Details for Patent: 8,470,851
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Title: | Substituted acetylenic imidazo[1,2-A]pyridine 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 (Chennai, IN), Metcalf, III; Chester A. (Needham, MA), Dalgarno; David C. (Brookline, MA), Sawyer; Tomi K. (Southborough, MA) |
Assignee: | ARIAD Pharmaceuticals, Inc. (Cambridge, MA) |
Filing Date: | Jan 25, 2012 |
Application Number: | 13/357,745 |
Claims: | 1. A compound of the formula: ##STR00179## 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, .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.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: ##STR00180## 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.e, 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, 4or 5. 3. A compound of claim 2 wherein Rings A and 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 IIb: ##STR00181## 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: ##STR00182## 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, .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; w is 0, 1, 2, 3, 4 or 5; x is 0, 1, 2 or 3; and, z is 1, 2, 3 or 4. 8. A compound of claim 7, wherein Rings A and 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 IIIb: ##STR00183## 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 pharmaceutically acceptable carrier. 13. A compound selected from the group consisting of: 3-(Imidazo [1 ,2-a]pyridin-3-ylethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(tr- ifluoromethyl)phenyl)benzamide; N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo [1 ,2-a]pyridin-3-ylethynyl)-4-methylbenzamide; 3-(Imidazo[1,2-a]pyridin-3-ylethynyl)-4-methyl-N-(4-(trifluoromethyl)pyri- din-2-yl)benzamide; N-(5-tert-butylisoxazol-3-yl)-3-(imidazo[1,2-a]pyridin-3-ylethynyl)-4-met- hylbenzamide; 3-(Imidazo[1,2-a]pyridin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1- -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phen- yl)-3-(imidazo[1,2-a]pyridin-3-ylethynyl)-4-methylbenzamide; 3-((8-Acetamidoimidazo[1,2-a]pyridin-3-yl)ethynyl)-4-methyl-N-(4-(trifluo- romethyl)pyridin-2-yl)benzamide; N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((8-acetamidoimidazo- [1,2-a]pyridin-3-yl)ethynyl)-4-methylbenzamide; 4-Methyl-3-((8-(4-(methylsulfonyl)phenylamino)imidazo[1,2-a]pyridin-3-yl)- ethynyl)-N -(4-(trifluoromethyl)pyridin-2-yl)benzamide; and 4-methyl-3-((8-(4-sulfamoylphenylamino)imidazo[1 ,2-a]pyridin-3-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, or a pharmaceutically acceptable salt thereof. 14. The compound, 3-(Imidazo[1,2-a]pyridin-3-ylethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol- -1-yl)-5-(trifluoromethyl)phenyl)benzamide. 15. The compound, N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-a]pyrid- in-3-ylethynyl)-4-methylbenzamide. 16. The compound, 3-(Imidazo[1,2-a]pyridin-3-ylethynyl)-4-methyl-N-(4-(trifluoromethyl)pyri- din-2-yl)benzamide. 17. The compound, N-(5-tert-butylisoxazol-3-yl)-3-(imidazo[1,2-a]pyridin-3-ylethynyl)-4-met- hylbenzamide. 18. The compound, 3-(Imidazo[1,2-a]pyridin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1- -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide. 19. The compound, N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phen- yl)-3-(imidazo[1,2-a]pyridin-3-ylethynyl)-4-methylbenzamide. 20. The compound, 3-((8-Acetamidoimidazo[1,2-a]pyridin-3-yl)ethynyl)-4-methyl-N-(4-(trifluo- romethyl)pyridin-2-yl)benzamide. 21. The compound, N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((8-acetamidoimidazo- [1,2-a]pyridin-3-yl)ethynyl)-4-methylbenzamide. 22. The compound, 4-Methyl-3-((8-(4-(methylsulfonyl)phenylamino)imidazo[1,2-a]pyridin-3-yl)- ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide. 23. The compound, 4-methyl-3-((8-(4-sulfamoylphenylamino)imidazo[1,2-a] pyridin-3-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide. 24. A compound selected from the group consisting of: TABLE-US-00004 ##STR00184## ##STR00185## ##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190## ##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195## ##STR00196## ##STR00197## ##STR00198## ##STR00199## ##STR00200## ##STR00201## ##STR00202## ##STR00203## ##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217## ##STR00218## ##STR00219## ##STR00220## ##STR00221## ##STR00222## ##STR00223## ##STR00224## ##STR00225## ##STR00226## ##STR00227## ##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232## ##STR00233## ##STR00234## or a pharmaceutically acceptable salt thereof. 25. A compound selected from the group consisting of: TABLE-US-00005 ##STR00235## ##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247## or a pharmaceutically acceptable salt thereof. 26. A composition comprising a compound selected from the group consisting of: 3-(Imidazo[1,2-a]pyridin-3-ylethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol- -1-yl)-5-(trifluoromethyl)phenyl)benzamide; N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-a]pyrid- in-3-ylethynyl)-4-methylbenzamide; 3-(Imidazo[1,2-a]pyridin-3-ylethynyl)-4-methyl-N-(4-(trifluoromethyl)pyri- din-2-yl)benzamide; N-(5-tert-butylisoxazol-3-yl)-3-(imidazo[1,2-a]pyridin-3-ylethynyl)-4-met- hylbenzamide; 3-(Imidazo[1,2-a]pyridin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1- -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phen- yl)-3-(imidazo[1,2-a]pyridin-3-ylethynyl)-4-methylbenzamide; 3-((8-Acetamidoimidazo[1,2-a]pyridin-3-yl)ethynyl)-4-methyl-N-(4-(trifluo- romethyl)pyridin-2-yl)benzamide; N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((8-acetamidoimidazo- [1,2-a]pyridin-3-yl)ethynyl)-4-methylbenzamide; 4-Methyl-3-((8-(4-(methylsulfonyl)phenylamino)imidazo[1,2-a]pyridin-3-yl)- ethynyl)-N -(4-(trifluoromethyl)pyridin-2-yl)benzamide; and 4-methyl-3-((8-(4-sulfamoylphenylamino)imidazo[1,2-a]pyridin-3-yl)ethynyl- )-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 27. A composition comprising a compound selected from the group consisting of: TABLE-US-00006 ##STR00248## ##STR00249## ##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287## ##STR00288## ##STR00289## ##STR00290## ##STR00291## ##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297## ##STR00298## or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 28. A composition comprising a compound selected from the group consisting of: TABLE-US-00007 ##STR00299## ##STR00300## ##STR00301## ##STR00302## ##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309## ##STR00310## ##STR00311## or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. |