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: ##STR00001## in which the variable groups are as defined herein, and to their preparation and use as protein kinase inhibitors.
Inventor(s):	Wang; Yihan (Newton, MA), Huang; Wei-Sheng (Acton, MA), Liu; Shuangying (Wellesley, MA), Shakespeare; William C. (Southbourgh, MA), Thomas; R. Mathew (Sharon, MA), Qi; Jiwei (West Roxbury, MA), Li; Feng (Winchester, MA), Zhu; Xiaotian (Newton, MA), Kohlmann; Anna (Winchester, MA), Dalgarno; David C. (Brookline, MA), Romero; Jan Antoinette C. (Somerville, MA), Zou; Dong (Concord, MA)
Assignee:	ARIAD Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	13/842,951
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 ##STR00451## wherein X.sup.1 is NR.sup.b1 or CR.sup.b; X.sup.3 is NR.sup.d1 or CR.sup.d; X.sup.4 is NR.sup.e1 or CR.sup.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).sub.r; each R.sup.a, R.sup.b, R.sup.d, R.sup.e, and R.sup.g is independently halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3, --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2 or and --NR.sup.1SO.sub.2NR.sup.1R.sup.2; provided that at least one of R.sup.a and R.sup.g is or includes --P(.dbd.O)(R.sup.3).sub.2 or a ring system containing --P(.dbd.O)(R.sup.3)-- as a ring member; and R.sup.b1, R.sup.d1 and R.sup.e1 are absent; or alternatively two adjacent substituents selected from R.sup.d, R.sup.d1, R.sup.e, and R.sup.e1, or two adjacent R.sup.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).sub.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.sup.1--; each R.sup.1 and R.sup.2 is independently H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl; each R.sup.3 is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl, or two adjacent R.sup.3 combine to form a ring system including a phosphorous atom; each R.sup.3a is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, or heteroaryl; alternatively, each NR.sup.1R.sup.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).sub.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: ##STR00452## wherein X.sup.1 is NR.sup.b1 or CR.sup.b; X.sup.3 is NR.sup.d1 or CR.sup.d; X.sup.4 is NR.sup.e1 or CR.sup.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).sub.r; each R.sup.a, R.sup.b, R.sup.d, R.sup.e, and R.sup.g is independently halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3, --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2 or and --NR.sup.1SO.sub.2NR.sup.1R.sup.2; provided that at least one of R.sup.a and R.sup.g is or includes --P(.dbd.O)(R.sup.3).sub.2 or a ring system containing --P(.dbd.O)(R.sup.3)-- as a ring member; and R.sup.b1, R.sup.d1 and R.sup.e1 are absent; or alternatively two adjacent substituents selected from R.sup.d, R.sup.d1, R.sup.e, and R.sup.e1, or two adjacent R.sup.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).sub.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.sup.1--; each R.sup.1 and R.sup.2 is independently H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl; each R.sup.3 is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl, or two adjacent R.sup.3 combine to form a ring system including a phosphorous atom; each R.sup.3a is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, or heteroaryl; alternatively, each NR.sup.1R.sup.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).sub.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: ##STR00453## 8. The method of claim 7, wherein R.sup.d is selected from F, Cl, C1-C4 alkyl, cyclopropyl, CF.sub.3, OMe, or OCF.sub.3. 9. The method of claim 7, wherein the ortho R.sup.a is selected from H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and --P(O)(R.sup.3).sub.2. 10. The method of claim 7, wherein the para R.sup.a is selected from halo, --CN, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --YP(.dbd.O)(YR.sup.3)(YR.sup.3), --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2. 11. The method of claim 7, wherein Ring E is aryl, and each R.sup.g is independently --SO.sub.2CH.sub.3, --SO.sub.2-iPr, --SO.sub.2NH-iPr, --SONH-nPr, --SO.sub.2NEt.sub.2, --P(O)(CH.sub.3).sub.2, --P(O)(Et).sub.2, --P(O)(i-Pr).sub.2, Me, OMe, --O-iPr, --OCF.sub.3, CN, --C(O)CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3, or --C(O)NH-iPr. 12. The method of claim 1, wherein which at least one R.sup.g is or contains --P(O)(R.sup.3).sub.2 and the para R.sup.a one of the following moieties: ##STR00454## ##STR00455## ##STR00456## 13. The method of claim 1 in which s is 1, 2, 3 or 4, and each of the substituents R.sup.a is independently selected from halo, --R.sup.1, --OR.sup.2, --NR.sup.1R.sup.2 and --P(.dbd.O)(R.sup.3).sub.2, wherein each R.sup.1 and R.sup.2 may be further substituted or unsubstituted. 14. The method of claim 1, wherein at least one substituent R.sup.a is --OR.sup.2 and R.sup.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.sup.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.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3, --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2; wherein each Y is independently a bond, --O--, --S-- or --NR.sup.1--. 16. The method of claim 1, wherein at least one substituent R.sup.a is --P(.dbd.O)(R.sup.3).sub.2 in which each R.sup.3 is, independently, a C1-C4 alkyl. 17. The method of claim 1, wherein L is NH, Ring E is aryl, and each R.sup.g is independently selected from halo, --R.sup.1, --OR.sup.2, --S(O).sub.rR.sup.2and --P(.dbd.O)(R.sup.3).sub.2. 18. The method of claim 1, wherein the at least one R.sup.g is --P(.dbd.O)(R.sup.3).sub.2 and R.sup.3 is --CH.sub.3 or --CH.sub.2CH.sub.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-methylpi- perazin-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-methylp- iperazin-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.sup.1 is N, X.sup.3 is N and X.sup.4 is CR.sup.e; (b) X.sup.1 is N, X.sup.3 is CR.sup.d and X.sup.4 is CR.sup.e; (c) X.sup.1 is CR.sup.b, X.sup.3 is N and X.sup.4 is CR.sup.e; or (d) X.sup.1 is CR.sup.b, X.sup.3 is CR.sup.d and X.sup.4 is CR.sup.e. 24. The method of claim 1 in which R.sup.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.sup.3 is CR.sup.d and X.sup.4 is CR.sup.e wherein R.sup.d and R.sup.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).sub.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.sup.a is independently selected from halo, --R.sup.1, --OR.sup.2, --NR.sup.1R.sup.2 and --P(.dbd.O)(R.sup.3).sub.2, wherein each R.sup.1 and R.sup.2 may be further substituted or unsubstituted. 27. The method of claim 26 in which at least one substituent R.sup.a is --OR.sup.2 and R.sup.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.sup.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.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3, --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2; wherein each Y is independently a bond, --O--, --S-- or --NR.sup.1--. 29. The method of claim 28 in which the heterocyclic or heteroaryl substituent R.sup.a is selected from the following: ##STR00457## ##STR00458## ##STR00459## 30. The method of claim 1 in which at least one substituent R.sup.a is --P(.dbd.O)(R.sup.3).sub.2 in which each R.sup.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.sup.g is independently selected from halo, --R.sup.1, --OR.sup.2, --S(O).sub.rR.sup.2and --P(.dbd.O)(R.sup.3).sub.2. 32. The method of claim 31 in which Ring E contains at least one R.sup.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.sup.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.sup.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.sup.g is --P(.dbd.O)(R.sup.3).sub.2 and is --P(.dbd.O)(R.sup.3).sub.2 is --P(.dbd.O)(CH.sub.3).sub.2 or --P(.dbd.O)(CH.sub.2CH.sub.3).sub.2. 36. The method of claim 29 in which L is NH; X.sup.1 is N; X.sup.3 is CR.sup.d; X.sup.4 is CR.sup.e; Ring A is aryl and optionally contains up to two additional R.sup.a; and Ring E is aryl and contains 1-3 R.sup.g, one of which being an ortho, meta or para --P(.dbd.O)(R.sup.3).sub.2. 37. The method of claim 1, wherein the compound of Formula VIa is a compound of Formula VIA-i or Formula VIA-ii: ##STR00460## wherein R.sup.f is selected from halo, .dbd.O, .dbd.S, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3, --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2 or --NR.sup.1SO.sub.2NR.sup.1R.sup.2; and E, R.sup.a, R.sup.d, R.sup.g, R.sup.1, R.sup.2, R.sup.3 and p are as defined in claim 1. 38. The method of claim 37 in which the ortho R.sup.a is H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or --P(O)(R.sup.3).sub.2. 39. The method of claim 37 in which R.sup.d is F, Cl, C1-C4 alkyl, cyclopropyl, CF.sub.3, OMe, or OCF.sub.3, or R.sup.f is H, --CH.sub.3 or halo. 40. The method of claim 38 in which R.sup.d is F, Cl, C1-C4 alkyl, cyclopropyl, CF.sub.3, OMe, or OCF.sub.3, or R.sup.f is H, --CH.sub.3 or halo. 41. The method of claim 1 in which Ring E is aryl, and each R.sup.g is independently --SO.sub.2CH.sub.3, --SO.sub.2-iPr, --SO.sub.2NH-iPr, --SONH-nPr, --SO.sub.2NEt.sub.2, --P(O)(CH.sub.3).sub.2, --P(O)(Et).sub.2, --P(O)(Pr).sub.2, Me, OMe, --O-iPr, --OCF.sub.3, CN, --C(O)CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3, or --C(O)NH-iPr. 42. The method of claim 37 in which Ring E is aryl, and each R.sup.g is independently --SO.sub.2CH.sub.3, --SO.sub.2-iPr, --SO.sub.2NH-iPr, --SONH-nPr, --SO.sub.2NEt.sub.2, --P(O)(CH.sub.3).sub.2, --P(O)(Et).sub.2, --P(O)(Pr).sub.2, Me, OMe, --O-iPr, --OCF.sub.3, CN, --C(O)CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3, or --C(O)NH-iPr. 43. The method of claim 38 in which Ring E is aryl, and each R.sup.g is independently --SO.sub.2CH.sub.3, --SO.sub.2-iPr, --SO.sub.2NH-iPr, --SONH-nPr, --SO.sub.2NEt.sub.2, --P(O)(CH.sub.3).sub.2, --P(O)(Et).sub.2, --P(O)(Pr).sub.2, Me, OMe, --O-iPr, --OCF.sub.3, CN, --C(O)CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3, or --C(O)NH-iPr. 44. The method of claim 39 in which Ring E is aryl, and each R.sup.g is independently --SO.sub.2CH.sub.3, --SO.sub.2-iPr, --SO.sub.2NH-iPr, --SONH-nPr, --SO.sub.2NEt.sub.2, --P(O)(CH.sub.3).sub.2, --P(O)(Et).sub.2, --P(O)(Pr).sub.2, Me, OMe, --O-iPr, --OCF.sub.3, CN, --C(O)CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3, or --C(O)NH-iPr. 45. The method of claim 40 in which Ring E is aryl, and each R.sup.g is independently --SO.sub.2CH.sub.3, --SO.sub.2-iPr, --SO.sub.2NH-iPr, --SONH-nPr, --SO.sub.2NEt.sub.2, --P(O)(CH.sub.3).sub.2, --P(O)(Et).sub.2, --P(O)(Pr).sub.2, Me, OMe, --O-iPr, --OCF.sub.3, CN, --C(O)CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3, or --C(O)NH-iPr. 46. The method of any of claim 37-40, 44 or 45 in which the para R.sup.a is or contains --P(O)(R.sup.3).sub.2 or is one of the following: ##STR00461## ##STR00462## ##STR00463## ##STR00464## 47. The method of any of claim 37-40, 44 or 45 in which at least one Fe is or contains --P(O)(R.sup.3).sub.2 and the para R.sup.a one of the following: ##STR00465## ##STR00466## ##STR00467## ##STR00468## 48. The method of claim 1 wherein the compound is selected from the following: ##STR00469## ##STR00470## ##STR00471## 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-t- riazine-2,4-diamine; 6-chloro-N3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N5-phenyl-1,2,4-tria- zine-3,5-diamine; 6-chloro-N3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsu- lfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N5-[4-(dimethylphosphoryl)phenyl]-N3-{2-methoxy-4-[4-(4-methylpi- perazin-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-dia- mine; 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-ylsul- fonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N3-[4-(dimethylphosphoryl)-2-ethylphenyl]-N5-[2-(propan-2-ylsulf- onyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N3-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N5-[2-(pr- opan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N3-[2-chloro-4-(dimethylphosphoryl)phenyl]-N5-[2-(propan-2-ylsul- fonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N3-[4-(dimethylphosphoryl)-2-fluorophenyl]-N5-[2-(propan-2-ylsul- fonyl)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)pipe- ridin-1-yl]phenyl}-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-d- iamine; and, 6-chloro-N3-[4-(diethylphosphoryl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsul- fonyl)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-methylpi- perazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine; 5-chloro-N2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N4-[4-(dimethy- lphosphoryl)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-(dim- ethylphosphoryl)-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-diami- ne; 5-chloro-N2-(5-cyclopropyl-1,3-oxazol-2-yl)-N4-{2-methoxy-4-[4-(4-meth- yl-4-oxido-1,4-azaphosphinan-1-yl]piperidin-1-yl]phenyl}pyrimidine-2,4-dia- mine; 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-m- ethoxyphenyl]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-methylpi- perazin-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-dia- mine; 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-(trifluoromet- hyl)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)ph- enyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine; 5-chloro-N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsu- lfonyl)phenyl]pyrimidine-2,4-diamine; 5-chloro-N2-[4-(dimethylphosphoryl)phenyl]-N4-[2-(propan-2-ylsulfonyl)phe- nyl]pyrimidine-2,4-diamine; 5-chloro-N4-[4-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpi- perazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine; N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)ph- enyl]pyrimidine-2,4-diamine; N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N4-[2-(propan-2-ylsu- lfonyl)phenyl]pyrimidine-2,4-diamine; 5-Chloro-N2-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsu- lfonyl)phenyl]pyrimidine-2,4-diamine; 5-Chloro-N2-[4-(dimethylphosphoryl)-2-methylphenyl]-N4-[2-(propan-2-ylsul- fonyl)phenyl]pyrimidine-2,4-diamine; 5-Chloro-N2-[4-(dimethylphosphoryl)-2-ethylphenyl]-N4-[2-(propan-2-ylsulf- onyl)phenyl]pyrimidine-2,4-diamine; 5-Chloro-N2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N4-[2-(pr- opan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; 5-Chloro-N2-[2-chloro-4-(dimethylphosphoryl)phenyl]-N4-[2-(propan-2-ylsul- fonyl)phenyl]pyrimidine-2,4-diamine; 5-Chloro-N2-[4-(dimethylphosphoryl)-2-fluorophenyl]-N4-[2-(propan-2-ylsul- fonyl)phenyl]pyrimidine-2,4-diamine; N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)ph- enyl]pyrimidine-2,4,5-triamine; N2-[2-methoxy-4-(4-oxido-1,4-azaphosphinan-4-yl)phenyl]-N4-[2-(propan-2-y- lsulfonyl)phenyl]pyrimidine-2,4-diamine; N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)ph- enyl]-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-phenylpyrim- idine-2,4-diamine; N2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N4-[2-(propan-2-ylsulfo- nyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine; N2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N4-[2-(propan-2-ylsulfo- nyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine; 5-chloro-N2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N4-[4-(dimethy- lphosphoryl)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-ylsulfo- nyl)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-(dim- ethylphosphoryl)-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-diami- ne; 5-chloro-N2-(5-cyclopropyl-1,3-oxazol-2-yl)-N4-{2-methoxy-4-[4-(4-meth- yl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-dia- mine; 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-m- ethoxyphenyl]pyrimidine-2,4-diamine; N-(3,5-dimethylphenyl)-N'-[4-(dimethylphosphoryl)phenyl]pyrimidine-4,6-di- amine; N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-2-methyl-N'-phenylpyrimi- dine-4,6-diamine; N3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsulfonyl)ph- enyl]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-ylsulfon- yl)phenyl]pyrimidine-4,6-diamine; N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N'-[2-(propan-2-ylsulfon- yl)phenyl]pyrimidine-4,6-diamine; N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N'-[2-(propan-2-ylsulfonyl)phe- nyl]pyrimidine-4,6-diamine; N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)ph- enyl]pyridine-2,4-diamine; N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)ph- enyl]-5-(trifluoromethyl)pyridine-2,4-diamine; N2-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)ph- enyl]-5-(trifluoromethyl)pyridine-2,4-diamine; N2-[4-(dimethylphosphoryl)-2-methylphenyl]-N4-[2-(propan-2-ylsulfonyl)phe- nyl]-5-(trifluoromethyl)pyridine-2,4-diamine; N2-[4-(dimethylphosphoryl)-2-ethylphenyl]-N4-[2-(propan-2-ylsulfonyl)phen- yl]-5-(trifluoromethyl)pyridine-2,4-diamine; N2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N4-[2-(propan-2-yl- sulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine; N2-[2-chloro-4-(dimethylphosphoryl)phenyl]-N4-[2-(propan-2-ylsulfonyl)phe- nyl]-5-(trifluoromethyl)pyridine-2,4-diamine; N2-[4-(dimethylphosphoryl)-2-fluorophenyl]-N4-[2-(propan-2-ylsulfonyl)phe- nyl]-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-(pr- opan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine; N3-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N5-[2-(p- ropan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine; N3-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-y- l]phenyl}-N5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine; N3-[4-(diethylphosphoryl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsulfonyl)phe- nyl]pyridazine-3,5-diamine; 6-chloro-N-(3,5-dimethylphenyl)-N'-[4-(dimethylphosphoryl)phenyl]-1,3,5-t- riazine-2,4-diamine; 6-chloro-N3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N5-phenyl-1,2,4-tria- zine-3,5-diamine; 6-chloro-N3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N5-[2-(propan-2-ylsu- lfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N5-[4-(dimethylphosphoryl)phenyl]-N3-{2-methoxy-4-[4-(4-methylpi- perazin-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-dia- mine; 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-ylsul- fonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N3-[4-(dimethylphosphoryl)-2-ethylphenyl]-N5-[2-(propan-2-ylsulf- onyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N3-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N5-[2-(pr- opan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N3-[2-chloro-4-(dimethylphosphoryl)phenyl]-N5-[2-(propan-2-ylsul- fonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N3-[4-(dimethylphosphoryl)-2-fluorophenyl]-N5-[2-(propan-2-ylsul- fonyl)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)pipe- ridin-1-yl]phenyl}-N5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-d- iamine; 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-methylpi- perazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine; or a pharmaceutically acceptable salt thereof.