Indolyl-pyridone derivatives having checkpoint kinase 1 inhibitory activity

10696,652

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]

Vernalis (R&D) Ltd. (Great Abington, Cambridge, GB)

Vernalis (R&D) Ltd. (Great Abington, GB)

1. A method of treating a mammal suffering from a cancer responsive to inhibition of CHK1 activity, comprising administering to the mammal an amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, effective to inhibit CHK1 activity, wherein the compound of formula (I) is: [chemical expression included] wherein R 1 , R 2 , R 5 and R 6 are independently selected from hydrogen, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methoxy, trifluoromethoxy, methylamino and dimethylamino; R 3 , and R 4 are independently selected from —N(R 11)—R 12 , -Alk-N(R 11)—R 12 and —O-Alk-N(R 11)—R 12 ; Alk is a straight or branched chain divalent C 1 -C 6 alkylene radical; R 7 and R 8 are independently selected from hydrogen, hydroxy, or C 1 -C 3 alkoxy; X is a straight chain divalent C 1 -C 3 alkylene radical, optionally substituted on one or more carbons by R 9 and/or R 10 ; R 9 and R 10 are independently selected from methyl, hydroxy, or fluoro; R 11 and R 12 are independently selected from methyl and ethyl, or R 11 is methyl or ethyl and R 12 is —N(R 18)—R 19 ; R 13 is hydrogen, C 1 -C 3 alkyl, fluoro-(C 1 -C 3)-alkyl, or a radical of formula -Alk-N(R 14)—R 15 ; R 14 and R 15 are independently selected from hydrogen, C 1 -C 3 alkyl, or fluoro-(C 1 -C 3)-alkyl; W is selected from —C(═O)—N(—R 16)— or —N(—R 17)—C(═O)—; R 16 or R 17 is selected from hydrogen, C 1 -C 3 alkyl, or fluoro-(C 1 -C 3)-alkyl; R 18 and R 19 are independently selected from methyl and ethyl; Y is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 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 (C 1 -C 6)alkyl, (C 1 -C 6)alkoxy, hydroxy, hydroxy(C 1 -C 6)alkyl, mercapto, mercapto(C 1 -C 6)alkyl, (C 1 -C 6)alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile, (—CN), oxo, phenyl, —COOH, —COOR A , —COR A , —SO 2 R A , —CONH 2 , —SO 2 NH 2 , —CONHR A , —SO 2 NHR A , —CONR A R B , —SO 2 NR A R B , —NH 2 , —NHR A , —NR A R B , —OCONH 2 , —OCONHR A , —OCONR A R B , —NHCOR A , —NHCOOR A , —NR B COOR A , —NHSO 2 OR A , —NR B SO 2 OR A , —NHCONH 2 , —NR A CONH 2 , —NHCONHR B , —NR A CONHR B , —NHCONR A R B , and —NR A CONR A R B wherein R A and R B are independently a (C 1 -C 6)alkyl group.

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

3. The method as claimed in claim 1 wherein R 1 , R 2 , R 5 and R 6 are each hydrogen.

4. The method as claimed in claim 1 wherein R 1 , R 2 , R 4 , R 5 and R 6 are each hydrogen.

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

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

7. The method as claimed in claim 1 wherein R 7 and R 8 are both hydrogen.

8. The method as claimed in claim 1 wherein X is —CH 2 —, —CH(CH 3)— or —C(CH 3) 2 —.

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

10. The method as claimed in claim 9 wherein the substituent or substituents on the phenyl ring is/are selected from methyl, trifluoromethyl, methoxy, fluoro, chloro, or cyano.

11. The method as claimed in claim 9 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.

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

13. The method as claimed in claim 1 wherein: R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are each hydrogen; Y is hydrogen or methyl; W is —NH—C(═O)— wherein the carbonyl group is linked to the pyrazole ring; R 3 is —N(R 11)—R 12 , -Alk-N(R 11)—R 12 , or —O-Alk-N(R 11)—R 12 ; R 11 and R 12 are independently selected from methyl and ethyl; or R 11 is methyl or ethyl and R 12 is —N(R 18)—R 19 wherein R 18 and R 19 are independently selected from methyl and ethyl; Alk is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 C(CH 3) 2 CH 2 — or is a divalent radical of formula (II): [chemical expression included] X is —CH 2 —, —CH(CH 3)— or —C(CH 3) 2 —; and Q is phenyl, optionally substituted by one or two substituents selected from C 1 -C 3 alkyl, fluoro-(C 1 -C 3)alkyl, C 1 -C 3 alkoxy, fluoro-(C 1 -C 3) alkoxy, halo, and cyano.

14. 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.

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

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

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