Heterocyclic inhibitors of ATR kinase

1. A compound of structural Formula (I):

or a salt thereof, wherein:

R 1 is selected from

 n is selected from 1 and 2, inclusive;

R 2 is a 5- to 10-membered heteroaryl, and is optionally substituted with one or more R 5 groups;

R 3 is methyl;

each R 4a and R 4b is independently selected from H, halogen, cyano, hydroxy, alkyl, C 3-7 cycloalkyl, haloalkyl, hydroxyalkyl, (C 3-7 cycloalkyl)alkyl, (5- to 10-membered heterocycloalkyl)alkyl, (alkoxy)alkyl, alkoxy, haloalkoxy, hydroxyalkoxy, (C 3-7 cycloalkyl)alkoxy, (5- to 10-membered heterocycloalkyl)alkoxy, (alkoxy)alkoxy, C 3-7 cycloalkyl, C 3-7 halocycloalkyl, C 3-7 hydroxycycloalkyl, (alkoxy)C 3-7 cycloalkyl, 5- to 10-membered heterocycloalkyl, (halo)5- to 10-membered heterocycloalkyl, (hydroxy)5- to 10-membered heterocycloalkyl, (alkoxy)5- to 10-membered heterocycloalkyl, NR 7 R 8 , C(O)R 6 , C(O)OR 6 , C(O)NR 7 R 8 , NR 7 C(O)NR 7 R 8 , NR 7 C(O)OR 6 , NR 7 C(O)R 6 , S(O)R 6 , S(O) 2 R 6 , S(NR 7 )R 8 , S(O)(NR 7 )R 8 , SO 2 NR 7 R 8 , oxo, and ═NR 10 ;

each R 5 is independently selected from amino, fluoro, chloro, cyano, C 1-3 alkyl, C 1-3 aminoalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 haloalkoxy, C 3-7 cycloalkyl, and 5- to 10-membered heterocycloalkyl;

each R 6 , R 7 , and R 8 is independently selected from H, C 1-3 alkyl, C 3-7 cycloalkyl, C 1-3 hydroxyalkyl, (C 1-3 alkoxy)C 1-3 alkyl, (C 3-7 cycloalkyl)C 1-3 alkyl, and 5- to 10-membered heterocycloalkyl and is optionally substituted with one or more R 9 ;

R 7 and R 8 , together with the nitrogen to which they are both attached, optionally form a 5- to 10-membered heterocycloalkyl ring containing one or two heteroatoms;

each R 6 , R 7 , or R 8 can form a ring with R 4 ;

each R 9 is independently selected from halo, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 3-7 cycloalkyl, 5- to 10-membered heterocycloalkyl, and C 1-3 alkoxy; and

each R 10 is independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 3-7 cycloalkyl, and 5- to 10-membered heterocycloalkyl.

2. The compound as recited in claim 1 , or a salt thereof, wherein

R 1 is selected from

R 4a is selected from H, alkyl, and C 3-7 cycloalkyl; and

R 4b is selected from S(O) 2 R 6 , C(O)R 6 , C(O)OR 6 , and C(O)NR 7 R 8 .

3. The compound as recited in claim 2 , or a salt thereof, wherein R 2 is selected from indolyl, indazolyl, benzo[d]imidazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridazinyl, and imidazolopyridazinyl, any of which is optionally substituted with one or more R 5 groups.

4. The compound as recited in claim 1 , having structural Formula (II):

or a salt thereof, wherein:

Y is selected from N and CR 5c ;

Z is selected from N and CR 5d ;

R 1 is selected from

 n is selected from 1 and 2, inclusive;

R 3 is methyl;

each R 4a and R 4b is independently selected from halogen, cyano, hydroxy, alkyl, C 3-7 cycloalkyl, haloalkyl, hydroxyalkyl, (C 3-7 cycloalkyl)alkyl, (5- to 10-membered heterocycloalkyl)alkyl, (alkoxy)alkyl, alkoxy, haloalkoxy, hydroxyalkoxy, (C 3-7 cycloalkyl)alkoxy, (5- to 10-membered heterocycloalkyl)alkoxy, (alkoxy)alkoxy, C 3-7 cycloalkyl, C 3-7 halocycloalkyl, C 3-7 hydroxycycloalkyl, (alkoxy)C 3-7 cycloalkyl, 5- to 10-membered heterocycloalkyl, (halo)5- to 10-membered heterocycloalkyl, (hydroxy)5- to 10-membered heterocycloalkyl, (alkoxy)5- to 10-membered heterocycloalkyl, NR 7 R 8 , C(O)R 6 , C(O)OR 6 , C(O)NR 7 R 8 , NR 7 C(O)NR 7 R 8 , NR 7 C(O)OR 6 , NR 7 C(O)R 6 , S(O)R 6 , S(O) 2 R 6 , S(NR 7 )R 8 , S(O)(NR 7 )R 8 , SO 2 NR 7 R 8 , oxo, and ═NR 10 ;

each R 5a and R 5b is independently selected from H, amino, fluoro, chloro, cyano, C 1-3 alkyl, C 1-3 aminoalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 haloalkoxy, C 3-7 cycloalkyl, and 5- to 10-membered heterocycloalkyl,

or R 5 and R 5b , together with the intervening atoms, combine to form a heteroaryl ring, which is optionally substituted with one or more R 5 groups;

each R 5c and R 5d is independently selected from fluoro, chloro, cyano, C 1-3 alkyl, C 1-3 aminoalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 haloalkoxy, C 3-7 cycloalkyl, and 5- to 10-membered heterocycloalkyl;

each R 5 is independently selected from amino, fluoro, chloro, cyano, C 1-3 alkyl, C 1-3 aminoalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 haloalkoxy, C 3-7 cycloalkyl, and 5- to 10-membered heterocycloalkyl;

each R 6 , R 7 , and R 8 is independently selected from H, C 1-3 alkyl, C 3-7 cycloalkyl, C 1-3 hydroxyalkyl, (C 1-3 alkoxy)C 1-3 alkyl, (C 3-7 cycloalkyl)C 1-3 alkyl, and 5- to 10-membered heterocycloalkyl and is optionally substituted with one or more R 9 ;

R 7 and R 8 , together with the nitrogen to which they are both attached, optionally form a 5- to 10-membered heterocycloalkyl ring containing one or two heteroatoms;

each R 6 , R 7 , or R 8 can form a ring with R 4 ;

each R 9 is independently selected from halo, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 3-7 cycloalkyl, 5- to 10-membered heterocycloalkyl, and C 1-3 alkoxy; and

each R 10 is independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 3-7 cycloalkyl, and 5- to 10-membered heterocycloalkyl.

5. The compound as recited in claim 4 , or a salt thereof, wherein

R 1 is selected from

R 4a is selected from H, alkyl, and C 3-7 cycloalkyl; and

R 4b is selected from S(O) 2 R 6 , C(O)R 6 , C(O)OR 6 , and C(O)NR 7 R 8 .

6. The compound as recited in claim 1 , having structural Formula III

or a salt thereof, wherein:

Y is selected from N and CR 5c ;

Z is selected from N and CR 5d ;

R 1 is selected from

R 4a is selected from H, alkyl, and C 3-7 cycloalkyl;

R 4b is selected from S(O) 2 R 6 , C(O)R 6 , C(O)OR 6 , and C(O)NR 7 R 8 ; and

each R 5c and R 5d is independently selected from H, fluoro, chloro, cyano, C 1-3 alkyl, C 1-3 aminoalkyl, and C 3-7 cycloalkyl, and 5- to 10-membered heterocycloalkyl;

R 5z is selected from H, fluoro, chloro, cyano, C 1-3 alkyl, C 1-3 aminoalkyl, C 1-3 hydroxyalkyl, and C 1-3 haloalkyl;

each R 6 , R 7 , and R 8 is independently selected from H, C 1-3 alkyl, C 3-7 cycloalkyl, C 1-3 hydroxyalkyl, (C 1-3 alkoxy)C 1-3 alkyl, (C 3-7 cycloalkyl)C 1-3 alkyl, and 5- to 10-membered heterocycloalkyl and is optionally substituted with one or more R 9 ;

R 7 and R 8 , together with the nitrogen to which they are both attached, optionally forms a 5- to 10-membered heterocycloalkyl ring containing one or two heteroatoms;

each R 9 is independently selected from halo, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 3-7 cycloalkyl, 5- to 10-membered heterocycloalkyl, and C 1-3 alkoxy;

R 10 is selected from H, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 3-7 cycloalkyl, and 5- to 10-membered heterocycloalkyl; and

n is selected from 1 and 2, inclusive.

7. The compound as recited in claim 1 , or a salt thereof, having a structure selected from

8. The compound as recited in claim 1 , or a salt thereof, having a structure selected from

9. A pharmaceutical composition comprising a compound as recited in claim 1 together with a pharmaceutically acceptable carrier.

10. A method of inhibition of ATR kinase comprising contacting ATR kinase with a compound as recited in claim 1 .

11. A method of treatment of an ATR kinase-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in claim 1 to a patient having said disease.

12. The method as recited in claim 11 wherein the disease is cancer.

13. The method as recited in claim 12 , wherein the cancer is a chemotherapy-resistant cancer.

14. The method as recited in claim 12 , wherein the cancer is a radiotherapy-resistant cancer.

15. The method as recited in claim 12 , wherein the cancer is an ALT-positive cancer.

16. The method as recited in claim 12 , wherein the cancer is a sarcoma.

17. The method as recited in claim 12 , wherein the cancer is selected from osteosarcoma and glioblastoma.

18. The method as recited in claim 12 , wherein the cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer.

19. The method as recited in claim 12 , wherein the cancer is selected from non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocellular carcinoma, and ovarian cancer.

20. A method of treatment of an ATR kinase-mediated disease comprising the administration to a patient having said disease:

a. a therapeutically effective amount of a compound as recited in claim 1 ; and

b. another therapeutic agent.

21. The method of claim 12 , wherein the method further comprises administering non-chemical methods of cancer treatment.

22. The compound as recited in claim 4 , or a salt thereof, wherein R 1 is selected from

23. The compound as recited in claim 22 , wherein R 4 is independently selected from alkyl, C 3-7 cycloalkyl, NR 7 R 8 , C(O)R 6 , C(O)OR 6 , C(O)NR 7 R 8 , NR 7 C(O)NR 7 R 8 , NR 7 C(O)OR 6 , NR 7 C(O)R 6 , S(O)R 6 , S(O) 2 R 6 , S(NR 7 )R 8 , S(O)(NR 7 )R 8 , SO 2 NR 7 R 8 , oxo, and =NR 10 .

24. The compound as recited in claim 4 , wherein R 1 is selected from

25. The compound as recited in claim 24 , wherein R 4 is independently selected from alkyl, C 3-7 cycloalkyl, NR 7 R 8 , C(O)R 6 , C(O)OR 6 , C(O)NR 7 R 8 , NR 7 C(O)NR 7 R 8 , NR 7 C(O)OR 6 , NR 7 C(O)R 6 , S(O)R 6 , S(O) 2 R 6 , S(NR 7 )R 8 , S(O)(NR 7 )R 8 , SO 2 NR 7 R 8 , oxo, and =NR 10 .