Claims for Patent: 9,012,462

Summary for Patent: 9,012,462

Title:	Phosphorous derivatives as kinase inhibitors
Abstract:	The invention features compounds of the general formula (I) in which the variable groups are as defined herein, and to their preparation and use. ##STR00001##
Inventor(s):	Wang; Yihan (Newton, MA), Huang; Wei-Sheng (Acton, MA), Liu; Shuangying (Wellesley, MA), Shakespeare; William C. (Southborough, MA), Thomas; R. Mathew (Sharon, MA), Qi; Jiwei (West Roxbury, MA), Li; Feng (Winchester, MA), Zhu; Xiaotian (Newton, MA), Kohlman; 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:	12/736,910
Patent Claims:	1. A compound of the formula: ##STR00457## 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.1R.sup.2, --SO.sub.2NR.sup.1R.sup.2 or --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. 2. The compound 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.1, or (d) X.sup.1 is CR.sup.b, X.sup.3 is CR.sup.d and X.sup.4 is Cr. 3. The compound of claim 1 in which R.sup.d is selected from Cl, F, C1-C4 alkyl, trihaloalkyl, cycloalkyl, C2-C4 alkenyl, and alkynyl. 4. The compound 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. 5. The compound 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. 6. The compound of claim 5 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. 7. The compound of claim 5 in which 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--. 8. The compound of claim 5 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. 9. The compound of claim 2 in which: (a) X.sup.1 is N, X.sup.3 is CR.sup.d and X.sup.4 is CR.sup.e; or (b) X.sup.1 is CR.sup.b, X.sup.3 is CR.sup.d and X.sup.4 is CR.sup.e; and R.sup.d is selected from Cl, F, C1-C4 alkyl, trihaloalkyl, cycloalkyl, C2-C4 alkenyl, and alkynyl. 10. The compound of claim 2 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. 11. The compound of claim 3 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. 12. The compound of claim 9 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. 13. The compound of claim 4 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 compound of claim 4 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. 15. The compound of claim 11 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. 16. The compound of claim 12 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. 17. The compound of claim 13 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. 18. The compound of claim 10 in which at least one substituent s 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, --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, --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).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--. 19. The compound of claim 11 in which 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.1R.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--. 20. The compound of claim 12 in which 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.3, --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--. 21. The compound of claim 13 in which 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--. 22. The compound of claim 6 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. 23. The compound of claim 7 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. 24. The compound of any of claim 7, 18, 19, 20, or 21, in which the heterocyclic or heteroaryl substituent R.sup.a is selected from the following: ##STR00458## ##STR00459## ##STR00460## ##STR00461## 25. The compound of claim 24 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. 26. The compound of claim 24 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. 27. The compound of claim 25 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. 28. The compound of claim 26 in which Ring E contains at least one R.sup.g in the ortho position, relative to the ring atom attached to L. 29. The compound of claim 27 in which Ring E contains at least one R.sup.g in the ortho position, relative to the ring atom attached to L. 30. The compound of claim 26 in which Ring E contains at least one R.sup.g in the meta position, relative to the ring atom attached to L. 31. The compound of claim 27 in which Ring E contains at least one R.sup.g in the meta position, relative to the ring atom attached to L. 32. The compound of claim 26 in which Ring E contains at least one R.sup.g in the para position, relative to the ring atom attached to L. 33. The compound of claim 27 in which Ring E contains at least one R.sup.g in the para position, relative to the ring atom attached to L. 34. A pharmaceutical composition containing a compound of claim 24 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 35. A pharmaceutical composition containing a compound of claim 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 36. A pharmaceutical composition containing a compound of claim 26 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 37. A pharmaceutical composition containing a compound of claim 27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 38. The compound of claim 1 selected from the following: ##STR00462## ##STR00463## ##STR00464## or a pharmaceutically acceptable salt thereof. 39. The compound of claim 1 selected from the following: 6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-phenyl-- 1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(pro- pan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.5-[4-(dimethylphosphoryl)phenyl]-N.sup.3-{2-methoxy-4-[4-(- 4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.5-[- 2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.5-[- 2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; N.sup.5-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N.sup.3-{2- -methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazi- ne-3,5-diamine; 6-chloro-N.sup.3-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(pro- pan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-methylphenyl]-N.sup.5-[2-(prop- an-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-ethylphenyl]-N.sup.5-[2-(propa- n-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N.su- p.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[2-chloro-4-(dimethylphosphoryl)phenyl]-N.sup.5-[2-(prop- an-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-fluorophenyl]-N.sup.5-[2-(prop- an-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)ph- enyl]-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl- )piperidin-1-yl]phenyl}-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-tria- zine-3,5-diamine; and, 6-chloro-N.sup.3-[4-(diethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(prop- an-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; or a pharmaceutically acceptable salt thereof. 40. The compound of claim 1 selected from the following: 5-chloro-N.sup.4-[4-(dimethylphosphoryl)phenyl]-N.sup.2-{2-methoxy-4-[4-(- 4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine; 5-chloro-N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-[- 4-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine; 5-chloro-N.sup.4-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)ph- enyl]-N.sup.2-[5-(propan-2-yl)-1,3-oxazol-2-yl]pyrimidine-2,4-diamine; 5-chloro-N.sup.2-[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-N.sup.4-[2-methoxy-4- -(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidine-2,4-diamine; N.sup.2-[5-(1,4'-bipiperidin-1'-yl)-1,3,4-thiadiazol-2-yl]-5-chloro-N.sup- .4-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidine-2,4-diamine; 5-chloro-N.sup.4-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N- .sup.2-{5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-yl}pyrimidine- -2,4-diamine; 5-chloro-N.sup.2-(5-cyclopropyl-1,3-oxazol-2-yl)-N.sup.4-{2-methoxy-4-[4-- (4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidine-- 2,4-diamine; 5-chloro-N.sup.2-(5-cyclopropyl-1,3-oxazol-2-yl)-N.sup.4-[4-(1-ethyl-4-ox- ido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidine-2,4-diamine; 5-chloro-N.sup.2-(2-cyclopropyl-1,3-oxazol-5-yl)-N.sup.4-[4-(diethylphosp- horyl)-2-methoxyphenyl]pyrimidine-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; 6-chloro-N.sup.5-[4-(dimethylphosphoryl)phenyl]-N'-{2-methoxy-4-[4-(4-met- hylpiperazin-1-yl)piperidin-1-yl]phenyl}-1,2,4-triazine-3,5-diamine; N.sup.5-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N'-{2-meth- oxy-[4(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazine-3,5- -diamine; and, 5-chloro-N.sup.4-[2-(dimethylphosphoryl)phenyl]-N.sup.2-{2-methoxy-4-[4-(- 4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine; or a pharmaceutically acceptable salt thereof. 41. The compound of claim 1 selected from the following: N.sup.4-(3,5-dimethylphenyl)-N.sup.2-[4-(dimethylphosphoryl)phenyl]-5-(tr- ifluoromethyl)pyrimidine-2,4-diamine; 5-chloro-N.sup.2-(4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-phenylp- yrimidine-2,4-diamine; N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-yls- ulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine; 5-chloro-N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(pro- pan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; 5-chloro-N.sup.2-[4-(dimethylphosphoryl)phenyl]-N.sup.4-[2-(propan-2-ylsu- lfonyl)phenyl]pyrimidine-2,4-diamine; 5-chloro-N.sup.4-[4-(dimethylphosphoryl)phenyl]-N.sup.2-{2-methoxy-4-[4-(- 4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine; N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-yls- ulfonyl)phenyl]pyrimidine-2,4-diamine; N.sup.2-[4-(Dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N.sup.4-[2-(pro- pan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; 5-Chloro-N.sup.2-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(pro- pan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; 5-Chloro-N.sup.2-[4-(dimethylphosphoryl)-2-methylphenyl]-N.sup.4-[2-(prop- an-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; 5-Chloro-N.sup.2-[4-(dimethylphosphoryl)-2-ethylphenyl]-N.sup.4-[2-(propa- n-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; 5-Chloro-N.sup.2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N.su- p.4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; 5-Chloro-N.sup.2-[2-chloro-4-(dimethylphosphoryl)phenyl]-N.sup.4-[2-(prop- an-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; 5-Chloro-N.sup.2-[4-(dimethylphosphoryl)-2-fluorophenyl]-N.sup.4-[2-(prop- an-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-yls- ulfonyl)phenyl]pyrimidine-2,4,5-triamine; N.sup.2-[2-methoxy-4-(4-oxido-1,4-azaphosphinan-4-yl)phenyl]-N.sup.4-[2-(- propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-yls- ulfonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine; 5-chloro-N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-[- 2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; 5-chloro-N.sup.2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.4-[- 2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; 5-chloro-N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-p- henylpyrimidine-2,4-diamine; N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-[2-(propan- -2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine; N.sup.2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.4-[2-(propan- -2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine; 5-chloro-N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-[- 4-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine; 5-chloro-N.sup.2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.4-[- 2-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4- -diamine; N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-[- 2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-methyl-N.sup.4-[- 2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine; 5-chloro-N.sup.4-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)ph- enyl]-N.sup.2-[5-(propan-2-yl)-1,3-oxazol-2-yl]pyrimidine-2,4-diamine; 5-chloro-N.sup.2-[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-N.sup.4-[2-methoxy-4- -(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidine-2,4-diamine; N.sup.2-[5-(1,4'-bipiperidin-1'-yl)-1,3,4-thiadiazol-2-yl]-5-chloro-N.sup- .4-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidine-2,4-diamine; 5-chloro-N.sup.4-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N- .sup.2-{5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-yl}pyrimidine- -2,4-diamine-4; 5-chloro-N.sup.2-(5-cyclopropyl-1,3-oxazol-2-yl)-N.sup.4-{2-methoxy-4-[4-- (4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidine-- 2,4-diamine; 5-chloro-N.sup.2-(5-cyclopropyl-1,3-oxazol-2-yl)-N.sup.4-[4-(1-ethyl-4-ox- ido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidine-2,4-diamine; 5-chloro-N.sup.2-(2-cyclopropyl-1,3-oxazol-5-yl)-N.sup.4-[4-(diethylphosp- horyl)-2-methoxyphenyl]pyrimidine-2,4-diamine; N-(3,5-dimethylphenyl)-N.sup.4-[4-(dimethylphosphoryl)phenyl]pyrimidine-4- ,6-diamine; N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-2-methyl-N'-phenylpyrimidine-4- ,6-diamine; N.sup.3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(propan-2-yls- ulfonyl)phenyl]pyridazine-3,5-diamine; N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-[3-fluoro-5-(trifluromethyl)- phenoxy]pyridazin-3-amine; 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; N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-yls- ulfonyl)phenyl]pyridine-2,4-diamine; N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-yls- ulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine; N.sup.2-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-yls- ulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine; N.sup.2-[4-(dimethylphosphoryl)-2-methylphenyl]-N.sup.4-[2-(propan-2-ylsu- lfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine; N.sup.2-[4-(dimethylphosphoryl)-2-ethylphenyl]-N.sup.4-[2-(propan-2-ylsul- fonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine; N.sup.2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N.sup.4-[2-(p- ropan-2-ylsulfonyl)phenyl]-5-(trifluoromethylpyridine-2,4-diamine; N.sup.2-[2-chloro-4-(dimethylphosphoryl)phenyl]-N.sup.4-[2-(propan-2-ylsu- lfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine; N.sup.2-[4-(dimethylphosphoryl)-2-fluorophenyl]-N.sup.4-[2-(propan-2-ylsu- lfonyl)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; N.sup.3-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-N.su- p.5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine; N.sup.3-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N.s- up.5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine; N.sup.3-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidi- n-1-yl]phenyl}-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diami- ne; N.sup.3-[4-(diethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(propan-2-y- lsulfonyl)phenyl]pyridazine-3,5-diamine; 6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-phenyl-- 1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(pro- pan-2-ylsulfonyl) phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.5-[4-(dimethylphosphoryl)phenyl]-N.sup.3-{2-methoxy-4-[4-(- 4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.5-[- 2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.5-[- 2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; N.sup.5-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N.sup.3-{2- -methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazi- ne-3,5-diamine; 6-chloro-N.sup.3-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(pro- pan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5 diamine; 6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-methylphenyl]-N.sup.5-[2-(prop- an-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-ethylphenyl]-N.sup.5-[2-(propa- n-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N.su- p.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[2-chloro-4-(dimethylphosphoryl)phenyl]-N.sup.5-[2-(prop- an-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-fluorophenyl]-N.sup.5-[2-(prop- an-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)ph- enyl]-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; 6-chloro-N.sup.3-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl- )piperidin-1-yl]phenyl}-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-tria- zine-3,5-diamine; 6-chloro-N.sup.3-[4-(diethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(prop- an-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; and, 5-chloro-N.sup.4-[2-(dimethylphosphoryl)phenyl]-N.sup.2-{2-methoxy-4-[4-(- 4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine; or a pharmaceutically acceptable salt thereof. 42. The compound of claim 1 of Formula VIA-i or Formula VIA-ii: ##STR00465## 43. The compound of claim 42 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. 44. The compound of claim 42 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. 45. The compound of claim 43 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. 46. The compound of claim 42 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. 47. The compound of claim 43 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, --OCF.sub.3, CN, --C(O)CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3, or --C(O)NH-iPr. 48. The compound of claim 44 in which Ring E is aryl, and each R.sup.g is independently --SO.sub.2CH.sub.3, --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, --OCF.sub.3, CN, --C(O)CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3, or --C(O)NH-iPr. 49. The compound of claim 45 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. 50. The compound of any of claim 42-45 or 47 in which the para R.sup.a is or contains --P(O)(R.sup.3).sub.2 or is one of the following: ##STR00466## ##STR00467## ##STR00468## ##STR00469## 51. The compound of any of claim 42-45 or 47 in 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: ##STR00470## ##STR00471## ##STR00472## ##STR00473## 52. The compound of any of claims 1, 2, 3-7, 8 and 9-33 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. 53. The compound of claim 52 in which Ring E contains at least one R.sup.g in the ortho position, relative to the ring atom attached to L. 54. The compound of claim 52 in which Ring E contains at least one R.sup.g in the meta position, relative to the ring atom attached to L. 55. The compound of claim 52 in which Ring E contains at least one R.sup.g in the para position, relative to the ring atom attached to L. 56. The compound of claim 52 in which at least one R.sup.g is P(.dbd.O)(R.sup.3).sub.2, and is --P(.dbd.O)(CH.sub.3).sub.2 or --P(.dbd.O)(CH.sub.2CH.sub.3).sub.2. 57. The compound of claim 24 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 1-3R.sup.g, one of which being an ortho, meta or para --P(.dbd.O)(R.sup.3).sub.2. 58. The compound of claim 53 in which 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. 59. The compound of claim 54 in which 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. 60. The compound of claim 55 in which 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. 61. A pharmaceutical composition containing a compound of claim 52 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 62. A pharmaceutical composition containing a compound of claim 56 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 63. A pharmaceutical composition containing a compound of claim 58 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 64. A pharmaceutical composition containing a compound of claim 59 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 65. A pharmaceutical composition containing a compound of claim 60 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 66. A pharmaceutical composition containing a compound of any of claim 1, 2, 3-7, 8, 9-23 or 38-41, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 67. The compound of claim 59, wherein the compound is ##STR00474## or a pharmaceutically acceptable salt thereof. 68. The compound of claim 38, wherein the compound is ##STR00475## or a pharmaceutically acceptable salt thereof. 69. The compound of claim 38, wherein the compound is ##STR00476## or a pharmaceutically acceptable salt thereof. 70. The compound of claim 40, wherein the compound is 5-chloro-N.sup.4-[4-(dimethylphosphoryl)phenyl]-N.sup.2-{2-methoxy-4-[4-(- 4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof. 71. The compound of claim 40, wherein the compound is 5-chloro-N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-[- 4-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof. 72. The compound of claim 40, wherein the compound is 5-chloro-N.sup.4-[2-(dimethylphosphoryl)phenyl]-N.sup.2-{2-methoxy-4-[4-(- 4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof.