Indolyl-Pyridone Derivatives Having Checkpoint Kinase 1 Inhibitory Activity

Abstract

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:

1 . (canceled) 
     
     
         2 . A process for preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         comprising removing the Boc group and SEM group from the compound of formula (II) to form a compound of formula (I) 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 2 , R 5  and R 6  are each 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. 
       
     
     
         3 . The process as claimed in  claim 2 , wherein the compound of formula (II) is a compound of formula (II′), 
       
         
           
           
               
               
           
         
         and wherein the compound of formula (II′) is formed by reacting a compound of formula (III) with a compound of formula (IV) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Q, Y, and X are as defined in  claim 1 . 
       
     
     
         4 . The process as claimed in  claim 3 , wherein the preparation of the compound of formula (II′) is carried out in dichloromethane. 
     
     
         5 . The process as claimed in  claim 3 , wherein the preparation of the compound of formula (II′) is carried out in the presence of trimethylamine. 
     
     
         6 . The process as claimed in  claim 2 , wherein the compound of formula (II) is a compound of formula (II″), 
       
         
           
           
               
               
           
         
         and wherein the compound of formula (II″) is formed by reacting a compound of formula (V) with a compound of formula (VI) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Q, Y, and X are as defined in  claim 1 . 
       
     
     
         7 . The process as claimed in  claim 6 , wherein the preparation of the compound of formula (II″) is carried out in dichloromethane. 
     
     
         8 . The process as claimed in  claim 6 , wherein the preparation of the compound of formula (II″) is carried out in the presence of trimethylamine. 
     
     
         9 . The process as claimed in  claim 3 , wherein the compound of formula (III) is formed by reacting a compound of formula (VII) with a compound of formula (VIII) under Suzuki coupling conditions to form the compound of formula (IX) 
       
         
           
           
               
               
           
         
         and then the nitro group of the compound of formula (IX) is reduced to —NH 2  to form the compound of formula (III); 
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Q, Y, and X are as defined in  claim 1 ; and 
         A is independently selected from hydrogen or C 1-3  alkyl, or both A groups may be taken together with the oxygen atom to which they are joined and the associated boron atom, to form a C 2  to C 6  cyclic boronic ester. 
       
     
     
         10 . A process as claimed in  claim 9 , wherein the compound of formula (VII) is formed by reacting the compound of formula (XIII) with a strong base and then boronic acid 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5  are as defined in  claim 1 . 
       
     
     
         11 . The process as claimed in  claim 6 , wherein the compound of formula (V) is formed by reacting a compound of formula (VII) with a compound of formula (X) under Suzuki coupling conditions to form the compound of formula (XII) 
       
         
           
           
               
               
           
         
         and then the ester of the compound of formula (XII) is hydrolysed to form the compound of formula (V); 
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Q, Y, and X are as defined in  claim 1 ; 
         V is ethyl or methyl; and 
         A is independently selected from hydrogen or a C 1-3  alkyl, or both A groups may be taken together with the oxygen atom to which they are joined and the associated boron atom, to form a C 2  to C 6  cyclic boronic ester. 
       
     
     
         12 . A process as claimed in  claim 11 , wherein the compound of formula (VII) is formed by reacting the compound of formula (XIII) with a strong base and then boronic acid 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5  are as defined in  claim 1 . 
       
     
     
         13 . The process as claimed in  claim 2 , 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. 
     
     
         14 . The process as claimed in  claim 2 , 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. 
     
     
         15 . The process as claimed in  claim 2 , 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. 
     
     
         16 . The process as claimed in  claim 2 , 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 18 )—R 19  wherein R 18  and R 19  are independently selected from methyl and ethyl. 
     
     
         17 . The process as claimed in  claim 2 , 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): 
       
         
           
           
               
               
           
         
       
     
     
         18 . The process as claimed in  claim 2 , wherein R 1 , R 2 , R 5  and R 6  are each hydrogen. 
     
     
         19 . The process as claimed in  claim 2 , wherein R 1 , R 2 , R 4 , R 5  and R 6  are each hydrogen. 
     
     
         20 . The process as claimed in  claim 2 , wherein Y is hydrogen or methyl. 
     
     
         21 . The process as claimed in  claim 2 , wherein W is —NH—C(═O)— wherein the carbonyl group is linked to the pyrazole ring. 
     
     
         22 . The process as claimed in  claim 2 , wherein R 7  and R 8  are both hydrogen. 
     
     
         23 . The process as claimed in  claim 2 , wherein X is —CH 2 —, —CH(CH 3 )— or —C(CH 3 ) 2 —. 
     
     
         24 . The process as claimed in  claim 2 , wherein Q is optionally substituted phenyl. 
     
     
         25 . The process as claimed in  claim 2 , wherein the substituent or substituents on the phenyl ring is/are selected from methyl, trifluoromethyl, methoxy, fluoro, chloro, or cyano. 
     
     
         26 . The process as claimed in  claim 2 , 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. 
     
     
         27 . The process as claimed in  claim 2 , wherein Q is cyclohexyl or pyrid-3-yl. 
     
     
         28 . The process as claimed in  claim 2 , 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 1  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. 
       
     
     
         29 . The process as claimed in  claim 2 , wherein R 1  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. 
     
     
         30 . The process as claimed in  claim 2 , 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 salts thereof.