Heterocyclic inhibitors of ATR kinase

Abstract

The present disclosure relates to heterocyclic compounds and methods which may be useful as inhibitors of ATR kinase for the treatment or prevention of cancer.

Claims

1. A method for preparing a compound of Formula 203 ##STR00351## wherein R.sup.1 and R.sup.2 are independently chosen from C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.3-6cycloalkyl, C.sub.3-6heterocycloalkyl, C.sub.5-10aryl, and 5-10 membered heteroaryl, any of which is optionally substituted with one or more R.sup.5 groups, or R.sup.1 and R.sup.2, together with the sulfur to which they are both attached, form a 4, 5, 6, or 7-membered heterocycloalkyl ring which is optionally substituted with one or more R.sup.5 groups; R.sup.3 is chosen from hydrogen, C.sub.1-6alkyl, and C.sub.1-6haloalkyl; R.sup.4 is chosen from C.sub.5-10aryl or 5-10 membered heteroaryl, either of which is optionally substituted with one or more R.sup.6 groups; each R.sup.5 is independently chosen from NR.sup.8R.sup.9, halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C.sub.3-6cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR.sup.8, NR.sup.7C(O)R.sup.8, NR.sup.7C(O)OR.sup.8, NR.sup.7C(O)NR.sup.8R.sup.9, C(O)R.sup.8, C(O)OR.sup.8, and C(O)NR.sup.8R.sup.9; each R.sup.6 is independently chosen from NR.sup.11R.sup.12, halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C.sub.3-6cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR.sup.11, NR.sup.10C(O)R.sup.11, NR.sup.10C(O)OR.sup.11, NR.sup.10C(O)NR.sup.11R.sup.12, C(O)R.sup.11, C(O)OR.sup.11, and C(O)NR.sup.11R.sup.12; each R.sup.7, R.sup.8 and R.sup.9 is independently chosen from hydrogen, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, and 3-6 membered heterocycloalkyl, any of which is optionally substituted with halo, hydroxy, C.sub.1-3alkyl, C.sub.1-3haloalkyl and C.sub.1-3alkoxy; or any two of R.sup.7, R.sup.8 and R.sup.9, together with the atom to which they are both attached can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and each R.sup.10, R.sup.11 and R.sup.12 is independently chosen from hydrogen, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, 3-6 membered heterocycloalkyl, any of which is optionally substituted with one or more groups chosen from halo, hydroxy and alkoxy; or any two of R.sup.10, R.sup.11 and R.sup.12, together with the atom to which they are both attached, can form a 3-7 membered cycloalkyl or heterocycloalkyl ring, said method comprising reacting a compound of formula 202 ##STR00352## with a compound of formula ##STR00353## to yield a compound of formula 203.

2. The method of claim 1, wherein said reacting occurs in the presence of PdCl.sub.2(dppf).

3. The method of claim 2, wherein said reacting occurs in the presence of dioxane.

4. The method of claim 1, wherein the compound of formula 203 comprises a mixture of diastereomers.

5. The method of claim 4, further comprising separating the mixture of diastereomers.

6. The method of claim 1, wherein R.sup.3 is chosen from methyl, fluoromethyl, difluoromethyl, and trifluoromethyl.

7. The method of claim 1, wherein R.sup.4 is 5-10 membered heteroaryl and is optionally substituted with one or more R.sup.6 groups.

8. The method of claim 7, wherein R.sup.4 is chosen from 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, 1H-indol-1-yl, 1H-indol-4-yl,1H-indazol-1-yl,1H-indazol-4-yl, 1H-benzo[d]imidazol-1-yl, 1H-benzo[d]imidazol-4-yl,1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2,3-c]pyridin-4-yl, pyrazolo[1,5-a]pyridin-3-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl, 1H-imidazo[4,5-c]pyridin-1-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl,1H-pyrazolo[3,4-b]pyridin-4-yl, 3H-imidazo[4,5-b]pyridin-7-yl, and 1H-benzo[d][1,2,3]triazol-1-yl, any of which is optionally substituted with one or two R.sup.6 groups.

9. The method of claim 7, wherein R.sup.4 is pyridine and is optionally substituted with one or more R.sup.6 groups.

10. The method of claim 1, wherein: each R.sup.6 is independently chosen from NR.sup.11R.sup.12, halogen, cyano, hydroxy, oxo, OR.sup.11, NR.sup.10C(O)R.sup.11, NR.sup.10C(O)OR.sup.11, NR.sup.10C(O)NR.sup.11R.sup.12, C(O)R.sup.11, C(O)OR.sup.11, and C(O)NR.sup.11R.sup.12; each R.sup.5 is independently chosen from C(O)R.sup.8, C(O)OR.sup.8, and C(O)NR.sup.8R.sup.9; R.sup.1 and R.sup.2 are independently chosen from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, and 3-6 membered heterocycloalkyl; and R.sup.4 is chosen from pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, pyrrolo[2,3-c]pyridin-4-yl, benzo[d]imidazol-1-yl, any of which is optionally substituted with one or two R.sup.6 groups.

11. The method of claim 10, wherein each R.sup.6 is independently selected from NR.sup.11R.sup.12, halogen, cyano, hydroxy, and oxo.

12. The method of claim 11, wherein R.sup.1 and R.sup.2 are independently chosen from methyl, cyclopropyl, and oxetan-3-yl.

13. A product of the method of claim 1.

14. A method for preparing a compound of Formula 205 ##STR00354## said method comprising reacting a compound of formula 204 ##STR00355## with a compound of formula ##STR00356## wherein R.sup.4 is 2-(methylamino)pyridin-4-yl, to yield a compound of formula 205.

15. The method of claim 14, wherein said reacting occurs in the presence of PdCl.sub.2(dppf).

16. The method of claim 15, wherein said reacting occurs in the presence of Na.sub.2CO.sub.3.

17. The method of claim 15, wherein said reacting occurs in the presence of dioxane.

18. The method of claim 15, wherein said reacting occurs in the presence of water.

19. The method of claim 15, further comprising separating the mixture of diastereomers.

20. The method of claim 19, wherein the step of separating the mixture of diastereomers is accomplished with chiral supercritical fluid chromatography (SFC).

21. A product of the method of claim 14.

Description

EXAMPLE 1

(1) ##STR00163##

(R)-dimethyl ((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

(2) ##STR00164##

(3) (R)-dimethyl((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone A reaction vial was charged with Int. B (100 mg, 0.30 mmol), Int. C (34 mg, 0.36 mmol), RuPhos Pd G4 (26 mg, 0.030 mmol), RuPhos (14 mg, 0.030 mmol), Cs.sub.2CO.sub.3 (293 mg, 0.90 mmol) and 1,4-dioxane (2 mL). The vial was purged with N.sub.2 and sealed. The reaction mixture was stirred at 85° C. for 16 h. The reaction mixture was cooled to RT, filtered through CELITE®, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 M NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=20-50%; 10 min; Column: Venusil ASB C18, 10 μm, 150A, 21.2 mm×250 mm) to afford the title compound (33.0 mg, 28% yield) as a white solid.

(4) .sup.1H NMR (500 MHz, DMSO) δ 11.72 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 7.89 (d, J=5.0 Hz, 1H), 7.59-7.49 (m, 1H), 7.41 (dd, J=3.3, 1.9 Hz, 1H), 5.92 (s, 1H), 4.45 (s, 1H), 4.06 (d, J=12.8 Hz, 1H), 3.96 (dd, J=11.3, 3.4 Hz, 1H), 3.75 (d, J=11.3 Hz, 1H), 3.64 (dd, J=11.3, 2.9 Hz, 1H), 3.53-3.47 (m, 1H), 3.45 (s, 6H), 3.15 (td, J=12.8, 3.8 Hz, 1H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.22N.sub.6O.sub.2S requires: 386, found: 387 [M+H].sup.+.

(5) The compounds reported in Table 2were synthesized using the method described for the previously disclosed Examples. The appropriate sulfoximines were prepared as described for Intermediates C.

(6) TABLE-US-00001 TABLE 1 Example compounds 2-9 Ex. Ex Structure IUPAC Name MWt [M + H] Method 2 1-({6-[(3R)-3-methyl- morpholin-4-yl]-2-{1H- pyrrolo[2,3-b]pyridin-4- yl}pyrimidin-4-yl}- imino)-1λ.sup.6-thiolan-1-one 412 413 1 3 diethyl ({6[(3R)-3- methylmorpholin-4-yl]- 2-{1H-pyrrolo[2,3-b]- pyridin-4-yl}pyrimidin- 4-yl}imino)-λ.sup.6-sulfanone 414 415 1 4 1-({6-[(3R)-3-methyl- morpholin-4-yl]-2-{1H- pyrrolo[2,3-b]pyridin-4- yl}pyrimidin-4-yl}- imino)-1λ.sup.6-thian-1-one 426 427 1 5 4-({6-[(3R)-3-methyl- morpholin-4-yl]-2-{1H- pyrrolo[2,3-b]pyridin-4- yl}pyrimidin-4-yl}- imino)-4λ.sup.6-1,4-oxathian- 4-one 428 429 1 6 methyl tetrahydropyran- 4-yl ({6-[(3R)-3-methyl- morpholin-4-yl]-2-{1H- pyrrolo[2,3-b]pyridin-4- yl}pyrimidin-4-yl}- imino)-λ.sup.6-sulfanone 456 457 1 7 0 methyl ethyl ({6-[(3R)-3- methylmorpholin-4-yl]- 2-{1H-pyrrolo[2,3-b]- pyridin-4-yl}pyrimidin- 4-yl}imino)-λ.sup.6-sulfanone 400 401 1 8 methyl 2-propyl ({6- [(3R)-3-methyl- morpholin-4-yl]-2-{1H- pyrrolo[2,3-b]pyridin-4- yl}pyrimidin-4-yl}- imino)-λ.sub.6-sulfanone 414 415 1 9 methyl (cyclopropyl)- methyl ({6-[(3R)-3- methylmorpholin-4-yl]- 2-{1H-pyrrolo[2,3-b]- pyridin-4-yl}pyrimidin- 4-yl}imino)-λ.sup.6-sulfanone 426 427 1

EXAMPLE 10

(7) ##STR00173##

(R)-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

Step 1

(8) ##STR00174##

(9) (R)-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: A solution of Int. D (45 mg, 0.148 mmol), Int. P (101 mg, 0.192 mmol) and K.sub.2CO.sub.3 (51 mg, 0.37 mmol) in dioxane (671 μL) and water (67 μL) was degassed with a stream of N.sub.2 for 1 minute. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (6.0 mg, 7.9 μmol) was added, the mixture was degassed with a stream of N.sub.2 for an additional 1 minute, and the reaction mixture was heated at 85° C. for 3 h. The reaction mixture was cooled to RT, filtered through CELITE®, washed with CH.sub.2Cl.sub.2 (2 mL) and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (32 mg, 34% yield) as a pale yellow solid.

(10) .sup.1H NMR (600 MHz, Methanol-d4) δ 8.31 (d, J=3.0 Hz, 1H), 7.66 (d, J=3.4 Hz, 1H), 6.71 (d, J=3.5 Hz, 1H), 6.31 (s, 1H), 4.63 (s, 1H), 4.19 (s, 1H), 4.04 (dd, J=11.9, 3.8 Hz, 1H), 3.83 (d, J=11.8 Hz, 1H), 3.75 (dd, J=11.9, 3.2 Hz, 1H), 3.61 (td, J=11.9, 2.9 Hz, 1H), 3.57 (d, J=5.4 Hz, 6H), 3.51 (t, J=13.5 Hz, 1H), 1.42 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.21FN.sub.6O.sub.2S requires: 404, found: 405 [M+H].sup.+.

EXAMPLE 11

(11) ##STR00175##

(R)-Dimethyl((2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

Step 1

(12) ##STR00176##

(13) (R)-dimethyl((2-(2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: A reaction vial was charged with Int. D (103 mg, 0.5 mmol), Int. G (280 mg, 0.68 mmol), Na.sub.2CO.sub.3 (216 mg, 2.04 mmol), PdCl.sub.2(dppf) (25 mg, 0.034 mmol), dioxane (3 mL) and H.sub.2O (1 mL). The vial was purged with N.sub.2 and sealed. The reaction mixture was stirred at 80° C. for 3 h. The reaction mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified by prep-TLC (50% EtOAc in hexanes) to afford the title compound (50 mg, 26% yield) as a white solid.

(14) MS (ES.sup.+) C.sub.26H.sub.30N.sub.6O.sub.4S.sub.2 requires: 554, found: 555 [M+H].sup.+.

Step 2

(15) ##STR00177##

(16) (R)-Dimethyl((2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: A mixture of the product from the previous step (50 mg, 0.09 mmol), NaOH (72 mg, 1.8 mmol), H.sub.2O (1 mL) and MeOH (2 mL) was stirred at 70° C. for 2 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. MeOH (30 mL) was added, the mixture was stirred for 5 min, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=30-60%; 18 min; Column: Welch XB-C18, 10 μm, 150 Å, 21.2 mm×250 mm) to afford the title compound (15 mg, 41% yield) as a white solid.

(17) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.53 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 7.81 (d, J=4.8 Hz 1H), 7.11 (s, 1H), 5.89 (s, 1H), 4.44 (s, 1H), 4.04 (s, 1H), 3.95 (s, 1H), 3.75 (d, J=12.6 Hz, 1H), 3.65 (s, 1H), 3.47 (d, J=19.4 Hz, 7H), 3.14 (s, 1H), 2.42 (s, 3H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+.

EXAMPLE 12

(18) ##STR00178##

(R)-1-(1-((6-(3-Methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1-oxido-1λ.SUP.6.-thiomorpholino)ethan-1-one

Step 1

(19) ##STR00179##

(20) Tert-butyl (R)-1-((6-(3-methylmorpholino)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1λ.sup.6-thiomorpholine-4-carboxylate 1-oxide A mixture Int. R (145 mg, 0.62 mmol), Int. T (300 mg, 0.62 mmol), Pd.sub.2(dba).sub.3 (57 mg, 0.062 mmol), X-phos (30 mg, 0.062 mmol) and Cs.sub.2CO.sub.3 (407 mg, 1.24 mmol) in dioxane (10 mL) was degassed with Ar for 5 minutes. The reaction mixture was heated to 100° C. and stirred for 3 h. The mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-50% EtOAc in hexanes) to afford the title compound (310 mg, 73% yield) as a yellow solid.

(21) MS (ES.sup.+) C.sub.32H.sub.39N.sub.7O.sub.6S.sub.2 requires: 681, found: 682 [M+H].sup.+.

Step 2

(22) ##STR00180##

(23) (R)-1-((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1λ.sup.6-thiomorpholine 1-oxide A mixture of the product from the previous step (300 mg, 0.44 mmol), TFA (1 mL) and CH.sub.2Cl.sub.2 (5 mL) was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to give a yellow oil. MeOH (5 mL) and NaOH (18 mg, 0.88 mmol) were added and the mixture was stirred at 60° C. for 1 h. The mixture was cooled to RT, H.sub.2O (10 mL) was added and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (3×15 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (150 mg, 80% yield) as a white solid.

(24) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.78 (s, 1H), 9.03 (s, 1H), 8.31 (d, J=5.1 Hz, 1H), 7.86 (d, J=5.0 Hz, 1H), 7.57 (s, 1H), 7.33 (s, 1H), 6.07 (s, 1H), 4.50 (s, 1H), 3.98 (d, J=11.4 Hz, 6H), 3.87-3.82 (m, 3H), 3.52 (s, 4H), 3.19 (s, 1H), 1.23 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.20H.sub.25N.sub.7O.sub.2S requires: 427, found: 428 [M+H].sup.+.

Step 3

(25) ##STR00181##

(26) (R)-1-(1-((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1-oxido-1λ.sup.6-thiomorpholino)ethan-1-one: To a solution of the product from the previous step (100 mg, 0.23 mmol) and Et.sub.3N (0.5 mL, 0.5 mmol) in CH.sub.2Cl.sub.2 (5 mL) at 0° C. was added acetyl chloride (18 mg, 0.23 mmol) and the resulting mixture was warmed to RT and stirred for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=25-55%; 15 min; Column: Welch XB-C18, 10 μm, 21.2×250 mm) to afford the title compound (36 mg, 33% yield) as a white solid.

(27) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.72 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.86 (d, J=5.0 Hz, 1H), 7.59-7.50 (m, 1H), 7.37 (dd, J=3.2, 2.0 Hz, 1H), 6.02 (s, 1H), 4.49 (s, 1H), 4.18 (s, 1H), 4.11-3.82 (m, 4H), 3.79-3.56 (m, 6H), 3.53-3.39 (m, 2H), 3.17 (s, 1H), 2.07 (d, J=2.0 Hz, 3H), 1.22 (d, J=6.6 Hz, 3H); MS (ES.sup.+) C.sub.22H.sub.27N.sub.7O.sub.3S requires: 469, found: 470 [M+H].sup.+.

EXAMPLE 13

(28) ##STR00182##

(R)-((2-(2-amino-6-chloropyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

Step 1

(29) ##STR00183##

(30) (R)-((2-(2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: A solution of Int. D (150 mg, 0.492 mmol), Int. Y (516 mg, 0.689 mmol) and K.sub.2CO.sub.3 (170 mg, 1.23 mmol) in dioxane (2.2 mL) and water (224 μL) was degassed with N.sub.2 for 1 minute. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2A (20.1 mg, 0.025 mmol) was added and the mixture was degassed with N.sub.2 for an additional 1 minute. The reaction mixture was heated at 85° C. for 3 h. The reaction mixture was cooled to RT, filtered through CELITE®, washed with CH.sub.2Cl.sub.2 and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=40-80%; 16 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (166 mg, 23% yield) as a pale yellow solid.

(31) MS (ES.sup.+) C.sub.24H.sub.29ClN.sub.6O.sub.3S requires: 516, found: 517 [M+H].sup.+.

Step 2

(32) ##STR00184##

(33) (R)-((2-(2-amino-6-chloropyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: To a solution of the product from the previous step (32 mg, 0.021 mmol) in CH.sub.2Cl.sub.2 (215 μL) was added TFA (33 μL, 0.43 mmol) and the resulting mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=20-60%; 20 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (12.2 mg, 91% yield) as an off-white solid.

(34) .sup.1H NMR (600 MHz, Methanol-d.sub.4) δ 7.15 (d, J=1.0 Hz, 1H), 7.10 (s, 1H), 6.20 (s, 1H), 4.58 (s, 1H), 4.19 (s, 1H), 4.03 (dd, J=11.6, 3.9 Hz, 1H), 3.83 (d, J=11.7 Hz, 1H), 3.73 (dd, J=11.7, 3.2 Hz, 1H), 3.59 (td, J=12.0, 3.1 Hz, 1H), 3.53 (d, J=4.1 Hz, 6H), 3.42 (td, J=13.1, 3.8 Hz, 1H), 1.37 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.16H.sub.21ClN.sub.6O.sub.2S requires: 396/398, found 397/399 [M+H].sup.+.

EXAMPLE 14

(35) ##STR00185##

(R)-((2-(2-amino-6-methylpyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

Step 1

(36) ##STR00186##

(37) (R)-((2-(2-((4-methoxybenzyl)amino)-6-methylpyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: A solution of (R)-((2-(2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone (synthesized as described for Example 13, step 1) (50 mg, 0.034 mmol), methylboronic acid (2.410 mg, 0.040 mmol) and K.sub.2CO.sub.3 (11.6 mg, 0.084 mmol) in dioxane (153 μL) and water (15 μL) was degassed with N.sub.2 for 30 seconds PdCl.sub.2(dppf)-CH.sub.2Cl2 (1.4 mg, 1.7 μmol) was added and the mixture was degassed with N.sub.2 for an additional 30 seconds. and the resulting mixture was heated at 120° C. for 6 h in a microwave reactor. The reaction mixture was cooled to RT, filtered through CELITE®, washed with CH.sub.2Cl.sub.2 and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 26 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (13.5 mg, 56% yield) as a pale yellow solid.

(38) MS (ES.sup.+) C.sub.25H.sub.32N.sub.6O.sub.3S requires: 496, found: 497 [M+H].sup.+.

Step 2

(39) ##STR00187##

(40) (R)-((2-(2-amino-6-methylpyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: To a solution of the product from the previous step (13.5 mg, 0.019 mmol) in CH.sub.2Cl.sub.2 (186 μL) was added TFA (29 μL, 0.37 mmol) and the resulting mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (8.6 mg, 76% yield) as an off-white solid.

(41) .sup.1H NMR (600 MHz, Methanol-d4) δ 7.69 (s, 1H), 7.47 (s, 1H), 6.04 (s, 1H), 4.51-4.45 (m, 1H), 4.09 (d, J=12.9 Hz, 1H), 4.00 (dd, J=11.5, 3.9 Hz, 1H), 3.80 (d, J=11.5 Hz, 1H), 3.72 (dd, J=11.6, 3.2 Hz, 1H), 3.57 (td, J=11.9, 3.2 Hz, 1H), 3.49 (s, 6H), 3.32-3.24 (m, overlap MeOH, 1H), 2.55 (s, 3H), 1.29 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.17H.sub.24N.sub.6O.sub.2S requires: 376, found 377 [M+H].sup.+.

EXAMPLE 15

(42) ##STR00188##

(R)-6-amino-4-(4-((dimethyl(oxo)-λ.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinonitrile

(43) ##STR00189##

(44) (R)-6-amino-4-(4-((dimethyl(oxo)-λ.sup.6-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinonitrile: A microwave vial was charged with Example 13 (95 mg, 0.076 mmol), Pd.sub.2(dba).sub.3 (7.0 mg, 7.6 μmol), DPPF (2.1 mg, 3.8 μmol), zinc (0.75 mg, 0.011 mmol), dicyanozinc (8.9 mg, 0.076 mmol) and DMA (380 μL). The vial was sealed and the reaction mixture was heated to 150° C. in a microwave reactor for 3 h. The reaction mixture was cooled to RT and directly purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-50%; 26 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (23.3 mg, 50% yield) as a pale yellow solid.

(45) .sup.1H NMR (600 MHz, Methanol-d.sub.4) δ 7.58 (s, 1H), 7.44 (s, 1H), 6.19 (s, 1H), 4.58 (s, 1H), 4.28-4.10 (m, 1H), 4.03 (dd, J=11.7, 3.9 Hz, 1H), 3.83 (d, J=11.7 Hz, 1H), 3.73 (dd, J=11.7, 3.2 Hz, 1H), 3.59 (td, J=12.0, 3.1 Hz, 1H), 3.54 (d, J=4.4 Hz, 6H), 3.41 (td, J=13.0, 4.0 Hz, 1H), 1.37 (d, J=6.9 Hz, 3H); MS (ES.sup.+) C.sub.17H.sub.21N.sub.7O.sub.2S requires: 387, found: 388 [M+H].sup.+.

EXAMPLE 16

(46) ##STR00190##

Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

Step 1

(47) ##STR00191##

(48) Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: A reaction vial was charged with Int. T (300 mg, 0.60 mmol), Int. E (80 mg, 0.67 mmol), Cs.sub.2CO.sub.3 (655 mg, 2.01 mmol), RuPhos Pd G3 (56 mg, 0.067 mmol), RuPhos (31 mg, 0.067 mmol) and dioxane (4 mL). The reaction mixture was purged with N.sub.2, sealed and heated at 80° C. for 3 h. The reaction mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-50% acetone in hexanes) to afford the title compound (130 mg, 37% yield) as a white solid.

(49) MS (ES.sup.+) C.sub.27H.sub.30N.sub.6O.sub.4S.sub.2 requires: 566, found: 567 [M+H].sup.+.

Step 2

(50) ##STR00192##

(51) Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: A reaction vial was charged with the product from the previous step (130 mg, 0.23 mmol), NaOH (184 mg, 4.6 mmol), H.sub.2O (1 mL) and MeOH (2 mL) and the mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was added MeOH (30 mL) and the resulting mixture was stirred for 5 min., filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=30-60%; 18 min; Column: Welch XB-C18, 10 μm, 150 Å, 21.2 mm×250 mm) to afford the title compound (20 mg, 21% yield) as a white solid.

(52) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.71 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.90 (dd, J=5.0, 1.8 Hz, 1H), 7.53 (d, J=2.9 Hz, 1H), 7.40 (s, 1H), 5.95 (s, 1H), 4.47 (s, 1H), 4.05 (s, 1H), 3.96 (d, J=8.5 Hz, 1H), 3.75 (d, J=11.2 Hz, 1H), 3.64 (d, J=11.4 Hz, 1H), 3.52 (t, J=13.9 Hz, 4H), 3.16 (s, 1H), 3.00 (s, 1H), 1.18 (dd, J=34.3, 27.3 Hz, 7H); MS (ES.sup.+) C.sub.2H.sub.24N.sub.6O.sub.2S requires: 412, found: 413 [M+H].sup.+.

EXAMPLE 17a and 17b

(53) ##STR00193##

(S)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

and

(54) ##STR00194##

(R)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

Step 1

(55) ##STR00195##

(56) (S)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone and (R)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: To a solution of ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone (synthesis is similar to that described for Example 16) (350 mg, 0.63 mmol) in MeOH (6 mL) and THF (2 mL) was added NaOH (1.5 mL, 4 N aqueous) and the reaction mixture was heated to 60° C. and stirred for 2 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-5% MeOH in CH.sub.2Cl.sub.2) to afford a mixture of the title compounds. The mixture of diastereomers was separated by Chiral SFC (Mobile phase: CO.sub.2/ethanol (1% MeOH Ammonia)=45/55; Flow rate: 80 g/min; 6.5 min; Column temperature: 35° C.; Back pressure: 100 bar; Column: Daicel CHIRALPAK® AD, 10 μm, 20 mm×250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 17a (43 mg, 18% yield, >99% ee) as a white solid and 17b (47 mg, 20% yield, >94% ee) as a white solid.

(57) 17a ((R)-ethyl(methyl)-λ.sup.6-sulfanone or (S)-ethyl (methyl)-λ.sup.6-sulfanone): .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.72 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.88 (d, J=5.0 Hz, 1H), 7.63-7.48 (m, 1H), 7.42 (d, J=2.0 Hz, 1H), 5.93 (s, 1H), 4.44 (s, 1H), 4.07 (d, J=12.7 Hz, 1H), 3.96 (dd, J=11.3, 3.2 Hz, 1H), 3.75 (d, J=11.3 Hz, 1H), 3.63 (dd, J=9.1, 5.7 Hz, 2H), 3.61 (d, J=7.5 Hz, 1H), 3.49 (td, J=11.8, 2.8 Hz, 1H), 3.38 (s, 3H), 3.15 (td, J=12.8, 3.6 Hz, 1H), 1.31 (t, J=7.4 Hz, 3H), 1.21 (t, J=7.3 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+; R.sub.t=2.72 min.

(58) 17b ((R)-ethyl(methyl)-λ.sup.6-sulfanone or (S)-ethyl (methyl)-λ.sup.6-sulfanone): .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.72 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.88 (d, J=5.0 Hz, 1H), 7.54 (d, J=3.4 Hz, 1H), 7.42 (d, J=3.3 Hz, 1H), 5.93 (s, 1H), 4.47 (s, 1H), 4.05 (d, J=13.2 Hz, 1H), 3.96 (dd, J=11.1, 3.4 Hz, 1H), 3.75 (d, J=11.4 Hz, 1H), 3.70-3.53 (m, 3H), 3.54-3.44 (m, 1H), 3.36 (d, J=13.0 Hz, 3H), 3.15 (td, J=12.7, 3.6 Hz, 1H), 1.32 (q, J=7.7 Hz, 3H), 1.21 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+; R.sub.t=3.28 min.

EXAMPLE 18 (18a and 18b)

(59) ##STR00196##

(R)-((2-(2-Amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ.SUP.6.-sulfanone

and

(60) ##STR00197##

(S)-((2-(2-Amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ.SUP.6.-sulfanone

Step 1

(61) ##STR00198##

(62) Cyclopropyl((2-(2-methoxy-6-((4-methoxybenzyl)amino)pyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)-λ.sup.6-sulfanone: A suspension of Int. Q (590 mg, 1.79 mmol), Int. S (790 mg, 2.14 mmol) and K.sub.2CO.sub.3 (741 mg, 5.37 mmol) in dioxane (15 mL) and water (3 mL) was degassed with N.sub.2 for 1 minute. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (73 mg, 0.090 mmol) was added and the mixture was degassed with N.sub.2 for an additional 1 minute. The reaction mixture was heated to 130° C. in a microwave reactor for 4 h. The mixture was cooled to RT, the layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-2% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (910 mg, 95% yield) as a yellow solid.

(63) MS (ES.sup.+) C.sub.27H.sub.34N.sub.6O.sub.4S requires: 538, found: 539 [M+H].sup.+.

Step 2

(64) ##STR00199##

(65) (S)-((2-(2-Amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ.sup.6-sulfanone and (R)-((2-(2-Amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ.sup.6-sulfanone: To a solution of the product from the previous step (910 mg, 1.69 mmol) in CH.sub.2Cl.sub.2 (7 mL) was added TFA (2.5 mL, 34 mmol) and the resulting mixture was stirred at 45° C. for 16 h. The mixture was cooled to RT and neutralized with 6 N NaOH to pH=7, followed by the addition of sat. aq. NaHCO.sub.3(30 mL) and the mixture was stirred vigorously for 5 min. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (3×50 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-3% MeOH in CH.sub.2Cl.sub.2) to afford a mixture of the title compounds (650 mg, 92% yield). The mixture of diastereomers was separated by Chiral SFC (Mobile phase: CO.sub.2/MeOH (0.2% MeOH Ammonia)=45/55; Flow rate: 80 g/min; 7 min; Column temperature: 35° C.; Back pressure: 100 bar; Column: Daicel CHIRALPAK® AD, 10 μm, 20 mm×250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, compounds 18a (167 mg, 26% yield, 98.6% ee) as a white solid and 18b (230 mg, 35% yield, >99% ee) as a white solid; (R)-cyclopropyl(methyl)-λ.sup.6-sulfanone and (S)-cyclopropyl(methyl)-λ.sup.6-sulfanone

(66) 18a: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.87 (s, 1H), 6.67 (s, 1H), 6.00 (s, 2H), 5.90 (s, 1H), 4.44-4.34 (m, 1H), 4.02 (d, J=13.2 Hz, 1H), 3.92 (dd, J=11.3, 3.2 Hz, 1H), 3.77 (s, 3H), 3.72 (d, J=11.4 Hz, 1H), 3.60 (dd, J=11.3, 3.1 Hz, 1H), 3.55 (s, 3H), 3.45 (td, J=11.6, 2.6 Hz, 1H), 3.09 (td, J=12.7, 3.8 Hz, 1H), 3.06-2.94 (m, 1H), 1.25-1.19 (m, 1H), 1.16 (app. d, overlap, J=6.6 Hz, 3H), 1.14-1.02 (m, 3H); MS (ES.sup.+) C.sub.1-9H.sub.26N.sub.6O.sub.3S requires: 418, found: 419 [M+H].sup.+; R.sub.t=3.03 min.

(67) 18b: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 6.88 (d, J=1.2 Hz, 1H), 6.68 (d, J=1.1 Hz, 1H), 5.99 (s, 2H), 5.90 (s, 1H), 4.43-4.34 (m, 1H), 4.03 (d, J=13.3 Hz, 1H), 3.92 (dd, J=11.3, 3.6 Hz, 1H), 3.77 (s, 3H), 3.71 (d, J=11.3 Hz, 1H), 3.60 (dd, J=11.4, 3.1 Hz, 1H), 3.55 (s, 3H), 3.45 (td, J=11.8, 3.1 Hz, 1H), 3.09 (td, J=12.8, 3.8 Hz, 1H), 3.01 (tt, J=7.9, 4.9 Hz, 1H), 1.25-1.19 (m, 1H), 1.16 (app. d, overlap, J=6.7 Hz, 3H), 1.14-1.05 (m, 2H); MS (ES.sup.+) C.sub.19H.sub.26N.sub.6O.sub.3S requires: 418, found: 419 [M+H].sup.+; Rt=3.71 min.

(68) Alternatively, Example 18b can also be prepared from Int. CC, Isomer 1b.

EXAMPLE 19

(69) ##STR00200##

(R)-((2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

Step 1

(70) ##STR00201##

(71) (R)-((2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: A suspension of Int. K (278 mg, 1.00 mmol), Int. D (304 mg, 1.00 mmol), Na.sub.2CO.sub.3 (212 mg, 2.00 mmol) and PdCl.sub.2(dppf) (75 mg, 0.1 mmol) in dioxane (20 mL) and H.sub.2O (4 mL) was degassed with Ar (3×). The reaction mixture was heated to 80° C. and stirred for 16 h under an atmosphere of Ar. The mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified by Prep-TLC (66% EtOAc in petroleum ether) to afford the title compound (130 mg, 31% yield) as a white solid.

(72) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.98 (s, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 5.95 (s, 1H), 4.42 (s, 1H), 4.01 (dd, J=43.8, 11.0 Hz, 2H), 3.75 (d, J=11.2 Hz, 1H), 3.63 (d, J=9.8 Hz, 1H), 3.46 (d, J=22.0 Hz, 7H), 3.16 (d, J=12.4 Hz, 1H), 1.20 (d, J=6.6 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.21CN.sub.6O.sub.2S requires: 420, found: 421 [M+H].sup.+.

EXAMPLE 20

(73) ##STR00202##

(R)-4-(4-((dimethyl(oxo)-λ.SUP.6.-sulfanylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile

Step 1

(74) ##STR00203##

(75) (R)-4-(4-((dimethyl(oxo)-λ.sup.6-sulfanylidene)amino)-6-(3-methylmorpholino)-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile: A mixture of Example 19 (40 mg, 0.096 mmol), ZnCN.sub.2 (113 mg, 0.96 mmol) and Pd(PPh.sub.3).sub.4 (110 mg, 0.096 mmol) in DMF (3 mL) was degassed with Ar. The reaction mixture was heated at 150° C. for 2 h in a microwave reactor. The mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile Phase: A=10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B=MeCN; Gradient: B=35-65%; 18 min; 30 mL/min; column: Welch XB-C18 21.2×250 mm, 10 μm) to afford the title compound (13 mg, 33% yield) as a white solid.

(76) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.38 (s, 1H), 8.32 (s, 1H), 7.94 (s, 1H), 7.61 (d, J=3.0 Hz, 1H), 5.96 (s, 1H), 4.44 (s, 1H), 4.09 (d, J=12.5 Hz, 1H), 3.97 (d, J=8.5 Hz, 1H), 3.75 (d, J=11.5 Hz, 1H), 3.64 (d, J=8.7 Hz, 1H), 3.53-3.41 (m, 7H), 3.16 (t, J=10.9 Hz, 1H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.21N.sub.7O.sub.2S requires: 411, found: 412 [M+H].sup.+.

EXAMPLE 21

(77) ##STR00204##

(R)-dimethyl((2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

Step 1

(78) ##STR00205##

(79) (R)-dimethyl((2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methyl-morpholino)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: A mixture of Example 19 (30 mg, 0.07 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (9 mg, 0.07 mmol), PdCl.sub.2(dppf) (5 mg, 0.007 mmol) and Cs.sub.2CO.sub.3 (70 mg, 0.21 mmol) in dioxane (6 mL) and H.sub.2O (1 mL) was degassed with Ar and heated to 80° C. and stirred for 16 h. The reaction mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile Phase: A=10 mM NH.sub.4HCO.sub.3 in water, B=MeCN; Gradient: B=30-60%; 18 min; 30 mL/min; column: Welch XB-C18 21.2×250 mm, 10 μm) to afford the title compound (4 mg, 14% yield) as a white solid.

(80) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.50 (s, 1H), 7.75 (s, 1H), 7.41 (d, J=2.7 Hz, 1H), 7.33 (s, 1H), 5.91 (s, 1H), 4.44 (s, 1H), 4.07 (d, J=13.4 Hz, 1H), 3.96 (d, J=7.7 Hz, 1H), 3.75 (d, J=11.4 Hz, 1H), 3.64 (d, J=8.5 Hz, 1H), 3.50 (d, J=9.0 Hz, 1H), 3.44 (s, 6H), 2.59 (s, 3H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+.

EXAMPLE 22

(81) ##STR00206##

(R)-dimethyl((6-(3-methylmorpholino)-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

Step 1

(82) ##STR00207##

(83) (R)-dimethyl((6-(3-methylmorpholino)-2-(1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)pyrimidin-4-yl)imino)-16-sulfanone: A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine (60 mg, 0.12 mmol), Int. D (37 mg, 0.12 mmol), Na.sub.2CO.sub.3 (25 mg, 0.24 mmol) and PdCl.sub.2(dppf) (9.0 mg, 0.012 mmol) in dioxane (6 mL) and H.sub.2O (1 mL) was degassed with Ar (3×). The reaction mixture was heated to 80° C. and stirred for 16 h under an atmosphere of Ar. The reaction mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified by Prep-TLC (66% EtOAc in petroleum ether) to afford the title compound (45 mg, 60% yield) as a yellow oil.

(84) MS (ES.sup.+) C.sub.36H.sub.35N.sub.7O.sub.2S requires: 629, found: 630 [M+H].sup.+.

Step 2

(85) ##STR00208##

(86) (R)-dimethyl((6-(3-methylmorpholino)-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: A solution of the product from the previous step in TFA (1 mL) and CH.sub.2Cl.sub.2 (4 mL) was stirred at RT for 4 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase preparative HPLC (Mobile Phase: A=10 mM NH.sub.4HCO.sub.3 in water, B=MeCN; Gradient: B=25-65%; 18 min; 30 mL/min; column: Welch XB-C18 21.2×250 mm, 10 um) to afford the title compound (14 mg, 52% yield) as a pale yellow solid.

(87) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 13.72 (s, 1H), 8.93 (s, 1H), 8.64 (d, J=4.7 Hz, 1H), 7.99 (d, J=4.8 Hz, 1H), 5.98 (s, 1H), 4.46 (s, 1H), 4.08 (d, J=12.9 Hz, 1H), 3.97 (d, J=8.0 Hz, 1H), 3.76 (d, J=11.4 Hz, 1H), 3.64 (d, J=8.4 Hz, 1H), 3.53-3.43 (m, 7H), 3.22-3.07 (m, 1H), 1.21 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.17H.sub.21N.sub.7O.sub.2S requires: 387, found: 388 [M+H].sup.+.

EXAMPLE 23

(88) ##STR00209##

(R)-((2-(1H-indazol-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

(89) ##STR00210##

(90) (R)-((2-(1H-indazol-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-dimethyl-λ.sup.6-sulfanone: A mixture of Int. D (0.21 g, 0.69 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.27 g, 0.83 mmol), K.sub.3PO.sub.4 (0.44 g, 2.1 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (40 mg, 0.055 mmol) in dioxane (9 mL) and water (2 mL) was degassed with a stream of N.sub.2 for ten minutes and then heated to 85° C. for 4 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was partitioned between EtOAc (30 mL) and H.sub.2O (30 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (8 mL) and THF (2 mL) at room temperature and to this solution was added concentrated HCl solution (ca. 12 N, 0.1 mL). The reaction mixture was heated to 60° C. for 20 minutes then stirred at RT for 18 h. To the reaction mixture was added sat. aq. NaHCO.sub.3(3 mL) and the mixture was concentrated under reduced pressure. The residue was partitioned between CH.sub.2Cl.sub.2 (25 mL) and H.sub.2O (25 mL), the layers were separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (2×25 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced. The residue was purified via silica gel chromatography (10-30% CH.sub.3CN in CH.sub.2Cl.sub.2) to afford the title compound (0.26 g, quantitative yield) as a yellow solid.

(91) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.08 (d, J=0.75 Hz, 1H), 8.20 (dd, J=7.28, 1.00 Hz, 1H), 7.61 (d, J=8.28 Hz, 1H), 7.46 (dd, J=8.28, 7.28 Hz, 1H), 5.91 (s, 1H), 4.39-4.51 (m, 1H), 3.97-4.19 (m, 2H), 3.74-3.90 (m, 2H), 3.56-3.73 (m, 2H), 3.45 (d, J=1.51 Hz, 6H), 3.26-3.39 (m, 1H), 1.36 (d, J=6.78 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.22N.sub.6O.sub.2S requires: 386, found: 387 [M+H].sup.+.

EXAMPLE 24

(92) ##STR00211##

(R)-dimethyl((2-(2-(methylamino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

(93) ##STR00212##

(94) (R)-dimethyl((2-(2-(methylamino)pyridin-4-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: A microwave vial was charged with Int. L (100 mg, 0.42 mmol), Int. D (65 mg, 0.21 mmol), Na.sub.2CO.sub.3 (133 mg, 1.26 mmol), Pd(dppf)Cl.sub.2 (24 mg, 0.03 mmol), dioxane (3 mL) and H.sub.2O (1 mL). The vial was purged with N.sub.2 and sealed. The reaction mixture was heated at 80° C. for 3 h. The reaction mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=25-55%; 18 min; Column: Welch XB-C18, 10 μm, 150 Å, 21.2 mm×250 mm) to afford the title compound (8 mg, 10% yield) as a white solid.

(95) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.06 (d, J=5.2 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J=5.3 Hz, 1H), 6.67 (s, 1H), 5.87 (s, 1H), 4.42-4.36 (m, 1H), 4.07-4.01 (m, 1H), 3.92 (d, J=12.1 Hz, 1H), 3.72 (d, J=11.3 Hz, 1H), 3.61 (d, J=8.5 Hz, 1H), 3.45 (d, J=2.5 Hz, 6H), 3.31 (s, 1H), 3.09 (s, 1H), 2.80 (d, J=4.8 Hz, 3H), 1.16 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.17H.sub.24N.sub.6O.sub.2S requires: 376, found: 377 [M+H].sup.+.

EXAMPLE 25

(96) ##STR00213##

(R)-((2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

(97) ##STR00214##

(98) (R)-((2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: A microwave vial was charged with Int. V (34 mg, 0.06 mmol), 4-bromo-6-methoxy-1H-pyrrolo[2,3-b]pyridine (14 mg, 0.06 mmol), CuI (1.2 mg, 0.006 mmol), LiCl (5 mg, 0.12 mmol), Pd(PPh.sub.3).sub.4 (7 mg, 0.006 mmol) and DMF (5 mL). The vial was purged with Ar, sealed and heated at 120° C. for 2 h in a microwave reactor. The reaction mixture was cooled to RT, sat. aq. KF (10 mL) was added and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=40-70%; 18 min; Column: Welch XB-C18, 10 μm, 21.2×250 mm) to afford the title compound (5 mg, 20% yield) as a white solid.

(99) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.55 (s, 1H), 7.35 (s, 1H), 7.26 (d, J=11.3 Hz, 2H), 5.92 (s, 1H), 4.43 (s, 1H), 4.03 (d, J=12.7 Hz, 1H), 3.95 (d, J=7.6 Hz, 1H), 3.91 (s, 3H), 3.75 (d, J=11.2 Hz, 1H), 3.63 (d, J=8.8 Hz, 1H), 3.46 (d, J=21.0 Hz, 7H), 3.14 (t, J=11.0 Hz, 1H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.3S requires: 416, found: 417 [M+H].sup.+.

EXAMPLE 26

(100) ##STR00215##

(R)-((2-(3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

(101) ##STR00216##

(102) (R)-((2-(3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: A microwave vial was charged with Int. V (150 mg, 0.268 mmol), Int. M (170 mg, 0.35 mmol), LiCl (23 mg, 0.54 mmol), CuI (5 mg, 0.027 mmol), Pd(PPh.sub.3).sub.4 (31 mg, 0.027 mmol) and DMF (2 mL). The reaction vial was degassed by bubbling Ar into it the solution, sealed and heated to 120° C. for 90 min. a microwave reactor. The reaction was resubmitted to the microwave cycle until it was judged completed by LCMS with new palladium catalyst added and the reaction vial degassed with Ar prior to each cycle. The reaction mixture was diluted with EtOAc (20 mL), filtered through CELITE®, and concentrated under reduced pressure. The residue was taken up in a 1 N HCl (10 mL) and washed with Et.sub.2O (5 mL) and hexanes (5 mL). The aqueous layer was then adjusted to pH >12 with 2 M aq. NaOH and extracted with CH.sub.2Cl.sub.2 (3×5 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Mobile phase: A=0.1% HCO.sub.2H/H.sub.2O, B=0.1% HCO.sub.2H/MeCN; Gradient: B=0-30%; 15 min; Column: Biotage SNAP Ultra C18 30 g, HP-Sphere C18 25 μm). The combined fractions were treated with 0.1 M aq. HCl, concentrated under reduced pressure and lyophilized to afford the titled compound (33.2 mg, 32% yield) as a white solid.

(103) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.71 (d, J=5.27 Hz, 1H) 8.52 (s, 1H) 8.16 (d, J=5.02 Hz, 1H) 5.91 (s, 1H) 4.36-4.52 (m, 1H) 4.13-4.25 (m, 1H) 4.08 (br dd, J=11.54, 3.76 Hz, 1H) 3.82-3.91 (m, 1H) 3.79 (br d, J=2.76 Hz, 1H) 3.64 (br d, J=3.01 Hz, 1H) 3.46-3.52 (m, 1H) 3.43 (s, 6H) 3.29-3.39 (m, 1H) 1.37 (d, J=6.78 Hz, 3H); MS (ES.sup.+) C.sub.17H.sub.21N.sub.7O.sub.2S requires: 387, found: 388 [M+H].sup.+.

EXAMPLE 27

(104) ##STR00217##

(R)-((2-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

Step 1

(105) ##STR00218##

(106) (R)-((2-(2-cyclopropyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: A mixture of Int. U (50 mg, 0.13 mmol), Int. V (72 mg, 0.13 mmol), CuI (2 mg, 0.013 mmol), LiCl (3 mg, 0.26 mmol), Pd(PPh.sub.3).sub.4 (15 mg, 0.013 mmol) and DMF (5 mL) was degassed with Ar (3×) and then heated at 120° C. for 2 h in a microwave reactor. The mixture was cooled to RT, sat. aq. Na.sub.2S.sub.2O.sub.3 (10 mL) was added, the layers were separated and the aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% EtOAc in hexanes) to afford the title compound (30 mg, 40% yield) as a yellow solid.

(107) MS (ES.sup.+) C.sub.28H.sub.32N.sub.6O.sub.4S.sub.2 requires: 580, found: 581 [M+H].sup.+.

Step 2

(108) ##STR00219##

(109) (R)-((2-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: A mixture of the product from the previous step (30 mg, 0.05 mmol), NaOH (4 mg, 0.1 mmol), H.sub.2O (1 mL) and MeOH (3 mL) was heated at 60° C. and stirred for 2 h. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=45-75; 15 min; Column: Welch XB-C18, 10 μm, 21.2×250 mm) to afford the title compound (2 mg, 10% yield) as a white solid.

(110) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.58 (s, 1H), 8.14 (d, J=5.0 Hz, 1H), 7.80 (d, J=5.0 Hz, 1H), 7.11 (s, 1H), 5.88 (s, 1H), 4.44 (s, 1H), 4.04 (d, J=12.9 Hz, 1H), 3.95 (d, J=10.9 Hz, 1H), 3.74 (d, J=11.4 Hz, 1H), 3.63 (d, J=8.2 Hz, 1H), 3.46 (d, J=25.8 Hz, 7H), 2.03 (s, 1H), 1.20 (d, J=6.7 Hz, 3H), 1.06-0.97 (m, 2H), 0.86 (d, J=3.0 Hz, 2H); MS (ES.sup.+) C.sub.21H.sub.26N.sub.6O.sub.2S requires: 426, found: 427 [M+H].sup.+.

EXAMPLE 28

(111) ##STR00220##

(R)-dimethyl((2-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

Step 1

(112) ##STR00221##

(113) (R)-((2-(2,3-diaminopyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: A microwave vial was charged with Int. J (450 mg crude, assumed 1.07 mmol), Int. D (250 mg, 0.82 mmol), Na.sub.2CO.sub.3 (260 mg, 2.46 mmol), Pd(dppf)Cl.sub.2 (48 mg, 0.06 mmol), dioxane (12 mL) and H.sub.2O (4 mL). The vial was purged with N.sub.2 and sealed. The reaction mixture was heated at 80° C. and stirred for 3 h. The reaction mixture was cooled to RT, filtered through CELITE®, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-15% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (350 mg, 100% yield) as a brown solid.

(114) MS (ES.sup.+) C.sub.16H.sub.23N.sub.7O.sub.2S requires: 377, found: 378 [M+H].sup.+.

Step 2

(115) ##STR00222##

(116) (R)-dimethyl((2-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methyl-morpholino)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: A mixture of the product from the previous step (150 mg, 0.4 mmol), HOAc (0.2 mL) and PPA (1 g) were charged in a 20 mL microwave vial and purged with N.sub.2 for 1 min. The vial was sealed and heated at 150° C. for 1.5 h. The reaction mixture was cooled to RT, sat. aq. K.sub.2CO.sub.3 (30 mL) was added and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B═MeCN; Gradient: B=25-55%; 18 min; Column: Welch XB-C18, 10 μm, 150 Å, 21.2 mm×250 mm) to afford the title compound (20 mg, 12% yield) as a white solid.

(117) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.99 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 7.89 (d, J=5.1 Hz, 1H), 5.97 (s, 1H), 4.47 (s, 1H), 4.14 (s, 1H), 3.95 (d, J=11.1 Hz, 1H), 3.74 (d, J=11.5 Hz, 1H), 3.63 (d, J=8.3 Hz, 1H), 3.47 (s, 7H), 3.19-3.11 (m, 1H), 2.58 (s, 3H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.23N.sub.7O.sub.2S requires: 401, found: 402 [M+H].sup.+.

EXAMPLE 29

(118) ##STR00223##

(R)-((2-(2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

(119) ##STR00224##

(120) (R)-((2-(2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: A reaction vial was charged with Int. D (120 mg, 0.39 mmol), 2-cyclopropyl-1H-benzo[d]imidazole (94 mg, 0.59 mmol), Pd.sub.2dba.sub.3 (18 mg, 0.02 mmol), XPhos (16 mg, 0.04 mmol), Cs.sub.2CO.sub.3 (380 mg, 1.17 mmol) and dioxane (6 mL). The vial was purged with N.sub.2 for 2 min., sealed and heated to 150° C. for 1 h in a microwave reactor. The reaction mixture was cooled to RT, filtered through CELITE®, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=40-70%; 15 min; Column: Agela C18, 10 μm, 150 Å, 21.2 mm×250 mm) to afford the title compound (83.0 mg, 50% yield) as a white solid.

(121) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.10 (dd, J=6.8, 2.3 Hz, 1H), 7.53 (dd, J=6.5, 2.2 Hz, 1H), 7.24-7.14 (m, 2H), 5.93 (s, 1H), 4.36 (s, 1H), 3.94 (dd, J=16.4, 8.5 Hz, 2H), 3.72 (d, J=11.4 Hz, 1H), 3.61 (dd, J=11.4, 2.9 Hz, 1H), 3.50-3.44 (m, 1H), 3.42 (s, 6H), 3.17 (td, J=13.0, 3.9 Hz, 1H), 3.09-3.01 (m, 1H), 1.21 (d, J=6.7 Hz, 3H), 1.17-1.11 (m, 2H), 1.09-1.02 (m, 2H); MS (ES.sup.+) C.sub.18H.sub.22N.sub.6O.sub.2S requires: 426, found: 427 [M+H].sup.+.

EXAMPLE 30

(122) ##STR00225##

(R)-dimethyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

(123) ##STR00226##

(124) (R)-dimethyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: A microwave vial was charged with Int. D (50 mg, 0.165 mmol), 2-methylbenzimidazole (44 mg, 0.329 mmol), XPhos Pd G2 (6.5 mg, 0.008 mmol) and K.sub.3PO.sub.4 (70 mg, 0.329 mmol). The vial was sealed, purged with Ar, dioxane (2 mL) was added and the solution was degassed by bubbling Ar and the resulting mixture was heated in at 150° C. for 1 h in a microwave reactor. The reaction mixture was cooled to RT, filtered through CELITE®, washed with CH.sub.2Cl.sub.2 and concentrated under reduced pressure. The residue was purified by flash chromatography (1-5% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (62 mg, 94% yield) as a white solid.

(125) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.22-8.39 (m, 1H) 7.63-7.89 (m, 1H) 7.30-7.54 (m, 2H) 5.86 (s, 1H) 4.25-4.41 (m, 1H) 4.05 (dd, J=11.54, 3.76 Hz, 1H) 3.90-3.98 (m, 1H) 3.70-3.89 (m, 2H) 3.53-3.68 (m, 1H) 3.26-3.51 (m, 7H) 3.06 (s, 3H) 1.36 (d, J=6.78 HZ, 3H) 1.10-1.32 (M, 1H) 0.91 (S, 1H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S REQUIRES: 400, FOUND: 401 [M+H].sup.+.

EXAMPLE 31

(126) ##STR00227##

Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

(127) Synthesis is similar to that described for Example 11, using Int. I.

(128) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.72 (s, 1H), 9.02 (d, J=2.3 Hz, 1H), 8.79 (s, 1H), 7.67 (t, J=2.7 Hz, 1H), 7.45 (s, 1H), 5.90 (s, 1H), 4.46 (s, 1H), 4.04 (s, 1H), 3.96 (d, J=7.8 Hz, 1H), 3.75 (d, J=11.4 Hz, 1H), 3.64 (d, J=10.5 Hz, 1H), 3.51 (dd, J=32.0, 6.9 Hz, 4H), 3.14 (s, 1H), 3.01 (d, J=7.6 Hz, 1H), 1.21 (t, J=7.1 Hz, 5H), 1.09 (d, J=7.8 Hz, 2H); MS (ES.sup.+) C.sub.20H.sub.24N.sub.6O.sub.2S requires: 412, found: 413 [M+H].sup.+.

EXAMPLE 32

(129) ##STR00228##

(S)-((6-(3-(fluoromethyl)morpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

(130) Synthesis is similar to that described for Example 11, using Int. O and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine.

(131) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.35 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.01 (d, J=5.1 Hz, 1H), 7.61-7.41 (m, 2H), 5.94 (s, 1H), 5.26-5.02 (m, 1H), 4.53 (s, 1H), 4.31-3.96 (m, 3H), 3.83-3.61 (m, 4H), 3.44 (d, J=4.8 Hz, 6H); MS (ES.sup.+) C.sub.18H.sub.21FN.sub.6O.sub.2S requires: 404, found: 405 [M+H].sup.+.

EXAMPLE 33

(132) ##STR00229##

(S)-((6-(3-(difluoromethyl)morpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

(133) Synthesis is similar to that described for Example 11, using Int. W and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine.

(134) .sup.1H NMR (400 MHz, Methanol-d4) δ 8.28 (d, J=5.1 Hz, 1H), 7.99 (d, J=5.2 Hz, 1H), 7.51 (dd, J=21.8, 3.5 Hz, 2H), 6.34 (td, J=56.1, 5.7 Hz, 1H), 6.06 (s, 1H), 4.25 (d, J=12.3 Hz, 1H), 4.06 (dd, J=11.4, 3.6 Hz, 2H), 3.78 (dd, J=12.3, 3.2 Hz, 1H), 3.67 (td, J=11.8, 3.1 Hz, 1H), 3.49 (t, J=7.2 Hz, 7H), 3.43 (dd, J=12.7, 3.8 Hz, 1H), 3.34 (s, 2H), 3.32 (s, 2H); MS (ES.sup.+) C.sub.18H.sub.20F.sub.2N.sub.6O.sub.2S requires: 422, found: 423 [M+H].sup.+.

EXAMPLE 34

(135) ##STR00230##

(R)-((2-(4-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

Step 1

(136) ##STR00231##

(137) (R)-((2-((3-fluoro-2-nitrophenyl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone A reaction vial was charged with Int. D (250 mg, 0.82 mmol), 3-fluoro-2-nitroaniline (192 mg, 1.23 mmol), Pd.sub.2dba.sub.3 (38 mg, 0.041 mmol), XPhos (35 mg, 0.082 mmol), Cs.sub.2CO.sub.3 (800 mg, 2.47 mmol) and dioxane (10 mL). The vial was purged with N.sub.2 for 2 min. and the reaction mixture was heated at 100° C. and stirred for 16 h. The reaction mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified via silica gel chromatography (50-75% EtOAc in hexanes) to afford the title compound (290 mg, 74% yield) as an orange solid.

(138) MS (ES.sup.+) C.sub.17H.sub.21FN.sub.6O.sub.4S requires: 424, found: 425 [M+H].sup.+.

Step 2

(139) ##STR00232##

(140) (R)-((2-((2-amino-3-fluorophenyl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: A reaction vessel was charged with the product from the previous step (280 mg, 0.66 mmol), 10% Pd/C (50 mg, 0.047 mmol) and EtOH (40 mL) under an atmosphere of N.sub.2. The suspension was degassed with N.sub.2 for 1 minute and purged with H.sub.2 for 1 minute. The reaction mixture was stirred under an atmosphere of H.sub.2 at 1 atm for 2 h. The reaction mixture was purged with N.sub.2, filtered through CELITE® and concentrated under reduced pressure to afford the title compound (260 mg, quantitative yield) as a red solid.

(141) MS (ES.sup.+) C.sub.17H.sub.23FN.sub.6O.sub.2S requires: 394, found: 395 [M+H].sup.+.

Step 3

(142) ##STR00233##

(143) (R)-((2-(4-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone A mixture of the product from the previous step (260 mg, 0.66 mmol) and acetic acid (132 mg, 2.21 mmol) in PPA (5 g) was heated at 150° C. for 3 h. The reaction was cooled to RT, diluted with water (50 mL) and 5 N aq. NaOH was added to adjust to pH=14. The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3 in water, B=MeCN; Gradient: B=35-65%; 15 min; Column: Agela C18, 10 μm, 150 Å, 21.2 mm×250 mm) to afford the title compound (146 mg, 53% yield) as a yellow solid.

(144) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.10 (d, J=8.2 Hz, 1H), 7.19 (td, J=8.2, 5.1 Hz, 1H), 7.06 (dd, J=10.6, 8.1 Hz, 1H), 5.92 (s, 1H), 4.35 (s, 1H), 4.03-3.85 (m, 2H), 3.72 (d, J=11.4 Hz, 1H), 3.61 (dd, J=11.4, 2.9 Hz, 1H), 3.47 (td, J=11.9, 3.0 Hz, 1H), 3.40 (d, J=2.1 Hz, 6H), 3.17 (td, J=12.9, 3.8 Hz, 1H), 2.85 (s, 3H), 1.21 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.23FN.sub.6O.sub.2S requires: 418, found: 419 [M+H].sup.+.

EXAMPLE 35

(145) ##STR00234##

(R)-1-(4-((dimethyl(oxo)-λ.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-1H-benzo[d]imidazole-6-carbonitrile

Step 1

(146) ##STR00235##

(147) (R)-4-amino-3-((4-((dimethyl(oxo)-λ.sup.6-sulfaneylidene)amino)-6-(3-methyl-morpholino)pyrimidin-2-yl)amino)benzonitrile: To a solution of (R)-3-((4-((dimethyl(oxo)-λ.sup.6-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)amino)-4-nitrobenzonitrile (synthesis is similar to that described for Example 34, step 1) (110 mg, 0.255 mmol) in EtOH (1.3 mL) were added ammonium chloride (54.5 mg, 1.02 mmol), water (425 μL), and iron (56.9 mg, 1.02 mmol) and the resulting mixture was stirred at 100° C. for 3 h. The reaction mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified via silica gel chromatography (5-20% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (83 mg, 81% yield) as a yellow solid.

(148) MS (ES.sup.+) C.sub.18H.sub.23N.sub.7O.sub.2S requires: 401, found: 402 [M+H].sup.+.

Step 2

(149) ##STR00236##

(150) (R)-1-(4-((dimethyl(oxo)-λ.sup.6-sulfaneylidene)amino)-6-(3-methylmorpholino)-pyrimidin-2-yl)-1H-benzo[d]imidazole-6-carbonitrile: To a solution of the product from the previous step (30 mg, 0.037 mmol) in toluene (75 μL) were added triethyl orthoformate (12 μL, 0.075 mmol) and Ts-OH hydrate (0.71 mg, 3.7 μmol) and the resulting mixture was heated at 110° C. and stirred for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 16 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (7.9 mg, 33% yield) as a white solid.

(151) .sup.1H NMR (600 MHz, Methanol-d4) δ 9.36 (s, 1H), 9.25-9.22 (m, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.69 (dd, J=8.4, 1.6 Hz, 1H), 5.91 (s, 1H), 4.47-4.39 (m, 1H), 4.08-3.98 (m, 2H), 3.82 (d, J=11.5 Hz, 1H), 3.75 (dd, J=11.5, 3.2 Hz, 1H), 3.60 (td, J=12.0, 3.2 Hz, 1H), 3.46 (s, 6H), 3.33-3.27 (m, overlap MeOH, 1H), 1.33 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.21N.sub.7O.sub.2S requires: 411, found: 412 [M+H].sup.+.

EXAMPLE 36

(152) ##STR00237##

(R)-dimethyl((2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

(153) ##STR00238##

(154) (R)-dimethyl((2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: To a suspension of (R)-((2-((2-aminopyridin-3-yl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone (synthesis is similar to that described for Example 34, step 2) (38 mg, 0.10 mmol) in triethyl orthoacetate (4 mL) was added p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol) and the resulting mixture was heated to 50° C. for 16 h. The reaction mixture was cooled to RT and directly purified by flash chromatography (0-10% MeOH in CH.sub.2Cl.sub.2 with 0.5% of aq. NH.sub.4OH) to afford the title compound (20 mg, 0.05 mmol) as a solid.

(155) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.63-8.83 (m, 1H) 8.52 (dd, J=4.77, 1.25 Hz, 1H) 7.20-7.34 (m, 2H) 5.82 (s, 1H) 4.17-4.39 (m, 1H) 4.04 (dd, J=11.54, 3.51 Hz, 1H) 3.91 (br d, J=12.30 Hz, 1H) 3.82 (d, J=11.54 Hz, 1H) 3.73 (dd, J=11.54, 3.01 Hz, 1H) 3.59 (td, J=11.86, 3.14 Hz, 1H) 3.27-3.45 (m, 7H) 3.04 (s, 3H) 1.34 (d, J=7.03 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.23N.sub.7O.sub.2S requires: 401, found: 402 [M+H].sup.+.

EXAMPLE 37

(156) ##STR00239##

((2-(2-Aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ.SUP.6.-sulfanone

Step 1

(157) ##STR00240##

(158) ((2-Chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ.sup.6-sulfanone: To a solution of (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized as described, Int. B, step 1) (4.6 g, 18.5 mmol) and Int. F (2.5 g, 18.5 mmol) in dioxane (80 mL) was added Pd.sub.2(dba).sub.3 (850 mg, 0.925 mmol), XantPhos (2.14 g, 3.7 mmol) and K.sub.2CO.sub.3(6.4 g, 46 mmol) under an atmosphere of N.sub.2 and the resulting mixture was heated at 90° C. and stirred for 4 h. The reaction mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified via silica gel chromatography (25-70% EtOAc in hexanes) to afford the title compound (1.8 g, 28% yield) as a white solid.

(159) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 5.86 (s, 1H), 5.07-4.74 (m, 5H), 4.23 (s, 1H), 3.87 (dd, J=11.3, 3.5 Hz, 2H), 3.65 (d, J=11.5 Hz, 1H), 3.53 (dd, J=11.5, 2.9 Hz, 1H), 3.43-3.31 (m, 4H), 3.05 (d, J=3.6 Hz, 1H), 1.12 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.13H.sub.19CN.sub.4O.sub.3S requires: 346, found: 347 [M+H].sup.+.

Step 2

(160) ##STR00241##

(161) ((2-(2-Aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)-(methyl)(oxetan-3-yl)-λ.sup.6-sulfanone: To a solution of the product from the previous step (120 mg, 0.34 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (61 mg, 0.51 mmol) in dioxane (4 mL) and H.sub.2O (1 mL) were added Pd(dppf)Cl.sub.2 (25 mg, 0.034 mmol) and K.sub.2CO.sub.3 (141 mg, 1.02 mmol) under an atmosphere of N.sub.2 and the resulting mixture was heated at 90° C. and stirred for 16 h. The reaction mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A=10 mM NH.sub.4HCO.sub.3/H.sub.2O, B=MeCN; Gradient: B=20-50%; 18 min; Column: Agela C18, 10 μm, 150 Å, 21.2 mm×250 mm) to afford the title compound (42 mg, 31% yield) as a white solid.

(162) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.99 (d, J=5.2 Hz, 1H), 7.50-7.03 (m, 2H), 5.97 (d, J=58.0 Hz, 3H), 5.10-4.75 (m, 5H), 4.49-4.26 (m, 1H), 4.15-3.97 (m, 1H), 3.95-3.88 (m, 1H), 3.71 (d, J=11.3 Hz, 1H), 3.60 (dd, J=11.4, 2.8 Hz, 1H), 3.52 (d, J=2.0 Hz, 3H), 3.45 (s, 1H), 3.10 (d, J=3.5 Hz, 1H), 1.16 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.24N.sub.6O.sub.3S requires: 404, found: 405 [M+H].sup.+.

EXAMPLES 38a and 38b

(163) ##STR00242##

(R)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ.SUP.6.-sulfanone

and

(164) ##STR00243##

(S)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ.SUP.6.-sulfanone

(165) Synthesis is similar to that described for Example 29, using the intermediate from the first step of the Example 37 procedure. The mixture of diastereomers (56 mg, 0.13 mmol) was separated by Chiral SFC (Mobile phase: CO.sub.2/MeOH (0.2% MeOH Ammonia)=55/45; Flow rate: 80 g/min; 6.3 min; Column temperature: 35° C.; Back pressure: 100 bar; Column: Daicel CHIRALPAK® OJ, 10 μm, 20 mm×250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 38a (14 mg, 25% yield, >99% ee) as a white solid and 38b (15 mg, 27% yield, >99% ee) as a white solid.

(166) 38a ((R)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone): .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.09-8.93 (m, 1H), 8.68-8.50 (m, 1H), 7.81-7.66 (m, 1H), 7.44-7.25 (m, 2H), 5.96-5.86 (m, 1H), 5.06 (dd, J=7.0, 1.1 Hz, 1H), 5.00-4.84 (m, 4H), 4.53-4.36 (m, 1H), 4.12-4.00 (m, 1H), 3.99-3.90 (m, 1H), 3.76-3.70 (m, 1H), 3.68-3.58 (m, 1H), 3.50 (dd, J=19.4, 1.5 Hz, 4H), 3.18 (d, J=3.6 Hz, 1H), 1.24-1.18 (m, 3H); MS (ES.sup.+) C.sub.20H.sub.24N.sub.6O.sub.3S requires: 428, found: 429 [M+H].sup.+; R.sub.t=0.95 min.

(167) 38b ((R)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone): .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.02 (s, 1H), 8.60 (d, J=8.0 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.49-7.20 (m, 2H), 5.92 (s, 1H), 5.11-5.01 (m, 1H), 4.99-4.85 (m, 4H), 4.47-4.39 (m, 1H), 4.15-4.02 (m, 1H), 3.99-3.91 (m, 1H), 3.72 (s, 1H), 3.66-3.59 (m, 1H), 3.51 (s, 4H), 3.23-3.11 (m, 1H), 1.22 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.2H.sub.24N.sub.6O.sub.3S requires: 428, found: 429 [M+H].sup.+; R.sub.t=1.31 min.

EXAMPLES 39a and 39b

(168) ##STR00244##

(R)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ.SUP.6.-sulfanone

and

(169) ##STR00245##

(S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ.SUP.6.-sulfanone

(170) Synthesis is similar to that described for Example 24. The mixture of diastereomers (26.8 mg, 0.069 mmol) was separated by Chiral SFC (Mobile phase: n-hexane (0.1% DEA):EtOH (0.1% DEA)=70:30; Flow rate: 80 g/min; 20 min; Column temperature: 35° C.; Back pressure: 100 bar; Column: Gilson-281, AY 20×250 mm, 10 μm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 39a (6.6 mg, 25% yield, >99% ee) as a white solid and 39b (7.1 mg, 27% yield, >99% ee) as a white solid.

(171) 39a ((R)-cyclopropyl(methyl)-λ.sup.6-sulfanone or (S)-cyclopropyl(methyl)-λ.sup.6-sulfanone): .sup.1H NMR (500 MHz, CD.sub.3OD) δ 8.03-7.91 (m, 1H), 7.53 (s, 1H), 7.49 (dd, J=5.5, 1.4 Hz, 1H), 5.97 (s, 1H), 4.48 (d, J=4.6 Hz, 1H), 4.11 (d, J=12.0 Hz, 1H), 4.02 (dd, J=11.3, 3.6 Hz, 1H), 3.82 (d, J=11.4 Hz, 1H), 3.75 (dd, J=11.5, 3.0 Hz, 1H), 3.65-3.56 (m, 4H), 3.25 (td, J=12.8, 3.8 Hz, 1H), 3.01 (td, J=7.9, 4.0 Hz, 1H), 1.42 (dd, J=10.2, 5.4 Hz, 1H), 1.31 (dd, J=11.1, 6.2 Hz, 4H), 1.20 (dt, J=11.3, 5.7 Hz, 2H); MS (ES.sup.+) C.sub.18H.sub.24N.sub.6O.sub.2S requires: 388, found: 389 [M+H].sup.+; R.sub.t=11.35 min.

(172) 39b ((R)-cyclopropyl(methyl)-λ.sup.6-sulfanone or (S)-cyclopropyl(methyl)-λ.sup.6-sulfanone): .sup.1H NMR (500 MHz, CD.sub.3OD) δ 7.97 (d, J=5.4 Hz, 1H), 7.53 (s, 1H), 7.49 (dd, J=5.5, 1.3 Hz, 1H), 5.97 (s, 1H), 4.50 (s, 1H), 4.08 (d, J=12.7 Hz, 1H), 4.02 (dd, J=11.4, 3.7 Hz, 1H), 3.82 (d, J=11.3 Hz, 1H), 3.75 (dd, J=11.4, 3.0 Hz, 1H), 3.66-3.55 (m, 4H), 3.25 (td, J=12.9, 3.9 Hz, 1H), 3.05-2.97 (m, 1H), 1.41 (dd, J=10.6, 5.2 Hz, 1H), 1.31 (dd, J=11.8, 5.8 Hz, 4H), 1.20 (dt, J=11.1, 5.6 Hz, 2H); MS (ES.sup.+) C.sub.18H.sub.24N.sub.6O.sub.2S requires: 388, found: 389 [M+H].sup.+; R.sub.t=15.22 min.

(173) Alternatively, Example 39a can also be prepared from Int. CC, Isomer 1b.

EXAMPLES 40a and 40b

(174) ##STR00246##

(R)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ.SUP.6.-sulfanone

and

(175) ##STR00247##

(S)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ.SUP.6.-sulfanone

(176) Synthesis is similar to that described for Example 29. The mixture of diastereomers (31 mg, 0.075 mmol) was separated by Chiral SFC (Mobile phase: CO.sub.2/MeOH (0.2% MeOH Ammonia)=50/50; Flow rate: 80 g/min; 10 min; Column temperature: 35° C.; Back pressure: 100 bar; Column: Daicel CHIRALPAK® OD, 10 μm, 20 mm×250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 40a (6.0 mg, 19% yield, >99% ee) as a white solid and 40b (5.0 mg, 16% yield, >98% ee) as a white solid.

(177) 40a ((R)-cyclopropyl(methyl)-λ.sup.6-sulfanone or (S)-cyclopropyl(methyl)-λ.sup.6-sulfanone): .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.01 (s, 1H), 8.60 (d, J=7.7 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.33 (dd, J=13.5, 7.5 Hz, 2H), 5.90 (s, 1H), 4.53-4.29 (m, 1H), 3.95 (d, J=7.7 Hz, 2H), 3.74 (d, J=11.2 Hz, 1H), 3.63 (d, J=11.3 Hz, 1H), 3.50 (d, J=19.7 Hz, 4H), 3.17 (s, 1H), 3.04 (s, 1H), 1.22 (d, J=6.7 Hz, 5H), 1.13 (d, J=19.3 Hz, 2H); MS (ES.sup.+) C.sub.2H.sub.24N.sub.6O.sub.2S requires: 412, found: 413 [M+H].sup.+; R.sub.t=3.50 min.

(178) 40b ((R)-cyclopropyl(methyl)-λ.sup.6-sulfanone or (S)-cyclopropyl(methyl)-λ.sup.6-sulfanone): .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.01 (s, 1H), 8.60 (d, J=7.7 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.33 (ddd, J=15.1, 13.9, 6.7 Hz, 2H), 5.90 (s, 1H), 4.42 (s, 1H), 4.04 (s, 1H), 3.95 (dd, J=11.3, 3.4 Hz, 1H), 3.74 (d, J=11.4 Hz, 1H), 3.63 (dd, J=11.5, 2.9 Hz, 1H), 3.55-3.45 (m, 4H), 3.22-3.14 (m, 1H), 3.10-3.01 (m, 1H), 1.28-1.18 (m, 5H), 1.17-1.07 (m, 2H); MS (ES.sup.+) C.sub.20H.sub.24N.sub.6O.sub.2S requires: 412, found: 413 [M+H].sup.+; Rt=4.44 min.

(179) Alternatively, Example 40b can also be prepared from Int. CC, Isomer 1b.

EXAMPLES 41a and 41b

(180) ##STR00248##

(R)-methyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(oxetan-3-yl)-λ.SUP.6.-sulfanone

and

(181) ##STR00249##

(S)-methyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(oxetan-3-yl)-λ.SUP.6.-sulfanone

(182) Synthesis is similar to that described for Example 29. The mixture of diastereomers (45 mg, 0.1 mmol) was separated by Chiral SFC (Mobile phase: n-Hexane (0.1% DEA): IPA (0.1% DEA)=35:65; Flow rate: 80 g/min; 20 min; Column temperature: 35° C.; Back pressure: 100 bar; Column: Gilson-281, sc 20×250 mm, 10 μm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 41a (7.0 mg, 16% yield, 99% ee) as a white solid and 41b (4.0 mg, 9.0% yield, >93% ee) as a white solid.

(183) 41a ((R)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone): .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.24 (dd, J=6.1, 3.1 Hz, 1H), 7.58 (dd, J=6.0, 3.0 Hz, 1H), 7.29-7.15 (m, 2H), 6.02-5.86 (m, 1H), 4.89 (dddd, J=17.8, 15.5, 7.8, 6.8 Hz, 5H), 4.40 (s, 1H), 3.92 (d, J=11.3 Hz, 2H), 3.72 (d, J=11.4 Hz, 1H), 3.65-3.55 (m, 1H), 3.44 (dd, J=15.6, 5.9 Hz, 4H), 3.22-3.12 (m, 1H), 2.88-2.77 (m, 3H), 1.29-1.12 (m, 3H); MS (ES.sup.+) C.sub.21H.sub.26N.sub.6O.sub.3S requires: 442, found: 443 [M+H].sup.+; R.sub.t=13.15 min.

(184) 41b ((R)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone): .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.30-8.15 (m, 1H), 7.66-7.51 (m, 1H), 7.23 (dd, J=6.0, 3.2 Hz, 2H), 5.95 (s, 1H), 4.84 (s, 5H), 4.41-4.30 (m, 1H), 4.03-3.88 (m, 2H), 3.75-3.67 (m, 1H), 3.64-3.58 (m, 1H), 3.42 (s, 4H), 3.23-3.12 (m, 1H), 2.83 (s, 3H), 1.20 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.21H.sub.26N.sub.6O.sub.3S requires: 442, found: 443[M+H].sup.+; R.sub.t=17.06 min.

EXAMPLES 42a and 42b

(185) ##STR00250##

(R)-((2-(2-amino-6-chloropyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ.SUP.6.-sulfanone

and

(186) ##STR00251##

(S)-((2-(2-amino-6-chloropyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ.SUP.6.-sulfanone

(187) Synthesis is similar to that described for Example 24. The mixture of diastereomers (100 mg, 0.18 mmol) was separated by Chiral SFC (Mobile phase: CO.sub.2/ethanol (1% MeOH Ammonia)=40/60; Flow rate: 80 g/min; 12 min; Column temperature: 35° C.; Back pressure: 100 bar; Column: Daicel CHIRALPAK® OJ, 10 μm, 20 mm×250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 42a (13 mg, 20% yield, >99% ee) as a white solid and 42b (20 mg, 31% yield, 96.7% ee) as a yellow solid.

(188) 42a ((R)-cyclopropyl(methyl)-λ.sup.6-sulfanone or (S)-cyclopropyl(methyl)-λ.sup.6-sulfanone): .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 7.41 (s, 2H), 5.97 (s, 1H), 4.45 (s, 1H), 4.05 (dd, J=29.3, 11.7 Hz, 2H), 3.82 (d, J=11.6 Hz, 1H), 3.74 (d, J=8.8 Hz, 1H), 3.63-3.55 (m, 4H), 3.26-3.21 (m, 1H), 3.02-2.95 (m, 1H), 1.41 (s, 1H), 1.31 (dd, J=11.6, 5.8 Hz, 4H), 1.20 (d, J=7.5 Hz, 2H); MS (ES.sup.+) C.sub.18H.sub.23ClN.sub.6O.sub.2S requires: 422, found: 423 [M+H].sup.+; R.sub.t=4.27 min.

(189) 42b ((R)-cyclopropyl(methyl)-λ.sup.6-sulfanone or (S)-cyclopropyl(methyl)-λ.sup.6-sulfanone): .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 7.25 (d, J=1.7 Hz, 2H), 5.88 (s, 1H), 4.36 (d, J=4.8 Hz, 1H), 4.00-3.86 (m, 2H), 3.70 (d, J=11.5 Hz, 1H), 3.62 (dd, J=11.5, 2.8 Hz, 1H), 3.52-3.43 (m, 4H), 3.18-3.10 (m, 1H), 2.92-2.83 (m, 1H), 1.31 (dd, J=11.3, 5.6 Hz, 1H), 1.22-1.17 (m, 4H), 1.09 (dd, J=9.5, 5.3 Hz, 2H); MS (ES.sup.+) C.sub.18H.sub.23ClN.sub.6O.sub.2S requires: 422, found: 423 [M+H].sup.+; Rt=5.48 min.

(190) Alternatively, Example 42a can also be prepared from Int. CC, Isomer 1b.

EXAMPLES 43a and 43b

(191) ##STR00252##

(R)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ.SUP.6.-sulfanone

and

(192) ##STR00253##

(S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ.SUP.6.-sulfanone

(193) Synthesis is similar to that described for Example 24. The mixture of diastereomers (36 mg, 0.089 mmol) was separated by Chiral SFC (Mobile phase: n-Hexane (0.1% DEA): EtOH (0.1% DEA)=60:40; Flow rate: 80 g/min; 17 min; Column temperature: 35° C.; Back pressure: 100 bar; Column: Gilson-281, AY 20*250 mm, 10 μm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 43a (9.0 mg, 23% yield, >99% ee) as a white solid and 43b (7.0 mg, 19% yield, >98% ee) as a white solid.

(194) 43a ((R)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone): .sup.1H NMR (500 MHz, CD.sub.3OD) δ 7.98 (d, J=5.7 Hz, 1H), 7.59-7.37 (m, 2H), 5.99 (s, 1H), 5.12 (d, J=2.4 Hz, 1H), 5.07-4.96 (m, 4H), 4.52-4.41 (m, 1H), 4.16-4.06 (m, 1H), 4.00 (d, J=3.7 Hz, 1H), 3.82 (d, J=11.4 Hz, 1H), 3.75 (d, J=3.0 Hz, 1H), 3.60 (d, J=2.9 Hz, 1H), 3.52 (s, 3H), 3.25 (d, J=4.1 Hz, 1H), 1.29 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.24N.sub.6O.sub.3S requires: 404, found: 405 [M+H].sup.+; R.sub.t=9.34 min.

(195) 43b ((R)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone): .sup.1H NMR (500 MHz, CD.sub.3OD) δ 7.86 (d, J=5.6 Hz, 1H), 7.44-7.29 (m, 2H), 5.87 (s, 1H), 4.99 (d, J=2.5 Hz, 1H), 4.89 (ddd, J=10.3, 7.5, 4.5 Hz, 4H), 4.40-4.32 (m, 1H), 4.02-3.85 (m, 2H), 3.64 (dt, J=11.4, 7.2 Hz, 2H), 3.47 (d, J=2.9 Hz, 1H), 3.39 (s, 3H), 3.16-3.07 (m, 1H), 1.17 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.18H.sub.24N.sub.6O.sub.3S requires: 404, found: 405 [M+H].sup.+; R.sub.t=12.75 min.

EXAMPLES 44a and 44b

(196) ##STR00254##

(R)-cyclopropyl(methyl)((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

and

(197) ##STR00255##

(S)-cyclopropyl(methyl)((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

(198) Synthesis is similar to that described for Example 30. The mixture of diastereomers (33.8 mg, 0.08 mmol) was separated by Chiral SFC (Mobile phase: n-Hexane (0.1% DEA): EtOH (0.1% DEA)=75:25; Flow rate: 80 g/min; 17 min; Column temperature: 35° C.; Back pressure: 100 bar; Column: Gilson-281, sc 20×250 mm, 10 μm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 44a (5.0 mg, 15% yield, >99% ee) as a white solid and 44b (5.0 mg, 15% yield, >93% ee) as a white solid.

(199) 44a ((R)-cyclopropyl(methyl)-λ.sup.6-sulfanone or (S)-cyclopropyl(methyl)-λ.sup.6-sulfanone): .sup.1H NMR (500 MHz, CD.sub.3OD) δ 8.32 (dd, J=6.4, 2.9 Hz, 1H), 7.69-7.54 (m, 1H), 7.38-7.20 (m, 2H), 5.97 (s, 1H), 4.45 (s, 1H), 4.07-3.91 (m, 2H), 3.85-3.72 (m, 2H), 3.67-3.56 (m, 1H), 3.49 (s, 3H), 2.97-2.86 (m, 4H), 1.40 (dd, J=12.6, 10.1 Hz, 1H), 1.35-1.25 (m, 5H), 1.18 (q, J=7.2 Hz, 2H); MS (ES.sup.+) C.sub.21H.sub.26N.sub.6O.sub.2S requires: 426, found: 427 [M+H].sup.+; R.sub.t=12.98 min.

(200) 44b ((R)-cyclopropyl(methyl)-λ.sup.6-sulfanone or (S)-cyclopropyl(methyl)-λ.sup.6-sulfanone): .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.31 (dd, J=6.5, 2.9 Hz, 1H), 7.67-7.51 (m, 1H), 7.29 (dd, J=6.1, 3.2 Hz, 2H), 5.97 (s, 1H), 4.44-4.34 (m, 1H), 4.02 (d, J=11.4 Hz, 2H), 3.80 (dd, J=22.8, 7.2 Hz, 2H), 3.60 (s, 1H), 3.49 (s, 3H), 2.95-2.87 (m, 4H), 1.43-1.29 (m, 6H), 1.21-1.12 (m, 2H); MS (ES.sup.+) C.sub.21H.sub.26N.sub.6O.sub.2S requires: 426, found: 427 [M+H].sup.+; R.sub.t=16.31 min.

(201) Alternatively, Example 44b can also be prepared from Int. CC, Isomer 1b.

EXAMPLES 45a and 45b

(202) ##STR00256##

(R)-((2-(2-amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ.SUP.6.-sulfanone

and

(203) ##STR00257##

(S)-((2-(2-amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ.SUP.6.-sulfanone

(204) Synthesis is similar to that described for Example 17. The mixture of diastereomers (300 mg, 0.691 mmol) was separated by Chiral SFC (Mobile phase: CO.sub.2, MeOH/CH.sub.3CN (1:1) (0.25% i-PrNH.sub.2)=65:35; Flow rate: 80 g/min; 5 min; Column temperature: 25° C.; Back pressure: 100 bar; Column: Chiral Technologies Chiralcel OX-H, 21×250 mm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 45a (94 mg, 31% yield, 95% ee) as a tan solid and 45b (125 mg, 42% yield, 96% ee) as a tan solid.

(205) 45a ((R)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone): .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 6.85 (s, 1H), 6.65 (s, 1H), 6.00 (s, 2H), 5.90 (s, 1H), 5.02-4.95 (m, 1H), 4.95 (t, J=6.8 Hz, 1H), 4.90-4.83 (m, 3H), 4.39 (s, 1H), 4.04 (d, J=13.2 Hz, 1H), 3.92 (d, J=11.5 Hz, 1H), 3.77 (s, 3H), 3.71 (d, J=11.3 Hz, 1H), 3.59 (d, J=11.3 Hz, 1H), 3.51 (s, 3H), 3.45 (t, J=12.0 Hz, 1H), 3.09 (t, J=12.9 Hz, 1H), 1.16 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.26N.sub.6O.sub.4S requires: 434, found: 435 [M+H].sup.+; R.sub.t=3.1 min.

(206) 45b ((R)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone or (S)-methyl(oxetan-3-yl)-λ.sup.6-sulfanone): .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 6.85 (s, 1H), 6.65 (s, 1H), 6.01 (s, 2H), 5.90 (s, 1H), 4.97 (dt, J=22.9, 6.7 Hz, 2H), 4.87 (d, J=8.1 Hz, 3H), 4.41 (s, 1H), 4.03 (d, J=13.3 Hz, 1H), 3.92 (d, J=10.9 Hz, 1H), 3.77 (s, 3H), 3.71 (d, J=11.4 Hz, 1H), 3.59 (d, J=11.4 Hz, 1H), 3.50 (s, 3H), 3.44 (t, J=11.9 Hz, 1H), 3.09 (t, J=12.3 Hz, 1H), 1.16 (d, J=6.7 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.26N.sub.6O.sub.4S requires: 434, found: 435 [M+H].sup.+; R.sub.t=3.4 min.

EXAMPLES 46a and 46b

(207) ##STR00258##

(R)-cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

and

(208) ##STR00259##

(S)-cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

(209) 46a ((R)-cyclopropyl(methyl)-λ.sup.6-sulfanone or (S)-cyclopropyl(methyl)-λ.sup.6-sulfanone); synthesized from Int. CC, Isomer 1a similar to that as described for Example 10: (20 mg, 32% yield, >99% ee) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.90 (d, J=5.0 Hz, 1H), 7.60-7.51 (m, 1H), 7.41 (s, 1H), 5.95 (s, 1H), 4.47 (s, 1H), 4.01 (dd, J=36.7, 10.5 Hz, 2H), 3.75 (d, J=11.1 Hz, 1H), 3.64 (d, J=8.7 Hz, 1H), 3.57-3.44 (m, 4H), 3.15 (t, J=12.7 Hz, 1H), 3.00 (s, 1H), 1.21 (d, J=6.7 Hz, 5H), 1.14-1.01 (m, 2H); MS (ES.sup.+) C.sub.20H.sub.24N.sub.6O.sub.2S requires: 412, found: 413 [M+H].sup.+; Rt=3.20 min.

(210) 46b ((R)-cyclopropyl(methyl)-λ.sup.6-sulfanone or (S)-cyclopropyl(methyl)-λ.sup.6-sulfanone); synthesized from Int. CC, Isomer 1b similar to that as described for Example 10: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.73 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.90 (d, J=5.0 Hz, 1H), 7.59-7.48 (m, 1H), 7.44-7.28 (m, 1H), 5.95 (s, 1H), 4.45 (s, 1H), 4.01 (dd, J=36.7, 10.5 Hz, 2H), 3.75 (d, J=11.5 Hz, 1H), 3.64 (d, J=9.4 Hz, 1H), 3.55 (s, 3H), 3.48 (d, J=11.8 Hz, 1H), 3.16 (s, 1H), 3.02 (s, 1H), 1.20 (d, J=6.7 Hz, 5H), 1.10 (s, 2H); MS (ES.sup.+) C.sub.2H.sub.24N.sub.6O.sub.2S requires: 412, found: 413 [M+H].sup.+; R.sub.t=2.09 min.

EXAMPLE 47

(211) ##STR00260##

(R)-((2-(1H-indol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

(212) ##STR00261##

(213) (R)-((2-(1H-indol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: To a solution of indole (43 mg, 0.360 mmol) in DMF (0.75 mL) 0° C. was added NaH (60% wt., 16 mg, 0.394 mmol) and the resulting solution was allowed to slowly warm up to RT and stirred over 15 min. The reaction mixture was added a solution of Int. D (100 mg, 0.328 mmol) in a DMF (0.75 mL) and the reaction mixture was heated to 100° C. and stirred for 16 h. The reaction mixture was cooled to RT, partitioned between water (15 mL) and EtOAc (5 mL), the layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5-100% EtOAc in hexanes) to afford the title compound (42 mg, 33% yield) as a white solid.

(214) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.77 (d, J=8.28 Hz, 1H) 8.20 (d, J=3.76 Hz, 1H) 7.62 (d, J=8.03 Hz, 1H) 7.30-7.46 (m, 1H) 7.12-7.27 (m, 1H) 6.64 (d, J=3.51 Hz, 1H) 5.75 (s, 1H) 4.38 (br d, J=8.28 Hz, 1H) 3.95-4.13 (m, 2H) 3.83 (s, 1H) 3.80 (br d, J=3.01 Hz, 1H) 3.59-3.69 (m, 1H) 3.50 (d, J=7.03 Hz, 1H) 3.44 (s, 4H) 3.34 (s, 1H) 1.36 (d, J=7.03 Hz, 3H) 1.23 (t, J=7.03 Hz, 1H) 0.91 (s, 1H); MS (ES.sup.+) C.sub.19H.sub.23N.sub.5O.sub.2S requires: 385, found: 386 [M+H].sup.+.

EXAMPLE 48

(215) ##STR00262##

(R)-dimethyl((2-(2-methylimidazo[1,2-a]pyridin-3-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

(216) ##STR00263##

(217) (R)-dimethyl((2-(2-methylimidazo[1,2-a]pyridin-3-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)-λ.sup.6-sulfanone hydrochloride: A reaction vial was charged with Int. D (50 mg, 0.0165 mmol), 2-methylimidazo[1,2-a]pyridine (33 mg, 0.25 mmol), Pd(OAc).sub.2 (1.8 mg, 0.008 mmol), tricyclohexylphosphonium tetrafluoroborate (6.3 mg, 0.017 mmol), pivalic acid (5.0 mg, 0.05 mmol) and K.sub.2CO.sub.3 (46 mg, 0.33 mmol). The vial was sealed, purged with Ar, DMF (1 mL) was added and the resulting mixture was heated to 110° C. for 1 h. The reaction mixture was cooled to RT, filtered through CELITE®, washed with CH.sub.2Cl.sub.2 and concentrated under reduced pressure. The residue was purified by flash chromatography (0-10% MeOH in CH.sub.2Cl.sub.2) followed by reverse phase chromatography (Mobile phase: A=0.1% HCO.sub.2H/H.sub.2O, B=0.1% HCO.sub.2H/MeCN; Gradient: B=5-50%; 15 min; Column: Biotage SNAP Ultra C18 30 g, HP-Sphere C18 25 μm). The combined fractions were treated with 0.1 M aq. HCl, concentrated under reduced pressure and lyophilized to afford the title compound (26 mg, 36% yield) as a white solid.

(218) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.23 (dt, J=7.03, 1.00 Hz, 1H) 8.01 (d, J=1.00 Hz, 2H) 7.48-7.56 (m, 1H) 5.96 (s, 1H) 4.33-4.47 (m, 2H) 3.91-3.99 (m, 3H) 3.70-3.81 (m, 2H) 3.60-3.69 (m, 1H) 3.45-3.54 (m, 1H) 3.43 (s, 6H) 3.15 (br d, J=3.76 Hz, 1H) 2.90 (s, 3H) 1.13-1.30 (m, 4H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+.

EXAMPLE 49

(219) ##STR00264##

(R)-6-amino-4-(4-((dimethyl(oxo)-λ.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinamide

Step 1

(220) ##STR00265##

(221) (R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-λ.sup.6-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinic acid: To a solution of Int. BB (30 mg, 0.063 mmol) in THF (225 μL), MeOH (45.0 μL) and water (45.0 μL) was added LiOH (1.5 mg, 0.063 mmol) and the resulting mixture was stirred at RT for 12 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=20-50%; 20 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (15 mg, 0.026 mmol, 41.3% yield) as a pale yellow solid.

(222) MS (ES.sup.+) C.sub.21H.sub.30N.sub.6O.sub.4S requires: 462, found: 463 [M+H].sup.+.

Step 2

(223) ##STR00266##

(224) (R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-λ.sup.6-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinamide: To a solution of the product form the previous step (15 mg, 0.026 mmol) in acetonitrile (130 μL) were added ammonium bicarbonate (8.2 mg, 0.10 mmol), EDC (9.97 mg, 0.052 mmol), HOBt hydrate (8.0 mg, 0.052 mmol) and DIPEA (14 μL, 0.078 mmol) and the resulting mixture was stirred at RT for 2 h. The mixture was filtered through a Whatman™ syringe filter (13 mm, 0.45 μm) and directly purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=20-50%; 16 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (12 mg, 80% yield) as a pale yellow solid.

(225) MS (ES.sup.+) C.sub.21H.sub.31N.sub.7O.sub.3S requires: 461, found: 462 [M+H].sup.+.

Step 3

(226) ##STR00267##

(227) (R)-6-amino-4-(4-((dimethyl(oxo)-λ.sup.6-sulfaneylidene)amino)-6-(3-methyl-morpholino)pyrimidin-2-yl)picolinamide: A solution of the product from the previous step (6.6 mg, 0.011 mmol) in TFA (57 μL) was stirred at 65° C. for 24 h. The mixture was cooled to RT, diluted with CH.sub.2Cl.sub.2 (2 mL) and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (4 mg, 55% yield) as a white solid.

(228) .sup.1H NMR (600 MHz, Methanol-d.sub.4) δ 8.10 (s, 1H), 7.81 (s, 1H), 6.11 (s, 1H), 4.54 (s, 1H), 4.19 (s, 1H), 4.02 (dd, J=11.4, 3.7 Hz, 1H), 3.82 (d, J=11.6 Hz, 1H), 3.73 (dd, J=11.7, 3.1 Hz, 1H), 3.59 (td, J=12.0, 2.8 Hz, 1H), 3.51 (s, 6H), 3.38-3.27 (m, overlap MeOH, 1H), 1.33 (d, J=6.9 Hz, 3H); MS (ES.sup.+) C.sub.17H.sub.23N.sub.7O.sub.3S requires: 405, found: 406 [M+H].sup.+.

EXAMPLE 50

(229) ##STR00268##

(R)-6-amino-4-(4-((dimethyl(oxo)-λ.SUP.6.-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-N-ethylpicolinamide

Step 1

(230) ##STR00269##

(231) (R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-λ.sup.6-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-N-ethylpicolinamide: A mixture of Int. BB (30 mg, 0.063 mmol) and ethanamine (2.0 M in THF, 629 μL, 1.26 mmol) was stirred at 65° C. for 16 h. Another aliquot of ethanamine (2.0 M THF, 629 μL, 1.259 mmol) was added and the mixture was heated at 65° C. for an additional 24 h. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 20 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (15 mg, 49% yield) as a pale yellow solid.

(232) MS (ES.sup.+) C.sub.23H.sub.35N.sub.7O.sub.3S requires: 489, found: 490 [M+H].sup.+.

Step 2

(233) ##STR00270##

(234) (R)-6-amino-4-(4-((dimethyl(oxo)-λ.sup.6-sulfaneylidene)amino)-6-(3-methyl-morpholino)pyrimidin-2-yl)-N-ethylpicolinamide: A solution of the product from the previous step (10 mg, 0.020 mmol) in TFA (102 μL) was stirred at 65° C. for 24 h. The mixture was cooled to RT, diluted with CH.sub.2Cl.sub.2 (2 mL) and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (6 mg, 44% yield) as a white solid.

(235) .sup.1H NMR (600 MHz, Methanol-d.sub.4) δ 8.02 (s, 1H), 7.71 (s, 1H), 6.13 (s, 1H), 4.56 (s, 1H), 4.21 (s, 1H), 4.03 (dd, J=11.7, 3.8 Hz, 1H), 3.83 (d, J=11.6 Hz, 1H), 3.73 (dd, J=11.6, 3.2 Hz, 1H), 3.59 (td, J=12.0, 2.4 Hz, 2H), 3.51 (s, 6H), 3.46 (q, J=7.3 Hz, 2H), 3.39-3.32 (m, overlap MeOH, 1H), 1.34 (d, J=6.8 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.27N.sub.7O.sub.3S requires: 433, found: 434 [M+H].sup.+.

EXAMPLE 51

(236) ##STR00271##

(R)-dimethyl((6-(3-methylmorpholino)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

(237) ##STR00272##

(238) (R)-dimethyl((6-(3-methylmorpholino)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: A microwave reaction vial was charged with Int. D (0.10 g, 0.33 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (0.10 g, 0.38 mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.030 g, 0.040 mmol) and K.sub.3PO.sub.4 (0.22 g, 1.04 mmol) in dioxane (3 mL) and water (0.8 mL) and the mixture was degassed with a stream of N.sub.2 for five minutes. The vial was sealed and heated at 100° C. for 40 minutes in a microwave reactor. The reaction mixture was cooled to RT, partitioned between EtOAc (20 mL) and brine (20 mL), the layers were separated and the aqueous layer was extracted EtOAc (2×20 mL). The combined organic layers were dried over MgSO.sup.4, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (1-8% MeOH in CH.sub.2Cl.sub.2) to afford the title compound (78 mg, 59% yield) as a white solid.

(239) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.71 (d, J=8.78 Hz, 1H), 8.41 (d, J=6.78 Hz, 1H), 7.19-7.35 (m, 1H), 6.79 (td, J=6.84, 1.38 Hz, 1H), 5.75 (s, 1H), 4.32-4.50 (m, 1H), 3.91-4.14 (m, 2H), 3.74-3.90 (m, 2H), 3.57-3.70 (m, 1H), 3.40 (d, J=7.78 Hz, 6H), 3.29 (td, J=12.74, 3.89 Hz, 1H), 2.87 (s, 3H), 1.33 (d, J=6.78 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.2S requires: 400, found: 401 [M+H].sup.+.

EXAMPLE 52

(240) ##STR00273##

(R)-((2-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

(241) ##STR00274##

(242) (R)-((2-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: To a solution of (R)-dimethyl((6-(3-methylmorpholino)-2-(2-(((triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazol-1-yl)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone (synthesis is similar to that described for Example 30, derived from Intermed. FF) (0.081 g, 0.14 mmol) in THF (5 mL) was added HF pyridine, 30% (HF ca. 70%, 1.3 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into sat. aq. NaHCO.sub.3(50 mL) and stirred vigorously for 15 min. The layers were separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (2×50 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified via reverse phase C18 chromatography (10-100% MeCN in 0.1% TFA/H.sub.2O). The combined fractions were made alkaline by the addition of sat. aq. NaHCO.sub.3and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (2×50 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (0.052 g, 88% yield) as a white solid.

(243) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.32-8.50 (m, 1H), 7.63-7.80 (m, 1H), 7.20-7.36 (m, 2H), 5.74 (s, 1H), 5.14 (s, 2H), 4.12-4.27 (m, 1H), 3.96 (br dd, J=11.42, 3.64 Hz, 1H), 3.81 (br d, J=13.05 Hz, 1H), 3.61-3.77 (m, 2H), 3.51 (td, J=11.92, 3.01 Hz, 1H), 3.19-3.36 (m, 8H), 1.27 (d, J=6.78 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.24N.sub.6O.sub.3S requires: 416, found: 417 [M+H].sup.+.

EXAMPLE 53

(244) ##STR00275##

(R)-((2-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ.SUP.6.-sulfanone

(245) ##STR00276##

(246) (R)-((2-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-λ.sup.6-sulfanone: A mixture of Int. D (0.152 g, 0.499 mmol), 2-(fluoromethyl)-1H-benzo[d]imidazole (0.090 g, 0.60 mmol), sodium tert-butoxide (0.086 g, 0.90 mmol) and t-BuBrettPhos Palladacycle G3 (0.021 g, 0.025 mmol) in dioxane (5 mL) was degassed with a stream of N.sub.2 for five minutes and the resulting mixture was heated to 80° C. for 18 h. The reaction mixture was cooled to RT, filtered through CELITE® and concentrated under reduced pressure. The residue was purified via silica gel chromatography (10% CH.sub.3CN in CH.sub.2Cl.sub.2) to afford the title compound (102 mg, 49% yield) as a white solid.

(247) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.40 (d, J=8.03 Hz, 1H), 7.77 (br d, J=7.53 Hz, 1H), 7.23-7.46 (m, 2H), 5.85-6.16 (m, 2H), 5.74 (s, 1H), 4.22 (br d, J=4.52 Hz, 1H), 3.80-4.02 (m, 2H), 3.60-3.79 (m, 2H), 3.52 (td, J=11.92, 3.01 Hz, 1H), 3.14-3.39 (m, 7H), 1.27 (d, J=6.78 Hz, 3H); MS (ES.sup.+) C.sub.19H.sub.23FN.sub.6O.sub.2S requires: 418, found: 419 [M+H].sup.+.

EXAMPLE 54

(248) ##STR00277##

(R)-dimethyl((2-(1-methyl-1H-imidazol-5-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ.SUP.6.-sulfanone

(249) ##STR00278##

(250) (R)-dimethyl((2-(1-methyl-1H-imidazol-5-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ.sup.6-sulfanone: A solution of Int. D (50 mg, 0.164 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole (77 mg, 0.20 mmol) in toluene (820 μL) was degassed with N.sub.2 for 1 minute. Pd(Ph.sub.3P).sub.4 (19 mg, 0.016 mmol) was added and the mixture was degassed with N.sub.2 for an additional 30 seconds, and the reaction mixture was heated at 110° C. for 16 h. The reaction mixture was cooled to RT, filtered through CELITE®, washed with CH.sub.2Cl.sub.2 and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; Gradient: B=0-30%; 20 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (5.4 mg, 6% yield) as a white solid.

(251) .sup.1H NMR (600 MHz, Methanol-d.sub.4) δ 8.88 (s, 1H), 8.12 (s, 1H), 5.97 (s, 1H), 4.42-4.36 (m, 1H), 4.28 (s, 3H), 4.03-3.94 (m, 2H), 3.80 (d, J=11.5 Hz, 1H), 3.71 (dd, J 11.6, 3.2 Hz, 1H), 3.57 (td, J=11.9, 3.1 Hz, 1H), 3.44 (s, 6H), 3.32-3.23 (n, overlap MeOH, 1H), 1.29 (d, J=6.8 Hz, 3H); MS (ES.sup.+) C.sub.15H.sub.22N.sub.6O.sub.2S requires: 350, found: 351 [M+H].sup.+.

(252) The compounds reported in Table 2 were synthesized using the method described for the previously disclosed Examples. The appropriate sulfoximines were prepared as described for Intermediates C.

(253) TABLE-US-00002 TABLE 2 Example compounds 55-125. Ex. Ex Structure IUPAC Name MWt [M + H] Method 55 (R)-1-(1-((6-(3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)-1-oxido-1λ.sup.6- thiomorpholino)propan- 1-one 483 484 12 56 0 Methyl (R)-1-((6-(3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)-1λ.sup.6- thiomorpholine-4- carboxylate 1-oxide 485 486 12 57 (1-Acetylpiperidin-4-yl)- (methyl)((6-((R)-3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)-λ.sup.6-sulfanone 497 498 12 58 Methyl 4-(S-methyl-N- (6-((R)-3-methyl- morpholino)-2-(1H- pyrrolo[2,3-b]pyridin-4- yl)pyrimidin-4-yl)- sulfonimidoyl)piperidine- 1-carboxylate 513 514 12 59 Methyl((6-((R)-3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)(1-propionyl- piperidin-4-yl)-λ.sup.6- sulfanone 511 512 12 60 Methyl((6-((R)-3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)(oxetan-3-yl)- λ.sup.6-sulfanone 428 429 12 61 (R)-cyclopropyl(1-((6-(3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)-1-oxido-1λ.sup.6- thiomorpholino)- methanone 495 496 12 62 (R)-2-methoxy-1-(1-((6- (3-methylmorpholino)-2- (1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)-1-oxido-1λ.sup.6- thiomorpholino)ethan-1- one 499 500 12 63 Isopropyl (R)-1-((6-(3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)-1λ.sup.6- thiomorpholine-4- carboxylate 1-oxide 513 514 12 64 Ethyl (R)-1-((6-(3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)-1λ.sup.6- thiomorpholine-4- carboxylate 1-oxide 499 500 12 65 (R)-1-((6-(3-methyl- morpholino)-2-(1H- pyrrolo[2,3-b]pyridin-4- yl)pyrimidin-4-yl)imino)- 1λ.sup.6-thiomorpholine 1- oxide 427 428 12 66 0 (R)-((2-(2-aminopyridin- 4-yl)-6-(3-methyl- morpholino)pyrimidin-4- yl)imino)dimethyl-λ.sup.6- sulfanone 362 363 24 67 (R)-2-hydroxy-1-(1-((6- (3-methylmorpholino)-2- (1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)-1-oxido-1λ.sup.6- thiomorpholino)ethan-1- one 485 486 12 68 (R)-((2-(imidazo[1,2-a]- pyridin-5-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)- imino)dimethyl-λ.sup.6- sulfanone 386 387 25 69 (R)-dimethyl((6-(3- methylmorpholino)-2- (7H-pyrrolo[2,3-d]- pyrimidin-4-yl)- pyrimidin-4-yl)imino)- λ.sup.6-sulfanone 387 388 11 70 (R)-((2-(2-ethyl-1H- benzo[d]imidazol-1-yl)- 6-(3-methyl- morpholino)pyrimidin-4- yl)imino)dimethyl-λ.sup.6- sulfanone 414 415 30 71 (R)-((2-(1H- benzo[d]imidazol-1-yl)- 6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 386 387 30 72 (R)-((2-(1H-benzo[d]- [1,2,3]triazol-1-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 387 388 30 73 (R)-((2-(6-fluoro-1H- indazol-4-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 404 405 25 74 (R)-((2-(3-hydroxy- phenyl)-6-(3-methyl- morpholino)pyrimidin-4- yl)imino)dimethyl-λ.sup.6- sulfanone 362 363 24 75 (R)-((2′-amino-6-(3- methylmorpholino)-[2,5′- bipyrimidin]-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 363 364 24 76 00 (R)-((2-(2-isopropyl-1H- benzo[d]imidazol-1-yl)- 6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 428 429 30 77 01 (R)-((2-(6-aminopyridin- 3-yl)-6-(3-methyl- morpholino)pyrimidin-4- yl)imino)dimethyl-λ.sup.6- sulfanone 362 363 24 78 02 (R)-dimethyl((6-(3- methylmorpholino)-2- (1H-pyrrolo[2,3-c]- pyridin-4-yl)pyrimidin-4- yl)imino)-λ.sup.6-sulfanone 386 387 25 79 03 (R)-((2-(1H-imidazo[4,5- c]pyridin-l-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 387 388 36 80 04 (R)-dimethyl((2-(6- methyl-1H-benzo[d]- imidazol-1-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- λ.sup.6-sulfanone 400 401 34 81 05 (R)-((2-(1H-imidazol-1- yl)-6-(3-methyl- morpholino)pyrimidin-4- yl)imino)dimethyl-λ.sup.6- sulfanone 336 337 30 82 06 (R)-dimethyl((2-(4- methyl-1H-imidazol-1- yl)-6-(3-methyl- morpholino)pyrimidin-4- yl)imino)-λ.sup.6-sulfanone 350 351 30 83 07 (R)-dimethyl((6-(3- methylmorpholino)-2-(2- (trifluoromethyl)-1H- benzo[d]imidazol-1-yl)- pyrimidin-4-yl)imino)- λ.sup.6-sulfanone 454 455 34 84 08 (R)-((2-(4,5-dimethyl- 1H-imidazol-1-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)- imino)dimethyl-λ.sup.6- sulfanone 364 365 30 85 09 (R)-((2-(1H-indazol-1- yl)-6-(3-methyl- morpholino)pyrimidin-4- yl)imino)dimethyl-λ.sup.6- sulfanone 386 387 30 86 0 (R)-((2-(2-(difluoro- methyl)-1H-benzo[d]- imidazol-1-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 436 437 34 87 (R)-dimethyl((6-(3- methylmorpholino)-2-(2- (2,2,2-trifluoroethoxy)- 1H-pyrrolo[2,3- b]pyridin-4-yl)pyrimidin- 4-yl)imino)-λ.sup.6-sulfanone 484 485 25 88 (R)-((2-(6-fluoro-1H- indol-4-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 403 404 11 89 (R)-((2-(2,5-dimethyl- 1H-imidazol-1-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 364 365 30 90 (R)-dimethyl((6-(3- methylmorpholino)-2-(2- (trifluoromethyl)-3H- imidazo[4,5-b]pyridin-7- yl)pyrimidin-4-yl)imino)- λ.sup.6-sulfanone 455 456 34 91 (R)-((2-(2-chloro-1H- imidazol-1-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 370 371 30 92 ((2-(1H-benzo[d]- imidazol-1-yl)-6-((R)-3- methylmorpholino)- pyrimidin-4-yl)imino)- (cyclopropyl)(methyl)- λ.sup.6-sulfanone 412 413 29 93 ((2-(6-aminopyridin-3- yl)-6-((R)-3-methyl- morpholino)pyrimidin-4- yl)imino)(cyclopropyl)- (methyl)-λ.sup.6-sulfanone 388 389 24 94 (R)-((2-(7-fluoro-2- methyl-1H-benzo[d]- imidazol-1-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 418 419 34 95 Cyclopropyl(methyl)((2- (2-methyl-1H-benzo[d]- imidazol-1-yl)-6-((R)-3- methylmorpholino)- pyrimidin-4-yl)imino)- λ.sup.6-sulfanone 426 427 29 96 0 Methyl((2-(2-methyl-1H- benzo[d]imidazol-1-yl)- 6-((R)-3-methyl- morpholino)pyrimidin-4- yl)imino)(oxetan-3-yl)- λ.sup.6-sulfanone 442 443 29 97 (R)-dimethyl((6-(3- methylmorpholino)-2- (pyridin-3-yl)pyrimidin- 4-yl)imino)-λ.sup.6-sulfanone 347 348 10 98 (R)-dimethyl((6-(3- methylmorpholino)-2- (pyridin-4-yl)pyrimidin- 4-yl)imino)-λ.sup.6-sulfanone 347 348 10 99 (R)-((2-(1H-indol-4-yl)- 6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 385 386 11 100 Methyl((6-((R)-3- methylmorpholino)-2- (1H-pyrrolo[2,3-c]- pyridin-4-yl)pyrimidin-4- yl)imino)(oxetan-3-yl)- λ.sup.6-sulfanone 428 429 11 101 (R)-((2-(1H-benzo[d]- imidazol-4-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 386 387 10 102 (R)-((2-(5,6-difluoro-1H- benzo[d]imidazol-1-yl)- 6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 422 423 29 103 (R)-dimethyl((6-(3- methylmorpholino)-2-(2- methylpyridin-4-yl)- pyrimidin-4-yl)imino)- λ.sup.6-sulfanone 361 362 10 104 (R)-4-(4-((dimethyl(oxo)- 16-sulfaneylidene)- amino)-6-(3-methyl- morpholino)pyrimidin-2- yl)-1H-pyrrolo[2,3-b]- pyridine-2-carbonitrile 411 412 11 105 (R)-((2-(2-amino-6- cyclopropylpyridin-4-yl)- 6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 402 403 14 106 0 (R)-((2-(6-fluoro-1H- benzo[d]imidazol-1-yl)- 6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 404 405 35 107 (R)-((2-(6-fluoro-2- methyl-1H-benzo[d]- imidazol-1-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 418 419 35 108 (R)-((2-(5-fluoro-2- methyl-1H-benzo[d]- imidazol-1-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 418 419 35 109 (R)-((2-(5-fluoro-1H- benzo[d]imidazol-1-yl)- 6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 404 405 35 110 (R)-((2-(1H-imidazo[4,5- c]pyridin-l-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 387 388 35 111 (R)-((2-(2-amino-6- methoxypyridin-4-yl)-6- (3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 392 393 17 112 (R)-6-amino-4-(4- ((dimethyl(oxo)-λ.sup.6- sulfaneylidene)amino)-6- (3-methylmorpholino)- pyrimidin-2-yl)-N- methylpicolinamide 419 420 50 113 ((2-(2-amino-6- chloropyridin-4-yl)-6- ((R)-3-methyl- morpholino)pyrimidin-4- yl)imino)(cyclopropyl)- (methyl)-λ.sup.6-sulfanone 422 423 13 114 (R)-dimethyl((6-(3- methylmorpholino)-2- (1H-pyrazol-3-yl)- pyrimidin-4-yl)imino)- λ.sup.6-sulfanone 336 337 10 115 (R)-((2-(2-methoxy- pyridin-4-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 377 378 10 116 0 ((2-(2-Amino-6- chloropyridin-4-yl)-6- ((R)-3-methyl- morpholino)pyrimidin-4- yl)imino)(methyl)- (oxetan-3-yl)-λ.sup.6- sulfanone 438 439 13 117 (R)-((2-(2-amino-6- ethoxypyridin-4-yl)-6-(3- methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 406 407 17 118 ((2-(2-Amino-6- methoxypyridin-4-yl)-6- ((R)-3-methyl- morpholino)pyrimidin-4- yl)imino)(methyl)- (oxetan-3-yl)-λ.sup.6- sulfanone 434 435 17 119 Methyl((6-((R)-3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)(pyridin-3-yl)- λ.sup.6-sulfanone 449 450 16 120 Methyl(1-methyl-1H- pyrazol-4-yl)((6-((R)-3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)-λ.sup.6-sulfanone 452 453 16 121 (R)-1-((2-(6-chloro-1H- pyrrolo[2,3-b]pyridin-4- yl)-6-(3-methyl- morpholino)pyrimidin-4- yl)imino)tetrahydro-1H- 1λ.sup.6-thiophene 1-oxide 446 447 19 122 (R)-((2′-amino-6-(3- methylmorpholino)-[2,4′- bipyrimidin]-4- yl)imino)dimethyl-λ.sup.6- sulfanone 363 364 25 123 (R)-((2-(2- hydroxypyridin-4-yl)-6- (3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ.sup.6-sulfanone 363 364 10 124 ((2-(1H-benzo[d]- imidazol-1-yl)-6-((R)-3- methylmorpholino)- pyrimidin-4-yl)imino)- (methyl)(oxetan-3-yl)-λ.sup.6- sulfanone 428 429 29 125 ((2-(2-Amino-6- methoxypyridin-4-yl)-6- ((R)-3-methyl- morpholino)pyrimidin-4- yl)imino)(cyclopropyl)- (methyl)-λ.sup.6-sulfanone 418 419 18

(254) The activity of the compounds in Examples 1-125 as ATR inhibitors is illustrated in the following assay. The other compounds listed below, which have not yet been made and/or tested, are predicted to have activity in this assay as well.

(255) TABLE-US-00003 Structure IUPAC Name 0 methyl 2,2,2- trifluoroethyl ({6- [(3R)-3- methylmorpholin- 4-yl]-2-{1H-pyrrolo [2,3-b]pyridin-4-yl} pyrimidin-4-yl}imino)- λ.sup.6-sulfanone
ATR/ATRIP Enzymatic Assay

(256) Human full-length FLAG-TEV-ATR and His.sub.6-ATRIP were co-expressed in HEK293 cells. The cell pellet (20 g) was harvested and lysed in 100 mL of lysis buffer (20 mM Tris-HCl pH 7.5 at room temperature, 137 mM NaCl, 10% glycerol, 1 mM DTT, 1% (v/v) Tween-20, 0.1% (v/v) NP-40, complete protease inhibitor cocktail tablets, phosphatase inhibitor cocktail tablets, 2 mM MgCl.sub.2, 0.2 mM EDTA, and 1 mM ATP). After sonication and centrifugation, the supernatant was incubated at 4° C. for 3 hours with 1 mL of anti-FLAG resin (Sigma catalog #A2220) that had been pre-equilibrated in buffer A (20 mM Tris-HCl pH 7.5 at room temperature, 137 mM NaCl, 10% glycerol, 1 mM DTT, 2 mM MgCl.sub.2, and 0.2 mM EDTA). The sample was loaded into a column, and then washed with buffer A three times. Protein was subsequently eluted with 2 ml of buffer B (buffer A+200 g/ml 3×FLAG peptide).

(257) The ability of new chemical matter to inhibit the ATR catalytic activity in this ATR/ATRIP complex was assessed using a Caliper-based assay. A 2× enzyme solution (i.e., 4 nM enzyme) was prepared using 1× Kinase Reaction Buffer (25 mM HEPES pH 8, 0.0055% Brij-35, 10 mM MnCl.sub.2, and 1 mM DTT). A 2× peptide solution was then prepared consisting of 10 uM FAM-labeled RAD17 peptide (GL Biochem, catalog #524315) in 1× Kinase Reaction Buffer supplemented with 2 μM ATP. 10 μL of the 2× enzyme solution was transferred to an assay plate containing 60 nL of test compound (from a 3× serial dilution) in 100% DMSO. Following a 30 minute incubation at 28° C., 10 μL of the 2× peptide solution was then transferred to the same assay plate. The reaction was allowed to incubate at 28° C. for 6 hours. After adding 30 μL of stop buffer (100 mM HEPES pH 7.5, 0.015% Brij-35, 0.2% Coating-3 Reagent (PerkinElmer, catalog #PN760050), and 50 mM EDTA), data were collected on a Caliper instrument. Conversion values were converted to inhibition values via the following equation: % inhibition=(max−conversion)/(max−min)*100, whereby “max” corresponds to the DMSO control and “min” corresponds to the low control. IC.sub.50 values were calculated using the following equation in XLFit: Y=Bottom+(Top−Bottom)/1+(IC.sub.50/X){circumflex over ( )}HillSlope).

(258) pCHK1 Cellular Assay

(259) Inhibitors of ATR kinase are effective at inhibiting the ATR-driven phosphorylation of the downstream target Chk1 kinase at Serine 345, following the addition of 4-nitroquinoline N-oxide, a chemical used to induce DNA damage. Cellular IC.sub.50 for the inhibitors of ATR described herein were measured in HT-29 colorectal adenocarcinoma cells. HT-29 cells were routinely maintained in McCoy's 5A media (ATCC Catalog #30-2007) supplemented with 10% fetal bovine serum (Sigma Catalog #F2442) and 1× Penicillin-Streptomycin (Gibco Catalog #15140-122) using a humidified incubator (37° C., 5% CO.sub.2, and ambient 02). In preparation for the CHK1 (p-Ser345) ALPHASCREEN® SUREFIRE® assay, cells were harvested and resuspended in McCoy's 5A media supplemented with 10% fetal bovine serum and 1× Penicillin-Streptomycin. Cells were seeded onto a 384-well black CELLSTAR® Tissue Culture Plate (VWR Catalog #89085-314) at a density of 13,000 cells/well in a volume of 40 μL. The microplate was incubated overnight (approximately 20 hours) at 37° C. with 5% CO.sub.2 and ambient 02. Stock solutions of the test compounds were prepared in 100% DMSO (Sigma, Catalog #D2650) and serially diluted 1:3 using 100% DMSO. Compounds were additionally diluted 1:33 in culture medium, and 10 L/well were transferred to the tissue culture plate. Following the compound addition the microplate was incubated at 37° C. for 90 minutes. 10 μL of 4-nitroquinoline N-oxide (Sigma Aldrich Catalog #N8141-1G) diluted in media (final concentration 12 uM) were added to the tissue culture plate followed by a 120 minute incubation at 37° C. The cells were then washed with PBS and lysed using 10 μL/well SUREFIRE® Kit lysis buffer diluted to 1× in water (PerkinElmer Catalog #TGRCHK1S50K), with mixing on an orbital shaker at 500 rpm for 20 min at RT. Lysates were frozen at −20° C. overnight.

(260) 4 μL/well of lysate was then transferred from the tissue culture plate to a 384-well, white, low volume, PROXIPLATE™ (PerkinElmer Catalog #600828). 5 μL/well of the acceptor bead solution, prepared by diluting SUREFIRE® Kit activation buffer (PerkinElmer Catalog #TGRCHK1S50K) and ALPHASCREEN® Protein A acceptor beads (PerkinElmer Catalog #6760617R) in SUREFIRE® Kit reaction buffer (PerkinElmer Catalog #TGRCHK1S50K), were added to the lysates under subdued light and incubated at room temperature for 120 min. 2 uL/well of the donor bead solution, prepared by diluting ALPHASCREEN® Streptavidin donor beads (PerkinElmer Catalog #6760617R) in SUREFIRE® Kit dilution buffer (PerkinElmer Catalog #TGRCHK1S50K), were added under subdued light and incubated at room temperature for an addition 120 minutes. The pCHK1 ALPHASCREEN® signal was measured using an ENVISION® plate reader (PerkinElmer). IC.sub.50 values were calculated using a four-parameter logistic curve fit using Genedata Screener software. Percent of control for each compound concentration was calculated by the following formula: 100*(Compound−Min)/(Max−Mn) where “Max” is the high control, DMSO, and “Min” is the low control, 5 uM ATR inhibitor.

(261) TABLE-US-00004 TABLE 3 ATR/ATRIP Enzyme IC.sub.50 values ATR- ATRIP pCHK1 Ex IC.sub.50, nM IC.sub.50 (nM)  1 1 46  2 5 64  3 2 44  4 8 86  5 3 48  6 N.A. 212  7 4 77  8 N.A. 167  9 N.A. 136  10 26 909  11 7 17  12 4 56  13 104 73  14 122 463  15 182 335  16 3 20  17a 4 38  17b 7 61  18a 258 408  18b 71 49  19 8 131  20 67 798  21 21 311  22 77 669  23 31 1718  24 36 1986  25 22 39  26 81 131  27 405 1855  28 246 575  29 10 92  30 3 47  31 1.6 14  32 259 10000  33 47 1617  34 3 895  35 195 1177  36 50 4668  37 306 87  38a 0.7 56  38b 1.4 563  39a 48 26  39b 525 1356  40a 0.8 402  40b 0.3 30  41a 15 945  41b 0.8 28  42a 31 25  42b 284 940  43a 153 44  43b 387 399  44a 6 902  44b 0.4 18  45a 110 65  45b 419 431  46a 8 179  46b 1 8  47 3 1372  48 34 263  49 159 7586  50 486 8232  51 55 439  52 0.9 44  53 0.5 14  54 978 3033  55 4 61  56 2 27  57 15 202  58 15 175  59 21 183  60 4 41  61 3 77  62 5 89  63 4 169  64 2 68  65 20 372  66 207 198  67 3 168  68 244 1448  69 59 676  70 3 48  71 2 138  72 23 4414  73 27 2317  74 73 6099  75 63 1668  76 17 408  77 135 3385  78 5 22  79 233 6070  80 6 720  81 353 219  82 134 670  83 45 1569  84 158 1828  85 20 7684  86 0.4 28  87 316 164  88 2 58  89 435 653  90 1072 133  91 334 228  92 4 46  93 115 48  94 326 10000  95 0.9 20  96 3 57  97 208 776  98 117 252  99 3 99 100 3 26 101 17 158 102 10 904 103 218 1217 104 88 244 105 14 757 106 3 351 107 7 339 108 2 110 109 2 341 110 143 4326 111 123 273 112 205 4888 113 72 51 114 480 1113 115 307 3623 116 105 58 117 277 564 118 158 136 119 17 175 120 26 250 121 24 133 122 594 6478 123 821 >10000 N.A. = not available
Anti-Tumor Effects in Mouse Xenografts

(262) The effect of compounds 1, 39a, 30, and 18b on tumor growth was assessed in a LoVo (human colorectal) mouse xenograft model. Female CD1 nude mice were injected subcutaneously in the right flank with a suspension of LoVo cells (1 million cells/100 ul PBS+100 ul Matrigel; cells purchased from ATCC and cultured following ATCC's guideline). After implantation, tumor volume (TV) was measured weekly and mice bearing tumors with volumes between 200-250 mm.sup.3 were randomized into treatment groups of 5 to 10 mice each. Mice were dosed by oral gavage, once daily for 21 days with either vehicle or 1, 39a, 30, and 18b at the doses reported in Table 4. The doses were scaled to the body weights (BW) of individual animals at a dosing volume of 10 mL/Kg. Throughout the duration of study tumor growth was assessed by caliper measurement and treatment response was determined by percent tumor growth inhibition (% TGI; calculated as TGI %=100−([TV.sub.end-treat−TV.sub.start-treat]/[TV.sub.end-cntrl−TV.sub.tart-cntrl]; where TV.sub.end-treat, TV.sub.start-treat, TV.sub.end-cntrl and TV.sub.tart-cntrl are the median tumor volumes for the compound treated and control groups respectively at the end and at the start of the study. Mouse body weight was measured bi-weekly, and reported as percentage of mean BW change from Day 1. Significant tumor growth inhibition was observed for all the compounds, as shown in Table 4, with no body weight loss.

(263) TABLE-US-00005 TABLE 4 Anti-tumor effect in LoVo xenograft model in CD1 nude mice Tumor Growth Body Weight Inhibition % Change % Ex. Dose (mg/Kg) (TGI %; day 21) (BW %; day 21)  1 100 96* +9.8  39a 25 59* +0.9 30 10 73* +7.3  18b 10 81* +0.4 * = p < 0.05 **, two-tailed test;

(264) All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein in their entireties. Where any inconsistencies arise, material literally disclosed herein controls.

(265) From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications of the disclosure to adapt it to various usages and conditions.