Substituted Lactams and Their Use as Anti-Cancer Agents

Abstract

This invention relates to certain substituted lactam compounds, particularly caprolactam compounds, which are useful for the treatment of cancer.

1 . Use of a compound of formula I for the treatment of cancer, wherein formula I comprises: 
     
       
         
         
             
             
         
       
     
     or a salt thereof, wherein
 n is 0, 1 or 2; 
 R1 is H, X 1 —(C 1-6 ) alkyl-, (C 1-12 )alkylC(O)—, X 2 —(C 2-4 ) alkenylene-, X 2 -(C 2-4 ) alkynylene-, X 1 —(C 3-9 )cycloalkyl-, X 2 -(C 3-9 )cycloalkene-, X 1 -aryl-, X 1 —(C 3-7 )cycloalkane-(C 1-6 )alkylene-, X 2 —(C 3-7 )cycloalkene-(C 1-6 )alkylene-, or X 1 -aryl-(C 1-6 )alkylene-; 
 X 1  is H, (C 1-14 )alkyl, (C 3-7 )cycloalkyl, (C 1-14 )alkyl substituted by (C 3-7 )cycloalkyl, —OR a , —SR a , —NO 2 , halo or (C 1-6 )alkylC(O)—; aryl, aryl-(C 1-12 )alkyl-, —OR a , —SR a , —NO 2 , halo, (C 1-12 )alkyl-C(O)—, mono- or di-(C 1-4 )alkylamino, amino(C 1-16 )alkyl-, or mono- or di-(C 1-4 )alkylamino(C 1-16 )alkyl; 
 X 2  is H, (C 1-14 )alkyl, (C 3-7 )cycloalkyl, (C 1-14 )alkyl substituted by (C 3-7 )cycloalkyl, —OR a —SR a , —NO 2 , halo or (C 1-6 )alkyl-C(O)—; aryl, aryl-(C 1-12 )alkyl-, amino(C 1-16 )alkyl- or mono- or di-(C 1-14 )alkylamino(C 1-16 )alkyl; 
 R a  is H, (C 1-18 )alkyl, aryl, or (C 1-18 )alkyl substituted by (C 3-7 )cycloalkyl, aryl, —OH, —O—(C 1-6 )alkyl or halo; 
 R 2 , R 3 , R 4  and R 5  are independently hydrogen or (C 1-18 )alkyl, R 5  is also phenyl or (C (C   1-16 )alkyl which is substituted by phenyl, wherein there is no more than a total of 18 carbon atoms in the combined R 2 , R 3 , R 4  and R 5  alkyl substituents, or R 2  and R 4  together or R 3  and R 5  together form an acetal group; 
 R6 is hydrogen or (C 1-6 ) alkyl; 
 R7 is H, (C 1-18 )alkyl, phenyl, pyridyl, (C 1-18 )alkyl substituted by (C 3-7 )cycloalkyl, —OR x , N 3 , halo, —N(R x ) 2 , R x , —O—(C 1-6 )alkyl, —OC(O)—(C 1-16 )alkyl or pyridyl; —Y—Rb or a substituted of formula IIa or IIIa 
 
     
       
         
         
             
             
         
       
     
     wherein
 R9 is from 0 to 3 substituents selected from (C 1-6 )alkyl, —OR a , —SR a , —NO 2 , halo, —N 3 , (C 1-12 )alkylC(O)-, mono- or di-(C 1-4 )alkylamino, amino(C 1-16 )alkyl-, mono- or di-(C 1-4 )alkylamino(C 1-16 )alkyl, (CH 2 ) 0-2 —C 5-7 cycloalkyl, (CH 2 ) 0-2 -heterocyclic, (CH 2 ) 0-2 —C 5-7 aryl, or (CH 2 ) 0-2 -heteroaryl; 
 Y is a linking group selected from —(C 1-10 )alkyl-, —(C 0-10 )alkylene-CO-N(R x )-(Co- 10 )alkylene-, —(C 0-10 )alkylene-N(R x )—CO—(C 0-10 )alkylene-, —(C 0-10 )alkylene-CO—O—(C 0-10 )alkylene-, —(C 1-10 )alkylene-O—C(O)—(C 1-10 )alkylene-, —(C 0-10 )alkylene-CO—(C 0-10 )alkylene-, —(C 0-10 )alkylene-(R x )N—CO—O—(C 0-10 )alkylene-, —(C 0-10 )alkylene-O—CO—(R x )N—(C 0-10 )alkylene- or —(C 0-18 )alkylene-arylene-(C 0-18 )alkylene-; 
 R x  is H, (C 1-4 )alkyl or phenyl; 
 R b  is (C 1-16 )alkyl or (C 1-16 )alkyl which is substituted by (C 3-7 )cycloalkyl, —OR x , N 3 , halo, —N(R x ) 2 , —O—(C 1-6 )alkyl, —OC(O)—(C 1-16 )alkyl or pyridyl; 
 R8 is H, halo, —N 3 , (C 1-16 )alkyl, -Z-(C 1-16 )alkyl, (C 1-16 )alkyl substituted by (C (C   3-7 )cycloalkyl, —N 3 , —N(R x ) 2 , -Z-het, —OR a  or —SR a , -Z-(C 1-16 )alkyl substituted by (C 3-7 )cycloalkyl, —N 3 , —N(R x ) 2 , -Z-het, —OR a  or —SR a , —O(C 1-16 )alkylene-N 3 , —O(C 1-16 )alkylene-N(R x ) 2 , —(C 0-6 )alkylene-OC(O)—(C 1-16 )alkyl, —(C 0-6 )alkylene-(O)C—O—(C 1-16 )alkyl, —(C 0-6 )alkylene-OC(O)—(C 3-7 )cycloalkyl, —(C 0-6 )alkylene-(O)C—O—(C 3-7 )cycloalkyl, pyridyl, —OC(O)O(C 1-12 )alkyl, —O—CO—X—R z , or —O—CO—(CH 2 ) m —O—(CH 2 ) m —X—R z  wherein X is a direct bond, (C 1-12 )alkylene, (C 1-12 )alkenylene or (C 1-12 )alkynylene and R z  is H, (C 3-9 )cycloalkyl, phenyl, phenyl substituted by one or more of chloro, methoxy, (C 1-18 )alkyl or (C 1-18 )alkoxy, pyrrolyl, furanyl, thiofuranyl, indolyl, benzofuranyl, benzothiofuranyl or pyridyl and each m is independently a number from 0 to 13,-Z-het, —OR a , —SR a , mono- or di-(C 1-4 )alkylamino, amino(C 1-16 )alkyl-, mono- or di-(C 1-4 )alkylamino(C 1-16 )alkyl, -Z-Si((C 1-6 )alkyl) 3  or a substituent selected from the following two formulae: 
 
     
       
         
         
             
             
         
       
       Z is a direct bond, —(C 1-12 )alkylene-, —(C 1-12 )alkylene-O—, —O—(C 1-12 )alkylene-, —(C 1-12 )alkylene-N(R x )—, —N(R x )—, —N(R x )—(C 1-12 )alkylene-, —N(R x )—C(O)—, —N(R x )—C(O)—(C 1-12 )alkylene-, —(C 1-12 )alkylene-N(R x )—C(O)—, —(C 1-8 )alkylene-N(R x )—C(O)—(C 1-8 )alkylene-, —(C 1-12 )alkylene-CO—N(R x )—, —CO—N(R x )—(C 1-12 )alkylene-, —(C 1-8 )alkylene-CO—N(R x )—(C 1-8 )alkylene-, —CO—N(R x )—, —(C 1-12 )alkylene-CO—O—, —(C 1-12 )alkylene-O—C(O)—, —OC(O)—(C 1-12 )alkylene-, —C(O)—O—(C 1-12 )alkylene-, —(C 1-12 )alkylene-CO—, —(C 1-8 )alkylene-CO—(C 1-8 )alkylene-, —CO—(C 1-12 )alkylene-, —C(O)—, —N(R x )—C(O)—O—, —N(R x )—C(O)—O—(C 1-12 )alkylene-, —(C 1-12 )alkylene-N(R x )—C(O)—O—, —(C 1-8 )alkylene-N(R x )—C(O)—O—(C 1-8 )alkylene-, —(C 1-12 )alkylene-O—CO—N(R x )—, —O—CO—N(R x )—(C 1-12 )alkylene-, —(C 1-8 )alkylene-O—CO—N(R x )—(C 1-8 )alkylene-, —O—CO—N(R x )—, —O—CO—O—, —(C 1-12 )alkylene-O—CO—O—, —O—CO—O—(C 1-12 )alkylene- or —(C 1-8 )alkylene-O—C(O)—O—(C 1-8 )alkylene-; 
       Z 1  is a direct bond, —(C 1-12 )alkylene-, —O—(C 1-12 )alkylene-, —N(R x )—(C 1-12 )alkylene-, —N(R x )—C(O)—(C 1-12 )alkylene-, —(C 1-8 )alkylene-N(R x )—C(O)—(C 1-8 )alkylene-, —CO—N(R x )—(C 1-12 )alkylene-, —(C 1-8 )alkylene-CO—N(R x )—(C 1-8 )alkylene-, —OC(O)—(C 1-12 )alkylene-, —C(O)—O—(C 1-12 )alkylene-, —(C 1-8 )alkylene-CO—(C 1-8 ))alkylene-, —CO—(C 1-12 )alkylene-, —C(O)—, —N(R x )—C(O)—O—(C 1-12 )alkylene-, —(C 1-8 )alkylene-N(R x )—C(O)—O—(C 1-8 )alkylene-, —O—CO—N(Rx)—(C 1-12 )alkylene-, —(C 1-8 )alkylene-O—CO—N(R x )—(C 1-8 )alkylene-, —O—CO—O—(C 1-12 )alkylene- or —(C 1-8 )alkylene-O—C(O)—O—(C 1-8 )alkylene-; 
       R10 is from 0 to 3 substituents selected from hydroxy, halo, -(C 1 17 )alkyl, —O—(C 1-17 )alkyl, —(CH 2 ) 1-6 —C 3-7 -cycloalkyl, —(CH 2 ) 0-10 -aryl or —(CH 2 ) 0-10 -het; 
       het is a heterocyclic or heteroaromatic ring; 
       p is  1-18 ; 
       with the proviso that when n is 2 and R 1  is (C 1-6 )alkyl-CH═CH— or (C 3-6 )cycloalkyl-CH═CH—then R 7  is not H or (C 1-8 )alkyl or R 8  is not —O—CO—X-R Z  or —O—CO—(CH 2 ) m—O—(CH   2 ) m —X-R Z  where X is a direct bond, (C 1-12 )alkylene, (C 1-12 )alkenylene or (C 1-12 )alkynylene and R z  is H, (C 3-9 )cycloalkyl, phenyl, phenyl substituted by one or more of chloro, methoxy, (C 1-18 )alkyl or (C 1-18 )alkoxy, pyrrolyl, furanyl, thiofuranyl, indolyl, benzofuranyl, benzothiofuranyl or pyridyl and each m is independently a number from 0 to 13, and with the further proviso that R 8  is not —OH when n is 2, R 7  is H or methyl and R 1  is 3-methylbut-1-enylene. 
     
   
   
       2 . Use of the compound of  claim 1 , or a salt thereof, wherein:
 n is 2;   R1 is X 1 —(C 1-6 ) alkyl-, X 2 —(C 2-4 ) alkenylene-, X 1 —(C 3-7 )cycloalkyl-, or X 1 —(C 3-3 )alkylene-;   X 1  is H, (C 1-12 )alkyl, (C 3-7 )cycloalkyl, —(C 1-12 )alkyl substituted by (C 3-7 )cycloalkyl, —OR a ; —SR a , —NO 2 , halo or (C 1-12 )alkylC(O)—; aryl, aryl-(C 1-12 )alkyl- or —OR a ;   X 2  is H, (C 1-12 )alkyl, (C 3-7 )cycloalkyl, —(C 1-12 )alkyl substituted by (C 3-7 )cycloalkyl, —OR a , —SR a , —NO 2 , halo or (C 1-12 )alkylC(O)-, aryl, aryl-(C 1-12 )alkyl-;   R a  is H, (C 1-18 )alkyl, aryl-, or (C 1-18 )alkyl substituted by (C 3-7 )cycloalkyl or aryl;   R 2 , R 3 , R 4  and R 5  are independently hydrogen or (C 1-4 )alkyl, wherein there is no more than a total of 8 carbon atoms, especially no more than 4 carbon atoms, in the combined R 2 , R 3 , R 4  and R 5  alkyl substituents;   R6 is hydrogen or (C 1-6 ) alkyl;   R7 is H, (C 1-8 )alkyl, R x , (C 1-18 )alkyl substituted by (C 3-7 )cycloalkyl, —OR x , N 3 , halo, —N(R x ) 2 , —O—(C 1-6 )alkyl, —OC(O)—(C 1-16 )alkyl or pyridyl; or a substituent of formula IIa or IIIa   
     
       
         
         
             
             
         
       
       R9 is from 0 to 3 substituents selected from (C 1-6 )alkyl, —OR a , —SR a , —NO 2 , halo, or —N 3 ; 
       Y is a linking group selected from —C(O)N(R x )—, —CO—O—, —(C 1-12 )alkylene-CO—O—, —CO—O—(C 1-12 )alkylene-, —(C 1-10 )alkylene-CO—O—(C 1-10 )alkylene-, —(C 1-10 )alkylene-O—C(O)—(C 1-10 )alkylene-, —CO—, —(C 1-12 )alkylene-CO—, —CO—(C 1-12 )alkylene-, —(C 1-10 )alkylene-CO—(C 1-10 )alkylene-, —(C 1-12 )alkylene-(R x )N—CO—, —(C 1-10 )alkylene-(R x )N—CO—O—(C 1-10 )alkylene-, or —(C 0-12 )alkylene-arylene-(C 0-12 )alkylene-; 
       R x  is H, (C 1-4 )alkyl or phenyl; 
       R8 is —N 3 , (C 1-16 )alkyl, -Z-(C 1-16 )alkyl, (C 1-16 )alkyl substituted by (C 3-7 )cycloalkyl, —N 3 , or —N(R x ) 2 ; -Z-(C 1-16 )alkyl substituted in the alkyl portion by (C 3-7 )cycloalkyl, —N 3 , or —N(R x ) 2 , —(C 0-6 )alkylene-(O)C—O—(C 1-16 )alkyl, or a substituent selected from the following two formulae: 
     
     
       
         
         
             
             
         
       
       Z is a direct bond, —(C 1-12 )alkylene-, —N(R x )—C(O)—, —N(R x )—C(O)—(C 1-12 )alkylene-, —(C 1-12 )alkylene-N(R x )—C(O)—, —(C 1-8 )alkylene-N(R x )—C(O)—(C 1-8 )alkylene-, —(C 1-12 )alkylene-CO—N(R x )—, —CO—N(R x )—(C 1-12 )alkylene-, —(C 1-8 )alkylene-CO—N(R x )—(C 1-8 )alkylene-, —CO—N(R x )—, —C(O)—O—(C 1-12 )alkylene-, —CO—(C 1-12 )alkylene-, —C(O)—, —N(R x )—C(O)—O—, —N(R x )—C(O)—O—(C 1-12 )alkylene-, —(C 1-12 )alkylene-N(R x )—C(O)—O—, —(C 1-8 )alkylene-N(R x )—C(O)—O——(C 1-8 )alkylene-, —(C 1-12 )alkylene-O—CO—N(R x )—, —O—CO—N(R x )—(C 1-12 )alkylene-, —(C 1-8 )alkylene-O—CO—N(R x )—(C 1-8 )alkylene- or —O—CO—N(R x )—; 
       Z 1  is a direct bond, —(C 1-12 )alkylene- or —C(O)—; 
       R10 is from 0 to 3 substituents selected from hydroxy, halo, —(C 1-17 )alkyl, —O—(C 1-17 )alkyl, —(CH 2 ) 1-6 —C 3-7 -c ycloalkyl, —(CH 2 ) 0-10 -aryl or —(CH 2 ) 0-10 -het; and 
       het is pyridyl. 
     
   
   
       3 . Use of the compound of  claim 1 , or a salt thereof, wherein:
 R1 is (C 1-6  alkyl)-ethenylene-;   R 2 , R 3  and R 4 , independently are hydrogen or (C 1-4 ) alkyl, wherein there is no more than a total of 4 carbon atoms in the combined R 2 , R 3 , R 4  and R 5  alkyl substituents;   R 5  is (C 1-4 )alkyl;   R6 is hydrogen or methyl;   R7 is H or (C 1-6 )alkyl;   R8 is H, —N 3 , (C 1-16 )alkyl, -Z-(C 1-16 )alkyl, (C 1-16 )alkyl substituted by (C 3-7 )cycloalkyl, —N 3 , or —N(R x ) 2 ; or -Z-(C 1-16 )alkyl substituted in the alkyl portion by (C 3-7 )cycloalkyl, —N 3 , or —N(R x ) 2 ;   R9 is (CH 2 ) 0-2 —C 5-7  cycloalkyl, (CH 2 ) 0-2 —C 5-7  hetero-cyclic, (CH 2 ) 0-2 —C 5-7 aryl, or (CH 2 ) 0-2 —C 5-7  hetero-aryl;   X is (C 1-12 ) alkylene or (C 2-12 ) alkenylene;   R10 is from 0 to 3 substituents selected from hydroxy, halo, —(C 1-18 )alkyl, —O—(C 1-8 )alkyl, —(CH 2 ) 1-6 —C 3-7  cycloalkyl, —(CH 2 ) 0-10 -aryl or —(CH 2 ) 0-10 -het;   het is pyridyl;   n is 2.   
   
   
       4 . Use of the compound of  claim 1 , or a salt thereof, wherein:
 R1 is —CH═CH-i-propyl or —CH═CH-t-butyl;   X 2  is H;   R 2 , R 3 , R 4 , and R 5  independently are hydrogen or methyl;   R6 is hydrogen;   R7 is H or (C 1-3 ) alkyl; and   n is 2.   
   
   
       5 . Use of the compound of  claim 1 , or a salt thereof, wherein:
 R 1  is X 1 -(C 3-7 )cycloalkane-(C 1-6 )alkylene- or X 2 —(C 3-9 )cycloalkene-;   X 1  is hydrogen;   X 2  is hydrogen;   R 2 , R 3 , R 4 , and R 5  independently are hydrogen or methyl;   R 6  is hydrogen;   R 7  is H or (C 1-3 ) alkyl;   R 8  is hydrogen; and   n is 2.   
   
   
       6 . Use of a compound of formula I of  claim 1 , or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of cancer. 
   
   
       7 . Use of a compound of formula I of  claim 2 , or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of cancer. 
   
   
       8 . Use of a compound of formula I of  claim 3 , or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of cancer. 
   
   
       9 . Use of a compound of formula I of  claim 4 , or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of cancer. 
   
   
       10 . Use of a compound of formula I of  claim 5 , or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of cancer. 
   
   
       11 . The use of  claim 1 , wherein the cancer is selected from the group consisting of all liquid and solid cancers that may arise in a subject. 
   
   
       12 . The use in  claim 1 , wherein the cancers comprise cancers of the colon, bladder, prostate, stomach, pancreas, breast, lung, liver, brain, testis, ovary, cervix, skin, vulva, small intestine, lymph glands, and blood cells.