IP Library › Granted Patent US 9,273,077

Granted Patent B2

US 9,273,077 · App. 13/842,951 · Granted Mar 1, 2016

Phosphorus derivatives as kinase inhibitors

Inventors: Yihan Wang (Newton, MA); Wei-Sheng Huang (Acton, MA); Shuangying Liu (Wellesley, MA); William C. Shakespeare (Southbourgh, MA); R. Mathew Thomas (Sharon, MA); Jiwei Qi (West Roxbury, MA); Feng Li (Winchester, MA); Xiaotian Zhu (Newton, MA); Anna Kohlmann (Winchester, MA); David C. Dalgarno (Brookline, MA); Jan Antoinette C. Romero (Somerville, MA); Dong Zou (Concord, MA)

Assignee: ARIAD Pharmaceuticals, Inc.

C07F9/65583 C07F9/588 C07F9/60 C07F9/6561 C07F9/6584 C07F9/65127 C07F9/65217 C07F9/65586 C07F9/65616 C07F9/65685 C07F9/650941 C07F9/657172

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Quick Facts

Patent No.: US 9,273,077
App. No.: 13/842,951
Granted: Mar 1, 2016
Kind: B2

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Abstract

The invention features compounds of the general formula: in which the variable groups are as defined herein, and to their preparation and use as protein kinase inhibitors.

Claims (203)

1. A method for treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula VIa

wherein

X 1 is NR b1 or CR b ;

X 3 is NR d1 or CR d ;

X 4 is NR e1 or CR e ;

Ring A and Ring E are each an independently selected aryl or heteroaryl ring, the heteroaryl ring being a 5- or 6-membered ring containing 1 to 4 heteroatoms selected from N, O and S(O) r ;

each R a , R b , R d , R e , and R g is independently halo, —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R 3a ) 3 , —NR 1 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 1 R 2 or and —NR 1 SO 2 NR 1 R 2 ; provided that at least one of R a and R g is or includes —P(═O)(R 3 ) 2 or a ring system containing —P(═O)(R 3 )— as a ring member;

and R b1 , R d1 and R e1 are absent;

or alternatively two adjacent substituents selected from R d , R d1 , R e , and R e1 , or two adjacent R a form, with the atoms to which they are attached, a fused, 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which contains 0-4 heteroatoms selected from N, O and S(O) r and which may bear up to four substituents;

L is O or NH;

r is 0, 1 or 2;

s is 1, 2, 3, 4 or 5;

p is 1, 2, 3 or 4;

each Y is independently a bond, —O—, —S— or —NR 1 —;

each R 1 and R 2 is independently H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl;

each R 3 is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl, or two adjacent R 3 combine to form a ring system including a phosphorous atom;

each R 3a is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, or heteroaryl;

alternatively, each NR 1 R 2 may be a 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 additional heteroatoms selected from N, O and S(O) r ; and

each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclic is optionally substituted;

or a pharmaceutically acceptable salt thereof;

wherein the cancer is selected from anaplastic large cell lymphoma, neuroblastomas, neuroectodermal tumors, glioblastoma, breast cancer, melanoma, inflammatory myofibroblastic tumors, squamous cell carcinoma, and non-small cell lung cancer.

2. A method for treating an ALK-driven cancer in a subject, the method comprising (a) providing a subject having an ALK-driven cancer characterized by the presence of an ALK gene or an ALK genetic translocation, and (b) administering to said subject a therapeutically effective amount of a compound of Formula VIa:

wherein

X 1 is NR b1 or CR b ;

X 3 is NR d1 or CR d ;

X 4 is NR e1 or CR e ;

Ring A and Ring E are each an independently selected aryl or heteroaryl ring, the heteroaryl ring being a 5- or 6-membered ring containing 1 to 4 heteroatoms selected from N, O and S(O) r ;

and R b1 , R d1 and R e1 are absent;

L is O or NH;

r is 0, 1 or 2;

s is 1, 2, 3, 4 or 5;

p is 1, 2, 3 or 4;

each Y is independently a bond, —O—, —S— or —NR 1 —;

each R 1 and R 2 is independently H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl;

each R 3a is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, or heteroaryl;

each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclic is optionally substituted;

or a pharmaceutically acceptable salt thereof.

3. The method of claim 2 , wherein said ALK-driven cancer is characterized by the presence of an ALK translocation.

4. The method of any of claims 1 - 3 , wherein the cancer is a non-small cell lung cancer (NSCLC).

5. A method of inhibiting the proliferation of a cell expressing ALK or an ALK translocation, the method comprising contacting the cell with a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit the proliferation.

6. The method of claim 5 , wherein the cell is a cancer cell in a patient and the compound or pharmaceutically acceptable salt thereof is administered to the patient.

7. The method of claim 1 or 2 , wherein the compound of Formula VIa is a compound of Formula VIA-i:

8. The method of claim 7 , wherein R d is selected from F, Cl, C1-C4 alkyl, cyclopropyl, CF 3 , OMe, or OCF 3 .

9. The method of claim 7 , wherein the ortho R a is selected from H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and —P(O)(R 3 ) 2 .

10. The method of claim 7 , wherein the para R a is selected from halo, —CN, —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —YP(═O)(YR 3 )(YR 3 ), —NR 1 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 1 R 2 and —NR 1 SO 2 NR 1 R 2 .

11. The method of claim 7 , wherein Ring E is aryl, and each R g is independently —SO 2 CH 3 , —SO 2 -iPr, —SO 2 NH-iPr, —SONH-nPr, —SO 2 NEt 2 , —P(O)(CH 3 ) 2 , —P(O)(Et) 2 , —P(O)(i-Pr) 2 , Me, OMe, —O-iPr, —OCF 3 , CN, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , or —C(O)NH-iPr.

12. The method of claim 1 , wherein which at least one R g is or contains —P(O)(R 3 ) 2 and the para R a one of the following moieties:

13. The method of claim 1 in which s is 1, 2, 3 or 4, and each of the substituents R a is independently selected from halo, —R 1 , —OR 2 , —NR 1 R 2 and —P(═O)(R 3 ) 2 , wherein each R 1 and R 2 may be further substituted or unsubstituted.

14. The method of claim 1 , wherein at least one substituent R a is —OR 2 and R 2 is selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.

15. The method of claim 1 , wherein at least one substituent R a is a 5-, 6- or 7-membered heterocyclic or 5- or 6-membered heteroaryl, linked to Ring A either directly or by an ether bond, and which may be further substituted with 1, 2 or 3 substituents independently selected from halo, —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R 3a ) 3 , —NR 1 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 1 R 2 and —NR 1 SO 2 NR 1 R 2 ; wherein each Y is independently a bond, —O—, —S— or —NR 1 —.

16. The method of claim 1 , wherein at least one substituent R a is —P(═O)(R 3 ) 2 in which each R 3 is, independently, a C1-C4 alkyl.

17. The method of claim 1 , wherein L is NH, Ring E is aryl, and each R g is independently selected from halo, —R 1 , —OR 2 , —S(O) r R 2 and —P(═O)(R 3 ) 2 .

18. The method of claim 1 , wherein the at least one R g is —P(═O)(R 3 ) 2 and R 3 is —CH 3 or —CH 2 CH 3 .

19. A method for treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from anaplastic large cell lymphoma, neuroblastomas, neuroectodermal tumors, glioblastoma, breast cancer, melanoma, inflammatory myofibroblastic tumors, squamous cell carcinoma, and non-small cell lung cancer.

20. A method for treating non-small cell lung cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof.

21. A method for treating non-small cell lung cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising 5-chloro-N4-[2-(dimethylphosphoryl)-phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. The method of claim 1 or 19 , wherein the cancer is non-small cell lung cancer.

23. The method of claim 1 in which:

(a) X 1 is N, X 3 is N and X 4 is CR e ;

(b) X 1 is N, X 3 is CR d and X 4 is CR e ;

(d) X 1 is CR b , X 3 is CR d and X 4 is CR e .

24. The method of claim 1 in which R d is selected from Cl, F, C1-C4 alkyl, trihaloalkyl, cycloalkyl, C2-C4 alkenyl, and alkynyl.

25. The method of claim 1 in which X 3 is CR d and X 4 is CR e wherein R d and R e , together with the atoms to which they are attached, form a fused, 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which contains 0-4 heteroatoms selected from N, O and S(O) r and which may bear up to four substituents.

26. The method of claim 1 in which s is 1, 2, 3 or 4, and each of the substituents R a is independently selected from halo, —R 1 , —OR 2 , —NR 1 R 2 and —P(═O)(R 3 ) 2 , wherein each R 1 and R 2 may be further substituted or unsubstituted.

27. The method of claim 26 in which at least one substituent R a is —OR 2 and R 2 is selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.

28. The method of claim 26 or 27 in which at least one substituent R a is a 5-, 6- or 7-membered heterocyclic or 5- or 6-membered heteroaryl moiety, linked to Ring A either directly or by an ether bond, and which may be further substituted with 1-3 substituents independently selected from halo, —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R 3a ) 3 , —NR 1 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 1 R 2 and —NR 1 SO 2 NR 1 R 2 ; wherein each Y is independently a bond, —O—, —S— or —NR 1 —.

29. The method of claim 28 in which the heterocyclic or heteroaryl substituent R a is selected from the following:

30. The method of claim 1 in which at least one substituent R a is —P(═O)(R 3 ) 2 in which each R 3 is, independently, a C1-C4 alkyl.

31. The method of claim 1 in which L is NH, Ring E is aryl, and each R g is independently selected from halo, —R 1 , —OR 2 , —S(O) r R 2 and —P(═O)(R 3 ) 2 .

32. The method of claim 31 in which Ring E contains at least one R g in the ortho position, relative to the ring atom attached to L.

33. The method of claim 31 in which Ring E contains at least one R g in the meta position, relative to the ring atom attached to L.

34. The method of claim 31 in which Ring E contains at least one R g in the para position, relative to the ring atom attached to L.

35. The method of any of claims 31 - 34 in which at least one R g is —P(═O)(R 3 ) 2 and is —P(═O)(R 3 ) 2 is —P(═O)(CH 3 ) 2 or —P(═O)(CH 2 CH 3 ) 2 .

36. The method of claim 29 in which L is NH; X 1 is N; X 3 is CR d ; X 4 is CR e ; Ring A is aryl and optionally contains up to two additional R a ; and Ring E is aryl and contains 1-3 R g , one of which being an ortho, meta or para —P(═O)(R 3 ) 2 .

37. The method of claim 1 , wherein the compound of Formula VIa is a compound of Formula VIA-i or Formula VIA-ii:

wherein R f is selected from halo, ═O, ═S, —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R 3a ) 3 , —NR 1 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 1 R 2 or —NR 1 SO 2 NR 1 R 2 ; and

E, R a , R d , R g , R 1 , R 2 , R 3 and p are as defined in claim 1 .

38. The method of claim 37 in which the ortho R a is H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or —P(O)(R 3 ) 2 .

39. The method of claim 37 in which R d is F, Cl, C1-C4 alkyl, cyclopropyl, CF 3 , OMe, or OCF 3 , or R f is H, —CH 3 or halo.

40. The method of claim 38 in which R d is F, Cl, C1-C4 alkyl, cyclopropyl, CF 3 , OMe, or OCF 3 , or R f is H, —CH 3 or halo.

41. The method of claim 1 in which Ring E is aryl, and each R g is independently —SO 2 CH 3 , —SO 2 -iPr, —SO 2 NH-iPr, —SONH-nPr, —SO 2 NEt 2 , —P(O)(CH 3 ) 2 , —P(O)(Et) 2 , —P(O)(Pr) 2 , Me, OMe, —O-iPr, —OCF 3 , CN, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , or —C(O)NH-iPr.

42. The method of claim 37 in which Ring E is aryl, and each R g is independently —SO 2 CH 3 , —SO 2 -iPr, —SO 2 NH-iPr, —SONH-nPr, —SO 2 NEt 2 , —P(O)(CH 3 ) 2 , —P(O)(Et) 2 , —P(O)(Pr) 2 , Me, OMe, —O-iPr, —OCF 3 , CN, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , or —C(O)NH-iPr.

43. The method of claim 38 in which Ring E is aryl, and each R g is independently —SO 2 CH 3 , —SO 2 -iPr, —SO 2 NH-iPr, —SONH-nPr, —SO 2 NEt 2 , —P(O)(CH 3 ) 2 , —P(O)(Et) 2 , —P(O)(Pr) 2 , Me, OMe, —O-iPr, —OCF 3 , CN, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , or —C(O)NH-iPr.

44. The method of claim 39 in which Ring E is aryl, and each R g is independently —SO 2 CH 3 , —SO 2 -iPr, —SO 2 NH-iPr, —SONH-nPr, —SO 2 NEt 2 , —P(O)(CH 3 ) 2 , —P(O)(Et) 2 , —P(O)(Pr) 2 , Me, OMe, —O-iPr, —OCF 3 , CN, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , or —C(O)NH-iPr.

45. The method of claim 40 in which Ring E is aryl, and each R g is independently —SO 2 CH 3 , —SO 2 -iPr, —SO 2 NH-iPr, —SONH-nPr, —SO 2 NEt 2 , —P(O)(CH 3 ) 2 , —P(O)(Et) 2 , —P(O)(Pr) 2 , Me, OMe, —O-iPr, —OCF 3 , CN, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , or —C(O)NH-iPr.

46. The method of any of claim 37 - 40 , 44 or 45 in which the para R a is or contains —P(O)(R 3 ) 2 or is one of the following:

47. The method of any of claim 37 - 40 , 44 or 45 in which at least one Fe is or contains —P(O)(R 3 ) 2 and the para R a one of the following:

48. The method of claim 1 wherein the compound is selected from the following:

or a pharmaceutically acceptable salt thereof.

49. The method of claim 1 wherein the compound is selected from the following:

6-chloro-N-(3,5-dimethylphenyl)-N′-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazine-2,4-diamine;

6-chloro-N3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N5-phenyl-1,2,4-triazine-3,5-diamine;

6-chloro-N3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;

6-chloro-N5-[4-(dimethylphosphoryl)phenyl]-N3-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-1,2,4-triazine-3,5-diamine;

6-chloro-N3-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;

6-chloro-N3-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;

N5-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N3-{2-methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazine-3,5-diamine;

6-chloro-N3-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;

6-chloro-N3-[4-(dimethylphosphoryl)-2-methylphenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;

6-chloro-N3-[4-(dimethylphosphoryl)-2-ethylphenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;

6-chloro-N3-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;

6-chloro-N3-[2-chloro-4-(dimethylphosphoryl)phenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;

6-chloro-N3-[4-(dimethylphosphoryl)-2-fluorophenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;

6-chloro-N3-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;

6-chloro-N3-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;

6-chloro-N3-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; and,

6-chloro-N3-[4-(diethylphosphoryl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;

or a pharmaceutically acceptable salt thereof.

50. The method of claim 1 wherein the compound is selected from the following:

5-chloro-N4-[4-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine;

5-chloro-N2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N4-[4-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine;

5-chloro-N4-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N2-[5-(propan-2-yl)-1,3-oxazol-2-yl]pyrimidine-2,4-diamine;

5-chloro-N2-[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-N4-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidine-2,4-diamine;

N2-[5-(1,4′-bipiperidin-1′-yl)-1,3,4-thiadiazol-2-yl]-5-chloro-N4-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidine-2,4-diamine;

5-chloro-N4-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N2-{5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-yl}pyrimidine-2,4-diamine;

5-chloro-N2-(5-cyclopropyl-1,3-oxazol-2-yl)-N4-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl]piperidin-1-yl]phenyl}pyrimidine-2,4-diamine;

5-chloro-N2-(5-cyclopropyl-1,3-oxazol-2-yl)-N4-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidine-2,4-diamine;

5-chloro-N2-(2-cyclopropyl-1,3-oxazol-5-yl)-N4-[4-(diethylphosphoryl)-2-methoxyphenyl]pyrimidine-2,4-diamine;

N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-2-methyl-N′-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine;

N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N′-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-4,6-diamine;

6-chloro-N5-[4-(dimethylphosphoryl)phenyl]-N3-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-1,2,4-triazine-3,5-diamine;

N5-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N3-{2-methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazine-3,5-diamine; and,

5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine;

or a pharmaceutically acceptable salt thereof.

51. The method of claim 1 wherein the compound is selected from the following:

N4-(3,5-dimethylphenyl)-N2-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine;

5-chloro-N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-phenylpyrimidine-2,4-diamine;

N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine;

5-chloro-N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

5-chloro-N2-[4-(dimethylphosphoryl)phenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

5-chloro-N4-[4-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine;

N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

5-Chloro-N2-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

5-Chloro-N2-[4-(dimethylphosphoryl)-2-methylphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

5-Chloro-N2-[4-(dimethylphosphoryl)-2-ethylphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

5-Chloro-N2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

5-Chloro-N2-[2-chloro-4-(dimethylphosphoryl)phenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

5-Chloro-N2-[4-(dimethylphosphoryl)-2-fluorophenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4,5-triamine;

N2-[2-methoxy-4-(4-oxido-1,4-azaphosphinan-4-yl)phenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

5-chloro-N2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

5-chloro-N2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

5-chloro-N2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N4-phenylpyrimidine-2,4-diamine;

N2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine;

5-chloro-N2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N4-[4-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine;

5-chloro-N2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N4-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine;

N2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

N2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-methyl-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;

5-chloro-N4-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N2-[5-(propan-2-yl)-1,3-oxazol-2-yl]pyrimidine-2,4-diamine;

5-chloro-N2-[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-N4-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidine-2,4-diamine;

N2-[5-(1,4′-bipiperidin-1′-yl)-1,3,4-thiadiazol-2-yl]-5-chloro-N4-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidine-2,4-diamine;

5-chloro-N4-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N2-{5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-yl}pyrimidine-2,4-diamine;

5-chloro-N2-(5-cyclopropyl-1,3-oxazol-2-yl)-N4-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine;

5-chloro-N2-(5-cyclopropyl-1,3-oxazol-2-yl)-N4-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidine-2,4-diamine;

5-chloro-N2-(2-cyclopropyl-1,3-oxazol-5-yl)-N4-[4-(diethylphosphoryl)-2-methoxyphenyl]pyrimidine-2,4-diamine;

N-(3,5-dimethylphenyl)-N′-[4-(dimethylphosphoryl)phenyl]pyrimidine-4,6-diamine;

N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-2-methyl-N′-phenylpyrimidine-4,6-diamine;

N3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine;

N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridazin-3-amine;

N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-2-methyl-N′-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine;

N-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N′-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine;

N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N′-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine;

N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N′-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine;

N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyridine-2,4-diamine;

N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine;

N2-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine;

N2-[4-(dimethylphosphoryl)-2-methylphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine;

N2-[4-(dimethylphosphoryl)-2-ethylphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine;

N2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine;

N2-[2-chloro-4-(dimethylphosphoryl)phenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine;

N2-[4-(dimethylphosphoryl)-2-fluorophenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine;

N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N′-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-4,6-diamine;

N3-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine;

N3-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine;

N3-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}-N5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine;

N3-[4-(diethylphosphoryl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine;