Indolyl-Pyridone Derivatives Having Checkpoint Kinase 1 Inhibitory Activity

20180244652

15/962306

April 25, 2018

A method of treating a mammal suffering from a cancer responsive to inhibition of protein kinase activity, by administering to the mammal an amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, effective to inhibit protein kinase activity, wherein the compound of formula (I) is: [chemical expression included]

1. A method of treating a mammal suffering from a cancer responsive to inhibition of protein kinase activity, comprising administering to the mammal an amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, effective to inhibit protein kinase activity, wherein the compound of formula (I) is: [chemical expression included] wherein R1, R2, R5 and R6 are independently selected from hydrogen, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methoxy, trifluoromethoxy, methylamino and dimethylamino; R3, and R4 are independently selected from hydrogen, hydroxy, C1-C3 alkyl, fluoro-(C1-C3)-alkyl, hydroxy-(C1-C3)-alkyl, C1-C3 alkoxy, fluoro-(C1-C3)-alkoxy, hydroxy-(C1-C3)-alkoxy, —N(R11)—R12, -Alk-N(R11)—R12, —O-Alk-N(R11)—R12, —C(═O)OH, carboxy-(C1-C3)-alkyl, or —C(═O)—NH—R13; Alk is a straight or branched chain divalent C1-C6 alkylene radical; R7 and R8 are independently selected from hydrogen, hydroxy, or C1-C3 alkoxy; X is a straight chain divalent C1-C3 alkylene radical, optionally substituted on one or more carbons by R9 and/or R10; R9 and R10 are independently selected from methyl, hydroxy, or fluoro; R11 is hydrogen, C1-C3 alkyl, or fluoro-(C1-C3)-alkyl, and R12 is C1-C3 alkyl or hydroxy-(C1-C6)-alkyl, either of which may be optionally substituted on the alkyl portion by phenyl, C1-C3 alkoxy-(C1-C3)-alkyl-, halo-(C1-C4)-alkyl, C3-C6 cycloalkyl, methylsulfonyl-(C1-C3)-alkyl or —N(R18)—R19; R13 is hydrogen, C1-C3 alkyl, fluoro-(C1-C3)-alkyl, or a radical of formula -Alk-N(R14)—R15; R14 and R15 are independently selected from hydrogen, C1-C3 alkyl, or fluoro-(C1-C3)-alkyl; W is selected from —C(═O)—N(—R16)— or —N(—R17)—C(═O)—; R16 or R17 is selected from hydrogen, C1-C3 alkyl, or fluoro-(C1-C3)-alkyl; R18 and R19 are selected from hydrogen, C1-C3 alkyl, or fluoro-(C1-C3)-alkyl; Y is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or halo; and Q is selected from optionally substituted phenyl, optionally substituted cyclohexyl, or an optionally substituted 6-membered monocyclic heteroaryl ring wherein optionally substituted means optionally substituted by at least one substituent selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, mercapto, mercapto(C1-C6)alkyl, (C1-C6)alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile, (—CN), oxo, phenyl, —COOH, —COORA, —CORA, —SO2RA, —CONH2, —SO2NH2, —CONHRA, —SO2NHRA, —CONRARB, —SO2NRARB, —NH2, —NHRA, —NRARB, —OCONH2, —OCONHRA, —OCONRARB, —NHCORA, —NHCOORA, —NRBCOORA, —NHSO2ORA, —NRBSO2ORA, —NHCONH2, —NRACONH2, —NHCONHRB, —NRACONHRB, —NHCONRARB, and —NRACONRARB wherein RA and RB are independently a (C1-C6)alkyl group.

2. The method as claimed in claim 1 wherein R3 or R4 is selected from —N(R11)—R12, -Alk-N(R11)—R12, or —O-Alk-N(R11)—R12, wherein R11 and R12 are independently selected from methyl and ethyl, or R11 is methyl or ethyl and R12 is —N(R18)—R19 wherein R18 and R19 are independently selected from methyl and ethyl.

3. The method as claimed in claim 1 wherein Alk is —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2C(CH3)2CH2— or is a divalent radical of formula (II): [chemical expression included]

4. The method as claimed in claim 1 wherein R1, R2, R5 and R6 are each hydrogen.

5. The method as claimed in claim 1 wherein R1, R2, R4, R5 and R6 are each hydrogen.

6. The method as claimed in claim 1 wherein Y is hydrogen or methyl.

7. The method as claimed in claim 1 wherein W is —NH—C(═O)— wherein the carbonyl group is linked to the pyrazole ring.

8. The method as claimed in claim 1 wherein R7 and R8 are both hydrogen.

9. The method as claimed in claim 1 wherein X is —CH2—, —CH(CH3)— or —C(CH3)2—.

10. The method as claimed in claim 1 wherein Q is optionally substituted phenyl.

11. The method as claimed in claim 10 wherein the substituent or substituents on the phenyl ring is/are selected from methyl, trifluoromethyl, methoxy, fluoro, chloro, or cyano.

12. The method as claimed in claim 10 wherein Q is 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 4-methoxy-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 3,4-difluoro-phenyl, 3,5-difluoro-phenyl, or 3-fluoro-4-methyl-phenyl.

13. The method as claimed in claim 1 wherein Q is cyclohexyl or pyrid-3-yl.

14. The method as claimed in claim 1 wherein: R1, R2, R4, R5, R6, R7 and R8 are each hydrogen; Y is hydrogen or methyl; W is —NH—C(═O)— wherein the carbonyl group is linked to the pyrazole ring; R3 is —N(R11)—R12, -Alk-N(R11)—R12, or —O-Alk-N(R11)—R12; R11 and R12 are independently selected from methyl and ethyl; or R11 is methyl or ethyl and R12 is —N(R18)—R19 wherein R18 and R19 are independently selected from methyl and ethyl; Alk is —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2C(CH3)2CH2— or is a divalent radical of formula (II): [chemical expression included] X is —CH2—, —CH(CH3)— or —C(CH3)2—; and Q is phenyl, optionally substituted by one or two substituents selected from C1-C3 alkyl, fluoro-(C1-C3)alkyl, C1-C3 alkoxy, fluoro-(C1-C3) alkoxy, halo, and cyano.

15. The method as claimed in claim 1, wherein the compound of Formula (I) is selected from the group consisting of: 1-Benzyl-1H-pyrazole-4-carboxylic acid [5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide, 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid [6-oxo-5-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid {5-[5-(4-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid [6-oxo-5-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid {5-[5-(cis-2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid {5-[5-(4-methyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-(1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid {5-[5-(4-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid {5-[5-(3-dimethylamino-2,2-dimethyl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-((R)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid {5-[5-(cis-2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid {5-[5-((S)-2-methyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid {5-[5-((R)-2-methyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid [5-(5-{[(3-dimethylamino-2,2-dimethyl-propyl)-ethyl-amino]-methyl}-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid {5-[5-(cis-2,6-dimethyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid {5-[5-(3-diethylamino-2,2-dimethyl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid {5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid {5-[5-(2,2-dimethyl-3-pyrrolidin-1-yl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid {5-[5-(2,2-dimethyl-3-piperidin-1-yl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, 1-Benzyl-1H-pyrazole-4-carboxylic acid {5-[5-(1-diethylaminomethyl-cyclopropylmethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide, and pharmaceutically acceptable salt thereof.

16. The method of claim 1, wherein the administration is parenteral administration.

17. The method of claim 1 further comprising administering the compound in combination with radiotherapy or chemotherapy.

07; 07; 61; 61; 61; 61

edspap.20180244652