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Details for Patent: 8,278,307

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Details for Patent: 8,278,307

Title:Monocyclic 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): Shakespeare; William C. (Southborough, MA), Huang; Wei-Sheng (Acton, MA), Dalgarno; David C. (Brookline, MA), Zhu; Xiaotian (Newton, MA), Thomas; R. Mathew (Sharon, MA), Wang; Yihan (Newton, MA), Qi; Jiwei (West Roxbury, MA), Sundaramoorthi; Rajeswari (Watertown, MA), Zou; Dong (Concord, MA), Metcalf, III; Chester A. (Needham, MA), Sawyer; Tomi K. (Southborough, MA), Romero; Jan Antoinette C. (Somerville, MA)
Assignee: ARIAD Pharmaceuticals, Inc. (Cambridge, MA)
Filing Date:May 08, 2007
Application Number:12/227,130
Claims:1. A compound of the Formula: ##STR00065## or a tautomer or a pharmaceutically acceptable salt thereof, wherein: Ring T represents ##STR00066## Ring A represents a 5- or 6-membered aryl or heteroaryl ring; Ring B represents a 5- or 6-membered aryl or heteroaryl ring; L.sup.1 is NR.sup.1C(O) or C(O)NR.sup.1; each R.sup.a and R.sup.t is independently selected from 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, --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--; each R.sup.1, R.sup.2 and R.sup.3 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle and heteroaryl, and in addition, NR.sup.2R.sup.3 may be a 5- or 6-membered saturated, partially saturated or unsaturated ring, which is optionally substituted and contains 0-2 additional heteroatoms selected from N, O and S(O).sub.r; each R.sup.4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; R.sup.b is selected from 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, --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, Ring C, and --L.sup.2-Ring D, wherein Y is independently a bond, --O--, --S-- or --NR.sup.3--; in which: (i) Ring C is a 5- or 6-membered heteroaryl or heterocyclic ring comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O).sub.r and which is optionally substituted with 1 to 5 substituents, R.sup.c; (ii) 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, and (CH.sub.2).sub.xNR.sup.3C(O)(CH.sub.2).sub.x, oriented in either direction; and, (iii) Ring D is a 5- or 6-membered heterocyclic or heteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O).sub.r and which is optionally substituted with 1 to 5 R.sup.d substituents; each R.sup.c and R.sup.d is independently halo, .dbd.O, .dbd.S, --CN, --NO.sub.2, --R.sup.4, --OR.sup.2, --NR.sup.2R.sup.3, --Si(R.sup.4).sub.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).sub.2, --NR.sup.2SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3 or --NR.sup.2SO.sub.2NR.sup.2R.sup.3; each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted; m is 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3; p is 1, 2, 3, 4 or 5; r is 0, 1 or 2; x is 0, 1, 2 or 3; z is 1, 2, 3 or 4; each optional substituent for an unsaturated carbon atom of an aryl or heteroaryl moiety and for a carbon atom of an alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl or non-aromatic heterocyclic group is selected from F, Cl, Br, I, --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, where M is a 1-6 carbon alkyl group; each optional substituent for an alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl or non-aromatic heterocyclic group alternatively is selected from .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; and each optional substituent on a nitrogen is selected from R.sup.4, --NR.sup.2R.sup.3, --C(.dbd.O)R.sup.2, --C(.dbd.O)OR.sup.2, --C(.dbd.O)SR.sup.2, --C(.dbd.O)NR.sup.2R.sup.3, --C(.dbd.NR.sup.2)NR.sup.2R.sup.3, --C(.dbd.NR.sup.2)OR.sup.2, --C(.dbd.NR.sup.2)R.sup.3, --COCOR.sup.2, --COMCOR.sup.2, --CN, --SO.sub.2R.sup.3, S(O)R.sup.3, --P(.dbd.O)(YR.sup.2)(YR.sup.2), --NR.sup.2SO.sub.2R.sup.3 and --NR.sup.2SO.sub.2NR.sup.2R.sup.3.

2. The compound of claim 1, wherein at least one of Rb is ##STR00067## or a tautomer or a pharmaceutically acceptable salt thereof, wherein: v is 0, 1, 2, 3, 4 or 5.

3. The compound according to claim 2, or a tautomer or a pharmaceutically acceptable salt thereof, wherein Ring C is a heteroaryl ring bearing a single C.sub.1-C.sub.6 alkyl substituent.

4. The compound of claim 3 or a tautomer or a pharmaceutically acceptable salt thereof, in which Ring C is selected from the following: ##STR00068##

5. The compound according to claim 2, or a tautomer or a pharmaceutically acceptable salt thereof, wherein Ring C is one of the following: ##STR00069##

6. The compound of claim 2, or a tautomer or a pharmaceutically acceptable salt thereof, having the formula: ##STR00070##

7. The compound of claim 6, or a tautomer or a pharmaceutically acceptable salt thereof, wherein R.sup.t is --CH.sub.3 or --C(O)NH.sub.2, v is 1, n is 0 or 1, m is 1, t is 1, R.sup.a is --CH.sub.3, R.sup.b is CF.sub.3 and R.sup.c is --CH.sub.3.

8. The compound according to claim 1, or a tautomer or a pharmaceutically acceptable salt thereof, wherein Rings A and B are aryl.

9. The compound of claim 1, or a tautomer or a pharmaceutically acceptable salt thereof, wherein at least one of R.sup.b is ##STR00071## 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; 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; alternatively, NR.sup.2R.sup.3 moiety may be a 5- or 6-membered saturated, partially saturated or unsaturated ring, which can be 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 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.

10. The compound according to claim 9, or a tautomer or a pharmaceutically acceptable salt thereof, wherein Rings A and B are aryl.

11. The compound of claim 9, or a tautomer or a pharmaceutically acceptable salt thereof, wherein Ring D is a substituted or unsubstituted piperazine ring and L.sup.2 is CH.sub.2.

12. The compound of claim 11, or a tautomer or a pharmaceutically acceptable salt thereof, having the formula: ##STR00072##

13. The compound of claim 12, or a tautomer or a pharmaceutically acceptable salt thereof, wherein R.sup.t is independently selected from --CH.sub.3 and --C(O)NH.sub.2, n is 0 or 1, m is 1, t is 1, R.sup.a is methyl, R.sup.b is CF.sub.3, and R.sup.d is selected from methyl and CH.sub.2CH.sub.2OH.

14. The compound of claim 9, or a tautomer or a pharmaceutically acceptable salt thereof, wherein Ring D is a substituted or unsubstituted heteroaryl ring.

15. The compound of claim 9 or a tautomer or a pharmaceutically acceptable salt thereof, in which Ring B-L.sup.2-Ring D is selected from the following: ##STR00073## ##STR00074##

16. The compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof, in which Ring T is selected from: ##STR00075##

17. The compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof, in which Ring T is selected from the following: ##STR00076##

18. The compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof, in which Ring A is selected from the following: ##STR00077##

19. The compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof, in which Ring B is selected from the following: ##STR00078## ##STR00079##

20. A compound selected from the following: ##STR00080## or a pharmaceutically acceptable salt thereof.

21. A compound selected from the following: 1-Methyl-5-(2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluorometh- yl-phenylcarbamoyl]-phenylethynyl)-1H-imidazole-2-carboxylic acid amide, 1-Methyl-5-(2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phen- ylcarbamoyl]-phenylethynyl)-1H-imidazole-2-carboxylic acid amide, 5-[5-(3-Imidazol-1-yl-5-trifluoromethylphenylcarbamoyl)-2-methyl-phenylet- hynyl]-1-methyl-1H-imidazole-2-carboxylic acid amide, N-{3-chloro-4-[(4-methylpiperazin-1-yl)methyl]phenyl}-4-methyl-3-[(1-meth- yl-1H-imidazol-5-yl)ethynyl]benzamide, 1-methyl-5-({2-methyl-5-[({4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluor- omethyl)phenyl}carbonyl)amino]phenyl}ethynyl)-1H-imidazole-2-carboxamide, and 5-[(5-{[4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-3-(trifluor- omethyl)phenyl]carbamoyl}-2-methylphenyl)ethynyl]-1-methyl-1H-imidazole-2-- carboxamide, or a pharmaceutically acceptable salt thereof.

22. The compound 1-Methyl-5-(2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluorometh- yl-phenylcarbamoyl]-phenylethynyl)-1H-imidazole-2-carboxylic acid amide or a pharmaceutically acceptable salt thereof.

23. The compound 1-Methyl-5-(2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phen- ylcarbamoyl]-phenylethynyl)-1H-imidazole-2-carboxylic acid amide or a pharmaceutically acceptable salt thereof.

24. The compound 5-[5-(3-Imidazol-1-yl-5-trifluoromethylphenylcarbamoyl)-2-methyl-phenylet- hynyl]-1-methyl-1H-imidazole-2-carboxylic acid amide or a pharmaceutically acceptable salt thereof.

25. The compound N-{3-chloro-4-[(4-methylpiperazin-1-yl)methyl]phenyl}-4-methyl-3-[(1-meth- yl-1H-imidazol-5-yl)ethynyl]benzamide or a pharmaceutically acceptable salt thereof.

26. The compound 1-methyl-5-({2-methyl-5-[({4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluor- omethyl)phenyl}carbonyl)amino]phenyl}ethynyl)-1H-imidazole-2-carboxamide or a pharmaceutically acceptable salt thereof.

27. The compound 5-[(5-{[4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-3-(trifluoromet- hyl)phenyl]carbamoyl}-2-methylphenyl)ethynyl]-1-methyl-1H-imidazole-2-carb- oxamide or a pharmaceutically acceptable salt thereof.

28. A composition comprising a compound of any of claim 1, 2, 8, 3, 5, 6, 7, 9, 10, 11, 14, 12, 13, 16 or 17, 18, 19, 4, 15, 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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