Cycloalkyl-Linked Diheterocycle Derivatives

Abstract

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein A, L, D, R 1 -R 15 , w, x, y, and z are defined herein. The novel cycloalkyl-linked diheterocycle derivatives that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. The present invention also relates to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.

What is claimed is: 
     
         1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 A and D are independently 5 or 6-membered heteroaryl optionally substituted by one or two R 7  groups; 
 L is —(C 4 -C 10  cycloalkyl)- optionally substituted by one to three substituents selected from the group consisting of halogen, cyano, C 1 -C 4  alkyl, hydroxy, and C 1 -C 4  alkoxy; 
 R 1  is hydrogen, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, —C(O)R 10a , or 5-6 membered heteroaryl, wherein the C 3 -C 6  cycloalkyl and the 5-6 membered heteroaryl are independently optionally substituted by one or two R 15  groups; 
 R 2  is hydrogen, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, —C(O)R 10b , or 5-6 membered heteroaryl, wherein the C 3 -C 6  cycloalkyl and the 5-6 membered heteroaryl are independently optionally substituted by one or two R 15  groups; 
 R 3 , R 4 , R 5  and R 6  are each independently hydrogen, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy or C 3 -C 6  cycloalkyl; 
 each R 7  is each independently hydrogen, halogen, cyano, C 1 -C 2  alkyl, hydroxy, C 1 -C 2  alkoxy, or —N(R 11 )(R 12 ), wherein the C 1 -C 2  alkyl and the C 1 -C 2  alkoxy are each independently optionally substituted by halogen or hydroxy; 
 R 10a  and R 10b  are each independently hydrogen, C 1 -C 4  alkyl, —[C(R 13 )(R 14 )] z —(C 4 -C 10  cycloalkyl), —[C(R 13 )(R 14 )] z -(4-6 membered heterocycloalkyl), —[C(R 13 )(R 14 )] z —(C 6 -C 10  aryl), or —[C(R 13 )(R 14 )] z -(5-10 membered heteroaryl), wherein the C 1 -C 4  alkyl, the C 4 -C 10  cycloalkyl, the 4-6 membered heterocycloalkyl, the C 6 -C 10  aryl, and the 5-10 membered heteroaryl in R 10a  and R 10b  are each independently optionally substituted by one, two or three halogen, cyano, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, —(CH 2 ) w —N(R 11 )(R 12 ), —(CH 2 ) w —C(O)N(R 11 )(R 12 ), —C(O)OR 11 , —N(R 11 )C(O)R 12 , —S(O) 2 R 11 , or —S(O)N(R 11 )(R 12 ) groups; 
 each R 11 , R 12 , R 13 , R 14  and R 15  is independently hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 3 -C 6  cycloalkyl, or 3-6 membered heterocycloalkyl, wherein the C 1 -C 4  alkyl, the C 3 -C 6  cycloalkyl, and the 3-6 membered heterocycloalkyl are each independently optionally substituted by one, two or three substituents selected from the group consisting of halogen, cyano, hydroxy, and methoxy; 
 w is 0, 1, 2 or 3; 
 x is 0 or 1; 
 y is 0 or 1, provided that at least one of x and y is 0; and 
 z is 0, 1, 2 or 3; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound or salt of  claim 1 , wherein A and D are independently thiadiazolyl, pyridazinyl optionally substituted by one or two R 7  groups, and 1,2,4-triazinyl optionally substituted by R 7 . 
     
     
         3 . The compound or salt of  claim 1  or  2 , wherein at least one of A and D is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound or salt of any of  claims 1 - 3 , wherein y is 0. 
     
     
         5 . A compound of formula (IVb) 
       
         
           
           
               
               
           
         
       
       wherein
 L is —(C 4 -C 10  cycloalkyl)- optionally substituted by one to three substituents selected from the group consisting of halogen, cyano, C 1 -C 4  alkyl, hydroxy, and C 1 -C 4  alkoxy; 
 R 1  is hydrogen, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, —C(O)R 10a , or 5-6 membered heteroaryl, wherein the C 3 -C 6  cycloalkyl and the 5-6 membered heteroaryl are independently optionally substituted by one or two R 15  groups; 
 R 2  is hydrogen, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, —C(O)R 10b , or 5-6 membered heteroaryl, wherein the C 3 -C 6  cycloalkyl and the 5-6 membered heteroaryl are independently optionally substituted by one or two R 15  groups; 
 R 3  and R 4  are each independently hydrogen, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, or C 3 -C 6  cycloalkyl; 
 R 10a  and R 10b  are each independently hydrogen, C 1 -C 4  alkyl, —[C(R 13 )(R 14 )] z —(C 4 -C 10  cycloalkyl), —[C(R 13 )(R 14 )] z -(4-6 membered heterocycloalkyl), —[C(R 13) (R 14 )] z —(C 6 -C 10  aryl), or —[C(R 13 )(R 14 )] z -(5-10 membered heteroaryl), wherein the C 1 -C 4  alkyl, the C 4 -C 10  cycloalkyl, the 4-6 membered heterocycloalkyl, the C 6 -C 10  aryl, and the 5-10 membered heteroaryl in R 10a  and R 10b  are each independently optionally substituted by one, two or three halogen, cyano, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, —(CH 2 ) w —N(R 11 )(R 12 ), —(CH 2 ) w —C(O)N(R 11 )(R 12 ), —C(O)OR 11 , —N(R 11 )C(O)R 12 , —S(O) 2 R 11 , or —S(O)N(R 11 )(R 12 ) groups; 
 each R 11 , R 12 , R 13 , R 14  and R 15  is independently hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 3 -C 6  cycloalkyl, or 3-6 membered heterocycloalkyl, wherein the C 1 -C 4  alkyl, the C 3 -C 6  cycloalkyl, and the 3-6 membered heterocycloalkyl are each independently optionally substituted by one, two or three substituents selected from the group consisting of halogen, cyano, hydroxy, and methoxy; 
 w is 0, 1, 2 or 3; 
 x is 0 or 1; and 
 z is 0, 1, 2 or 3; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound or salt of  claim 1  or  5 , wherein x is 1. 
     
     
         7 . The compound or salt of any  claims 1 ,  5  or  6 , wherein L is 
       
         
           
           
               
               
           
         
       
       optionally substituted by one to three substituents selected from the group consisting of halogen, cyano, C 1 -C 4  alkyl, hydroxy, and C 1 -C 4  alkoxy. 
     
     
         8 . The compound or salt of  claim 7 , wherein L is 
       
         
           
           
               
               
           
         
       
       optionally substituted by one to three substituents selected from the group consisting of halogen, cyano, C 1 -C 4  alkyl, hydroxy, and C 1 -C 4  alkoxy. 
     
     
         9 . The compound or salt of  claim 8 , wherein L is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound or salt of any of  claims 7 - 9 , wherein
 R 1  is —C(O)R 10a  and R 2  is hydrogen, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, —C(O)R 10b , or 5-6 membered heteroaryl, wherein the C 3 -C 6  cycloalkyl and the 5-6 membered heteroaryl are independently optionally substituted by one or two R 15  groups; or   R 2  is —C(O)R 10b  and R 1  is hydrogen, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, —C(O)R 10b , or 5-6 membered heteroaryl, wherein the C 3 -C 6  cycloalkyl and the 5-6 membered heteroaryl are independently optionally substituted by one or two R 15  groups; or   R 1  is —C(O)R 10a  and R 2  is —C(O)R 10b .   
     
     
         11 . The compound or salt of  claim 10 , wherein R 1  is —C(O)R 10a  and R 2  is —C(O)R 10b . 
     
     
         12 . The compound or salt of  claim 11 , wherein R 10a  is —[C(R 13 )(R 14 )] z —(C 4 -C 10  cycloalkyl), —[C(R 13 )(R 14 )] z -(4-6 membered heterocycloalkyl), —[C(R 13 )(R 14 )] z —(C 6 -C 10  aryl), or —[C(R 13 )(R 14 )] z -(5-10 membered heteroaryl) and R 10b  is —[C(R 13 )(R 14 )] z —(C 4 -C 10  cycloalkyl), —[C(R 13 )(R 14 )] z -(4-6 membered heterocycloalkyl), —[C(R 13 )(R 14 )] z —(C 6 -C 10  aryl), or —[C(R 13 )(R 14 )] z -(5-10 membered heteroaryl), wherein the C 4 -C 10  cycloalkyl, the 4-6 membered heterocycloalkyl, the C 6 -C 10  aryl, and the 5-10 membered heteroaryl in R 10a  and R 10b  are each independently optionally substituted by one, two or three halogen, cyano, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, —(CH 2 ) w —N(R 11 )(R 12 ), —(CH 2 ) w —C(O)N(R 11 )(R 12 ), —C(O)OR 11 , —N(R 11 )C(O)R 12 , —S(O) 2 R 11 , or —S(O)N(R 1 )(R 12 ) groups. 
     
     
         13 . The compound or salt of  claim 12 , wherein R 10a  is —[C(R 13 )(R 14 )] z —(C 6  aryl) or —[C(R 13 )(R 14 )] z -(5-6 membered heteroaryl) and R 10b  is —[C(R 13 )(R 14 )] z -(6 aryl) or —[C(R 13 )(R 14 )] z -(5-6 membered heteroaryl), wherein the C 6  aryl and the 5-6 membered heteroaryl in R 10a  and R 10b  are each independently optionally substituted by one or two halogen or C 1 -C 4  alkyl groups. 
     
     
         14 . The compound or salt of  claim 13 , wherein R 10a  is —[C(R 13 )(R 14 )] z -(5-6 membered heteroaryl) and R 10b  is —[C(R 13 )(R 14 )] z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R 10a  and R 10b  are each independently optionally substituted by one or two C 1 -C 4  alkyl groups. 
     
     
         15 . The compound or salt of  claim 14 , wherein each R 13  and R 14  is hydrogen and each z is 1. 
     
     
         16 . The compound or salt of  claim 15 , wherein R 10a  is —CH 2 -pyridinyl and R 10b  is —CH 2 -pyridinyl, wherein each pyridinyl is optionally substituted by one or two C 1 -C 4  alkyl groups. 
     
     
         17 . A compound, which is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A pharmaceutical composition comprising a compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         19 . A combination of a compound of any of  claims 1 - 17 , or a pharmaceutically acceptable salt thereof, with an anti-tumor agent or with radiation therapy, for the treatment of cancer. 
     
     
         20 . A method of treating abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound of any of  claims 1 - 17 , or a pharmaceutically acceptable salt thereof, that is effective in treating abnormal cell growth.