Claims for Patent: 9,273,077

Summary for Patent: 9,273,077

Title:	Phosphorus derivatives as kinase inhibitors
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.
Inventor(s):	Yihan Wang, Wei-Sheng Huang, Shuangying Liu, William C. Shakespeare, R. Mathew Thomas, Jiwei Qi, Feng Li, Xiaotian Zhu, Anna Kohlmann, David C. Dalgarno, Jan Antoinette C. Romero, Dong Zou
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US13/842,951
Patent Claims:	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 X1 is NRb1 or CRb; X3 is NRd1 or CRd; X4 is NRe1 or CRe; 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 Ra, Rb, Rd, Re, and Rg is independently halo, —CN, —NO2, —R1, —OR2, —O—NR1R2, —NR1R2, —NR1—NR1R2, —NR1—OR2, —C(O)YR2, —OC(O)YR2, —NR1C(O)YR2, —SC(O)YR2, —NR1C(═S)YR2, —OC(═S)YR2, —C(═S)YR2, —YC(═NR1)YR2, —YC(═N—OR1)YR2, —YC(═N—NR1R2)YR2, —YP(═O)(YR3)(YR3), —Si(R3a)3, —NR1SO2R2, —S(O)rR2, —SO2NR1R2 or and —NR1SO2NR1R2; provided that at least one of Ra and Rg is or includes —P(═O)(R3)2 or a ring system containing —P(═O)(R3)— as a ring member; and Rb1, Rd1 and Re1 are absent; or alternatively two adjacent substituents selected from Rd, Rd1, Re, and Re1, or two adjacent Ra 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 —NR1—; each R1 and R2 is independently H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl; each R3 is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl, or two adjacent R3 combine to form a ring system including a phosphorous atom; each R3a is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, or heteroaryl; alternatively, each NR1R2 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 X1 is NRb1 or CRb; X3 is NRd1 or CRd; X4 is NRe1 or CRe; 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 Ra, Rb, Rd, Re, and Rg is independently halo, —CN, —NO2, —R1, —OR2, —O—NR1R2, —NR1R2, —NR1—NR1R2, —NR1—OR2, —C(O)YR2, —OC(O)YR2, —NR1C(O)YR2, —SC(O)YR2, —NR1C(═S)YR2, —OC(═S)YR2, —C(═S)YR2, —YC(═NR1)YR2, —YC(═N—OR1)YR2, —YC(═N—NR1R2)YR2, —YP(═O)(YR3)(YR3), —Si(R3a)3, —NR1SO2R2, —S(O)rR2, —SO2NR1R2 or and —NR1SO2NR1R2; provided that at least one of Ra and Rg is or includes —P(═O)(R3)2 or a ring system containing —P(═O)(R3)— as a ring member; and Rb1, Rd1 and Re1 are absent; or alternatively two adjacent substituents selected from Rd, Rd1, Re, and Re1, or two adjacent Ra 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 —NR1—; each R1 and R2 is independently H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl; each R3 is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl, or two adjacent R3 combine to form a ring system including a phosphorous atom; each R3a is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, or heteroaryl; alternatively, each NR1R2 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. 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 Rd is selected from F, Cl, C1-C4 alkyl, cyclopropyl, CF3, OMe, or OCF3. 9. The method of claim 7, wherein the ortho Ra is selected from H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and —P(O)(R3)2. 10. The method of claim 7, wherein the para Ra is selected from halo, —CN, —R1, —OR2, —O—NR1R2, —NR1R2, —NR1—NR1R2, —NR1—OR2, —C(O)YR2, —OC(O)YR2, —NR1C(O)YR2, —SC(O)YR2, —NR1C(═S)YR2, —YP(═O)(YR3)(YR3), —NR1SO2R2, —S(O)rR2, —SO2NR1R2 and —NR1SO2NR1R2. 11. The method of claim 7, wherein Ring E is aryl, and each Rg is independently —SO2CH3, —SO2-iPr, —SO2NH-iPr, —SONH-nPr, —SO2NEt2, —P(O)(CH3)2, —P(O)(Et)2, —P(O)(i-Pr)2, Me, OMe, —O-iPr, —OCF3, CN, —C(O)CH3, —C(O)NH2, —C(O)NHCH3, or —C(O)NH-iPr. 12. The method of claim 1, wherein which at least one Rg is or contains —P(O)(R3)2 and the para Ra 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 Ra is independently selected from halo, —R1, —OR2, —NR1R2 and —P(═O)(R3)2, wherein each R1 and R2 may be further substituted or unsubstituted. 14. The method of claim 1, wherein at least one substituent Ra is —OR2 and R2 is selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl. 15. The method of claim 1, wherein at least one substituent Ra 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, —NO2, —R1, —OR2, —O—NR1R2, —NR1R2, —NR1—NR1R2, —NR1—OR2, —C(O)YR2, —OC(O)YR2, —NR1C(O)YR2, —SC(O)YR2, —NR1C(═S)YR2, —OC(═S)YR2, —C(═S)YR2, —YC(═NR1)YR2, —YC(═N—OR1)YR2, —YC(═N—NR1R2)YR2, —YP(═O)(YR3)(YR3), —Si(R3a)3, —NR1SO2R2, —S(O)rR2, —SO2NR1R2 and —NR1SO2NR1R2; wherein each Y is independently a bond, —O—, —S— or —NR1—. 16. The method of claim 1, wherein at least one substituent Ra is —P(═O)(R3)2 in which each R3 is, independently, a C1-C4 alkyl. 17. The method of claim 1, wherein L is NH, Ring E is aryl, and each Rg is independently selected from halo, —R1, —OR2, —S(O)rR2and —P(═O)(R3)2. 18. The method of claim 1, wherein the at least one Rg is —P(═O)(R3)2 and R3 is —CH3 or —CH2CH3. 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) X1 is N, X3 is N and X4 is CRe; (b) X1 is N, X3 is CRd and X4 is CRe; (c) X1 is CRb, X3 is N and X4 is CRe; or (d) X1 is CRb, X3 is CRd and X4 is CRe. 24. The method of claim 1 in which Rd is selected from Cl, F, C1-C4 alkyl, trihaloalkyl, cycloalkyl, C2-C4 alkenyl, and alkynyl. 25. The method of claim 1 in which X3 is CRd and X4 is CRe wherein Rd and Re, 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 Ra is independently selected from halo, —R1, —OR2, —NR1R2 and —P(═O)(R3)2, wherein each R1 and R2 may be further substituted or unsubstituted. 27. The method of claim 26 in which at least one substituent Ra is —OR2 and R2 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 Ra 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, —NO2, —R1, —OR2, —O—NR1R2, —NR1R2, —NR1—NR1R2, —NR1—OR2, —C(O)YR2, —OC(O)YR2, —NR1C(O)YR2, —SC(O)YR2, —NR1C(═S)YR2, —OC(═S)YR2, —C(═S)YR2, —YC(═NR1)YR2, —YC(═N—OR1)YR2, —YC(═N—NR1R2)YR2, —YP(═O)(YR3)(YR3), —Si(R3a)3, —NR1SO2R2, —S(O)rR2, —SO2NR1R2 and —NR1SO2NR1R2; wherein each Y is independently a bond, —O—, —S— or —NR1—. 29. The method of claim 28 in which the heterocyclic or heteroaryl substituent Ra is selected from the following: 30. The method of claim 1 in which at least one substituent Ra is —P(═O)(R3)2 in which each R3 is, independently, a C1-C4 alkyl. 31. The method of claim 1 in which L is NH, Ring E is aryl, and each Rg is independently selected from halo, —R1, —OR2, —S(O)rR2and —P(═O)(R3)2. 32. The method of claim 31 in which Ring E contains at least one Rg 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 Rg 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 Rg 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 Rg is —P(═O)(R3)2 and is —P(═O)(R3)2 is —P(═O)(CH3)2 or —P(═O)(CH2CH3)2. 36. The method of claim 29 in which L is NH; X1 is N; X3 is CRd; X4 is CRe; Ring A is aryl and optionally contains up to two additional Ra; and Ring E is aryl and contains 1-3 Rg, one of which being an ortho, meta or para —P(═O)(R3)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 Rf is selected from halo, ═O, ═S, —CN, —NO2, —R1, —OR2, —O—NR1R2, —NR1R2, —NR1—NR1R2, —NR1—OR2, —C(O)YR2, —OC(O)YR2, —NR1C(O)YR2, —SC(O)YR2, —NR1C(═S)YR2, —OC(═S)YR2, —C(═S)YR2, —YC(═NR1)YR2, —YC(═N—OR1)YR2, —YC(═N—NR1R2)YR2, —YP(═O)(YR3)(YR3), —Si(R3a)3, —NR1SO2R2, —S(O)rR2, —SO2NR1R2 or —NR1SO2NR1R2; and E, Ra, Rd, Rg, R1, R2, R3 and p are as defined in claim 1. 38. The method of claim 37 in which the ortho Ra is H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or —P(O)(R3)2. 39. The method of claim 37 in which Rd is F, Cl, C1-C4 alkyl, cyclopropyl, CF3, OMe, or OCF3, or Rf is H, —CH3 or halo. 40. The method of claim 38 in which Rd is F, Cl, C1-C4 alkyl, cyclopropyl, CF3, OMe, or OCF3, or Rf is H, —CH3 or halo. 41. The method of claim 1 in which Ring E is aryl, and each Rg is independently —SO2CH3, —SO2-iPr, —SO2NH-iPr, —SONH-nPr, —SO2NEt2, —P(O)(CH3)2, —P(O)(Et)2, —P(O)(Pr)2, Me, OMe, —O-iPr, —OCF3, CN, —C(O)CH3, —C(O)NH2, —C(O)NHCH3, or —C(O)NH-iPr. 42. The method of claim 37 in which Ring E is aryl, and each Rg is independently —SO2CH3, —SO2-iPr, —SO2NH-iPr, —SONH-nPr, —SO2NEt2, —P(O)(CH3)2, —P(O)(Et)2, —P(O)(Pr)2, Me, OMe, —O-iPr, —OCF3, CN, —C(O)CH3, —C(O)NH2, —C(O)NHCH3, or —C(O)NH-iPr. 43. The method of claim 38 in which Ring E is aryl, and each Rg is independently —SO2CH3, —SO2-iPr, —SO2NH-iPr, —SONH-nPr, —SO2NEt2, —P(O)(CH3)2, —P(O)(Et)2, —P(O)(Pr)2, Me, OMe, —O-iPr, —OCF3, CN, —C(O)CH3, —C(O)NH2, —C(O)NHCH3, or —C(O)NH-iPr. 44. The method of claim 39 in which Ring E is aryl, and each Rg is independently —SO2CH3, —SO2-iPr, —SO2NH-iPr, —SONH-nPr, —SO2NEt2, —P(O)(CH3)2, —P(O)(Et)2, —P(O)(Pr)2, Me, OMe, —O-iPr, —OCF3, CN, —C(O)CH3, —C(O)NH2, —C(O)NHCH3, or —C(O)NH-iPr. 45. The method of claim 40 in which Ring E is aryl, and each Rg is independently —SO2CH3, —SO2-iPr, —SO2NH-iPr, —SONH-nPr, —SO2NEt2, —P(O)(CH3)2, —P(O)(Et)2, —P(O)(Pr)2, Me, OMe, —O-iPr, —OCF3, CN, —C(O)CH3, —C(O)NH2, —C(O)NHCH3, or —C(O)NH-iPr. 46. The method of any of claim 37-40, 44 or 45 in which the para Ra is or contains —P(O)(R3)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)(R3)2 and the para Ra 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; 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; 6-chloro-N3-[4-(diethylphosphoryl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsulfonyl)phenyl]-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.