Compositions useful for treating disorders related to kit and PDGFR

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

W is selected from hydrogen and

wherein Ring A is selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, cycloalkyl, and heterocyclyl;

Z is selected from C 1 -C 6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclic heterocyclylalkyl, wherein each of C 1 -C 6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, and monocyclic and bicyclic heterocyclylalkyl is independently substituted with 0-5 occurrences of R C ;

L is selected from —N(R 1 )—C(O)—, —N(R 1 )C(O)N(R 1 )—, —N(R 1 )C(O)N(R 1 )—(C 1 -C 6 alkylene)-, N(R 1 )—(C 1 -C 6 alkylene)-, —N(R 1 )—C(O)—(C 1 -C 6 alkylene)-, —N(R 1 )—S(O) 2 and —N(R 1 )—S(O) 2 —(C 1 -C 6 alkylene)-, wherein each C 1 -C 6 alkylene is independently substituted with 0-5 occurrences of R 2 ;

each R A is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, —N(R 1 )(R 1 ), cyano, and —OR 1 ;

each R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxyl, halo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, —N(R 1 )(R 1 ), and cyano;

each R C is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halo, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano, —C(O)R 1 , —OC(O)R 1 , —C(O)OR 1 , —SR 1 , —S(O) 2 R 1 , —S(O) 2 —N(R 1 )(R 1 ), —(C 1 -C 6 alkylene)-S(O) 2 —N(R 1 )(R 1 ), —N(R 1 )(R 1 ), —C(O)—N(R 1 )(R 1 ), —N(R 1 )(R 1 )—C(O)R 1 , (C 1 -C 6 alkylene)-N(R 1 )—C(O)R 1 , —NR 1 S(O) 2 R 1 , —P(O)(R 1 )(R 1 ), and —OR 1 , wherein each of C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkynyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclic heterocyclylalkyl is independently substituted with 0-5 occurrences of R a ; or 2 R C together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring substituted with 0-5 occurrences of R a ;

each R D is independently selected from halo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxyl, halo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, —N(R 2 )(R 2 ), and cyano;

each R 1 is independently selected from hydrogen, hydroxyl, halo, thiol, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 thioalkyl, —NR″R″, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C 1 -C 6 alkyl, cycloalkyl, and heterocyclyl is independently substituted with 0-5 occurrences of R b ; or 2 R 1 together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;

each R 2 is independently selected from hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, —NR′R′; or 2 R 2 together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;

each R a and R b is independently selected from hydrogen, halo, cyano, hydroxyl, C 1 -C 6 alkoxyl, —C(O)R′, C(O)OR′, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, —NR′R′, and cycloalkyl, wherein cycloalkyl is substituted with 0-5 occurrences of R′;

each R′ is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, halo, hydroxyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, and cyano; or 2 R′ together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;

each R″ is hydrogen, C 1 -C 6 alkyl, —C(O)—C 1 -C 6 alkyl, —C(O)—NR′R′R, or —C(S)—NR′R′; and

each q and r is independently 0, 1, 2, 3, or 4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II:

wherein Z, L, Ring A, R A , R D , q, and r are as defined in claim 1 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula III:

wherein Z, L, R A , and q are as defined in claim 1 .

4. The compound of any one of claims 1 to 3 , or a pharmaceutically acceptable salt thereof, wherein L is —N(R 1 )—C(O)—(C 1 -C 6 alkylene)-.

5. The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein Ring A is monocyclic or bicyclic aryl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is monocyclic or bicyclic aryl, each independently substituted with 0-5 occurrences of R C .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is monocyclic or bicyclic heteroaryl, each independently substituted with 0-5 occurrences of R C .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is pyrazolyl substituted with 0-5 occurrences of R C .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R A is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, —N(R 1 )(R 1 ), and cyano.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R C is independently selected from C 1 -C 6 alkyl, halo, C 1 -C 6 hydroxyalkyl, —C(O)R 1 , —OC(O)R 1 , —C(O)OR 1 , —SR 1 , —S(O) 2 R 1 , —S(O) 2 —N(R 1 )(R 1 ), —N(R 1 )(R 1 ), —C(O)—N(R 1 )(R 1 ), —NR 1 S(O) 2 R 1 , and —OR 1 , wherein each C 1 -C 6 alkyl is independently substituted with 0-5 occurrences of R a ; or 2 R C together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring substituted with 0-5 occurrences of R a .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from hydrogen, hydroxyl, halo, thiol, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, and —NR″R″, wherein each C 1 -C 6 alkyl is independently substituted with 0-5 occurrences of R b ; or 2 R 1 together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

13. A method of treating mastocytosis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

14. A method of treating gastrointestinal stromal tumor (GIST), the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

15. A method of treating acute myeloid leukemia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

17. The compound of claim 16 which is

or a pharmaceutically acceptable salt thereof.

18. The method of claim 13 , wherein the mastocytosis is systemic mastocytosis (SM) or cutaneous mastocytosis (CM).

19. The method of claim 18 , wherein the systemic mastocytosis (SM) is selected from indolent (ISM), smoldering (SSM), aggressive (ASM), SM with associated hematologic non-mast cell lineage disease (SM-AHNMD), and mast cell leukemia (MCL).

20. The method of claim 19 , wherein the systemic mastocytosis (SM) is aggressive (ASM).

21. The method of claim 19 , wherein the systemic mastocytosis (SM) is SM with associated hematologic non-mast cell disease (SM-AHNMD).

22. The method of claim 19 , wherein the systemic mastocytosis (SM) is mast cell leukemia (MCL).

23. The method of claim 14 , wherein the patient has a D842V mutation in PDGFRα in Exon 18.

24. The method of claim 14 , wherein the patient is refractory to treatment with imatinib, sunitinib, and/or regorafenib.

25. The method of claim 14 , wherein the patient has unrespectable GIST.

26. The method of any one of claim 13 , 14 , or 15 , wherein the patient has a mutation in Exon 17 in KIT.

27. The method of claim 26 , wherein the patient has a D816 mutation in KIT in Exon 17.

28. The method of claim 27 , wherein the D816 mutation is D816V.

29. The compound of claim 16 which is

or a pharmaceutically acceptable salt thereof.

30. The compound of claim 16 which is

or a pharmaceutically acceptable salt thereof.

31. The compound of claim 16 which is

or a pharmaceutically acceptable salt thereof.

32. The compound of claim 16 which is

or a pharmaceutically acceptable salt thereof.

33. The compound of claim 16 which is

or a pharmaceutically acceptable salt thereof.

34. The compound of claim 16 which is

or a pharmaceutically acceptable salt thereof.

35. A method of treating mastocytosis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any of claim 17 or 29 - 34 , or a pharmaceutically acceptable salt thereof.

36. A method of treating gastrointestinal stromal tumor (GIST), the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any of claim 17 or 29 - 34 , or a pharmaceutically acceptable salt thereof.

37. A method of treating acute myeloid leukemia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any of claim 17 or 29 - 34 , or a pharmaceutically acceptable salt thereof.

38. The method of claim 35 , wherein the mastocytosis is systemic mastocytosis (SM) or cutaneous mastocytosis (CM).

39. The method of claim 38 , wherein the systemic mastocytosis (SM) is selected from indolent (ISM), smoldering (SSM), aggressive (ASM), SM with associated hematologic non-mast cell lineage disease (SM-AHNMD), and mast cell leukemia (MCL).

40. The method of claim 39 , wherein the systemic mastocytosis (SM) is aggressive (ASM).

41. The method of claim 39 , wherein the systemic mastocytosis (SM) is SM with associated hematologic non-mast cell disease (SM-AHNMD).

42. The method of claim 39 , wherein the systemic mastocytosis (SM) is mast cell leukemia (MCL).

43. The method of claim 36 , wherein the patient has a D842V mutation in PDGFRα in Exon 18.

44. The method of claim 36 , wherein the patient is refractory to treatment with imatinib, sunitinib, and/or regorafenib.

45. The method of claim 36 , wherein the patient has unresectable GIST.

46. The method of claim 35 , wherein the patient has a mutation in Exon 17 in KIT.

47. The method of claim 46 , wherein the patient has a D816 mutation in KIT in Exon 17.

48. The method of claim 47 , wherein the D816 mutation is D816V.

49. The method of claim 36 , wherein the patient has a mutation in Exon 17 in KIT.

50. The method of claim 49 , wherein the patient has a D816 mutation in KIT in Exon 17.

51. The method of claim 50 , wherein the D816 mutation is D816V.

52. The method of claim 37 , wherein the patient has a mutation in Exon 17 in KIT.

53. The method of claim 52 , wherein the patient has a D816 mutation in KIT in Exon 17.

54. The method of claim 53 , wherein the D816 mutation is D816V.