Indolyl-Pyridone Derivatives Having Checkpoint Kinase 1 Inhibitory Activity

Abstract

Compounds of formula (I) have checkpoint kinase 1 (CHK1) inhibitory activity: 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 ; W is selected from —C(═O)—N(—R 16 )— or —N(—R 17 )—C(═O)—; 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.

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.