Benzoxazole kinase inhibitors 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 mTor, tyrosine kinases, and/or lipid kinases such as PI3 kinase. Also provided in the present invention are methods of using these compositions to modulate activities of one or more of these kinases, especially for therapeutic applications.

1 . A method of treating a disorder comprising administering to a subject in need thereof an effective amount of an isolated compound or pharmaceutically acceptable salt of a compound of Formula II-A-1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 1  is N and X 2  is N; 
         R 1  is hydrogen, -L-C 1-10 alkyl, -L-C 3-8 cycloalkyl, -L-C 1-10 alkylheterocyclyl, -L-heteroalkyl or -L-heterocyclyl, each of which is unsubstituted or substituted by one or more independent R 3  substituents; 
         L is a bond, C═O, —C(═O)O—, —C(═O)N(R 31 )—, —S—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R 31 )—, or —N(R 31 )—; 
         k is 1: 
         E 2  is H; 
         W 2  is —O—, —NR 7 —, —S(O) 0-2 —, —C(O)—, —C(O)N(R 7 )—, —N(R 7 )C(O)—, —N(R 7 )C(O)N(R 8 )—, —N(R 7 )S(O)—, —N(R 7 )S(O) 2 —, —C(O)O—, —CH(R 7 )N(C(O)OR 8 )—, —CH(R 7 )N(C(O)R 8 )—, —CH(R 7 )N(SO 2 R 8 )—, —CH(R 7 )N(R 8 )—, —CH(R 7 )C(O)N(R 8 )—, —CH(R 7 )N(R 8 )C(O)—, —CH(R 7 )N(R 8 )S(O)—, or —CH(R 7 )N(R 8 )S(O) 2 —; 
         R 3  is hydrogen, halogen , —OH, —R 31 , —CF 3 , —OCF 3 , —OR 31 , —NR 31 R 32 , —NR 34 R 35 , —C(O)R 31 , or —CO 2 R 31 ; 
         R 2  is hydrogen, halogen, —OH, —R 31 , —CF 3 , —OCF 3 , —OR 31 , —NR 31 R 32 , —NR 34 R 35 , —C(O)R 31 , —CO 2 R 31 , —C(═(O)NR 31 R 32 , —C(═O)NR 34 R 35 , —NO 2 , —CN, —S(O) 0-2 R 31 , —SO 2 NR 31 R 32 , —SO 2 NR 34 R 35 , —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 C(═O)SR 33 , —NR 31 (C═NR 32 )NR 33 R 32 , —NR 31 C(═NR)OR 33 , —NR 31 C(═NR 32 )SR 33 , —OC(═O)OR 33 , —OC(═O)NR 31 R 32 , —OC(═O)SR 31 , —SC(═O)OR 31 , —P(O)OR 31 OR 32 , —SC(═O)NR 31 R 32 , bicyclic aryl, substituted monocyclic aryl, hetaryl, C 1-10 alkyl, C 3-8 cycloalkyl, C 1-10 alkyl-C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-10 alkyl, C 3-8 cycloalkyl-C 2-10 alkenyl, C 3-8 cycloalkyl-C 2-10 alkynyl, C 2-10 alkyl-monocyclic aryl, monocyclic aryl-C 2-10 alkyl, C 1-10 alkylbicycloaryl, bicycloaryl-C 1-10 alkyl, substituted C 1-10 alkylaryl, substituted aryl-C 1-10 alkyl, C 1-10 alkylhetaryl, C 1-10 alkylheterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 alkenylaryl, C 2-10 alkenylhetaryl, C 2-10 alkenylheteroalkyl, C 2-10 alkenylheterocycicyl, C 2-10 alkynylaryl, C 2-10 alkynylhetaryl, C 2-10 alkynylheteroalkyl, C 2-10 alkynylheterocylyl, C 2-10 alkenyl-C 3-8 cycloalkyl, C 2-10 alkynyl-C 3-8 cycloalkenyl, C 1-10 alkoxy C 1-10 alkoxyC 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkynyl, heterocyclyl, heterocyclyl C 1-10 alkyl, heterocyclylC 2-10 alkenyl, heterocyclyl-C 2-10 alkynyl, aryl-C 2-10 alkenyl, aryl-C 2-10 alkynyl, aryl-heterocyclyl, hetaryl-C 1-10 alkyl, hetaryl-C 2-10 alkenyl, hetaryl-C 2-10 alkynyl, hetaryl-C 3-8 cycloalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein each of said bicyclic aryl, monocyclic aryl, or heteroaryl moiety is unsubstituted or is substituted with one or more independent halo, —OH, —R 31 , —CF 3 , —OCF 3 , —OR 31 , —NR 31 R 32 , —NR 34 R 35 , —C(O)R 31 , —CO 2 R 31 , —C(═O)NR 31 R 32 , —C(═O)NR 34 R 35 , —NO 2 , —CN, —S(O) 0-2 R 31 , —SO 2 NR 31 R 32 , —SO 2 NR 34 R 35 , —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 33 , —NR 31 C(═NR 32 )NR 33 R 32 , —NR 31 C(═NR 32 )OR 33 , —NR 31 C(N═NR 32 )SR 33 , —OC(═O)OR 33 , —C(═O)NR 31 R 32 , —OC(═O)SR 31 , —SC(═O)OR 31 , —P(O)OR 31 OR 32 , or —SC(═O)NR 31 R 32 , and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, —OH, —R 31 , —CF 3 , —OCF 3 , —OR 31 , —O-aryl, —NR 31 R 32 , —NR 34 R 35 , —C(O)R 31 , —CO 2 R 31 , —C(═O)NR 34 R 35 , or —C(═O)NR 31 R 32 ; 
         each of R 31 , R 32 , and R 33  is independently H or unsubstituted C 1-10 alkyl; 
         R 34  and R 35  in —NR 34 R 35 , —C(═O)NR 34 R 35 , or —SO 2 NR 34 R 35 , are taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR 31 R 32 , hydroxyl, halogen, oxo, aryl, hetaryl, C 1-6 alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen atom; and 
         each of R 7  and R 8  is independently hydrogen or C 1-10 alkyl. 
       
     
     
         2 . The method according to  claim 1 , wherein R 1  is -L-C 1-10 alkyl, -L-C 3-8 cycloalkyl, -L-C 1-10 alkylheterocyclyl, or -L-heterocyclyl, each of which is unsubstituted or substituted by one or more independent R 3  substituents; and R 3  is hydrogen, —OH, —OR 31 , —NR 31 R 32 , or —C(O)R 31 . 
     
     
         3 . The method according to  claim 1 , wherein W 2  is —NR 7 —, —N(R 7 )C(O)—, or —N(R 7 )S(O) 2 —, and wherein R 7  is hydrogen. 
     
     
         4 . The method according to  claim 1 , wherein R 2  is H. 
     
     
         5 . The method according to  claim 1 , wherein R 1  is -L-C 1-10 alkyl or -L-C 3-8 cycloalkyl, each of which is unsubstituted or substituted by one or more independent R 3  substituents, wherein R 3  is hydrogen, —OH, —OR 31 , or —C(O)R 31 . 
     
     
         6 . The method according to  claim 1 ,  36  or  38 , wherein said disorder is selected from the group consisting of hyperproliferative disorder, bone disorder, inflammatory disease, immune disease, nervous system disease, metabolic disease, angiogenic disease, ophthalmic disease, respiratory disease, and cardiac disease. 
     
     
         7 . The method according to  claim 6 , wherein said hyperproliferative disorder is cancer. 
     
     
         8 . The method according to  claim 7 , wherein said cancer is selected from the group consisting of fibrosarcoma, pancreatic cancer, renal cancer, liver cancer, melanoma, nasopharyngeal cancer, gastric cancer, ovarian cancer, leukemia, myeloma, breast cancer, prostate cancer, colorectal cancer, lung cancer, glioblastoma, uterine cancer, bladder cancer, mesothelioma, head cancer, neck cancer, and cervical cancer. 
     
     
         9 . The method according to  claim 8 , wherein said cancer is renal cancer. 
     
     
         10 . The method according to  claim 9 , wherein said renal cancer is renal cell carcinoma. 
     
     
         11 . The method according to  claim 8 , wherein said cancer is breast cancer. 
     
     
         12 . The method according to  claim 8 , wherein said cancer is uterine cancer. 
     
     
         13 . The method according to  claim 8 , wherein said cancer is bladder cancer. 
     
     
         14 . The method according to  claim 8 , wherein said cancer is colorectal cancer. 
     
     
         15 . The method according to  claim 8 , wherein said cancer is lung cancer. 
     
     
         16 . The method according to  claim 8 , wherein said cancer is glioblastoma. 
     
     
         17 . The method according to  claim 6 , wherein said disorder is mediated by a protein kinase or a lipid kinase. 
     
     
         18 . The method according to  claim 17 , wherein said protein kinase is mTorC1 and/or mTorC2. 
     
     
         19 . The method according to  claim 6 , further comprising administering a second biologically active agent. 
     
     
         20 . The method according to  claim 19 , wherein said biologically active agent is an anti-cancer agent. 
     
     
         21 . The method according to  claim 20 , wherein said anti-cancer agent is an anti-hormone. 
     
     
         22 . The method according to  claim 21 , wherein said anti-hormone is an anti-estrogen. 
     
     
         23 . The method according to  claim 20 , wherein said anti-cancer agent is a growth factor inhibitor. 
     
     
         24 . The method according to  claim 23 , wherein said growth factor inhibitor is herceptin. 
     
     
         25 . The method according to  claim 20 , wherein said anti-cancer agent is an angiogenesis inhibitor. 
     
     
         26 . The method according to  claim 25 , wherein said angiogenesis inhibitor is bevacizumab and trastuzumab. 
     
     
         27 . The method according to  claim 25 , wherein said angiogenesis inhibitor is sorafenib. 
     
     
         28 . The method according to  claim 20 , wherein said anti-cancer agent is a mitotic inhibitor. 
     
     
         29 . The method according to  claim 28 , wherein said mitotic inhibitor is paclitaxel or docetaxel. 
     
     
         30 . The method according to  claim 8 , wherein said cancer is prostate cancer. 
     
     
         31 . The method according to  claim 12 , wherein said cancer is endometrial cancer. 
     
     
         32 . The method according to  claim 21 , wherein said anti-hormone is an anti-androgen. 
     
     
         33 . The method according to  claim 20 , wherein said anti-cancer agent is an antimetabolite. 
     
     
         34 . The method according to  claim 33 , wherein said antimetabolite is gemcitabine. 
     
     
         35 . The method according to  claim 1 , wherein R 31  and R 32  are each H. 
     
     
         36 . The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         wherein R 1  is -L-C 1-10 alkyl, -L-C 3-8 cycloalkyl, -L-C 1-10 alkylheterocyclyl, or -L-heterocyclyl, each of which is unsubstituted or substituted by one or more independent R 3  substituents; and R 3  is hydrogen, —OH, —OR 31 , —NR 31 R 32 , or —C(O)R 31 . 
       
     
     
         37 . The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         wherein R 1  is -L-C 1-10 alkyl, -L-C 3-8 cycloalkyl, or -L-C 1-10 alkylheterocyclyl. 
       
     
     
         38 . The method according to  claim 37 , wherein R 1  is isopropyl. 
     
     
         39 . The method according to  claim 37 , wherein R 1  is