Substituted acetylenic imidazo[1,2-A]pyrazine compounds as kinase inhibitors

1. A compound of the formula:

or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof wherein:

Ring A is a 5- or 6-membered aryl or heteroaryl ring;

Ring B is a 5- or 6-membered aryl or heteroaryl ring;

L 1 is selected from NR 1 C(O), C(O)NR 1 , NR 1 C(O)O, NR 1 C(O)NR 1 , and OC(O)NR 1 ;

each occurrence of R a and R b is independently selected from the group consisting of halo, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 and —NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, —O—, —S— or —NR 3 —;

R e , at each occurrence, is independently selected from the group consisting of halo, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 and —NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, —O—, —S— or —NR 3 —;

R 1 , R 2 and R 3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; or R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring, which contains 0-2 heteroatoms selected from N, O and S(O) r ;

each occurrence of R 4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl;

each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl and heterocyclyl moieties is optionally substituted with one or more groups selected from the group consisting of halo, —CN, —R 4 , —OR 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 , —NR 2 R 3 , —(CO)YR 2 , —O(CO)YR 2 , —NR 2 (CO)YR 2 , —S(CO)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )Y′R 2 , —COCOR 2 , —COMCOR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NO 2 , —NR 2 SO 2 R 2 , —NR 2 SO 2 NR 2 R 3 , ═O, ═S, ═NH, ═NNR 2 R 3 , ═NNHC(O)R 2 , ═NNHCO 2 R 2 , and ═NNHSO 2 R 2 , wherein M is a 1-6 carbon alkyl group;

each of the aryl and heteroaryl moieties is optionally substituted on an unsaturated carbon atom with one or more groups selected from the group consisting of halo, —CN, —R 4 , —OR 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 , —NR 2 R 3 , —(CO)YR 2 , —O(CO)YR 2 , —NR 2 (CO)YR 2 , —S(CO)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S) YR 2 , —C(═S)YR 2 , —YC(═NR 3 )Y′R 2 , —COCOR 2 , —COMCOR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NO 2 , —NR 2 SO 2 R 2 , and —NR 2 SO 2 NR 2 R 3 ;

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

p is 0, 1, 2, 3, 4 or 5;

r is 0, 1 or 2; and

s is 0, 1, 2, 3 or 4

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 of the formula:

wherein:

Ring C is a 5- or 6-membered heterocyclyl or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O) r ;

R c , at each occurrence, is independently selected from halo, ═O, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —Si(R 2 ) 3 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 and —NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, —O—, —S— or —NR 3 —; and,

v is 0, 1, 2, 3, 4 or 5.

3. A compound of claim 2 wherein Ring A and Ring B are independently a 5- or 6-membered aryl.

4. A compound of claim 3 wherein Ring C is imidazolyl.

5. A compound of claim 4 of Formula IIa:

6. A compound of claim 5 wherein s is 0; m, p and v are 1; R a and R c are methyl; and R b is CF 3 .

7. A compound of claim 1 having the formula:

wherein:

Ring D represents a 5 or 6 membered heterocyclyl or heteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O) r ;

L 2 is (CH 2 ) z , O(CH 2 ) x , NR 3 (CH 2 ) x , S(CH 2 ) x or (CH 2 ) x NR 3 C(O)(CH 2 ) x in either direction;

R d , at each occurrence, is selected from the group consisting of H, halo, ═O, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 and —NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, —O—, —S— or —NR 3 —;

R 2 and R 3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; or R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring, which contains 0-2 heteroatoms selected from N, O and S(O) r ;

each occurrence of R 4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl;

each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is optionally substituted with one or more groups selected from the group consisting of halo, —CN, —R 4 , —OR 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 , —NR 2 R 3 , —(CO)YR 2 , —O(CO)YR 2 , —NR 2 (CO)YR 2 , —S(CO)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )Y′R 2 , —COCOR 2 , —COMCOR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NO 2 , —NR 2 SO 2 R 2 , —NR 2 SO 2 NR 2 R 3 , ═O, S, ═NH, ═NNR 2 R 3 , ═NNHC(O)R 2 , ═NNHCO 2 R 2 , and ═NNHSO 2 R 2 , wherein M is a 1-6 carbon alkyl group;

each of the aryl and heteroaryl moieties is optionally substituted on an unsaturated carbon atom with one or more groups selected from the group consisting of halo, —CN, —R 4 , —OR 2 , —S(O) r R 2 , —SO 2 NR 2 R 3 , —NR 2 R 3 , —(CO)YR 2 , —O(CO)YR 2 , —NR 2 (CO)YR 2 , —S(CO)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )Y′R 2 , —COCOR 2 , —COMCOR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NO 2 , —NR 2 SO 2 R 2 , and —NR 2 SO 2 NR 2 R 3 ;

w is 0, 1, 2, 3, 4or 5;

x is 0, 1, 2 or 3; and,

z is 1, 2, 3 or 4.

8. A compound of claim 7 , wherein Ring A and Ring B are independently a 5- or 6-membered aryl.

9. A compound of claim 8 , wherein Ring D is piperazinyl and L 2 is CH 2 .

10. A compound of claim 9 of Formula IIIa:

11. A compound of claim 10 wherein s is 0, m is 1, p is 1, R a is methyl, R b is CF 3 , and R d is methyl or —CH 2 CH 2 OH.

12. A composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutical acceptable carrier, diluent or vehicle.

13. A compound selected from the group consisting of:

N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methylbenzamide;

3-(Imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; and

N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methylbenzamide;

or a pharmaceutically acceptable salt thereof.

14. The compound, N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methylbenzamide.

15. The compound, 3-(Imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methyl-N-(4((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide.

16. The compound, N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methylbenzamide.

17. A composition comprising a compound selected from the group consisting of:

N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methylbenzamide;

3-(Imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; and

N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methylbenzamide;

or a pharmaceutically acceptable salt thereof and a pharmaceutical acceptable carrier, diluent or vehicle.

18. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

19. A composition comprising a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof and a pharmaceutical acceptable carrier, diluent or vehicle.