Aminothiazole compounds as c-Kit inhibitors

1. A compound of one of the following formulae (Ig) or (Ih):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is H, (C 1 -C 6 ) alkyl, —(CH 2 )C(O)OH, or —C(O)N(R 7 ) 2 ;

R 2 is (C 1 -C 6 ) alkyl, —C(O)R 8 , or —C(O)NR 9 R 10 ;

each R 3 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or OH;

each R 4 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, CN, —(C(R 6 ) 2 ) p -heterocycloalkyl wherein the heterocycloalkyl comprises a 4- to 7-membered ring and 1 to 3 heteroatoms selected from N, O, and S, or —(C(R 6 ) 2 ) p -heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, and wherein the heterocycloalkyl or heteroaryl is optionally substituted with one or more substituents each independently selected from (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, and (C 1 -C 6 ) dialkylamino;

R 5 is H, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) haloalkyl;

each R 6 is independently H or (C 1 -C 6 ) alkyl;

each R 7 is independently H or (C 1 -C 6 ) alkyl;

R 8 is (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 2 -C 6 ) alkenyl, (C 1 -C 3 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S;

R 9 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 7 ) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S;

R 10 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 7 ) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, (C 1 -C 6 ) dialkylamino, and —OH, and wherein the (C 1 -C 6 ) alkyl is optionally substituted with one or more R 11 ;

or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituent each independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) hydroxyalkyl, —(CH 2 ) q —NH 2 , —(CH 2 ) q —(C 1 -C 6 ) alkylamino, —(CH 2 ) q —(C 1 -C 6 ) dialkylamino, —C(O)(C 1 -C 6 ) alkyl, —OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more (C 1 -C 6 ) alkyl;

R 11 is (C 1 -C 6 ) alkoxy, —OH, —NH 2 , (C 1 -C 6 ) alkylamino, (C 1 -C 6 ) dialkylamino, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C 1 -C 6 ) alkyl and OH; and

each p and q is independently 0, 1 or 2.

2. The compound of claim 1 , wherein R 5 is H.

3. The compound of claim 1 , wherein R 4 is (C 1 -C 6 ) haloalkyl.

4. The compound of claim 1 , wherein R 4 is CF 3 .

5. The compound of claim 1 , wherein R 3 is methyl.

6. The compound of claim 1 , wherein R 1 is H and R 2 is —C(O)NR 9 R 10 .

7. The compound of claim 6 , wherein R 9 is (C 1 -C 6 ) alkyl and R 10 is (C 1 -C 6 ) alkyl substituted with one R 11 .

8. The compound of claim 7 , wherein R is —OH.

9. The compound of claim 6 , wherein R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl ring comprising 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituents each independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) hydroxyalkyl, —(CH 2 ) q —(C 1 -C 6 ) dialkylamino, —C(O)(C 1 -C 6 ) alkyl, OH, or 6-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with (C 1 -C 6 ) alkyl.

10. A compound selected from:

3-((2-(3,3-dimethylureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-1);

4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)-3-((2-ureidothiazol-5-yl)ethynyl)benzamide (I-2);

methyl (5-((2-methyl-5-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)ethynyl)thiazol-2-yl)carbamate (I-3);

4-methyl-3-((2-(3-methylureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-4);

3-((2-(3-(2-methoxyethyl)ureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-5);

4-methyl-3-((2-(3-(2-morpholinoethyl)ureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-6);

3-((2-(3-(2-methoxyethyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-7);

3-((2-(3-ethyl-3-methylureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-8);

3-((2-(3-(2-(dimethylamino)ethyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-9);

3-((2-(3-(2-hydroxyethyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-10);

3-((2-(3-(2-(dimethylamino)ethyl)ureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-11);

4-methyl-3-((2-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-12);

4-methyl-3-((2-(3-((1-methylpiperidin-4-yl)methyl)ureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-13);

4-methyl-3-((2-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-14);

3-((2-(3-(2-hydroxy-2-methylpropyl)ureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-15);

4-methyl-3-((2-(3-methyl-3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-16);

3-((2-(3-cyclopropylureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-17);

3-((2-(3-(2-(3-hydroxypyrrolidin-1-yl)ethyl)ureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-18);

4-methyl-3-((2-(3-methyl-3-(2-(pyrrolidin-1-yl)ethyl)ureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-19);

4-methyl-3-((2-(3-methyl-3-((1-methylpyrrolidin-2-yl)methyl)ureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-20);

3-((2-(3-(2-hydroxy-2-methylpropyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-21);

3-((2-(3-(4-hydroxycyclohexyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-22);

4-methyl-N-(5-((2-methyl-5-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)ethynyl)thiazol-2-yl)piperazine-1-carboxamide (I-23);

3-hydroxy-3-methyl-N-(5-((2-methyl-5-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)ethynyl)thiazol-2-yl)azetidine-1-carboxamide (I-24);

4-methyl-N-(5-((2-methyl-5-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)ethynyl)thiazol-2-yl)piperidine-1-carboxamide (I-25);

4-methyl-3-((2-(3-(pyridin-4-ylmethyl)ureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-26);

4-(2-hydroxyethyl)-N-(5-((2-methyl-5-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)ethynyl)thiazol-2-yl)piperazine-1-carboxamide (I-27);

4-methyl-3-((2-(3-methyl-3-(2-(methylamino)ethyl)ureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-28);

4-methyl-3-((2-(3-methyl-3-(1-methylpiperidin-4-yl)ureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-29);

N-(5-((2-methyl-5-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)ethynyl)thiazol-2-yl)piperazine-1-carboxamide (I-30);

3-((2-(3-(4-aminobutyl)ureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-31);

4-methyl-3-((2-(3-methyl-3-(1-methylpiperidin-3-yl)ureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-32);

3-((2-(3-(4-aminocyclohexyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-33);

2-((dimethylamino)methyl)-N-(5-((2-methyl-5-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)ethynyl)thiazol-2-yl)morpholine-4-carboxamide (I-34);

N-(5-((2-methyl-5-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)ethynyl)thiazol-2-yl)morpholine-4-carboxamide (I-35);

3-((2-(3-(3-aminopropyl)ureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-36);

4-acetyl-N-(5-((2-methyl-5-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)ethynyl)thiazol-2-yl)piperazine-1-carboxamide (I-37);

3-((2-(3-(2-aminoethyl)ureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-38);

4-methyl-3-((2-(3-methyl-3-(1-methylazetidin-3-yl)ureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-39);

3-(dimethylamino)-N-(5-((2-methyl-5-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)ethynyl)thiazol-2-yl)pyrrolidine-1-carboxamide (I-40);

N-(5-((2-methyl-5-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)ethynyl)thiazol-2-yl)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide (I-41);

2-fluoro-5-((2-(3-methylureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-42);

2-fluoro-N-(4-(trifluoromethyl)pyridin-2-yl)-5-((2-ureidothiazol-5-yl)ethynyl)benzamide (I-43);

3-((2-(3-methylureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-44);

4-fluoro-3-((2-(3-methylureido)thiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-45);

3-((2-(3-(2-methoxyethyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)benzamide (I-46);

N-(2-methoxy-3-(trifluoromethyl)phenyl)-3-((2-(3-(2-methoxyethyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methylbenzamide (I-47);

N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((2-(3-(2-methoxyethyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methylbenzamide (I-48);

3-((2-(cyclopropanecarboxamido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-49);

3-((2-(cyclopropanecarboxamido)thiazol-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (I-50);

3-((2-acetamidothiazol-5-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I 51);

4-methyl-3-((2-pivalamidothiazol-5-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (I-52);

N-(4-methyl-3-((2-(3-methyl-3-(1-methylpiperidin-4-yl)ureido)thiazol-5-yl)ethynyl)phenyl)-4-(trifluoromethyl)picolinamide (I-53);

N-(3-((2-(3-(2-methoxyethyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (I-54);

N-(4-methyl-3-((2-(3-methyl-3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)thiazol-5-yl)ethynyl)phenyl)-4-(trifluoromethyl)picolinamide (I-55);

N-(3-((2-(3,3-dimethylureido)thiazol-5-yl)ethynyl)-4-methylphenyl)-3-(trifluoromethoxy)benzamide (I-56);

N-(4-methyl-3-((2-(3-methylureido)thiazol-5-yl)ethynyl)phenyl)-4-(trifluoromethyl)picolinamide (I-57);

N-(3-((2-(3-(2-(dimethylamino)ethyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (I-58);

N-(3-((2-(3-(2-(diethylamino)ethyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (I-59);

N-(3-((2-(3-(2-hydroxyethyl)-3-methylureido)thiazol-5-yl)ethynyl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (I-60);

N-(3-((2-(3-(2-methoxyethyl)-3-methylureido)thiazol-5-yl)ethynyl)phenyl)-4-(trifluoromethyl)picolinamide (I-61); and

N-(4-fluoro-3-((2-(3-(2-methoxyethyl)-3-methylureido)thiazol-5-yl)ethynyl)phenyl)-4-(trifluoromethyl)picolinamide (I-62),

or a pharmaceutically acceptable salt thereof.

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

12. The compound of claim 9 , wherein R 9 and R 10 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring that is azetidinyl, morpholinyl, piperidinyl, or piperazinyl, and which is optionally substituted with one or more substituent each independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) hydroxyalkyl, —(CH 2 ) q —(C 1 -C 6 ) dialkylamino, —C(O)(C 1 -C 6 ) alkyl, —OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more (C 1 -C 6 ) alkyl.

13. The compound of claim 12 , wherein said heterocycloalkyl ring is substituted with one substituent that is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) hydroxyalkyl, —(CH 2 ) q —(C 1 -C 6 ) dialkylamino, —C(O)(C 1 -C 6 ) alkyl, —OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more (C 1 -C 6 ) alkyl.

14. The compound of claim 12 , wherein said heterocycloalkyl ring is substituted with one substituent that is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) hydroxyalkyl, —(CH 2 ) q —(C 1 -C 6 ) dialkylamino, —C(O)(C 1 -C 6 ) alkyl, or —OH.