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Details for Patent: 8,461,167

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Details for Patent: 8,461,167

Title:Acetylenic heteroaryl compounds
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): Wang; Yihan (Newton, MA), Zhu; Xiaotian (Newton, MA), Sundaramoorthi; Rajeswari (Watertown, MA), Huang; Wei-Sheng (Acton, MA), Zou; Dong (Concord, MA), Thomas; R. Mathew (Sharon, MA), Qi; Jiwei (West Roxbury, MA), Romero; Jan Antoinette C. (Somerville, MA), Dalgarno; David C. (Brookline, MA), Shakespeare; William C. (Southborough, MA), Sawyer; Tomi K. (Southborough, MA), Metcalf, III; Chester A. (Needham, MA)
Assignee: ARIAD Pharmaceuticals, Inc. (Cambridge, MA)
Filing Date:May 08, 2007
Application Number:12/227,002
Claims:1. A compound of the Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00109## wherein: Ring T represents a substituted or unsubstituted 6-membered heteroaryl ring, comprising 2 nitrogens; Ring A represents a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1-4 R.sup.a groups; Ring B represents a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1-5 R.sup.b groups; L.sup.1 is selected from NR.sup.1C(O) and C(O)NR.sup.1; at each occurrence, R.sup.a and R.sup.b are 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.4).sub.3, --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; wherein the --NR.sup.2R.sup.3 moiety is optionally a 5- or 6-membered saturated, partially saturated or unsaturated ring, which is optionally substituted and which contains 0-2 additional 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, heteroaryl; (a) X.sup.1 is CH or CR.sup.t1 wherein R.sup.t1 is halo, OR.sup.5, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, carbon linked heteroaryl, carbon linked heterocyclyl; wherein R.sup.5 is H, alkyl, alkenyl alkynyl; X.sup.2 is N; and X.sup.3 is CR.sup.t4; wherein R.sup.t4 is H, halo, --CN, --NO.sub.2, --R.sup.2, --OR.sup.2, --C(O)YR.sup.2, --OC(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.2)(YR.sup.2), --Si(R.sup.4).sub.3, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3; or, (b) X.sup.1 is CR.sup.t, X.sup.2 is N and X.sup.3 is CR.sup.t3, wherein R.sup.t is selected from --CN, --NO.sub.2, --OR.sup.6, --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.4).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 R.sup.6 is cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl and wherein R.sup.t3 is selected from H or R.sup.a; (b)-1: at least one of R.sup.t, R.sup.t3, R.sup.a and R.sup.b is or contains a YP(.dbd.O)(YR.sup.4)(YR.sup.4), a Si(R.sup.4).sub.3 or --YC(.dbd.NR.sup.3)YR.sup.2 substituent; or (b)-2: at least one of R.sup.a and R.sup.t is or contains a --NR.sup.2C(.dbd.S)OR.sup.2, --OC(.dbd.S)YR.sup.2, or --C(.dbd.S)OR.sup.2 substituent; or (b)-3: at least one of R.sup.b and R.sup.t3 is or contains a --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, or --C(.dbd.S)YR.sup.2 substituent; each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclyl moieties are optionally substituted; m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4 or 5; r is 0, 1 or 2.

2. A compound of claim 1 wherein: X.sup.1 is CH or CR.sup.t1; X.sup.2 is N; X.sup.3 is CR.sup.t4.

3. A compound of any of claim 1 or 2 having Formula III: ##STR00110## wherein: Ring C represents a 5- or 6-membered heterocyclic or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms selected from O, N and S(O).sub.r and is optionally substituted on carbon or heteroatom(s); R.sup.c, at each occurrence, is independently selected from the group consisting of halo, .dbd.O, .dbd.S, --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.4).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 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, heterocyclic and heteroaryl; wherein the --NR.sup.2R.sup.3 moiety is optionally a 5- or 6-membered saturated, partially saturated or unsaturated ring, which is optionally substituted and which contains 0-2 additional 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, heterocyclic and heteroaryl; each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocycle moieties is optionally substituted; v is 0, 1, 2, 3, 4or 5 and t is 0, 1, 2, 3, or 4.

4. A compound of claim 3 wherein Ring C is a substituted or unsubstituted heteroaryl ring.

5. A compound of claim 4 wherein Ring C is a substituted or unsubstituted imidazole ring.

6. A compound of claim 5 selected from the following formulae: ##STR00111##

7. A compound of any of claim 1 or 2 having Formula IV: ##STR00112## wherein: Ring D represents a 5- or 6-membered heterocyclic or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms independently selected from N, O, S(O).sub.r and is optionally substituted with 1-5 R.sup.d groups; 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 and the linkage unit can be used in either direction; R.sup.d, at each occurrence, is selected from the group consisting of halo, .dbd.O, .dbd.S, --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.4).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 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, heterocyclic and heteroaryl; wherein the --NR.sup.2R.sup.3 moiety is optionally a 5- or 6-membered saturated, partially saturated or unsaturated ring, which is optionally substituted and which contains 0-2 additional 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, heterocyclic and heteroaryl; each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocycle moieties is optionally substituted; w is selected from 0, 1, 2, 3, 4 or 5; x is 0, 1, 2 or 3; z is 1, 2, 3 or 4; and t is 0, 1, 2, 3, or 4.

8. A compound of claim 7 wherein Ring D is a substituted or unsubstituted heteroaryl.

9. A compound of claim 7 wherein Ring D is a substituted or unsubstituted piperazine ring and L.sup.2 is CH.sub.2.

10. A compound of claim 9 selected from the following formulae: ##STR00113##

11. A composition comprising a compound of any of claim 1 or 2; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or vehicle.

12. A composition comprising a compound of claim 3; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or vehicle.

13. A composition comprising a compound of claim 7; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or vehicle.

14. A compound selected from the group consisting of: 4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}- -3-(pyrimidin-5-ylethynyl)benzamide; 3-{[2-(2-amino-2-oxoethyl)pyrimidin-5-yl]ethynyl}-4-methyl-N-[4-(trifluor- omethyl)pyridin-2-yl]benzamide; and N-[4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-3-(trifluoromethyl)p- henyl]-4-methyl-3-(pyrimidin-5-ylethynyl)benzamide, or a pharmaceutically acceptable salt thereof.

15. A composition comprising a compound selected from the group consisting of: 4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}- -3-(pyrimidin-5-ylethynyl)benzamide; 3-{[2-(2-amino-2-oxoethyl)pyrimidin-5-yl]ethynyl}-4-methyl-N-[4-(trifluor- omethyl)pyridin-2-yl]benzamide; and N-[4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-3-(trifluoromethyl)p- henyl]-4-methyl-3-(pyrimidin-5-ylethynyl)benzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or vehicle.

16. A compound selected from the group consisting of: ##STR00114## ##STR00115## or a pharmaceutically acceptable salt thereof.

17. A composition comprising compound selected from the group consisting of: ##STR00116## ##STR00117## or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or vehicle.
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