Inhibitors of erk and methods of use

Abstract

The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as ERK (MAPK). Also provided are methods of using such compounds or compositions, and methods of using these compositions to modulate the activities of one or more of these kinases, especially for therapeutic applications such as the treatment disorders such as cancer.

1 - 64 . (canceled) 
     
     
         65 . A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula II-E and an anti-cancer agent; wherein the compound of Formula II-E has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         R 1  is 3- to 6-membered heterocyclyl, —C 1-10 alkyl-(3- to 6-membered heterocyclyl), -(3- to 6-membered heterocyclyl)-C 1-10 alkyl, -(3- to 6-membered heterocyclyl)-C 3-10 aryl, or -(3- to 6-membered heterocyclyl)-C 1-10 hetaryl, each of which is unsubstituted or substituted by one or more independent R 10  or R 11 substituents; 
         R 21  is halogen, -L-C 1-10 heteroalkyl, -L-C 3-10 aryl, -L-C 1-10 hetaryl, -L-C 3-10 cycloalkyl, -L-C 1-10 heterocyclyl, -L-C 1-10 alkyl-C 3-10 aryl, -L-C 1-10 alkyl-C 1-10 hetaryl, -L-C 1-10 alkyl-C 3-10 cycloalkyl, -L-C 1-10 alkyl-C 1-10 heterocyclyl, -L-C 2-10 alkenyl-C 3-10 aryl, -L-C 2-10 alkenyl-C 1-10 hetaryl, -L-C 2-10 alkenyl-C 3-10 cycloalkyl, -L-C 2-10 alkenyl-C 1-10 heterocyclyl, -L-C 2-10 alkynyl-C 3-10 aryl, -L-C 1-10 heteroalkyl-C 3-10 aryl, -L-C 1-10 heteroalkyl-C 1-10 hetaryl, -L-C 1-10 heteroalkyl-C 3-10 cycloalkyl, or -L-C 1-10 heteroalkyl-C 1-10 heterocyclyl, each of which is substituted by one or more independent R 12  substituents; 
         L is a bond, —O—, —N(R 31 )—, —S(O) 0-2 —, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R 31 )—, —N(R 31 )C(═O)—, —NR 31 C(═O)O—, —NR 31 C(═O)NR 32 —, —NR 31 S(O) 0-2 —, —S(O) 0-2 N(R 31 )—, —C(═S)O—, —C(═O)S—, —NR 31 C(═NR 32 )NR 32 —, —NR 31 C(═NR 32 )O—, —NR 31 C(═NR 32 )S—, —OC(═O)O—, —OC(═O)NR 31 —, —OC(═O)S—, —SC(═O)S—, —P(O)OR 31 —, or —SC(═O)NR 31 —; 
         R 72  is hydrogen, —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, —C 1-10 heteroalkyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, —C 1-10 heterocyclyl, —OH, —CF 3 , —C(O)R 31 , —CO 2 R 31 , —C(═O)NR 31 , —S(O) 0-2 R 31 , —C(═S)OR 31 , or —C(═O)SR 31 ; 
         R 10  is —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, —C 1-10 heteroalkyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, or —C 1-10 heterocyclyl, each of which is optionally substituted by one or more independent R 11  substituents; 
         R 11  and R 12  are independently hydrogen, halogen, —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, —C 1-10 heteroalkyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, —C 1-10 heterocyclyl, —OH, —CF 3 , —OCF 3 , —OR 31 , —NR 31 R 32 , —C(O)R 31 , —CO 2 R 31 , —C(═O)NR 31 , —NO 2 , —CN, —S(O) 0-2 R 31 , —SO 2 NR 31 R 32 , —NR 31 C(═O)R 32 , -NR 31 C(═O)OR 32 , —NR 31 C(═O)NR 32 R 33 , —NR 31 S(O) 0-2 R 32 , —C(═S)OR 31 , —C(═O)SR 31 , —NR 31 C(═NR 32 )NR 32 R 33 , —NR 31 C(═NR 32 )R 33 , —NR 31 C(═NR 32 )SR 33 , —OC(═O)OR 33 , —OC(═O)NR 31 R 32 , —OC(═O)SR 31 , —SC(═O)SR 31 , —P(O)OR 31 OR 32 , or —SC(═O)NR 31 NR 32 ; and 
         each of R 31 , R 32 , and R 33  is independently hydrogen, halogen, —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, —C 1-10 heteroalkyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, or —C 1-10 heterocyclyl, or —R 31  together with R 32  form a heterocyclic ring. 
       
     
     
         66 . The method of  claim 65 , wherein R 21  is halogen, -L-C 1-10 heteroalkyl, -L-C 3-10 aryl, -L-C 1-10 hetaryl, -L-C 3-10 cycloalkyl, or -L-C 1-10 heterocyclyl, each of which is substituted by one or more independent R 12  substituents. 
     
     
         67 . The method of  claim 65 , wherein L is a bond, —O—, —N(R 31 )—, —S(O) 0-2 —, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R 31 )—, or —N(R 31 )C(═O)—. 
     
     
         68 . The method of  claim 65 , wherein L is a bond. 
     
     
         69 . The method of  claim 65 , wherein R 21  is -L-C 1-10 hetaryl substituted by one or more independent R 12  substituents; and wherein L is a bond. 
     
     
         70 . The method of  claim 69 , wherein the C 1-10 hetaryl of R 21  is selected from the group consisting of pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl. 
     
     
         71 . The method of  claim 69 , wherein each R 12  substituent is independently selected from the group consisting of —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, —C 1-10 heteroalkyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, —C 1-10 heterocyclyl, —OH, —CF 3 , —OCF 3 , and —OR 31 ; wherein each R 31  is independently hydrogen or —C 1-10  alkyl. 
     
     
         72 . The method of  claim 71 , wherein each R 12  substituent is independently selected from the group consisting -Me, -Et, -i-Pr, -n-Pr, OH, -OMe, -OEt, and -OPr. 
     
     
         73 . The method of  claim 65 , wherein R 1  is 3- to 6-membered heterocyclyl, unsubstituted or substituted by one or more independent R 10  or R 11  substituents. 
     
     
         74 . The method of  claim 65 , wherein R 1  is -(3- to 6-membered heterocyclyl)-C 1-10 alkyl, unsubstituted or substituted by one or more independent R 10  or R 11  substituents. 
     
     
         75 . The method of  claim 65 , wherein R 1  is -(3- to 6-membered heterocyclyl)-C 3-10 aryl, unsubstituted or substituted by one or more independent R 10  or R 11  substituents. 
     
     
         76 . The method of  claim 65 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       unsubstituted or substituted by one or more independent R 10  or R 11  substituents. 
     
     
         77 . The method of  claim 65 , wherein R 1  is substituted with one or more R 10  substituents. 
     
     
         78 . The method of  claim 77 , wherein each R 10  is independently —C 1-10  alkyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, or —C 1-10 heterocyclyl. 
     
     
         79 . The method of  claim 65 , wherein R 72  is H. 
     
     
         80 . The method of  claim 65 , wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, non-small cell lung cancer, thyroid cancer, seminomas, melanoma, bladder cancer, liver cancer, kidney cancer, myelodysplastic syndrome, acute myelogenous leukemia, and colorectal cancer. 
     
     
         81 . The method of  claim 80 , wherein the cancer is melanoma or colorectal cancer. 
     
     
         82 . The method of  claim 65 , wherein the anti-cancer agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens. 
     
     
         83 . The method of  claim 65 , further comprising radiation therapy.