Compounds useful for inhibiting chk1

Abstract

Aryl- and heteroaryl-substituted urea compounds useful in the treatment of diseases and conditions related to DNA damage or lesions in DNA replication are disclosed. Methods of making the compounds, and their use as therapeutic agents, for example, in treating cancer and other diseases characterized by defects in DNA replication, chromosome segregation, or cell division also are disclosed.

1 - 30 . (canceled) 
   
   
       31 . A method of treating a cancer selected from the group consisting of a colorectal cancer, a breast cancer, a leukemia, a melanoma, a renal cell carcinoma, an ovarian cancer, a lung carcinoma, a cervical cancer, a colon cancer, and a prostate cancer which comprises administering to a patient in need thereof a therapeutically effective amount of a compound having a formula 
     
       
         
         
             
             
         
       
     
     wherein:
 Y′ is O or S; 
 W′ is 
 
     
       
         
         
             
             
         
       
     
     optionally substituted with from one to four substituents selected from the group consisting of C 1-6 alkyl, aryl, N(R 7 ) 2 , OR 7 , N 3 , CN, C(O)R 7 , C 1-3 alkylenearyl, C 1-3 alkyleneN(R 2 ) 2 , halo, and 
     
       
         
         
             
             
         
       
       Z′ is selected from the group consisting of: 
     
     
       
         
         
             
             
         
       
     
     wherein
 Q′ is OR 7 ; 
 J′ is selected from the group consisting of CR 8 , NR 8 , O, and S; 
 K′ is selected from the group consisting of CR 9 , NR 9 , O, and S; 
 L′ is selected from the group consisting of CR 10 , NR 10 , O, and S; 
 M′ is selected from the group consisting of CR 11 , NR 11 , O, and S; 
 
     and provided when Z′ is a six-membered ring J′, K′, L′, and M′ cannot be O or S; 
     wherein:
 R 7  is C 1-3 alkyleneC 3-8 heterocycloalkyl; 
 R 8 , R 9 , and R 10  are each independently selected from the group consisting of hydrogen, halo, optionally substituted C 1-6 alkyl, C 2-6 alkenyl, OCF 3 , NO 2 , CN, NC, N(R 7 ) 2 , OR 7 , CO 2 R 7 , C(O)N(R 7 ) 2 , C(O)R 7 , N(R 13 )C(O)R 7 , N(R 13 )C(O)OR 7 , N(R 7 )C(O)OR 7 , N(R 7 )C(O)C 1-3 alkyleneC(O)R 7 , N(R 7 )C(O)C 1-3 alkyleneC(O)OR 7 , N(R 7 )C(O)C 1-3 alkyleneOR 7 , N(R 7 )C(O)C 1-3 alkyleneNHC(O)OR 7 , N(R 7 )C(O)C 1-3 alkyleneSO 2 NR 7 , CF 3 , C 1-3 alkyleneN(R 12 )SO 2 aryl, C 1-3 alkyleneN(R 12 )SO 2 heteroaryl, C 1-3 alkyleneOC 1-3 alkylenearyl, C 1-3 alkyleneN(R 12 )C 1-3 alkylenearyl, C 1-3 alkyleneN(R 12 )C 1-3 alkyleneheteroaryl, C 1-3 alkyleneN(R 12 )C(O)R 7 , C 1-3 alkyleneN(R 12 )C(O)C 1-3 alkyleneOR 2 , C 1-3 alkyleneN(R 12 )C(O)aryl, C 1-3 alkyleneN(R 12 )C(O)C 1-3 alkyleneN(R 12 ) 2 , C 1-3 alkyleneN(R 12 )C(O)heteroaryl, C 1-3 alkyleneOR 7 , and SR 7 , wherein R 7  is as defined above; 
 R 11  is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, and halo; 
 R 12  is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heteroaryl, C 1-3 alkylenearyl, and SO 2 C 1-6 alkyl, or two R 12  groups are taken together to form an optionally substituted 3- to 6-membered ring; and 
 R 13  is hydrogen; 
 or a pharmaceutically acceptable salt thereof.