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Details for Patent: 8,778,942

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Details for Patent: 8,778,942

Title:Substituted acetylenic imidazo[1,2-A]pyrazine compounds as kinase inhibitors
Abstract: This invention relates to compounds of the general formula: ##STR00001## in which the variable groups are as defined herein, and to their preparation and use.
Inventor(s): Zou; Dong (Concord, MA), Huang; Wei-Sheng (Acton, MA), Thomas; R. Mathew (Sharon, MA), Romero; Jan Antoinette C. (Somerville, MA), Qi; Jiwei (West Roxbury, MA), Wang; Yihan (Newton, MA), Zhu; Xiaotian (Newton, MA), Shakespeare; William C. (Southborough, MA), Sundaramoorthi; Rajeswari (Watertown, MA), Metcalf, III; Chester A. (Needham, MA), Dalgarno; David C. (Brookline, MA), Sawyer; Tomi K. (Southborough, MA)
Assignee: ARIAD Pharmaceuticals, Inc. (Cambridge, MA)
Filing Date:Mar 13, 2013
Application Number:13/801,619
Claims:1. A compound of the formula: ##STR00166## 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.sup.1 is selected from NR.sup.1C(O), C(O)NR.sup.1, NR.sup.1C(O)O, NR.sup.1C(O)NR.sup.1, and OC(O)NR.sup.1; each occurrence of R.sup.a and R.sup.b is independently selected from the group consisting of halo, --CN, --NO.sub.2, --R.sup.4, --OR.sup.2, --NR.sup.2R.sup.3, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.2C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.3)YR.sup.2, --YP(.dbd.O)(YR.sup.4)(YR.sup.4), --Si(R.sup.2).sub.3, --NR.sup.2SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3 and --NR.sup.2SO.sub.2NR.sup.2R.sup.3, wherein each Y is independently a bond, --O--, --S-- or --NR.sup.3--; R.sup.e, at each occurrence, is independently selected from the group consisting of halo, --CN, --NO.sub.2, --R.sup.4, --OR.sup.2, --NR.sup.2R.sup.3, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.2C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.3)YR.sup.2, --YP(.dbd.O)(YR.sup.4)(YR.sup.4), --Si(R.sup.2).sub.3, --NR.sup.2SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3 and --NR.sup.2SO.sub.2NR.sup.2R.sup.3, wherein each Y is independently a bond, --O--, --S-- or --NR.sup.3--; R.sup.1, R.sup.2 and R.sup.3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; or R.sup.2 and R.sup.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).sub.r; each occurrence of R.sup.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.sup.4, --OR.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3, --NR.sup.2R.sup.3, --(CO)YR.sup.2, --O(CO)YR.sup.2, --NR.sup.2(CO)YR.sup.2, --S(CO)YR.sup.2, --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.3)Y'R.sup.2, --COCOR.sup.2, --COMCOR.sup.2, --YP(.dbd.O)(YR.sup.4)(YR.sup.4), --Si(R.sup.2).sub.3, --NO.sub.2, --NR.sup.2SO.sub.2R.sup.2, --NR.sup.2SO.sub.2NR.sup.2R.sup.3, .dbd.O, .dbd.S, .dbd.NH, .dbd.NNR.sup.2R.sup.3, .dbd.NNHC(O)R.sup.2, .dbd.NNHCO.sub.2R.sup.2, and .dbd.NNHSO.sub.2R.sup.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.sup.4, --OR.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3, --NR.sup.2R.sup.3, --(CO)YR.sup.2, --O(CO)YR.sup.2, --NR.sup.2(CO)YR.sup.2, --S(CO)YR.sup.2, --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S) YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.3)Y'R.sup.2, --COCOR.sup.2, --COMCOR.sup.2, --YP(.dbd.O)(YR.sup.4)(YR.sup.4), --Si(R.sup.2).sub.3, --NO.sub.2, --NR.sup.2SO.sub.2R.sup.2, and --NR.sup.2SO.sub.2NR.sup.2R.sup.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: ##STR00167## 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).sub.r; R.sup.c, at each occurrence, is independently selected from halo, .dbd.O, --CN, --NO.sub.2, --R.sup.4, --OR.sup.2, --NR.sup.2R.sup.3, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.2C(O)YR.sup.2, --Si(R.sup.2).sub.3, --SC(O)YR.sup.2, --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.3)YR.sup.2, --YP(.dbd.O)(YR.sup.4)(YR.sup.4), --NR.sup.2SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3 and --NR.sup.2SO.sub.2NR.sup.2R.sup.3, wherein each Y is independently a bond, --O--, --S-- or --NR.sup.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: ##STR00168##

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

7. A compound of claim 1 having the formula: ##STR00169## 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).sub.r; L.sup.2 is (CH.sub.2).sub.z, O(CH.sub.2).sub.x, NR.sup.3(CH.sub.2).sub.x, S(CH.sub.2).sub.x or (CH.sub.2).sub.xNR.sup.3C(O)(CH.sub.2).sub.x in either direction; R.sup.d, at each occurrence, is selected from the group consisting of H, halo, .dbd.O, --CN, --NO.sub.2, --R.sup.4, --OR.sup.2, --NR.sup.2R.sup.3, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.2C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.3)YR.sup.2, --YP(.dbd.O)(YR.sup.4)(YR.sup.4), --Si(R.sup.2).sub.3, --NR.sup.2SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3 and --NR.sup.2SO.sub.2NR.sup.2R.sup.3, wherein each Y is independently a bond, --O--, --S-- or --NR.sup.3--; R.sup.2 and R.sup.3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; or R.sup.2 and R.sup.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).sub.r; each occurrence of R.sup.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.sup.4, --OR.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3, --NR.sup.2R.sup.3, --(CO)YR.sup.2, --O(CO)YR.sup.2, --NR.sup.2(CO)YR.sup.2, --S(CO)YR.sup.2, --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.3)Y'R.sup.2, --COCOR.sup.2, --COMCOR.sup.2, --YP(.dbd.O)(YR.sup.4)(YR.sup.4), --Si(R.sup.2).sub.3, --NO.sub.2, --NR.sup.2SO.sub.2R.sup.2, --NR.sup.2SO.sub.2NR.sup.2R.sup.3, .dbd.O, S, .dbd.NH, .dbd.NNR.sup.2R.sup.3, .dbd.NNHC(O)R.sup.2, .dbd.NNHCO.sub.2R.sup.2, and .dbd.NNHSO.sub.2R.sup.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.sup.4, --OR.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3, --NR.sup.2R.sup.3, --(CO)YR.sup.2, --O(CO)YR.sup.2, --NR.sup.2(CO)YR.sup.2, --S(CO)YR.sup.2, --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.3)Y'R.sup.2, --COCOR.sup.2, --COMCOR.sup.2, --YP(.dbd.O)(YR.sup.4)(YR.sup.4), --Si(R.sup.2).sub.3, --NO.sub.2, --NR.sup.2SO.sub.2R.sup.2, and --NR.sup.2SO.sub.2NR.sup.2R.sup.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.sup.2 is CH.sub.2.

10. A compound of claim 9 of Formula IIIa: ##STR00170##

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

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]pyraz- in-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)phen- yl)-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]pyraz- in-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)phen- yl)-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]pyraz- in-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)phen- yl)-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: ##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176## or a pharmaceutically acceptable salt thereof.

19. A composition comprising a compound selected from the group consisting of: ##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182## or a pharmaceutically acceptable salt thereof and a pharmaceutical acceptable carrier, diluent or vehicle.
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