5- and 6-azaindole compounds for inhibition of Bcr-Abl tyrosine kinases

1. A compound of formula (I-A):

or a pharmaceutically acceptable salt thereof, wherein:

X is NR 3′ or CR 3 ,

Y is NR 2 or CR 4 ,

wherein when X is NR 3′ then Y is CR 4 , Y has a double bond to CR 5 , and X has a single bond to CR 5 ; or when X is CR 3 then Y is NR 2 , Y has a single bond to CR 5 , and X has a double bond to CR 5 ;

m is an integer from 0 to 3;

each R 1 is independently -D, —F, C 1 -C 3 alkyl, C 1 -C 3 alkylene-NR 7 R 8 , C 1 -C 3 alkylene-NR 7′ R 8′ , C 1 -C 3 alkylene-OH, C 1 -C 3 alkylene-CN, C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-OH, C 1 -C 2 alkylene-(4- to 8-membered heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , C 1 -C 2 alkylene-(4- to 8-membered heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , C 1 -C 2 alkylene-(C 3 -C 7 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , or C 1 -C 2 alkylene-(C 3 -C 7 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R 1 are optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;

R 2 is —H, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms;

R 3 is —H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, halogen, or —CN;

R 3′ is —H, C 1 -C 3 alkyl, —C 3 -C 6 cycloalkyl, or —CN;

R 4 is —H, C 1 -C 3 alkyl, or halogen, wherein said C 1 -C 3 alkyl is optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms;

R 5 is 5 to 10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R 9 groups;

each R 7 is independently —H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylene-CN, or C 1 -C 6 heteroalkyl;

each R 8 is independently —H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylene-CN, or C 1 -C 6 heteroalkyl;

each pair of R 7′ and R 8′ taken together with the nitrogen atom to which they are attached independently form a 3- to 8-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;

each R 9 is independently halogen, —OR 10 , —NR 7 R 8 , C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, —CN, S(O) n C 1 -C 3 alkyl, or S(O) n C 3 -C 6 cycloalkyl,

wherein n is an integer from 0 to 2; and

each R 10 is independently —H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with hydroxyl, C 1 -C 3 alkoxy, and/or 1-6 deuterium atoms.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I-A) is a compound of formula (I-A-i) or formula (I-A-ii):

wherein

m is an integer 0 to 2;

each R 1 is independently —F, C 1 -C 3 alkyl, C 1 -C 3 alkylene-NR 7 R 8 , C 1 -C 3 alkylene-NR 7′ R 8′ , C 1 -C 3 alkylene-OH, C 1 -C 3 alkylene-CN, C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , C 1 -C 3 alkylene-CN, C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-OH, C 1 -C 2 alkylene-(C 4 -C 6 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , or C 1 -C 2 alkylene-(C 4 -C 6 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene in R 1 are optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;

R 2 is —H, —CH 3 , CD 3 , —CHF 2 , or —CH 2 CH 3 ;

R 3 is —H, C 1 -C 3 alkyl, C 3 -cycloalkyl, halogen, or —CN;

R 3′ is —H, C 1 -C 3 alkyl, C 3 -cycloalkyl, or —CN;

R 4 is —H, —CH 3 ,-CD 3 , —CHF 2 , —CH 2 CH 3 , or halogen;

R 5 is 5 to 10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:

wherein indicates a single or double bond, and wherein said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R 9 groups;

each R 7 is independently —H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkyl-CN, or C 2 -C 3 heteroalkyl;

each R 8 is independently —H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkyl-CN, or C 2 -C 3 heteroalkyl;

each pair of R 7′ and R 8′ taken together with the nitrogen atom to which they are attached independently form a 4-to-6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;

each R 9 is independently halogen, —OR 10 , C 1 -C 3 alkyl, —CF 2 H, —CF 3 , C 3 -C 6 cycloalkyl, or —CN, and

each R 10 is independently —H, C 1 -C 3 alkyl, —CD 3 , —CF 2 H, —CF 3 , or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with hydroxyl and/or C 1 -C 3 alkoxy and/or 1-6 deuterium atoms.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

each R 1 is independently —F, C 1 -C 3 alkylene-NR 7 R 8′ , or C 1 -C 3 alkylene-OH; and

wherein each pair of R 7′ and R 8′ of R 1 taken together with the nitrogen atom to which they are attached independently form a 4-to-6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted by —H or C 1 -C 3 alkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 5 is 5 to 10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:

wherein indicates a single or double bond, and wherein said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R 9 groups.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 2 is —CH 3 , —CD 3 , or —CH 2 CH 3 ;

R 3 is —H, —F, —CH 3 , or —CN;

R 3′ is —H or —CH 3 ; and

R 4 is —H, —F or —CH 3 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

each R 9 is independently —F, —Cl, —OR 10 , —CH 3 , or —CN, and

each R 10 is independently —H, —CH 3 , —CD 3 , or —CH 2 CH 3 , wherein said —CH 3 or said —CH 2 CH 3 is optionally substituted with hydroxyl and/or —OCH 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I-A) is a compound of formula (I-A-i) or formula (I-A-ii):

wherein

m is an integer 0 or 1;

R 1 is —F, C 1 -C 3 alkylene-NR 7 R 8′ , or C 1 -C 3 alkylene-OH;

R 2 is —CH 3 , —CD 3 , or —CH 2 CH 3 ;

R 3 is —H, —F, —CH 3 , or —CN;

R 3′ is —H or —CH 3 ;

R 4 is —H, —F or —CH 3 ;

R 5 is 5 to 10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:

wherein indicates a single or double bond, and wherein said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R 9 groups;

each pair of R 7′ and R 8′ taken together with the nitrogen atom to which they are attached independently form a 4-to-6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted by —H or C 1 -C 3 alkyl;

each R 9 is independently —F, —Cl, —OR 10 , —CH 3 , or —CN, and

each R 10 is independently —H, —CH 3 , —CD 3 , or —CH 2 CH 3 , wherein said —CH 3 or said —CH 2 CH 3 is optionally substituted with hydroxyl and/or —OCH 3 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I-A) is a compound of formula (I-A-i) or formula (I-A-ii):

wherein

m is an integer 0 or 1;

R 1 is —F;

R 2 is —CH 3 ;

R 3 is —H or —CH 3 ;

R 3′ is —H or —CH 3 ;

R 4 is —CH 3 ;

R 5 is a 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:

wherein said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R 9 groups;

each R 9 is independently —F or —OR 10 , and

each R 10 is independently —H, —CH 3 , or —CD 3 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

each R 9 is independently —F, —OR 10 , or —CH 3 , and

each R 10 is independently —H, —CH 3 , —CD 3 , —CF 2 H, or —CF 3 .

10. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

11. A method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia, in a human in need thereof, comprising administering to the human the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

12. The method of claim 11 , wherein the leukemia is refractory leukemia.

13. The method of claim 12 , wherein the human having refractory leukemia has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in specific amino acid substitutions selected from the group consisting of M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, and T315I.

14. The method of claim 13 , wherein the human having refractory leukemia has a mutation in the Bcr-Abl tyrosine kinase gene resulting in specific amino acid substitution T315I.

15. The method of claim 11 , further comprising administering one or more pharmaceutical agents.

16. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising the compound of claim 16 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

18. A compound having the structure of:

or a pharmaceutically acceptable salt thereof.

19. A method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia, in a human in need thereof, comprising administering to the human the compound of claim 18 , or a pharmaceutically acceptable salt thereof.

20. The method of claim 19 , wherein the leukemia is refractory leukemia.

21. The method of claim 20 , wherein the human having refractory leukemia has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in specific amino acid substitutions selected from the group consisting of M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, and T315I.

22. The method of claim 21 , wherein the human having refractory leukemia has a mutation in the Bcr-Abl tyrosine kinase gene resulting in specific amino acid substitution T315I.

23. The method of claim 19 , further comprising administering one or more pharmaceutical agents.

24. A pharmaceutical composition, comprising the compound of claim 18 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

25. A method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia, in a human in need thereof, comprising administering to the human the compound of claim 16 , or a pharmaceutically acceptable salt thereof.

26. The method of claim 25 , wherein the leukemia is refractory leukemia.

27. The method of claim 26 , wherein the human having refractory leukemia has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in specific amino acid substitutions selected from the group consisting of M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, and T315I.

28. The method of claim 27 , wherein the human having refractory leukemia has a mutation in the Bcr-Abl tyrosine kinase gene resulting in specific amino acid substitution T315I.

29. The method of claim 25 , further comprising administering one or more pharmaceutical agents.

30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 2 is —H or —CH 3 ;

R 3 is —H;

R 3′ is —H; and

R 4 is —H or —CH 3 .

31. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

32. A method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia, in a human in need thereof, comprising administering to the human the compound of claim 31 , or a pharmaceutically acceptable salt thereof.

33. The method of claim 32 , wherein the leukemia is refractory leukemia.

34. The method of claim 33 , wherein the human having refractory leukemia has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in specific amino acid substitutions selected from the group consisting of M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, and T315I.

35. The method of claim 34 , wherein the human having refractory leukemia has a mutation in the Bcr-Abl tyrosine kinase gene resulting in specific amino acid substitution T315I.

36. The method of claim 32 , further comprising administering one or more pharmaceutical agents.

37. A pharmaceutical composition, comprising the compound of claim 31 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

38. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

39. A method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia, in a human in need thereof, comprising administering to the human the compound of claim 38 , or a pharmaceutically acceptable salt thereof.

40. The method of claim 39 , wherein the leukemia is refractory leukemia.

41. The method of claim 40 , wherein the human having refractory leukemia has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in specific amino acid substitutions selected from the group consisting of M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, and T315I.

42. The method of claim 41 , wherein the human having refractory leukemia has a mutation in the Bcr-Abl tyrosine kinase gene resulting in specific amino acid substitution T315I.

43. The method of claim 39 , further comprising administering one or more pharmaceutical agents.

44. A pharmaceutical composition, comprising the compound of claim 38 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.