Phosphorous derivatives as kinase inhibitors
The invention features compounds of the general formula (I) in which the variable groups are as defined herein, and to their preparation and use.
1. A compound of the formula:
wherein
X 1 is NR b1 or CR b ;
X 3 is NR d1 or CR d ;
X 4 is NR e1 or CR e ;
Ring A and Ring E are each an independently selected aryl or heteroaryl ring, the heteroaryl ring being a 5- or 6-membered ring containing 1 to 4 heteroatoms selected from N, O and S(O) r ;
each R a , R b , R d , R e , and R g is independently halo, —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R 3a ) 3 , —NR 1 SO 2 R 2 , —S(O) 1 R 2 , —SO 2 NR 1 R 2 or —NR 1 SO 2 NR 1 R 2 ; provided that at least one of R a and R g is or includes —P(═O)(R 3 ) 2 or a ring system containing —P(═O)(R 3 )— as a ring member;
and R b1 , R d1 and R e1 are absent;
or alternatively two adjacent substituents selected from R d , R d1 , R e , and R e1 , or two adjacent R a form, with the atoms to which they are attached, a fused, 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which contains 0-4 heteroatoms selected from N, O and S(O) r and which may bear up to four substituents;
L is O or NH;
r is 0, 1 or 2;
s is 1, 2, 3, 4 or 5;
p is 1, 2, 3 or 4;
each Y is independently a bond, —O—, —S— or —NR 1 —;
each R 1 and R 2 is independently H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl;
each R 3 is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl, or two adjacent R 3 combine to form a ring system including a phosphorous atom;
each R 3a is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, or heteroaryl;
alternatively, each NR 1 R 2 may be a 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 additional heteroatoms selected from N, O and S(O) r ; and
each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclic is optionally substituted,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 in which:
(a) X 1 is N, X 3 is N and X 4 is CR e ;
(b) X 1 is N, X 3 is CR d and X 4 is CR e ;
(c) X 1 is CR b , X 3 is N and X 4 is CR 1 , or
(d) X 1 is CR b , X 3 is CR d and X 4 is Cr.
3. The compound of claim 1 in which R 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 3 is CR d and X 4 is CR e wherein R d and R e , together with the atoms to which they are attached, form a fused, 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which contains 0-4 heteroatoms selected from N, O and S(O) r and which may bear up to four substituents.
5. The compound of claim 1 in which s is 1, 2, 3 or 4, and each of the substituents R a is independently selected from halo, —R 1 , —OR 2 , —NR 1 R 2 and —P(═O)(R 3 ) 2 — wherein each R 1 and R 2 may be further substituted or unsubstituted.
6. The compound of claim 5 in which at least one substituent R a is —OR 2 and R 2 is selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.
7. The compound of claim 5 in which at least one substituent R a is a 5-, 6- or 7-membered heterocyclic or 5- or 6-membered heteroaryl, linked to Ring A either directly or by an ether bond, and which may be further substituted with 1, 2 or 3 substituents independently selected from halo, —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R 3a ) 3 , —NR 1 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 1 R 2 and —NR 1 SO 2 NR 1 R 2 ; wherein each Y is independently a bond, —O—, —S— or —NR 1 —.
8. The compound of claim 5 in which at least one substituent R a is —P(═O)(R 3 ) 2 in which each R 3 is, independently, a C1-C4 alkyl.
9. The compound of claim 2 in which:
(a) X 1 is N, X 3 is CR d and X 4 is CR e ; or
(b) X 1 is CR b , X 3 is CR d and X 4 is CR e ;
and R 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 a is independently selected from halo, —R 1 , —OR 2 , —NR 1 R 2 and —P(═O)(R 3 ) 2 , wherein each R 1 and R 2 may be further substituted or unsubstituted.
11. The compound of claim 3 in which s is 1, 2, 3 or 4, and each of the substituents R a is independently selected from halo, —R 1 , —OR 2 , —NR 1 R 2 and —P(═O)(R 3 ) 2 , wherein each R 1 and R 2 may be further substituted or unsubstituted.
12. The compound of claim 9 in which s is 1, 2, 3 or 4, and each of the substituents R a is independently selected from halo, —R 1 , —OR 2 , —NR 1 R 2 and —P(═O)(R 3 ) 2 , wherein each R 1 and R 2 may be further substituted or unsubstituted.
13. The compound of claim 4 in which s is 1, 2, 3 or 4, and each of the substituents R a is independently selected from halo, —R 1 , —OR 2 , —NR 1 R 2 and —P(═O)(R 3 ) 2 , wherein each R 1 and R 2 may be further substituted or unsubstituted.
14. The compound of claim 4 in which at least one substituent R a is —OR 2 and R 2 is selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.
15. The compound of claim 11 in which at least one substituent R a is —OR 2 and R 2 is selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.
16. The compound of claim 12 in which at least one substituent R a is —OR 2 and R 2 is selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.
17. The compound of claim 13 in which at least one substituent R a is —OR 2 and R 2 is selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.
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 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R) 3 , —NR 1 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 1 R 2 and —NR 1 SO 2 NR 1 R 2 ; wherein each Y is independently a bond, —O—, —S— or —NR 1 —.
19. The compound of claim 11 in which at least one substituent R a is a 5-, 6- or 7-membered heterocyclic or 5- or 6-membered heteroaryl, linked to Ring A either directly or by an ether bond, and which may be further substituted with 1, 2 or 3 substituents independently selected from halo, —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R 3a ) 3 , —NR 1 SO 2 R 2 , —S(O) 1 R 2 , —SO 2 NR 1 R 2 and —NR 1 SO 2 NR 1 R 2 ; wherein each Y is independently a bond, —O—, —S— or —NR 1 —.
20. The compound of claim 12 in which at least one substituent R a is a 5-, 6- or 7-membered heterocyclic or 5- or 6-membered heteroaryl, linked to Ring A either directly or by an ether bond, and which may be further substituted with 1, 2 or 3 substituents independently selected from halo, —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 3 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R 3a ) 3 , —NR 1 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 1 R 2 and —NR 1 SO 2 NR 1 R 2 ; wherein each Y is independently a bond, —O—, —S— or —NR 1 —.
21. The compound of claim 13 in which at least one substituent R a is a 5-, 6- or 7-membered heterocyclic or 5- or 6-membered heteroaryl, linked to Ring A either directly or by an ether bond, and which may be further substituted with 1, 2 or 3 substituents independently selected from halo, —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R 3a ) 3 , —NR 1 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 1 R 2 and —NR 1 SO 2 NR 1 R 2 ; wherein each Y is independently a bond, —O—, —S— or —NR 1 —.
22. The compound of claim 6 in which at least one substituent R a is —P(═O)(R 3 ) 2 in which each R 3 is, independently, a C1-C4 alkyl.
23. The compound of claim 7 in which at least one substituent R a is P(═O)(R 3 ) 2 in which each R 3 is, independently, a C1-C4 alkyl.
24. The compound of any of claim 7 , 18 , 19 , 20 , or 21 , in which the heterocyclic or heteroaryl substituent R a is selected from the following:
25. The compound of claim 24 in which at least one substituent R a is P(═O)(R 3 ) 2 in which each R 3 is, independently, a C1-C4 alkyl.
26. The compound of claim 24 in which L is NH, Ring E is aryl, and each R g is independently selected from halo, —R 1 , —OR 2 , —S(O) r R 2 and —P(═O)(R 3 ) 2 .
27. The compound of claim 25 in which L is NH, Ring E is aryl, and each R g is independently selected from halo, —R 1 , —OR 2 , —S(O) r R 2 and —P(═O)(R 3 ) 2 .
28. The compound of claim 26 in which Ring E contains at least one R 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 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 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 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 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 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:
or a pharmaceutically acceptable salt thereof.
39. The compound of claim 1 selected from the following:
6-chloro-N 3 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 5 -phenyl-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 5 -[4-(dimethylphosphoryl)phenyl]-N 3 -{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
N 5 -[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N 3 -{2-methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[5-(dimethylphosphoryl)-2-methoxyphenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[4-(dimethylphosphoryl)-2-methylphenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[4-(dimethylphosphoryl)-2-ethylphenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[2-chloro-4-(dimethylphosphoryl)phenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[4-(dimethylphosphoryl)-2-fluorophenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; and,
6-chloro-N 3 -[4-(diethylphosphoryl)-2-methoxyphenyl]-N 5 -[2-(propan-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 4 -[4-(dimethylphosphoryl)phenyl]-N 2 -{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine;
5-chloro-N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -[4-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine;
5-chloro-N 4 -[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N 2 -[5-(propan-2-yl)-1,3-oxazol-2-yl]pyrimidine-2,4-diamine;
5-chloro-N 2 -[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-N 4 -[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidine-2,4-diamine;
N 2 -[5-(1,4′-bipiperidin-1′-yl)-1,3,4-thiadiazol-2-yl]-5-chloro-N 4 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidine-2,4-diamine;
5-chloro-N 4 -[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N 2 -{5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-yl}pyrimidine-2,4-diamine;
5-chloro-N 2 -(5-cyclopropyl-1,3-oxazol-2-yl)-N 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 2 -(5-cyclopropyl-1,3-oxazol-2-yl)-N 4 -[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidine-2,4-diamine;
5-chloro-N 2 -(2-cyclopropyl-1,3-oxazol-5-yl)-N 4 -[4-(diethylphosphoryl)-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 5 -[4-(dimethylphosphoryl)phenyl]-N′-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-1,2,4-triazine-3,5-diamine;
N 5 -[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N′-{2-methoxy-[4(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazine-3,5-diamine; and,
5-chloro-N 4 -[2-(dimethylphosphoryl)phenyl]-N 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 4 -(3,5-dimethylphenyl)-N 2 -[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine;
5-chloro-N 2 -(4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -phenylpyrimidine-2,4-diamine;
N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine;
5-chloro-N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
5-chloro-N 2 -[4-(dimethylphosphoryl)phenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
5-chloro-N 4 -[4-(dimethylphosphoryl)phenyl]-N 2 -{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine;
N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
N 2 -[4-(Dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
5-Chloro-N 2 -[5-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-methylphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-ethylphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
5-Chloro-N 2 -[2-chloro-4-(dimethylphosphoryl)phenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-fluorophenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4,5-triamine;
N 2 -[2-methoxy-4-(4-oxido-1,4-azaphosphinan-4-yl)phenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;
5-chloro-N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
5-chloro-N 2 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
5-chloro-N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -phenylpyrimidine-2,4-diamine;
N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine;
N 2 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine;
5-chloro-N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -[4-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine;
5-chloro-N 2 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N 4 -[2-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine;
N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-methyl-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine;
5-chloro-N 4 -[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N 2 -[5-(propan-2-yl)-1,3-oxazol-2-yl]pyrimidine-2,4-diamine;
5-chloro-N 2 -[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-N 4 -[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidine-2,4-diamine;
N 2 -[5-(1,4′-bipiperidin-1′-yl)-1,3,4-thiadiazol-2-yl]-5-chloro-N 4 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidine-2,4-diamine;
5-chloro-N 4 -[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N 2 -{5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-yl}pyrimidine-2,4-diamine-4;
5-chloro-N 2 -(5-cyclopropyl-1,3-oxazol-2-yl)-N 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 2 -(5-cyclopropyl-1,3-oxazol-2-yl)-N 4 -[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidine-2,4-diamine;
5-chloro-N 2 -(2-cyclopropyl-1,3-oxazol-5-yl)-N 4 -[4-(diethylphosphoryl)-2-methoxyphenyl]pyrimidine-2,4-diamine;
N-(3,5-dimethylphenyl)-N 4 -[4-(dimethylphosphoryl)phenyl]pyrimidine-4,6-diamine;
N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-2-methyl-N′-phenylpyrimidine-4,6-diamine;
N 3 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 5 -[2-(propan-2-ylsulfonyl)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-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;
N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyridine-2,4-diamine;
N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine;
N 2 -[5-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine;
N 2 -[4-(dimethylphosphoryl)-2-methylphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine;
N 2 -[4-(dimethylphosphoryl)-2-ethylphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine;
N 2 -[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethylpyridine-2,4-diamine;
N 2 -[2-chloro-4-(dimethylphosphoryl)phenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine;
N 2 -[4-(dimethylphosphoryl)-2-fluorophenyl]-N 4 -[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;
N 3 -[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine;
N 3 -[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine;
N 3 -{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}-N 5 -[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine;
N 3 -[4-(diethylphosphoryl)-2-methoxyphenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine;
6-chloro-N 3 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 5 -phenyl-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 5 -[2-(propan-2-ylsulfonyl) phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 5 -[4-(dimethylphosphoryl)phenyl]-N 3 -{2-methoxy-4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
N 5 -[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N 3 -{2-methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[5-(dimethylphosphoryl)-2-methoxyphenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5 diamine;
6-chloro-N 3 -[4-(dimethylphosphoryl)-2-methylphenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[4-(dimethylphosphoryl)-2-ethylphenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[2-chloro-4-(dimethylphosphoryl)phenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[4-(dimethylphosphoryl)-2-fluorophenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine;
6-chloro-N 3 -[4-(diethylphosphoryl)-2-methoxyphenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine; and,
5-chloro-N 4 -[2-(dimethylphosphoryl)phenyl]-N 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:
43. The compound of claim 42 in which the ortho R a is H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or —P(O)(R 3 ) 2 .
44. The compound of claim 42 in which R d is F, Cl, C1-C4 alkyl, cyclopropyl, CF 3 , OMe, or OCF 3 , or R f is H, —CH 3 or halo.
45. The compound of claim 43 in which R d is F, Cl, C1-C4 alkyl, cyclopropyl, CF 3 , OMe, or OCF 3 , or R f is H, —CH 3 or halo.
46. The compound of claim 42 in which Ring E is aryl, and each R g is independently —SO 2 CH 3 , —SO 2 -iPr, —SO 2 NH-iPr, —SONH-nPr, —SO 2 NEt 2 , —P(O)(CH 3 ) 2 , —P(O)(Et) 2 , —P(O)(Pr) 2 , Me, OMe, —O-iPr, —OCF 3 , CN, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , or, —C(O)NH-iPr.
47. The compound of claim 43 in which Ring E is aryl, and each R g is independently —SO 2 CH 3 , —SO 2 -iPr, —SO 2 NH-iPr, —SONH-nPr, —SO 2 NEt 2 , —P(O)(CH 3 ) 2 , —P(O)(Et) 2 , —P(O)(Pr) 2 , Me, OMe, —OCF 3 , CN, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , or —C(O)NH-iPr.
48. The compound of claim 44 in which Ring E is aryl, and each R g is independently —SO 2 CH 3 , —SO 2 NH-iPr, —SONH-nPr, —SO 2 NEt 2 , —P(O)(CH 3 ) 2 , —P(O)(Et) 2 , —P(O)(Pr) 2 , Me, OMe, —OCF 3 , CN, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , or —C(O)NH-iPr.
49. The compound of claim 45 in which Ring E is aryl, and each R g is independently —SO 2 CH 3 , —SO 2 -iPr, —SO 2 NH-iPr, —SONH-nPr, —SO 2 NEt 2 , —P(O)(CH 3 ) 2 , —P(O)(Et) 2 , —P(O)(Pr) 2 , Me, OMe, —O-iPr, —OCF 3 , CN, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , or —C(O)NH-iPr.
50. The compound of any of claim 42 - 45 or 47 in which the para R a is or contains —P(O)(R 3 ) 2 or is one of the following:
51. The compound of any of claim 42 - 45 or 47 in which at least one R g is or contains —P(O)(R 3 ) 2 and the para R a one of the following:
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 g is independently selected from halo, —R 1 , —OR 2 , —S(O) r R 2 and —P(═O)(R 3 ) 2 .
53. The compound of claim 52 in which Ring E contains at least one R 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 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 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 g is P(═O)(R 3 ) 2 , and is —P(═O)(CH 3 ) 2 or —P(═O)(CH 2 CH 3 ) 2 .
57. The compound of claim 24 in which L is NH; X 1 is N; X 3 is CR d ; X 4 is CR e ; Ring A is aryl and optionally contains up to two additional R a ; and Ring E is aryl and contains 1-3R g , one of which being an ortho, meta or para —P(═O)(R 3 ) 2 .
58. The compound of claim 53 in which the at least one R g is —P(═O)(R 3 ) 2 and R 3 is —CH 3 or —CH 2 CH 3 .
59. The compound of claim 54 in which the at least one R g is —P(═O)(R 3 ) 2 and R 3 is —CH 3 or —CH 2 CH 3 .
60. The compound of claim 55 in which the at least one R g is —P(═O)(R 3 ) 2 and R 3 is —CH 3 or —CH 2 CH 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
or a pharmaceutically acceptable salt thereof.
68. The compound of claim 38 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
69. The compound of claim 38 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
70. The compound of claim 40 , wherein the compound is 5-chloro-N 4 -[4-(dimethylphosphoryl)phenyl]-N 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 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 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 4 -[2-(dimethylphosphoryl)phenyl]-N 2 -{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof.