Substituted triazinyl acrylamide derivatives and methods of use

1. A compound of Formula III

wherein R 5 is selected from H, C 1-4 alkyl and C 1-4 alkyl substituted with 5-10 membered heterocyclyl;

wherein R 26 is selected from 5-10 membered heterocyclyl, phenyl arid C 3-6 cycloalkyl;

or wherein R 5 and R 26 together form a nitrogen containing 5-10-membered heterocyclic ring;

wherein R 27 is selected from H, C 1-4 alkyl, fluoro, chloro, NO 2 , CN, CF 3 , C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, —OR 28 , —OC(O)R 28 , —NR 28 R 28 , —COOR 2 , —C(O)R 28 , —C(O)NR 28 R 28 , —SO 2 R 28 , —SO 2 NR 28 R 28 , —NR 28 C(O)NR 28 R 28 , —NR 28 C(O)R 2 , —NR 28 (COOR 28 ), —NR 28 SO 2 NR 28 R 28 , —NR 28 SO 2 R 28 , —OCC(O)NR 28 R 28 , C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, phenyl, 5-6 membered heterocyclyl, C 1-4 alkoxy, phenyloxy, 5-10 membered heterocyclyloxy C 1-4 haloalkyl, phenyl-C 1-4 alkyl, phenyl-C 1-4 alkoxy, 5-10 membered heterocyclyl-C 1-4 alkyl, and 5-10 membered heterocyclyl-C 1-4 alkoxy;

wherein R 28 is selected from H, C 1-4 alkyl, phenyl, and 5-6-membered heterocyclyl;

wherein heterocyclyl is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, CF 3 , —OR 28 , —OC(O)R 28 , —NR 28 R 28 , —COOR 2 , —C(O)R 28 , —C(O)NR 28 R 28 , —SO 2 R 28 , —NR 28 SO 2 R 28 , —OC(O)NR 28 R 28 , and C 1 -C 3 alkyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;

wherein phenyl is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, CF 3 , —OR 28 , —OC(O)R 28 , —NR 28 R 28 , —COOR 2 , —C(O)R 28 , —C(O)NR 28 R 28 , —SO 2 R 28 , —SO 2 NR 28 R 28 , —NR 28 C(O)NR 28 R 28 , —NR 28 C(O)R 2 , —NR 28 (COOR 28 ), —NR 28 SO 2 NR 28 R 28 , —NR 28 SO 2 R 28 , —OC(O)NR 28 R 28 , and C 1 -C 3 alkyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;

wherein cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, CF 3 , —OR 28 , —OC(O)R 28 , —NR 28 R 28 , —COOR 2 , —C(O)R 28 , —C(O)NR 28 R 28 , —SO 2 R 28 , —SO 2 NR 28 R 28 , —NR 28 C(O)NR 28 R 28 , —NR 28 C(O)R 2 , —NR 28 (COOR 28 ), —NR 28 SO 2 NR 28 R 28 , —NR 28 SO 2 R 28 , —OC(O)NR 28 R 28 , and C 1 -C 3 alkyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;

and a pharmaceutically acceptable salt thereof.

2. Compound of claim 1 wherein R 5 is selected from H, methyl and C 1-3 alkyl substituted with optionally substituted morpholinyl, optionally substituted piperdinyl or optionally substituted piperazinyl;

wherein R 26 is selected from optionally substituted indazolyl, optionally substituted benzopyrrolyl, optionally substituted phenyl and optionally substituted cyclopropyl;

or wherein R 5 and R 26 together form an optionally substituted heterocyclic ring selected from pyrrolidinyl, morpholinyl, piperdinyl, piperazinyl, tetrahydroisoquinolinyl and tetrahyciroquinolinyl;

wherein R 27 is selected from H, C 1-4 alkyl, fluoro, chloro, CN, CF 3 , —OR 28 , —OC(O)R 28 , —NR 28 R 28 , —COOR 2 , —C(O)R 28 , —C(O)NR 28 R 28 , —SO 2 R 28 , —SO 2 NR 28 R 28 , phenyl, 5-6 membered heterocyclyl, C 1-4 haloalkyl, phenyl-C 1-4 alkyl, phenyl-C 1-4 alkoxy, 5-10 membered heterocyclyl-C 1-4 alkyl, and 5-10 membered heterocyclyl-C 1-4 alkoxy;

wherein R 28 is selected from H, methyl, ethyl and optionally substituted phenyl;

wherein heterocyclyl is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, CF 3 , —OR 28 , —OC(O)R 28 , NR 28 R 28 , —COOR 28 , —C(O)R 28 , —C(O)NR 28 R 28 , C 1 -C 3 alkyl substituted with optionally substituted phenyl or optionally substituted 5-6 membered heterocyclyl;

wherein phenyl is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, CF 3 , —OR 28 , —OC(O)R 28 , —NR 28 R 28 , —COOR 28 , —C(O)R 28 , —C(O)NR 28 R 28 , C 1 -C 3 alkyl substituted with optionally substituted phenyl or optionally substituted 5-6 membered heterocyclyl;

wherein cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, CF 3 , —OR 28 , —OC(O)R 28 , —NR 28 R 28 , —COOR 28 , —C(O)R 28 , —C(O)NR 28 R, C 1 -C 3 alkyl substituted with optionally substituted phenyl or optionally substituted 5-6 membered heterocyclyl;

and a pharmaceutically acceptable salt thereof.

3. Compound of claim 2 wherein R 5 is selected from H, methyl and C 1-3 alkyl substituted with optionally substituted morpholinyl, optionally substituted piperdinyl or optionally substituted piperazinyl;

wherein R 26 is selected from optionally substituted indazolyl, optionally substituted benzopyrrolyl, arid optionally substituted phenyl;

or wherein R 5 and R 26 together form an optionally substituted heterocyclic ring selected from morpholinyl, piperdinyl, piperazinyl, tetrahydroisoquinolinyl and tetrahydroquinolinyl;

wherein R 27 is selected from H, methyl, fluoro, chloro, methoxy, phenylpropoxy, 1-methylpiperazinylpropoxy, morpholinylpropoxy and 1-methylpiperidinylpropoxy; and

wherein R 28 is selected from H, methyl, ethyl and optionally substituted phenyl;

wherein heterocyclyl is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, phenyl, fluoro, chloro, —OR 28 , CF 3 , —OC(O)R 28 , —NR 28 R 28 , —COOR 28 , —C(O)R 28 , —C(O)NR 28 R 28 , and C 1 -C 3 alkyl substituted with optionally substituted phenyl or optionally substituted 5-6 membered heterocyclyl;

wherein phenyl is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl, 5-6 membered heterocyclyl, fluoro, chloro, CF 3 , —OR 28 , —OC(O)R 28 , —NR 28 R 28 , —COOR 28 , —C(O)R 28 , —C(O)NR 28 R 28 , and C 1 -C 3 alkyl substituted with optionally substituted phenyl or optionally substituted 5-6 membered heterocyclyl;

wherein cycloalkyl is optionally substituted with optionally substituted phenyl;

and a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of claim 1 .

5. A method of treating cancer in a subject, said cancer is selected from esophagus tumor, glioma, Non-small-cell lung cancer, stomach tumor, kidney cell, sarcoma, Liver tumor, pancreas tumor, prostate tumor, bladder tumor, cervix tumor, breast tumor, carcinoma, head & neck tumor, ovary tumor and colorectal tumor, said method comprising administering an effective amount of a compound of claim 1 .

6. A method of treating polycystic kidney disease in a subject, said method comprising administering an effective amount of a compound of claim 1 .

7. Compound of claim 1 and a pharmaceutically acceptable salt thereof selected from

N-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide;

N-{4-[4-(3,4,5-trimethoxy-phenyJ.amino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide;

N-(3-{4-[(1-benzyl-1H-indazol-5-yl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-phenyl)-acrylamide;

N-{4-[4-(1-benzyl-1H-indazol-5-yl)-methyl-amino)-[1,3,5]triazin-2-ylamino}-phenyl)-acrylamide;

N-(4-{4-[(1-benzyl-1H-indazol-5-yl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-phenyl)-acrylamide;

N-{3-[4-(1-benzyl-1H-indazol-5-ylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide;

N-{3-[4-(1-pyridin-2-ylmethyl-1H-indazol-5-ylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide;

N-{3-[4-(3-chloro-phenylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide;

N-(3-{4-[(3-chloro-phenyl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-phenyl)-acrylamide;

N-{3-[4-(7-chloro-3,4-dihydro-2H-quinolin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide;

N-{3-[4-(2-phenyl-cyclopropylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide;

N-{5-[4-(1-benzyl-1H-indazol-5-ylamino)-[1,3,5]triazin-2-ylamino]-2-methoxy-pheny}-acrylamide;

N-(5-{4-[(1-benzyl-1H-indazol-5-yl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-2-methoxy-phenyl)-acrylamide;

N-[5-[4-(3-chloro-phenylamino)-[1,3,5]triazin-2-ylamino]-2-(3-morpholin-4-yl-propoxy)-phenyl]-acrylamide;

N-[5-[4-1-benzyl-1H-indazol-5-ylamino)-[1,3,5]triazin-2-ylamino]-2-(3-morpholin-4-yl-propoxy)-phenyl]-acrylamide;

N-[5-{4-[(1-benzyl-1H-indazol-5-yl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-2-(3-morpholin-4-yl-propoxy)-phenyl]-acrylamide;

N-[5-[4-(7-chloro-3,4-dihydro-2H-quinolin-1-yl)-[1,3,5]triazin-2-ylamino]-2-(3-morpholin-4-yl-propoxy)-phenyl]-acrylamide;

N-[5-{4-[(3-chloro-phenyl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-2-(3-morpholin-4-yl-propoxy)-phenyl]-acrylamide;

N-[5-{4-[(3-chloro-phenyl)-methyl-amino]-[1,3,5]triazin-2-ylamino)-2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-acrylamide;

N-{5-[4-(3-chloro-phenylamino)-[1,3,5]triazin-2-ylamino]-2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-acrylamide;

N-{5-[4-(1-benzyl-1H-indazol-5-ylamino)-[1,3,5]triazin-2-ylamino]-2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-acrylamide;

N-{5-{4-[(1-benzyl-1H-indazol-5-yl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-acrylamide;

N-{5-[4-(7-chloro-3,4-dihydro-2H-quinolin-1-yl)-[1,3,5]triazin-2-ylamino]-2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-acrylamide;

N-(3-{4-[(4-benzyloxy-phenyl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-phenyl)-acrylamide;

N-{3-[4-(4-benzyloxy-phenylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide;

N-{3-[4-(1-benzyl-1H-indol-5-ylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide;

N-(3-{4-[(1-benzyl-1H-indol-5-yl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-phenyl)-acrylamide;

N-(3-{4-[(4-benzyloxy-3-chloro-phenyl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-phenyl)-acrylamide;

N-{3-[4-(4-benzyloxy-3-chloro-phenylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide;

N-[5-[4-(1-benzyl-1H-indol-5-ylamino)-[1,3,5]triazin-2-ylamino]-2-(3-morpholin-4-yl-propoxy)-phenyl]-acrylamide;

N-[5-{4-[(1-benzyl-1H-indol-5-yl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-2-(3-morpholin-4-yl-propoxy)-phenyl]-acrylamide;

N-[5-{4-[(4-benzyloxy-3-chloro-phenyl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-2-(3-morpholin-4-yl-propoxy)-phenyl]-acrylamide; and

N-[5-[4-(4-benzyloxy-3-chloro-phenylamino)-[1,3,5]triazin-2-ylaminol]-2-(3-morpholin-4-yl-propoxy)-phenyl]-acrylamide.