, J=13.2 Hz, 2H). LCMS m/z 456.15 [M+H].sup.+

Compounds 338-342

[0766] Compounds 338-342 (Table 44) were prepared in two steps from intermediate C202 according to the method described for compound 337. Any modifications to methods are noted in Table 44 and accompanying footnotes.

TABLE-US-00045 TABLE 44 Method of preparation, structure, physicochemical data for compounds 338-342 Compound Method/Product Alcohol .sup.1H NMR; LCMS m/z [M + H].sup.+ 338 [01075] [01076] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.43 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 16.1 Hz, 1H), 7.11-7.02 (m, 1H), 6.96 (d, J = 7.8 Hz, 2H), 6.67 (d, J = 8.3 Hz, 1H), 5.92 (q, J = 6.5 Hz, 1H), 4.04 (dt, J = 9.9, 4.3 Hz, 2H), 3.38 (p, J = 13.3, 10.9 Hz, 3H), 3.28-3.01 (m, 4H), 2.69 (tt, J = 11.6, 3.7 Hz, 1H), 2.15 (dt, J = 14.0, 6.4 Hz, 2H), 1.46 (s, 1H). LCMS m/z 474.22 [M + H.sup.+] 339 [01077] [01078] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.53-7.36 (m, 2H), 7.19 (ddd, J = 11.1, 7.7, 2.1 Hz, 1H), 7.05 (ddt, J = 8.1, 3.9, 1.7 Hz, 1H), 6.91 (dd, J = 7.9, 1.0 Hz, 1H), 6.63 (dd, J = 8.4, 1.0 Hz, 1H), 5.51 (p, J = 7.0 Hz, 1H), 3.97 (dd, J = 10.9, 5.0 Hz, 2H), 3.42-3.23 (m, 4H), 2.70 (dtd, J = 13.4, 9.7, 8.8, 4.8 Hz, 1H), 2.55 (s, 2H), 2.15 (qt, J = 12.9, 4.6 Hz, 2H), 1.53 (d, J = 13.2 Hz, 2H). LCMS m/z 472.2 [M + H.sup.+] 340 [01079] [01080] LCMS m/z 500.24 [M + H.sup.+] 341 [01081] [01082] .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.42 (tdd, J = 8.4, 6.1, 5.1 Hz, 2H), 7.19 (ddd, J = 11.3, 7.7, 2.1 Hz, 1H), 7.10-7.01 (m, 1H), 6.88 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 6.62 (ddd, J = 8.4, 1.8, 1.0 Hz, 1H), 4.80 (d, J = 7.2 Hz, 1H), 4.71 (d, J = 6.7 Hz, 1H), 4.03-3.90 (m, 2H), 3.27-2.91 (m, 2H), 2.79-2.65 (m, 1H), 2.58-2.39 (m, 2H), 2.32-2.08 (m, 4H), 1.63-1.47 (m, 2H). LCMS m/z 470.26 [M + H.sup.+] 342 [01083] [01084] 1H NMR (400 MHz, Methanol- d4) δ 7.49-7.35 (m, 2H), 7.25- 7.16 (m, 1H), 7.11-7.01 (m, 1H), 6.90 (dd, J = 7.8, 0.9 Hz, 1H), 6.62 (dd, J = 8.3, 0.9 Hz, 1H), 5.87 (t, J = 6.9 Hz, 1H), 3.97 (dt, J = 9.4, 4.1 Hz, 2H), 3.31 (dt, J = 3.3, 1.7 Hz, 2H), 3.02 (dd, J = 20.1, 7.0 Hz, 4H), 2.71 (tt, J = 11.7, 3.8 Hz, 1H), 2.15 (qt, J = 12.5, 4.5 Hz, 2H), 1.62-1.46 (m, 2H). LCMS m/z 474.27 [M + H.sup.+] .sup.1Hydrolysis of ester observed during nucleophilic aromatic substitution step. .sup.2342 was isolated by SFC from 338, stereochemistry unknown.

Compounds 343-344

[0767] Compounds 343-344 (Table 45) were prepared in three steps from intermediate S34 and the appropriate amine according to the method described for 244. Any modifications to methods are noted in Table 45 and accompanying footnotes.

TABLE-US-00046 TABLE 45 Method of preparation, structure and physicochemical data for compounds 343-344 Compound Method/Product Amine .sup.1H NMR; LCMS m/z [M + H].sup.+ 343 [01085] [01086] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.35 (dt, J = 10.8, 8.4 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.10 (ddd, J = 11.3, 7.8, 2.1 Hz, 1H), 6.99 (ddd, J = 8.0, 4.0, 1.6 Hz, 1H), 6.72 (dd, J = 7.8, 1.0 Hz, 1H), 6.46 (dd, J = 8.3, 0.9 Hz, 1H), 4.79 (p, J = 7.7 Hz, 1H), 3.95 (dt, J = 12.1, 4.2 Hz, 2H), 3.36-3.25 (m, 2H), 3.15 (ddd, J = 6.6, 5.2, 3.0 Hz, 1H), 2.80 (ddt, J = 12.6, 7.9, 4.1 Hz, 2H), 2.66- 2.54 (m, 1H), 2.34 (ddd, J = 12.5, 9.8, 7.1 Hz, 2H), 2.19 (qt, J = 12.4, 4.4 Hz, 2H), 1.46 (d, J = 13.5 Hz, 2H). LCMS m/z 455.05 [M + H.sup.+] 344 [01087] [01088] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.56 (t, J = 8.1 Hz, 1H), 7.46 (dt, J = 10.7, 8.4 Hz, 1H), 7.26 (ddd, J = 10.3, 7.6, 2.1 Hz, 1H), 7.18- 7.08 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 4.60 (p, J = 7.5 Hz, 1H), 4.08-3.93 (m, 2H), 3.23 (ddq, J = 9.5, 6.6, 3.1 Hz, 1H), 3.10 (p, J = 8.4 Hz, 1H), 2.86 (ddt, J = 11.8, 7.3, 4.0 Hz, 2H), 2.73 (ddd, J = 12.3, 7.5, 4.9 Hz, 1H), 2.48 (qd, J = 11.5, 8.5 Hz, 2H), 2.40- 2.24 (m,3H), 2.19 (ddd, J = 11.0, 7.7, 2.3 Hz, 1H), 2.07- 1.90 (m, 4H), 1.66 (d, J = 13.0 Hz, 2H). LCMS m/z 495.29 [M + H.sup.+] [0768] 1. PyBrop amination was performed at 80° C., and ester hydrolysis was performed using NaOH as base.

Preparation of C211

1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-8-benzyloxy-4-(3,4-difluorophenyl)-6-fluoro-3-tetrahydropyran-4-yl-isoquinoline (C211)

[0769] ##STR01089## ##STR01090##

Step 1: 1-benzyloxy-3-bromo-5-fluoro-2-iodo-benzene (C205)

[0770] To a suspension of C204 (14.5 g, 45.76 mmol), K.sub.2CO.sub.3 (10 g, 72.36 mmol) and NaI (1.74 g, 11.61 mmol) in acetone (130 mL), BnBr (5.8 mL, 48.76 mmol) was added and the reaction was stirred at room temperature for 18 hours. The mixture was filtered, washed with Et.sub.2O (50 mL), and concentrated to afford C205 (19.4 g, 99%) as a light brown solid. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.48 (d, J=7.5 Hz, 2H), 7.45-7.39 (m, 2H), 7.37-7.32 (m, 1H), 7.09 (dt, J=8.1, 2.2 Hz, 1H), 6.56 (dt, J=10.2, 2.2 Hz, 1H), 5.13 (s, 2H). LCMS m/z 405.67 [M+H].sup.+

Step 2: 2-benzyloxy-6-bromo-4-fluoro-benzaldehyde (C206)

[0771] To a 1.3 M THF solution of isopropylmagnesium chloride (Lithium Chloride (I)) (2.65 mL of 1.3 M, 3.4450 mmol) in anhydrous THF (6 mL) at −60° C., a solution of C205 (1.2 g, 2.8009 mmol) in anhydrous THF (11 mL) was added dropwise over 5 minutes, and stirred for 1 hour. Then, 4-formylmorpholine (855.00 mg, 0.75 mL, 7.4264 mmol) was added. The mixture was stirred from −65° C. to −40° C. over 2 hours. MTBE (100 mL) was added followed by saturated aqueous NH.sub.4Cl (20 mL), the organic phase was washed successively with saturated aqueous NH.sub.4Cl (2×20 mL) and brine (2×20 mL), dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (0-15% EtOAc in heptane) afforded C206 (620 mg, 67%). .sup.1H NMR (300 MHz, Chloroform-d) δ 10.40 (s, 1H), 7.49-7.30 (m, 5H), 7.02 (dd, J=7.9, 2.2Hz, 1H), 6.74 (dd, J=10.3, 2.2 Hz, 1H), 5.16 (s, 2H). LCMS m/z 331.0 [M+H].sup.+

Step 3: 2-benzyloxy-4-fluoro-6-(2-tetrahydropyran-4-ylethynyl)benzaldehyde (C207)

[0772] Under nitrogen atmosphere, to a solution of C206 (165 mg, 0.4323 mmol) in anhydrous dioxane (2 mL), diisopropylamine (361.00 mg, 0.5 mL, 3.5675 mmol), C71 (118.80 mg, 0.12 mL, 0.6515 mmol), copper iodide (6.1 mg, 0.0320 mmol), Pd(PPh.sub.3)Cl.sub.2 (12.4 mg, 0.0176 mmol) and a 1 M THF solution of TBAF (0.63 mL of 1 M, 0.6300 mmol) were added and the reaction was heated at 50° C. for 5. MTBE (20 mL) and EtOAc (5 mL) were added, the mixture was washed with 5% aqueous NaHCO.sub.3 (5×10 mL) and brine (2×10 mL), dried over Na.sub.2SO.sub.4, and concentrated. Purification by silica gel chromatography (0-45% EtOAc in heptane) afforded C207 (120 mg, 76%). .sup.1H NMR (300 MHz, Chloroform-d) δ 10.5 (s, 1H), 7.47-7.31 (m, 5H), 6.80 (dd, J=8.8, 2.3Hz, 1H), 6.68 (dd, J=10.5, 2.3Hz, 1H), 5.17 (s, 2H), 4.00-3.91 (m, 2H), 3.62-3.52 (m, 2H), 2.93 (sept, J=4.2Hz, 1H), 2.00-1.88 (m, 2H), 1.86-1.72 (m, 2H), .sup.19F NMR (282 MHz, Chloroform-d) δ −101.7 (t, J=9.7Hz, 1F), LCMS m/z 339.2 [M+H].sup.+

Step 4: 2-benzyloxy-4-fluoro-6-(2-tetrahydropyran-4-ylethynyl)benzaldehyde oxime (C208)

[0773] To a solution of C207 (718 mg, 2.12 mmol) in DCE (4.5 mL) and acetonitrile (7.5 mL) at 0° C., pyridine (3.42 g, 3.5 mL, 43.27 mmol) was added, followed by NH.sub.2OH—HCl (440 mg, 6.3318 mmol) and stirred at 0° C. for 35 min. The mixture was diluted with EtOAc (100 mL) and water (50 mL), the organic phase was washed successively with an aqueous solution of HCl 1N (2×25 mL), water (25 mL), brine, dried over Na.sub.2SO.sub.4, and concentrated to give a mixture of E/Z C208 (710 mg, 79%). Major isomer described: .sup.1H NMR (300 MHz, Chloroform-d) δ 8.56 (s, 1H), 7.49-7.29 (m, 5H), 6.80 (dd, J=8.8, 2.6 Hz, 1H), 6.64 (dd, J=10.6, 2.3 Hz, 1H), 5.18 (s, 2H), 3.96 (ddd, J=11.5, 5.9, 3.7 Hz, 2H), 3.57 (ddd, J=11.5, 8.1, 2.9 Hz, 2H), 2.91 (tt, J=8.2, 4.1 Hz, 1H), 2.01-1.86 (m, 2H), 1.86-1.69 (m, 2H). .sup.19F NMR (282 MHz, Chloroform-d) δ −108.58-109.64 (m, 1F). LCMS m/z 354.2 [M+H].sup.+

Step 5: 8-benzyloxy-4-bromo-6-fluoro-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C209)

[0774] To a solution of C208 (710 mg, 2.0091 mmol) in DMA (5.5 mL), CuBr.sub.2 (1.15 g, 5.1488 mmol) was added and the reaction was heated at 60° C. for 1 h. The mixture was cooled to 0° C. and aqueous solution of NH.sub.4OH and water (2:1, 6 mL) were slowly added, and the mixture was stirred at 0° C. for 20 min. The solids were filtered and washed with water. The residue was dissolved in dichloromethane, dried over Na.sub.2SO.sub.4, and concentrated. Purification by trituration with MTBE (7 mL) and washes with heptane afforded C209 (479 mg, 53%). .sup.1H NMR (300 MHz, Chloroform-d) δ 9.11 (br. s., 1H), 7.49-7.34 (m, 6H), 6.76 (dd, J=10.1, 1.9 Hz, 1H), 5.24 (s, 2H), 4.14 (dd, J=11.2, 4.1 Hz, 2H), 3.59 (t, J=11.4 Hz, 2H), 3.18 (br. s, 2H), 1.57-1.45 (m, 3H). .sup.19F NMR (282 MHz, Chloroform-d) δ −103.29-104.31 (m, 1F). LCMS m/z 432.1 [M+H].sup.+

Step 6: 8-benzyloxy-4-(3,4-difluorophenyl)-6-fluoro-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C210)

[0775] C210 was prepared by Suzuki coupling of C209 with (3,4-difluorophenyl)boronic acid according to the method described for C41. .sup.1H NMR (300 MHz, Chloroform-d) δ 9.21 (s, 1H), 7.50-7.33 (m, 6H), 7.09 (ddd, J=10.1, 7.6, 2.1 Hz, 1H), 7.00 (ddd, J=8.2, 4.3, 1.6 Hz, 1H), 6.72 (dd, J=10.3, 2.1 Hz, 1H), 6.29 (dd, J=10.0, 1.5 Hz, 1H), 5.25 (s, 2H), 4.03-3.92 (m, 2H), 3.39-3.19 (m, 2H), 2.72 (br. s., 1H), 1.57-1.54 (m, 2H), 1.47-1.36 (m, 2H). LCMS m/z 466.2 [M+H].sup.+

Step 7: 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-8-benzyloxy-4-(3,4-difluorophenyl)-6-fluoro-3-tetrahydropyran-4-yl-isoquinoline (C211)

[0776] C211 was prepared by amination of C210 using DABCO according to the method described for S2. .sup.1H NMR (300 MHz, acetonitrile-d.sub.3) δ 7.73-7.64 (m, 2H), 7.63-7.55 (m, 3H), 7.53-7.45 (m, 1H), 7.38 (dd, J=10.7, 2.5 Hz, 1H), 7.24 (ddd, J=10.9, 7.6, 2.1 Hz, 1H), 7.13-7.04 (m, 1H), 6.83 (dd, J=9.8, 2.5 Hz, 1H), 5.36 (s, 2H), 4.13-3.99 (m, 6H), 3.89 (dd, J=11.6, 4.3 Hz, 2H), 3.34-3.18 (m, 2H), 2.86-2.70 (m, 7H), 2.09-1.98 (m, 2H), 1.62-1.48 (m, 2H). LCMS m/z 560.5 [M+H].sup.+

Compounds 345-346

[0777] Compounds 345-346 (Table 46) were prepared in two steps from intermediate C211 according to the method described for compound 337. Any modifications to methods are noted in Table 46 and accompanying footnotes

TABLE-US-00047 TABLE 46 Method of preparation, structure, physicochemical data for compounds 345-346 .sup.1H NMR; LCMS m/z Compound Method/Product Alcohol [M + H].sup.+ 345 [01091] [01092] .sup.1H NMR (300 MHz, Chloroform-d) δ 9.31 (d, J = 1.5 Hz, 1H), 7.37- 7.27 (m, 1H), 7.08- 6.99 (m, 1H), 6.93 (ddd, J = 6.1, 4.0, 1.9 Hz, 1H), 6.69 (dd, J = 10.0, 2.3 Hz, 1H), 6.27 (dd, J = 10.3, 2.3 Hz, 1H), 5.82-5.68 (m, 1H), 4.02 (d, J = 10.9 Hz, 2H), 3.42-3.21 (m, 3H), 3.13-2.97 (m, 2H), 2.76-2.57 (m, 3H), 2.22-2.02 (m, 2H), 1.44 (d, J = 12.6 Hz, 2H). LCMS m/z 474.2 [M + H.sup.+] 346 [01093] [01094] .sup.1H NMR (300 MHz, Chloroform-d) δ 9.00 (s, 1H), 8.26 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.36-7.27 (m, 1H), 7.12-7.00 (m, 1H), 6.98-6.91 (m, 1H), 6.81 (dd, J = 10.1, 2.2 Hz, 1H), 6.37 (dd, J = 10.4, 2.5 Hz, 1H), 3.89 (d, J = 11.4 Hz, 2H), 3.29-3.15 (m, 2H), 2.64-2.51 (m, 1H), 1.86- 1.67 (m, 2H), 1.33 (d, J = 12.9 Hz, 2H). LCMS m/z 496.1 [M + H.sup.+]

Compounds 347-348

[0778] Compounds 347-348 (Table 47) were prepared in two steps from intermediate S35 and the appropriate phenol according to the method described for 336. Any modifications to methods are noted in Table 47 and accompanying footnotes.

TABLE-US-00048 TABLE 47 Method of preparation, structure, physicochemical data for compounds 347-348 .sup.1H NMR; LCMS m/z Compound Method/Product Phenol [M + H].sup.+ 347 [01095] [01096] .sup.1H NMR (300 MHz, DMSO- d.sub.6) δ 12.96 (s, 1H), 10.21 (s, 1H), 8.03 (dd, J = 9.0, 2.3 Hz, 2H), 7.59 (dt, J = 11.0, 8.5 Hz, 1H), 7.53-7.40 (m, 2H), 7.30 (dd, J = 9.0, 2.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 3.72 (d, J = 11.3 Hz, 2H), 3.09 (q, J = 5.2 Hz, 2H), 2.59- 2.52 (m, 2H), 1.61 (dd, J = 12.2, 4.2 Hz, 1H), 1.37 (t, J = 12.0 Hz, 2H). LCMS m/z 478.39 [M + H.sup.+] 348 [01097] [01098] .sup.1H NMR (300 MHz, DMSO- d.sub.6) δ 13.10 (s, 1H), 10.11 (s, 1H), 7.83 (dt, J = 7.6, 1.4 Hz, 1H), 7.78 (t, J = 1.9 Hz, 1H), 7.58 (dt, J = 11.6, 8.3 Hz, 2H), 7.53-7.41 (m, 3H), 7.18-7.10 (m, 1H), 7.01 (dd, J = 7.8, 1.0 Hz, 1H), 6.60 (dd, J = 8.4, 0.9 Hz, 1H), 3.69 (d, J = 11.0 Hz, 2H), 3.08 (td, J = 11.4, 10.9, 6.3 Hz, 2H), 1.57 (qd, J = 12.4, 4.3 Hz, 2H), 1.35 (t, J = 12.2 Hz, 2H). LCMS m/z 478.44 [M + H.sup.+] .sup.1Hydrolysis was performed with LiOH after the nucleophilic aromatic substitution andbefore benzyl ether deprotection.

Compound 349

4-[4-(3,4-difluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]benzoic acid (349)

[0779] ##STR01099## ##STR01100##

Step 1: tert-butyl 4-[8-benzyloxy-4-(3,4-difluorophenyl)-3-tetrahydropyran-4-yl-1-isoquinolyl]benzoate (C212)

[0780] To a mixture of S35 (67 mg, 0.144 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (70 mg, 0.2301 mmol) and Pd(PPh.sub.3).sub.4 (10 mg, 0.0086 mmol) in DMF (3.5 mL) was added an aqueous solution of Na.sub.2CO.sub.3 (400 μL of 2M, 0.80 mmol) under nitrogen atmosphere and the reaction was heated in a microwave reactor at 130° C. for 1 hours. Water was added and the mixture was extracted with EtOAc. The organic phases were combined, washed successively with water and brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (10 to 100% of EtOAc in hexanes) afforded C212 (75 mg, 86%). LCMS m/z 608.41 [M+H].sup.+

Step 2: tert-butyl 4-[4-(3,4-difluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]benzoate (C213)

[0781] A suspension of palladium on carbon (22 mg of 10% w/w, 0.02067 mmol) and C212 (75 mg, 0.1234 mmol) in MeOH (20 mL) and EtOAc (10 mL) was purged with hydrogen and stirred at RT for 4 h. The mixture was filtered and concentrated. Purification by silica gel chromatography (10 to 50% of EtOAc in hexanes) afforded C213 (40 mg, 63%). LCMS m/z 517.91 [M+H].sup.+

Step 3: 4-[4-(3,4-difluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]benzoic acid (349)

[0782] C213 (38 mg, 0.0734 mmol) was treated with a solution of HCl (4 mL of 4M, 16.00 mmol) in dioxane and the reaction was heated in a microwave reactor at 80° C. for 45 min. The mixture was concentrated and the residue was triturated successively with acetonitrile, water, dichloromethane and MeOH to afford 349 (35 mg, 91%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.41 (s, 1H), 8.11-7.88 (m, 2H), 7.77-7.38 (m, 5H), 7.27-7.17 (m, 1H), 6.91 (d, J=7.6 Hz, 1H), 6.71 (dd, J=8.4, 1.0 Hz, 1H), 3.84 (d, J=11.4 Hz, 2H), 3.20 (q, J=10.6 Hz, 2H), 2.80-2.70 (m, 1H), 2.10-1.97 (m, 2H), 1.52 (t, J=14.5 Hz, 2H) ppm. LCMS m/z 462.37 [M+H].sup.+

Compound 350

3-[4-(3,4-difluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]benzoic acid (350)

[0783] ##STR01101## ##STR01102##

Step 1: tert-butyl 3-[8-benzyloxy-4-(3,4-difluorophenyl)-3-tetrahydropyran-4-yl-1-isoquinolyl]benzoate (C214)

[0784] To a mixture of S35, tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (71 mg, 0.2334 mmol) and Pd(PPh.sub.3).sub.4 (11 mg, 0.009519 mmol) in DMF (3.5 mL), an aqueous solution of Na.sub.2CO.sub.3 (400 μL of 2M, 0.8000 mmol) was added under nitrogen and the reaction was heated in a microwave reactor at 130° C. for 1 hours. Water was added and the mixture was extracted with EtOAc. The organic phases were combined, washed successively with water and brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (10 to 50% of EtOAc in hexanes) afforded C214 (72 mg, 81%). LCMS m/z 608.45 [M+H].sup.+

Step 2: tert-butyl 3-[4-(3,4-difluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]benzoate (C215)

[0785] A suspension of palladium on carbon (21 mg of 10% w/w, 0.01973 mmol) and C214 (72 mg, 0.1185 mmol) in MeOH (15 mL) and EtOAc (30 mL) was purged with hydrogen and stirred at room temperature for 18 hours. The mixture was filtered and concentrated. Purification by silica gel chromatography (10 to 50% of EtOAc in hexanes) afforded C215 (43 mg, 70%). LCMS m/z 518.0 [M+H].sup.+

Step 3: 3-[4-(3,4-difluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]benzoic acid (350)

[0786] C215 (43 mg, 0.08308 mmol) was treated with a solution of HCl (2.5 mL of 4M, 10.00 mmol) in dioxane and the reaction was heated in a microwave reactor at 80° C. for 45 min. The mixture was concentrated and purification by silica gel chromatography (0 to 20% of MeOH in dichloromethane) afforded 350 (34 mg, 77%) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 10.42 (s, 1H), 8.07 (t, J=1.7 Hz, 1H), 8.00 (dt, J=7.7, 1.5 Hz, 1H), 7.77 (dt, J=7.7, 1.4 Hz, 1H), 7.70-7.44 (m, 4H), 7.31-7.17 (m, 1H), 7.00-6.87 (m, 1H), 6.72 (dd, J=8.4, 1.0 Hz, 1H), 3.85 (d, J=11.2 Hz, 2H), 3.22 (dd, J=11.8, 7.0 Hz, 2H), 2.85-2.68 (m, 1H), 2.03 (q, J=12.9, 12.1 Hz, 2H), 1.53 (t, J=12.3 Hz, 2H). LCMS m/z 462.37 [M+H].sup.+

Compound 351

3-[4-(3,4-difluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]propanoic acid (351)

[0787] ##STR01103##

Step 1: tert-butyl 3-[8-benzyloxy-4-(3,4-difluorophenyl)-3-tetrahydropyran-4-yl-1-isoquinolyl]propanoate (C216)

[0788] To a mixture of S35 (65 mg, 0.1395 mmol) and Pd(PPh.sub.3).sub.4 (13 mg, 0.01125 mmol) in THF (1.5 mL), bromo-(3-tert-butoxy-3-oxo-propyl)zinc (1.5 mL of 0.5M, 0.7500 mmol) was slowly added under nitrogen and the reaction was heated at 90° C. for 60 min. The mixture was concentrated, dissolved in dichloromethane, washed successively with an aqueous solution of NaOH (0.5 M, 6 mL), water and brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (10 to 100% of EtOAc in hexanes) afforded C216 (78 mg, 100%). LCMS m/z 559.94 [M+H].sup.+

Step 2: tert-butyl 3-[4-(3,4-difluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]propanoate (C217)

[0789] A suspension of palladium on carbon (25 mg of 10% w/w, 0.02349 mmol) and C216 (78 mg, 0.139 mmol) in MeOH (20 mL) and EtOAc (10 mL) was purged with hydrogen and stirred at RT for 4 h. The mixture was concentrated to afford C217 (65 mg, 99%). LCMS m/z 469.98 [M+H].sup.+

Step 3: 3-[4-(3,4-difluorophenyl)-8-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]propanoic acid (351)

[0790] C217 (65 mg, 0.1384 mmol) was treated with a solution of HCl (4 mL of 4M, 16.00 mmol) in dioxane and the reaction was heated in a microwave reactor at 80° C. for 45 min. The mixture was concentrated and purification by silica gel chromatography (0 to 20% of MeOH in dichloromethane) afforded 351 (50 mg, 76%). .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.72 (t, J=8.1 Hz, 1H), 7.48-7.40 (m, 1H), 7.25 (dd, J=8.0, 0.8 Hz, 1H), 7.12 (t, J=8.9 Hz, 1H), 7.03 (d, J=5.4 Hz, 1H), 6.82 (dd, J=8.3, 0.9 Hz, 1H), 4.02 (d, J=12.4 Hz, 2H), 3.36 (s, 3H), 3.30 (d, J=8.8 Hz, 1H), 3.12-2.86 (m, 3H), 2.21 (q, J=13.0, 12.4 Hz, 2H), 1.61 (d, J=12.8 Hz, 2H). LCMS m/z 414.45 [M+H].sup.+

Compounds 352-357

[0791] Compounds 352-357 (Table 48) were prepared in three steps from intermediate S36 and the appropriate amine according to the method described for 244. Any modifications to methods are noted in Table 48 and accompanying footnotes.

TABLE-US-00049 TABLE 48 Method of preparation, structure, physicochemical data for compounds 352-357 Compound Method/Product Amine .sup.1H NMR; LCMS m/z [M + H].sup.+ 352 [01104] [01105] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.27 (t, J = 9.00 Hz, 1H), 7.15 (bs, 1H), 7.06 (d, J = 5.4 Hz, 1H), 6.89-6.83 (m, 2H), 6.48 (s, 1H), 6.28 (d, J = 7.6 Hz, 1H) 4.66 (t, J = 5.84 Hz, 1H), 3.07-3.02 (m, 1H), 2.30 (s, 3H), 1.47 (d, J = 6.68 Hz, 3H), 1.23 (d, J = 10.0 Hz, 6H). LCMS m/z 383 [M + H.sup.+] 353 [01106] [01107] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.35 (s, 1H) 7.26 (t, J = 9.7 Hz, 1H), 7.14 (d, J = 7.16 Hz, 1H), 7.06 (s, 1H), 6.90-6.83 (m, 2H), 6.27-6.24 (m, 1H), 6.08 (bs, 1H) 4.98-4.93 (m, 1H), 3.12-3.02 (m, 2H), 2.79- 2.76 (m, 1H), 2.59-2.68 (m, 2H), 2.50-2.29 (m, 5H), 1.23- 1.14 (m, 6H). LCMS m/z 409 [M + H.sup.+] 354 [01108] [01109] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.25 (s, 1H), 7.28 (t, J = 9.1 Hz, 1H), 7.20-7.12 (m, 1H), 7.12-7.04 (m, 1H), 6.91-6.81 (m, 2H), 6.63 (s, 1H), 6.28 (dd, J = 7.4, 2.2 Hz, 1H), 4.55 (s, 1H), 3.09-3.01 (m, 1H), 2.30 (d, J = 9.92 Hz, 3H), 1.46 (d, J = 6.08 Hz, 3H), 1.29-1.20 (m, 6H). LCMS m/z 383 [M + H.sup.+] 355 [01110] [01111] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.56 (s, 1H), 8.57 (s, 1H), 7.28 (t, J = 9.0 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 7.11-7.05 (m, 1H), 6.91-6.80 (m, 2H), 6.27 (d, J = 7.8 Hz, 1H), 6.04 (s, 1H), 3.97 (d, J = 5.4 Hz, 2H), 3.07-2.97 (m, 1H), 2.30 (s, 3H), 1.25-1.18 (m, 6H), 1.08 (d, J = 8.9 Hz, 4H). LCMS m/z 409 [M + H.sup.+] 356 [01112] [01113] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.33-7.29 (m, 2H), 7.23-7.17 (m, 2H), 7.10 (s, 1H), 7.04 (d, 1H), 6.35 (bs, 1H), 3.92 (d, J = 5.8 Hz, 2H), 3.06-3.01 (m, 1H), 2.74-2.67 (m, 2H), 2.30 (s, 3H), 1.16-1.23 (m, 6H). LCMS m/z 383 [M + H.sup.+] 357 [01114] [01115] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.3 (s, 1H), 7.28 (t, J = 8.84 Hz, 1H), 7.14 (d, J = 7 Hz, 1H), 7.06 (t, J = 5.64 Hz, 1H), 6.89- 6.83 (m, 2H), 6.48 (bs, 1H), 6.29 (d, J = 7.6 Hz, 1H), 4.11 (s, 2H), 3.07-3.00 (m, 1H), 2.30 (s, 3H), 1.24 (d, J = 6.16 Hz, 6H). LCMS m/z 369 [M + H.sup.+] .sup.1PyBrop amination was performed at 60° C., .sup.2Benzyl ester was removed during hydrogenation/benzyl ether deprotection step. .sup.3t-Butyl ester was deprotected with HCl in dioxane.

Preparation of C221

8-benzyloxy-2-chloro-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-quinoline (C221)

[0792] ##STR01116##

Step 1: 4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-quinolin-8-ol (C218)

[0793] To a solution of C84 (4 g, 10.431 mmol) in EtOH (25 mL), Pd/C (3.9963 g, 37.55 mmol) was degassed under nitrogen. The reaction was purged with hydrogen and stirred at room temperature for 12 hours. The mixture was filtered through a celite plug and concentrated to afford C218 (2.8 g, 89%). LCMS m/z 296.0 [M+H].sup.+

Step 2: 8-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-quinoline (C219)

[0794] To a solution of C218 (1.9 g, 6.4330 mmol) in DMF (7 mL), NaH (643 mg, 16.08 mmol) and BnCl (1.63 g, 1.48 mL, 12.87 mmol) were added and the reaction was stirred at room temperature for 12 hours. The mixture was diluted with EtOAc and water was added, the organic phase was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated. Purification by silica gel chromatography (0 to 50% EtOAc in hexanes) afforded C219 (2.4 g, 90%). LCMS m/z 386.0 [M+H].sup.+

Step 3: 8-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-1-oxido-quinolin-1-ium (C220)

[0795] To a solution of C219 (2.51 g, 6.51 mmol) in dichloromethane (25 mL) at 0° C., m-CPBA (2.25 g, 13.02 mmol) was added and the reaction mixture was stirred at room temperature for 13 hours. The mixture was diluted with water and extracted with dichloromethane. The organic phases were combined, washed with brine, Na.sub.2SO.sub.4, and concentrated. Purification by silica gel chromatography (0 to 30% EtOAc in hexanes) afforded C220 (2.1 g, 75%). LCMS m/z 402.0 [M+H].sup.+ as off white solid.

Step 4: 8-benzyloxy-2-chloro-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-quinoline (C221)

[0796] To a solution of C220 in toluene (2 mL) was added POCl.sub.3 (1.76 g, 1.07 mL, 11.46 mmol) followed by DMF (8.38 mg, 0.009 mL, 0.115 mmol) and the mixture was refluxed for 2 hours. The mixture was concentrated, diluted with dichloromethane, quenched with an aqueous solution of NaHCO.sub.3 solution and extracted with dichloromethane. The organic phases were combined, washed with brine, Na.sub.2SO.sub.4, and concentrated. Purification by silica gel chromatography (0 to 50% EtOAc in hexanes) afforded C221 (290 mg, 60%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.54(d, J=7.2 Hz, 2H), 7.44-7.35 (m, 5H), 7.31-7.16 (m, 3H), 6.65 (d, J=8.4Hz, 1H), 5.35 (s,2H), 3.05-3.25 (m, 1H), 2.31 (s, 1H), 1.28(d, J=6.64 Hz, 6H).

Compounds 358-360

[0797] Compounds 358-360 (Table 49) were prepared in three steps from intermediate C221 according to the method described for 254. Any modifications to methods are noted in Table 49 and accompanying footnotes.

TABLE-US-00050 TABLE 49 Method of preparation, structure, physicochemical data for compounds 358-360 Compound Method/Product Amine .sup.1H NMR; LCMS m/z [M + H].sup.+ 358 [01117] [01118] .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 8.55-8.72 (bs, 1H), 7.26 (t, J = 8.72 Hz, 1H), 7.19 (d, J = 6.88 Hz, 1H), 7.08-7.12 (m, 1H), 6.98-6.94 (m, 1H), 6.90 (d, J = 7.16 Hz, 1H) 6.28 (d, J = 8.04 Hz, 1H), 4.36-4.28 (m, 4H), 3.23-3.19 (m, 2H) 2.30 (s, 3H), 1.00-0.97 (m, 6H). LCMS m/z 394 [M + H.sup.+] 359 [01119] [01120] .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 8.62-8.81 (bs, 1H), 7.27 (t, J = 8.72 Hz, 1H), 7.21 (d, J = 7.32, Hz, 1H), 7.12-7.15 (m, 1H), 7.01 (t. J = 7.84 Hz, 1H), 6.91 (d, J = 7.48 Hz, 1H), 6.31 (d, J = 8.24 Hz, 1H) 3.72 (d, J = 7.64 Hz, 2H), 3.60- 3.53 (m, 2H), 3.44-3.39 (m, 1H), 3.15-3.11 (m, 1H), 2.30 (s, 3H), 2.18-2.12 (m, 2H), 1.07-1.00 (m, 6H). LCMS m/z 409 [M + H.sup.+] 360 [01121] [01122] .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 8.75-8.97 (bs, 1H), 7.27 (t, J = 8.64 Hz, 1H), 7.21 (d, J = 7.4, Hz, 1H), 7.12-7.15 (m, 1H), 7.00 (t, J = 7.76 Hz, 1H), 6.91 (d, J = 7.24 Hz, 1H), 6.30 (d, J = 8.4 Hz, 1H), 3.74-3.69 (m, 2H), 3.57-3.53 (m, 2H), 3.45-3.41 (m, 1H), 3.10-3.07 (m, 1H), 2.30 (s, 3H), 2.12 (d, J = 7.32 Hz, 2H) 1.07-1.00 (m, 6H). LCMS m/z 409 [M + H.sup.+]

Compound 361

3-[4-(3,4-difluorophenyl)-8-hydroxy-3-isopropyl-1-oxo-2-isoquinolyl]propanoic acid (361)

[0798] ##STR01123## ##STR01124##

Step 1: methyl 3-[[2-benzyloxy-6-[1-(3,4-difluorophenyl)-3-methyl-2-oxo-butyl]benzoyl]amino]propanoate (C223)

[0799] To a solution of C222 (which was prepared using the same procedure as for C133) (80 mg, 0.1715 mmol), HATU (92 mg, 0.2420 mmol), and methyl 3-aminopropanoate (hydrochloride salt) (33 mg, 0.2364 mmol) in DMF (2 mL), DIEA (70 0.4019 mmol) was added. The reaction was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc, washed with a saturated aqueous solution of NH.sub.4Cl, and the organic phase was dried with Na.sub.2SO.sub.4 and concentrated. Purification by silica gel chromatography (50 to 100% EtOAc in heptane) afforded C223 as a white solid, which was used directly in the next step.

Step 2: methyl 3-[8-benzyloxy-4-(3,4-difluorophenyl)-3-isopropyl-1-oxo-2-isoquinolyl]propanoate (C224)

[0800] To a solution of C223 in dichloromethane (2 mL), was added MsOH (10 μL, 0.1541 mmol) and the reaction was stirred at RT for 6 h. The mixture was concentrated and purified by silica gel chromatography (50 to 100% EtOAc in heptane) to afford C224 which was used directly in the next step.

Step 3: methyl 3-[4-(3,4-difluorophenyl)-8-hydroxy-3-isopropyl-1-oxo-2-isoquinolyl]propanoate (C225)

[0801] To a vial loaded with palladium on carbon (9 mg, 0.0086 mmol), C224 was added as a solution in MeOH (8 mL) under inert atmosphere, the vial was purged with H.sub.2 and the reaction was stirred at RT for 18 h. The mixture was filtered through a Celite® plug and concentrated. Purification by silica gel chromatography (0 to 30% EtOAc in Heptane) afforded C225 (2.2 mg, 3% yield over three steps).

Step 4: 3-[4-(3,4-difluorophenyl)-8-hydroxy-3-isopropyl-1-oxo-2-isoquinolyl]propanoic acid (361)

[0802] To a solution of C225 in a mixture of THF (1.2 mL), MeOH (0.4 mL), H.sub.2O (0.4 mL), LiOH (4 mg, 0.167 mmol) was added and the reaction was stirred at RT for 1 h. An aqueous solution of 1 MHCl was added to adjust the pH to ˜3, and the aqueous phase was extracted with dichloromethane and then concentrated to afford 361(2.6 mg, 4%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.57-7.51 (m, 2H), 7.37-7.23 (m, 2H), 7.12-7.05 (m, 1H), 6.95-6.89 (m, 1H), 3.88 (p, J=6.8 Hz, 1H), 3.41-3.22 (m, 12H), 2.28 (ddd, J=9.5, 6.3, 5.2 Hz, 2H), 1.10 (dd, J=6.8, 6.0 Hz, 6H). LCMS m/z 388.44 [M+H].sup.+

Assays for Detecting and Measuring AAT Modulator Properties of Compounds

[0803] A. AAT Function Assay (MSD Assay NL20-SI Cell Line)

[0804] Alpha-1 antitrypsin (AAT) is a SERPIN (serine protease inhibitor) that inactivates enzymes by binding to them covalently. This assay measured the amount of functionally active AAT in a sample in the presence of the disclosed compounds 1-361 by determining the ability of AAT to form an irreversible complex with human neutrophil Elastase (hNE). In practice, the sample (cell supernatant, blood sample, or other) was incubated with excess hNE to allow AAT-Elastase complex to be formed with all functional AAT in the sample. This complex was then captured to a microplate coated with an anti-AAT antibody. The complex captured to the plate was detected with a labeled anti-Elastase antibody and quantitated using a set of AAT standards spanning the concentration range present in the sample. Meso Scale Discovery (MSD) plate reader, Sulfo-tag labeling, and microplates were used to provide high sensitivity and wide dynamic range.

TABLE-US-00051 MATERIALS: Reagents/Plates Concentration Goat anti-human Alpha-1-Antitrypsin  1 mL @ 1 mg/mL Polyclonal Antibody Use at 5 μg/mL in phosphate buffered saline (PBS) Human Neutrophil Elastase 100 μg lyophilized Stock at 3.4 pM (0.1 mg + 1 mL PBS) Working at lug/mL (34 nm) in MSD Assay buffer (1% bovine serum albumin (BSA)) Mouse anti-human Neutrophil Elastase Monoclonal Antibody 900 μg/mL Sulfo-tagged @12:1 using MSD Gold Sulfo-tag N- hydroxysuccinimide (NHS) ester; use at 0.45 μg/mL in MSD Assay buffer (1% BSA) M-AAT (Alpha-1-Antitrypsin)  5 mg lyophilized MSD Blocker A (BSA) 250 mL 5% solution in PBS for blocking 1% solution in PBS for assay buffer MSD Read Buffer T (4X) with Surfactant  1 L or 250 mL MSD 384 high bind plates Polypropylene for dilution 384 well plate Tissue culture treated black well 384 well plate INSTRUMENT(S): Meso Sector S600 Bravo Washer dispenser Multidrop Combi

[0805] Assay Protocol

[0806] Day 1 Cell Culture [0807] 1. Harvest NL20 human bronchial epithelial cells expressing human Z-AAT in OptiMEM™ containing Pen/Strep (P/S) [0808] 2. Seed at 16,000 cells/well in 30 μL (384 well plate) [0809] 3. Centrifuge plates briefly up to speed (1200 rpm) and place into 37° C. incubator overnight

[0810] Day 2: Compound Addition and Coating Plates with Capture Antibody

[0811] Compound Addition: [0812] 1. Dispense 40 μL of OptiMEM™ (P/S) with doxycycline (1:1000 stock=0.1 μM final) to each well of the compound plate using a multidrop Combi in hood [0813] 2. Remove cell plate from incubator, flip/blot and take immediately to Bravo to transfer compounds [0814] 3. Return plates to incubator overnight

[0815] Coat MSD Plates [0816] 1. Dilute capture antibody (Polyclonal Goat anti-AAT) to 5 μg/mL (1:200) in PBS (no BSA). [0817] 2. Dispense 25 μL of diluted capture antibody into all wells of MSD 384-well High Bind plate using the Multidrop equipped with a standard cassette. [0818] 3. Incubate overnight at 4° C.

[0819] Prepare Blocker A (BSA) Solutions [0820] 1. Prepare solution of 5% MSD Blocker A (BSA) following the manufacturer's instructions. [0821] 2. Further dilute the 5% MSD Blocker A in PBS to 1% (Blocker A) as needed.

[0822] Day 3: Run MSD Assay

[0823] Block Plates [0824] 1. Wash plate 1× with 50 μL Wash buffer (PBS+0.5% Tween 20), and adds 35 μL 5% Block A buffer to block non-specific binding on washer dispenser [0825] 2. Rotate plates on shaker for 1 hour at 600 rpm

[0826] Prepare M-AAT Standards [0827] 1. Dilute M-AAT stock to 1.6 μg/mL in 1% BSA Blocker A (Stock in −70° C.); then prepare 12×1:2 serial dilutions in 1% Blocker A [0828] 2. The top starting final concentration on MSD plate is 320 ng/mL. These dilutions correspond to a final concentration of 320, 160, 80, 40, 20, 10, 5, 2.5, 1.25, 0.625, 0.312, 0.156 ng/mL.

[0829] Dilution Plate [0830] 1. Add 80 μL of 1% Assay buffer to all wells except columns 1/24 (standards) with Multidrop Combi [0831] 2. Add diluted standards to columns 1 and 24 [0832] 3. Centrifuge dilution plates 1200 rpm briefly

[0833] Cell Plate [0834] 1. Aspirate columns which will have the standards from the cell plates in the hood using 16-pin aspirator

[0835] Prepare Human Neutrophil Elastase (hNE) [0836] 1. Prepare 1 μg/mL Human Neutrophil Elastase by diluting in 1% Blocker A. [0837] a. Small 100 μg vial—add 1 mL PBS (100 μg/mL) [0838] i. This can then be diluted 1:100 in 1% Assay Buffer for a final 1 μg/mL concentration

[0839] MSD—Add hNE (20 μL/Well) [0840] 1. After the MSD plate has blocked for at least 1 hour, wash plate 1× with 50 μL Wash buffer (PBS+0.5% Tween 20) and then add 20 μL hNE to each well

[0841] Bravo—Cell Plate—Dilution Plate—MSD Plate

[0842] Using the Bravo aspirate 10 μL from the cell plate, transfer to the dilution plate (9-fold dilution) [0843] 1. Mix 25 μL 3×, then aspirate 5 μL, transfer to MSD plate (5-fold dilution) [0844] 2. Mix 10 μL 3×. Total dilution is 45 fold. [0845] 3. Shake plates at 600 rpm for 1.5 hours

[0846] Add Functional Detection hNE Antibody [0847] 1. Wash plate 1× with wash buffer [0848] 2. Add 25 μL Sulfo-tagged anti-Elastase Monoclonal Mouse anti-Elastase) diluted to 0.45 μg/mL (1:2000) in 1% Blocker A into all wells of the functional activity MSD plates using the washer/dispenser [0849] Note: The dilution required for sufficient signal must be determined for each new lot of labeled antibody. [0850] 3. Incubate at RT shaking at 600 rpm for 1 hour.

[0851] Final Wash and MSD Imager Read [0852] 1. Wash the plate 1×, and add 25 μL of Wash Buffer to the plate. [0853] 2. Make 2× Read buffer [0854] 3. Remove wash buffer from MSD plate [0855] 4. Transfer 35 μL 2× Read Buffer to MSD plate using Bravo and take to MSD to read immediately
Data analysis in MSD Discovery Workbench 4.0 software and EC.sub.50 values were determined using Genedata.

[0856] B. Biochemical Assay (Z-AAT Elastase Activity Assay)

[0857] This assay measured the modulation of compounds 1-361 on Z-AAT SERPIN activity using purified Z-AAT protein and purified human neutrophil elastase (hNE). Normally, when active monomeric Z-AAT encounters a protease such as trypsin or elastase, it forms a 1:1 covalent “suicide” complex in which both the AAT and protease are irreversibly inactivated. However, compounds binding to Z-AAT can lead to a decrease in SERPIN activity. In such cases, when a protease encounters compound-bound Z-AAT, the protease cleaves and inactivates Z-AAT without itself being inactivated.

[0858] Materials

[0859] Reagents [0860] PBS buffer (media prep)+0.01% BRIJ35 detergent (Calbiochem catalog #203728) [0861] Opti-MEM media (Fisher 11058-021) [0862] Human neutrophil elastase (hNE, Athens Research #16-14-051200) [0863] 3.4 μM stock (0.1 mg/mL) prepared in 50 mM Na Acetate, pH 5.5, 150 mM NaCl, stored at −80° C. [0864] Elastase substrate V (ES V, fluorescent peptide substrate MeOSuc-Ala-Ala-Pro-Val-AMC, Calbiochem catalog #324740) [0865] 20 mM stock in DMSO, stored at −20° C. [0866] Purified Z-AAT protein from human plasma; [0867] 12.9 μM (0.67 mg/mL) Z-AAT Vertex Cambridge Sample 4942, from patient #061-SSN, stored at −80C

[0868] Plates [0869] Corning 4511 (384 well black low volume)

[0870] Instruments [0871] PerkinElmer® EnVision™

[0872] Assay Protocol

[0873] Pre-Incubation of Z-AAT with Compounds [0874] 1. 7.5 μL of Z-AAT (20 nM) was incubated with Compounds 1-361 in a GCA plate for 1 hour at room temperature

[0875] Addition of hNE [0876] 1. 7.5 ul of HNE solution (3 nM in PBS+0.01% BRIJ35) added into GCA plate [0877] 2. Incubate plate for 30 minutes to allow Z-AAT/HNE suicide complex formation.

[0878] Addition of Substrate and Read Plate on PE Envision [0879] 1. 7.5 μL of substrate (300 μM solution of elastase substrate (ES V) in PBS+0.01% BRIJ35) dispensed per well into GCA plate [0880] 2. Immediately read on Envision.

[0881] C. EC50 and Z-AAT Elastase Activity Data for Compounds 1-361

[0882] The compounds of formula (I) are useful as modulators of AAT activity. Table 50 below illustrates the EC.sub.50 of the compounds 1-361 using procedures described in Section A above. Table 50 below also provides the Z-AAT elastase activity using procedures described in Section B above. In Table 50 below, the following meanings apply for both EC.sub.50 and IC.sub.50: “+++” means<1.2 μM; “++” means between 1.2 μM and 3.0 μM; “+” means greater than 3.0 μM; and “N/A” means activity not assessed. For IC.sub.50, “N.D.” means activity not detected up to 30 μM.

TABLE-US-00052 TABLE 50 EC50 and IC50 data for Compounds 1-361 NL20 Z-AAT Elastase Compound Functional Activity No. EC50 (μM) IC50 (μM) 1 + N.D. 2 + N.D. 3 ++ + 4 +++ +++ 5 +++ + 6 +++ ++ 7 ++ N.D. 8 +++ +++ 9 +++ +++ 10 +++ +++ 11 ++ + 12 +++ + 13 + N.D. 14 +++ +++ 15 ++ + 16 +++ +++ 17 + N.D. 18 ++ N.D. 19 ++ + 20 +++ N.D. 21 +++ +++ 22 +++ +++ 23 ++ ++ 24 +++ +++ 25 + N.D. 26 + N.D. 27 + +++ 28 ++ + 29 + N.D. 30 + ++ 31 + + 32 + + 33 ++ + 34 ++ N.D. 35 +++ + 36 +++ + 37 +++ +++ 38 ++ N.D. 39 +++ +++ 40 + N.D. 41 + +++ 42 + N.D. 43 + N.D. 44 + + 45 +++ +++ 46 +++ + 47 +++ +++ 48 +++ N.D. 49 +++ +++ 50 +++ + 51 +++ N.D. 52 ++ N.D. 53 +++ + 54 +++ + 55 ++ + 56 +++ ++ 57 +++ +++ 58 +++ N.D. 59 ++ +++ 60 ++ + 61 ++ + 62 + N.D. 63 + + 64 + N.D. 65 +++ + 66 + N.D. 67 ++ + 68 +++ + 69 +++ ++ 70 + N.D. 71 ++ + 72 ++ N.D. 73 ++ + 74 + N.D. 75 + N.D. 76 + N.D. 77 + N.D. 78 + N.D. 79 ++ N.D. 80 +++ + 81 +++ + 82 ++ + 83 ++ N.D. 84 +++ + 85 +++ + 86 ++ + 87 ++ + 88 ++ + 89 +++ + 90 ++ + 91 + N.D. 92 + N.D. 93 + N.D. 94 ++ N.D. 95 + N.D. 96 + N.D. 97 +++ ++ 98 +++ ++ 99 +++ + 100 +++ + 101 +++ ++ 102 +++ N.D. 103 ++ N.D. 104 ++ N.D. 105 + N.D. 106 ++ + 107 ++ + 108 ++ + 109 ++ + 110 +++ +++ 111 +++ + 112 +++ + 113 ++ + 114 + N.D. 115 + N.D. 116 + N.D. 117 + N.D. 118 +++ ++ 119 +++ + 120 +++ + 121 + N.D. 122 +++ N.D. 123 ++ N.D. 124 +++ + 125 +++ + 126 + N.D. 127 +++ +++ 128 ++ N.D. 129 +++ N.D. 130 ++ N.D. 131 ++ N.D. 132 ++ + 133 ++ N.D. 134 +++ N.D. 135 +++ + 136 + N.D. 137 ++ N.D. 138 ++ N.D. 139 ++ N.D. 140 + N.D. 141 + + 142 +++ + 143 + N.D. 144 + N.D. 145 + N.D. 146 + N.D. 147 ++ N.D. 148 + N.D. 149 + N.D. 150 + N.D. 151 + N.D. 152 + N.D. 153 + N.D. 154 + N.D. 155 + N.D. 156 + N.D. 157 + N.D. 158 + N.D. 159 + N.D. 160 + N.D. 161 + N.D. 162 + N.D. 163 + N.D. 164 + N.D. 165 ++ N.D. 166 +++ +++ 167 ++ N.D. 168 + N.D. 169 ++ + 170 + N.D. 171 + N.D. 172 + N.D. 173 +++ + 174 ++ N.D. 175 + + 176 + N.D. 177 + N.D. 178 + N.D. 179 + N.D. 180 + N.D. 181 + N.D. 182 +++ ++ 183 +++ N.D. 184 +++ N.D. 185 +++ N.D. 186 + N.D. 187 +++ N.D. 188 +++ ++ 189 +++ + 190 ++ N.D. 191 + N.D. 192 ++ N.D. 193 ++ N.D. 194 ++ N.D. 195 + N.D. 196 + N.D. 197 + + 198 ++ + 199 + N.D. 200 + N.D. 201 +++ ++ 202 +++ + 203 ++ + 204 + N.D. 205 +++ ++ 206 + N.D. 207 + N.D. 208 ++ N.D. 209 + N.D. 210 +++ N.D. 211 + N.D. 212 ++ N.D. 213 +++ + 214 + N.D. 215 ++ N.D. 216 +++ + 217 +++ + 218 +++ + 219 ++ N.D. 220 +++ + 221 ++ N.D. 222 + N.D. 223 + + 224 + + 225 + + 226 + N.D. 227 + + 228 + N.D. 229 + N.D. 230 + N.D. 231 + N.D. 232 + N.D. 233 + N.D. 234 ++ +++ 235 + N.D. 236 +++ N.D. 237 + + 238 ++ + 239 ++ N.D. 240 +++ N.D. 241 +++ + 242 +++ +++ 243 ++ N.D. 244 ++ + 245 +++ + 246 +++ +++ 247 +++ + 248 + + 249 ++ + 250 + N.D. 251 + N.D. 252 ++ N.D. 253 +++ +++ 254 +++ ++ 255 ++ +++ 256 +++ +++ 257 +++ ++ 258 +++ +++ 259 +++ +++ 260 +++ + 261 +++ N.D. 262 +++ + 263 ++ + 264 +++ ++ 265 +++ + 266 +++ ++ 267 +++ +++ 268 +++ +++ 269 +++ ++ 270 +++ ++ 271 + N.D. 272 ++ N.D. 273 +++ + 274 +++ N.D. 275 ++ N.D. 276 +++ + 277 +++ N.D. 278 ++ + 279 +++ +++ 280 +++ + 281 ++ + 282 + N.D. 283 +++ N.D. 284 +++ N.D. 285 ++ + 286 ++ + 287 ++ N.D. 288 ++ ++ 289 + + 290 + N.D. 291 + + 292 + N.D. 293 ++ + 294 + N.D. 295 + N.D. 296 + N.D. 297 + N.D. 298 + N.D. 299 + N.D. 300 + N.D. 301 + N.D. 302 +++ + 303 ++ + 304 + N.D. 305 + N.D. 306 + N.D. 307 + + 308 + + 309 ++ + 310 ++ N.D. 311 ++ N.D. 312 + + 313 + N.D. 314 +++ N.D. 315 ++ N.D. 316 + N.D. 317 + N.D. 318 ++ N.D. 319 ++ N.D. 320 + N.D. 321 + N.D. 322 + + 323 +++ N.D. 324 ++ N.D. 325 + + 326 + N.D. 327 + + 328 + + 329 + N.D. 330 + + 331 + N.D. 332 + N.D. 333 +++ + 334 ++ N.D. 335 +++ + 336 +++ + 337 +++ N.D. 338 ++ N.D. 339 ++ N.D. 340 + N.D. 341 ++ N.D. 342 + N.D. 343 +++ N.D. 344 +++ N.D. 345 +++ N.D. 346 +++ + 347 +++ N.D. 348 ++ N.D. 349 ++ N.D. 350 + N.D. 351 ++ N.D. 352 ++ N.D. 353 + N.D. 354 + N.D. 355 ++ N.D. 356 + N.D. 357 + N.D. 388 ++ N.D. 359 ++ N.D. 360 + N.D. 361 + N.D.

Other Embodiments

[0883] This description provides merely exemplary embodiments of the disclosed subject matter. One skilled in the art will readily recognize from the disclosure and accompanying claims, that various changes, modifications and variations can be made therein without departing from the spirit and scope of the disclosure as defined in the following claims.