Pyrimidine inhibitors of kinase activity

1. A compound of formula (I)

or a pharmaceutically acceptable salt, solvate, prodrug, or a combination thereof, wherein

m is 0, 1, 2, 3, or 4;

L 1 is NH or O;

each occurrence of R 1 , when present, is independently alkyl, alkenyl, alkynyl, halogen, haloalkyl, CN, NO 2 , —OR Z1 , —OC(O)R Z2 , —SR Z1 , —S(O)R Z2 , —S(O) 2 R Z2 , —S(O) 2 N(R Z3 )(R Z4 ), —N(R Z3 )(R Z4 ), —N(R Z3 )C(O)R Z2 , —N(R Z3 )C(O)OR Z2 , —N(R Z3 )S(O) 2 R Z2 , —N(R Z3 )C(O)N(R Z3 )(R Z4 ), —N(R Z3 )S(O) 2 N(R Z3 )(R Z4 ), —C(O)R Z1 , —C(O)OR Z1 , —C(O)N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-OR Z1 , —(C 1-6 alkylenyl)-OC(O)R Z2 , —(C 1-6 alkylenyl)-SR Z1 , —(C 1-6 alkylenyl)-S(O)R Z2 , —(C 1-6 alkylenyl)-S(O) 2 R Z2 , —(C 1-6 alkylenyl)-S(O) 2 N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-N(R Z3 )C(O)R Z2 , —(C 1-6 alkylenyl)-N(R Z3 )C(O)OR Z2 , —(C 1-6 alkylenyl)-N(R Z3 )S(O) 2 R Z2 , —(C 1-6 alkylenyl)-N(R Z3 )C(O)N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-N(R Z3 )S(O) 2 N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-C(O)R Z1 , —(C 1-6 alkylenyl)-C(O)OR Z1 , or -(C 1-6 alkylenyl)-C(O)N(R Z3 )(R Z4 );

R 2 is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, CN, NO 2 , G 2 , —OR 6 , —OC(O)R 7 , —SR 6 , —S(O)R 7 , —S(O) 2 R 7 , —S(O) 2 N(R 8 )(R 9 ), —N(R 8 )(R 9 ), —N(R 8 )C(O)R 7 , —N(R 8 )C(O)OR 7 , —N(R 8 )S(O) 2 R 7 , —N(R 8 )C(O)N(R 8 )(R 9 ), —N(R 8 )C(O)—(C 1-6 alkylenyl)-N(R 8 )(R 9 ), —N(R 8 )S(O) 2 N(R 8 )(R 9 ), —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 8 )(R 9 ), —(C 1-6 alkylenyl)-G 3 , —(C 1-6 alkylenyl)-OR 6 , —(C 1-6 alkylenyl)-OC(O)R 7 , —(C 1-6 alkylenyl)-SR 6 , —(C 1-6 alkylenyl)-S(O)R 7 , —(C 1-6 alkylenyl)-S(O) 2 R 7 , —(C 1-6 alkylenyl)-S(O) 2 N(R 8 )(R 9 ), —(C 1-6 alkylenyl)-N(R 8 )(R 9 ), —(C 1-6 alkylenyl)-N(R 8 )C(O)R 7 , —(C 1-6 alkylenyl)-N(R 8 )C(O)OR 7 , —(C 1-6 alkylenyl)-N(R 8 )S(O) 2 R 7 , —(C 1-6 alkylenyl)-N(R 8 )C(O)N(R 8 )(R 9 ), —(C 1-6 alkylenyl)-N(R 8 )S(O) 2 N(R 8 )(R 9 ), —(C 1-6 alkylenyl)-C(O)R 6 , —(C 1-6 alkylenyl)-C(O)OR 6 , and —(C 1-6 alkylenyl)-C(O)N(R 8 )(R 9 );

R 3 is benzimidazolyl, indazolyl, benzothiazolyl, benzoxazolyl, or quinolinyl; each of which is independently unsubstitued or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, G 3 , —(C 1-6 alkylenyl)-G 3 , —O(alkyl), —O(haloalkyl), —SR Z1 , —S(O)R Z2 , —S(O) 2 R Z2 , —C(O)N(R Z3 )(R Z4 ), and haloalkyl; with the proviso that when R 3 is quinolinyl, then R 2 is substituted with 1, 2, 3, or 4 substituents wherein one of the substituents is G 2 ,

R 4 is alkyl, haloalkyl, halogen, or —CN;

R 5 is hydrogen, alkyl, haloalkyl, halogen, or —CN;

each occurrence of R 6 and R 9 are each independently hydrogen, alkyl, haloalkyl, —(C 1-6 alkylenyl)-CN, —(C 1-6 alkylenyl)-OH, —(C 1-6 alkylenyl)-C(O)OH, G 3 , or —(C 1-6 alkylenyl)-G 3 ;

each occurrence of R 7 is independently alkyl, haloalkyl, —(C 1-6 alkylenyl)-CN, —(C 1-6 alkylenyl)-OH, G 3 , or —(C 1-6 alkylenyl)-G 3 ;

each occurrence of R 8 is independently hydrogen, alkyl, or haloalkyl;

G 2 is a heterocycle optionally substituted with 1, 2, 3, 4, or 5 R 10 groups;

each occurrence of G 3 is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 R 10 groups;

each occurrence of R 10 is independently alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, CN, NO 2 , —OR Z1 , —OC(O)R Z2 , —SR Z1 , —S(O)R Z2 , —S(O) 2 R Z2 , —S(O) 2 N(R Z3 )(R Z4 ), —N(R Z3 )(R Z4 ), —N(R Z3 )C(O)R Z2 , —N(R Z3 )C(O)OR Z2 , —N(R Z3 )S(O) 2 R Z2 , —N(R Z3 )C(O)N(R Z3 )(R Z4 ), —N(R Z3 )S(O) 2 N(R Z3 )(R Z4 ), —C(O)R Z1 , —C(O)OR Z1 , —C(O)N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-OR Z1 , -(C 1-6 alkylenyl)-OC(O)R Z2 , —(C 1-6 alkylenyl)-SR Z1 , —(C 1-6 alkylenyl)-S(O)R Z2 , —(C 1-6 alkylenyl)-S(O) 2 R Z2 , —(C 1-6 alkylenyl)-S(O) 2 N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-N(R Z3 )C(O)R Z2 , —(C 1-6 alkylenyl)-N(R Z3 )C(O)OR Z2 , —(C 1-6 alkylenyl)-N(R Z3 )S(O) 2 R Z2 , —(C 1-6 alkylenyl)-N(R Z3 )C(O)N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-N(R Z3 )S(O) 2 N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-C(O)R Z1 , —(C 1-6 alkylenyl)-C(O)OR Z1 , or —(C 1-6 alkylenyl)-C(O)N(R Z3 )(R Z4 );

each occurrence of R Z1 , R Z3 , and R Z4 , are each independently hydrogen, alkyl, or haloalkyl; and

each occurrence of R Z2 is independently alkyl or haloalkyl.

2. The compound according to claim 1 having formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and R 1 is OR Z1 .

3. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof having formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is NH; and

R 3 is indazolyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl; each of which is optionally substituted.

4. The compound according to claim 1 having formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is NH;

R 3 is indazolyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl; each of which is optionally substituted;

R 5 is hydrogen;

m is 1; and

R 1 is OR Z1 .

5. The compound according to claim 1 having formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is NH;

R 3 is indazolyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl; each of which is optionally substituted;

R 5 is hydrogen; and

R 2 is an optionally substituted monocyclic heterocycle.

6. The compound according to claim 5 having formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

R 2 is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, haloalkyl, G 2 , and N(R 8 )(R 9 ).

7. The compound according to claim 5 having formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

R 2 is substituted with one G 2 group.

8. The compound according to claim 1 having formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is NH;

m is 0 or 1;

R 1 is OR Z1 ,

R 2 is a monocyclic heterocycle substituted with one G 2 group;

G 2 is an optionally substituted monocyclic heterocycle; and

R 3 is indazolyl substituted with one or two substituents independently selected from the group consisting of alkyl and —S(O) 2 R Z2 .

9. The compound according to claim 1 having formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is NH;

R 3 is optionally substituted quinolinyl; and

R 2 is a monocyclic heterocycle substituted with 1, 2, or 3 substituents wherein one of the substituents is G 2 , and the others are independently selected from the group consisting of alkyl and haloalkyl.

10. The compound according to claim 1 having formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is NH;

R 3 is optionally substituted quinolinyl; and

R 2 is a monocyclic heterocycle substituted with one G 2 group.

11. The compound according to claim 1 having formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is O;

R 3 is optionally substituted quinolinyl; and

R 2 is a monocyclic heterocycle substituted with 1, 2, or 3 substituents wherein one of the substituents is G 2 , and the others are independently selected from the group consisting of alkyl and haloalkyl.

12. The compound according to claim 1 having formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is O;

R 3 is optionally substituted quinolinyl; and

R 2 is a monocyclic heterocycle substituted with one G 2 group.

13. The compound according to claim 1 having formula (I-i) or a pharmaceutically acceptable salt or solvate thereof

wherein R Z1 , R 2 , R 3 , R 4 , R 5 , and L 1 are as set forth in claim 1 .

14. The compound according to claim 13 having formula (I-i), or a pharmaceutically acceptable salt or solvate thereof, wherein

R 3 is indazolyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl; each of which is optionally substituted.

15. The compound according to claim 13 having formula (I-i), or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is NH; and

R 3 is indazolyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl; each of which is optionally substituted.

16. The compound according to claim 13 having formula (I-i) or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is NH;

R 3 is indazolyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl; each of which is optionally substituted; and

R 5 is hydrogen.

17. The compound according to claim 13 having formula (I-i), or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is NH;

R 3 is indazolyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl; each of which is optionally substituted;

R 5 is hydrogen; and

R 2 is an optionally substituted monocyclic heterocycle.

18. The compound according to claim 17 having formula (I-i), or a pharmaceutically acceptable salt or solvate thereof, wherein

R 2 is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, haloalkyl, G 2 , and N(R 8 )(R 9 ).

19. The compound according to claim 17 having formula (I-i), or a pharmaceutically acceptable salt or solvate thereof, wherein

R 2 is substituted with one G 2 group.

20. The compound according to claim 13 having formula (I-i), or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is NH;

R 2 is a monocyclic heterocycle substituted with one G 2 group;

G 2 is an optionally substituted monocyclic heterocycle; and

R 3 is indazolyl substituted with one or two substituents independently selected from the group consisting of alkyl and —S(O) 2 R Z2 .

21. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of

5-bromo-N 2 -[4-(4-ethylpiperazin-1-yl)phenyl]-N 4 -[2-(trifluoromethyl)-1H-benzimidazol-5-yl]pyrimidine-2,4-diamine;

N 4 -(2-benzyl-1H-benzimidazol-5-yl)-5-bromo-N 2 -[4-(4-ethylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine;

5-bromo-N 2 -[4-(4-ethylpiperazin-1-yl)phenyl]-N 4 -[2-(2-phenylethyl)-1H-benzimidazol-5-yl]pyrimidine-2,4-diamine;

N 4 -(1-benzyl-1H-benzimidazol-5-yl)-5-bromo-N 2 -[4-(4-ethylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine;

N 4 -(1-benzyl-1H-benzimidazol-6-yl)-5-bromo-N 2 -[4-(4-ethylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine;

5-bromo-N 2 -[4-(4-ethylpiperazin-1-yl)phenyl]-N 4 -(2-methyl-1H-benzimidazol-4-yl)pyrimidine-2,4-diamine;

5-bromo-N 2 -[4-(4-ethylpiperazin-1-yl)phenyl]-N 4 -1H-indazol-5-ylpyrimidine-2,4-diamine;

5-chloro-N 2 -[4-(4-ethylpiperazin-1-yl)phenyl]-N 4 -1H-indazol-5-ylpyrimidine-2,4-diamine;

N 2 -[4-(4-ethylpiperazin-1-yl)phenyl]-N 4 -1H-indazol-5-yl-5-methylpyrimidine-2,4-diamine;

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-(1H-indazol-5-ylamino)pyrimidine-5-carbonitrile;

N 2 -[4-(4-ethylpiperazin-1-yl)phenyl]-N 4 -1H-indazol-5-yl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -1H-indazol-5-ylpyrimidine-2,4-diamine;

5-bromo-N 4 -1H-indazol-5-yl-N 2 -{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine;

N 4 -1,3-benzothiazol-5-yl-5-bromo-N 2 -[4-(4-ethylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine;

5-bromo-N 2 -[4-(4-ethylpiperazin-1-yl)phenyl]-N 4 -(2-methyl-1,3-benzoxazol-4-yl)pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -(2-methyl-1H-benzimidazol-4-yl)pyrimidine-2,4-diamine;

5-chloro-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -(2-methyl-1H-benzimidazol-4-yl)pyrimidine-2,4-diamine;

5-chloro-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -(1-methyl-1H-indazol-5-yl)pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -(1-methyl-1H-indazol-5-yl)pyrimidine-2,4-diamine;

5-bromo-N 4 -(6-chloro-1H-indazol-5-yl)-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -(6-methyl-1H-indazol-5-yl)pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -(2-methyl-1,3-benzothiazol-5-yl)pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -[6-(isopropylsulfonyl)-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -[6-(isopropylthio)-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-chloro-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -(2-methyl-1,3-benzoxazol-5-yl)pyrimidine-2,4-diamine;

5-chloro-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -[6-(isopropylsulfonyl)-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -[6-(isopropylsulfonyl)-1-methyl-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-bromo-N 4 -[6-(isopropylsulfonyl)-1-methyl-1H-indazol-5-yl]-N 2 -{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -[6-(isopropylsulfonyl)-2-methyl-2H-indazol-5-yl]pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -[6-(ethylsulfonyl)-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-N 4 -[6-(ethylsulfonyl)-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-bromo-N 4 -[6-(ethylsulfonyl)-1H-indazol-5-yl]-N 2 -(2-methoxy-4-morpholin-4-ylphenyl)pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -[6-(ethylsulfonyl)-1-methyl-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-N 4 -[1-methyl-6-(methylsulfonyl)-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-{[5-bromo-2-({4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}amino)pyrimidin-4-yl]amino}-N,1-dimethyl-1H-indazole-6-carboxamide;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-N 4 -[6-(ethylsulfonyl)-1-methyl-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-bromo-N 2 -{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-N 4 -[1-methyl-6-(methylsulfonyl)-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-{[5-bromo-2-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]amino}-N,1-dimethyl-1H-indazole-6-carboxamide;

5-bromo-N 4 -[6-(ethylsulfonyl)-1-methyl-1H-indazol-5-yl]-N 2 -(2-methoxy-4-morpholin-4-ylphenyl)pyrimidine-2,4-diamine;

5-bromo-N 2 -(2-methoxy-4-morpholin-4-ylphenyl)-N 4 -[1-methyl-6-(methylsulfonyl)-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-({5-bromo-2-[(2-methoxy-4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}amino)-N,1-dimethyl-1H-indazole-6-carboxamide;

5-bromo-N 4 -[6-(ethylsulfonyl)-1-methyl-1H-indazol-5-yl]-N 2 -[4-(4-isopropylpiperazin-1-yl)-2-methoxyphenyl]pyrimidine-2,4-diamine;

5-bromo-N 2 -[4-(4-isopropylpiperazin-1-yl)-2-methoxyphenyl]-N 4 -[1-methyl-6-(methylsulfonyl)-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-[(5-bromo-2-{[4-(4-isopropylpiperazin-1-yl)-2-methoxyphenyl]amino}pyrimidin-4-yl)amino]-N,1-dimethyl-1H-indazole-6-carboxamide;

5-bromo-N 2 -[4-(1,1-dioxidothiomorpholin-4-yl)phenyl]-N 4 -[6-(ethylsulfonyl)-1-methyl-1H-indazol-5-yl]pyrimidine-2,4-diamine;

5-bromo-N 4 -[6-(ethylsulfonyl)-1-methyl-1H-indazol-5-yl]-N 2 -{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine;

5-bromo-N 2 -{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N 4 -(2-phenylquinolin-6-yl)pyrimidine-2,4-diamine;

5-bromo-N 2 -{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N 4 -(2-phenylquinolin-7-yl)pyrimidine-2,4-diamine;

5-bromo-N 2 -{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N 4 -quinolin-6-ylpyrimidine-2,4-diamine;

5-bromo-N 2 -{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N 4 -quinolin-7-ylpyrimidine-2,4-diamine; and

5-bromo-N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-4-(quinolin-7-yloxy)pyrimidin-2-amine.

22. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carrier.