Indolyl-Pyridone Derivatives Having Checkpoint Kinase 1 Inhibitory Activity

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof:

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 hydrogen, hydroxy, C 1 -C 3 alkyl, fluoro-(C 1 -C 3 )-alkyl, hydroxy-(C 1 -C 3 )-alkyl, C 1 -C 3 alkoxy, fluoro-(C 1 -C 3 )-alkoxy, hydroxy-(C 1 -C 3 )-alkoxy,—N(R 11 )—R 12 , -Alk-N(R 11 )—R 12 , —O-Alk-N(R 11 )—R 12 , —C(═O)OH, carboxy-(C 1 -C 3 )-alkyl, or —C(═O)—NH—R 13 ;

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 is hydrogen, C 1 -C 3 alkyl, or fluoro-(C 1 -C 3 )-alkyl, and

R 12 is C 1 -C 3 alkyl or hydroxy-(C 1 -C 6 )-alkyl, either of which may be optionally substituted on the alkyl portion by phenyl, C 1 -C 3 alkoxy-(C 1 -C 3 )-alkyl-, halo-(C 1 -C 4 )-alkyl, C 3 -C 6 cycloalkyl, methylsulfonyl-(C 1 -C 3 )-alkyl or —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;

or R 11 and R 12 , or R 14 and R 15 , together with the nitrogen atom to which they are respectively attached, form an optionally substituted, 4- to 6-membered, monocyclic heterocyclic ring having no more than three additional heteroatoms independently selected from oxygen, sulphur and nitrogen;

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 selected from hydrogen, C 1 -C 3 alkyl, or fluoro-(C 1 -C 3 )-alkyl, or R 18 and R 19 together with the nitrogen atom to which they are respectively attached, form an optionally substituted, 4- to 6-membered, monocyclic heterocyclic ring having no more than three additional heteroatoms independently selected from oxygen, sulphur and nitrogen;

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.

2 . (canceled)

3 . (canceled)

4 . A compound as claimed in claim 1 wherein R 3 or R 4 is selected from —N(R 11 )—R 12 , -Alk-N(R 11 )—R 12 , or —O-Alk-N(R 11 )—R 12 , wherein R 11 and R 12 together with the nitrogen atom to which they are attached form an optionally substituted, 5- to 6-membered, monocyclic heterocyclic ring having no more than three additional heteroatoms independently selected from oxygen, sulphur and nitrogen.

5 . A compound as claimed in claim 4 wherein R 11 and R 12 together with the nitrogen atom to which they are attached form a piperidine, morpholine, or piperazine ring, optionally substituted by C 1 -C 3 alkyl, hydroxy-(C 1 -C 3 alkyl)- or fluoro.

6 . A compound as claimed in claim 5 wherein R 11 and R 12 together with the nitrogen atom to which they are attached form piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 1-methyl-piperidin-4-yl, 1-methyl-piperazin-4-yl, or 1-fluoro-piperidin-4-yl.

7 . A compound as claimed in claim 1 wherein R 3 or R 4 is selected from —N(R 11 )—R 12 , -Alk-N(R 11 )—R 12 , or —O-Alk-N(R 11 )—R 12 , wherein 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 8 )—R 19 wherein R 18 and R 19 are independently selected from methyl and ethyl.

8 . A compound 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):

9 . A compound as claimed in claim 1 wherein R 1 , R 2 , R 5 and R 6 are each hydrogen.

10 . A compound as claimed in claim 1 wherein R 1 , R 2 , R 4 , R 5 and R 6 are each hydrogen.

11 . A compound as claimed in claim 1 wherein Y is hydrogen or methyl.

12 . A compound as claimed in claim 1 wherein W is —NH—C(═O)— wherein the carbonyl group is linked to the pyrazole ring.

13 . A compound as claimed in claim 1 wherein R 7 and R 8 are both hydrogen.

14 . A compound as claimed in claim 1 wherein X is —CH 2 —, —CH(CH 3 )— or —C(CH 3 ) 2 —.

15 . A compound as claimed in claim 1 wherein Q is optionally substituted phenyl.

16 . A compound as claimed in claim 15 wherein the substituent or substituents on the phenyl ring is/are selected from methyl, trifluoromethyl, methoxy, fluoro, chloro, or cyano.

17 . A compound as claimed in claim 15 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.

18 . A compound as claimed in claim 1 wherein Q is cyclohexyl or pyrid-3-yl.

19 . A compound 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 together with the nitrogen atom to which they are attached form an optionally substituted, 5- to 6-membered, monocyclic heterocyclic ring having no more than three additional heteroatoms independently selected from oxygen, sulphur and nitrogen; or 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):

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.

20 . A compound as claimed in claim 19 wherein R 11 and R 12 together with the nitrogen atom to which they are attached form a piperidine, morpholine, or piperazine ring, optionally substituted by C 1 -C 3 alkyl or fluoro.

21 . A compound 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 salts thereof.

22 . 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 as claimed in claim 1 effective to inhibit protein kinase activity.

23 . The method of claim 22 further comprising administering the compound in combination with radiotherapy or chemotherapy.

24 . A method of treating of a mammal suffering from an autoimmune disorder responsive to inhibition of protein kinase activity, comprising administering to the mammal an amount of a compound as claimed in claim 1 effective to inhibit protein kinase activity.

25 . The method of claim 34 , wherein the autoimmune disorder is one of organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, and osteoarthritis.