Heterocyclic compounds useful as pdk1 inhibitors

Abstract

The present invention provides compounds useful as inhibitors of PDK1. The present invention also provides compositions thereof, and methods of treating PDK1-mediated diseases.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is hydrogen or optionally substituted C 1-6  aliphatic; 
         X is —C(O); 
         L 1  is a covalent bond or an optionally substituted C 1-4  alkylene; 
         A 1  is an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylene, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         L 2  is a covalent bond or an optionally substituted alkylene; 
         Ring A 2  is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A is optionally substituted with 1-4 R x  groups; 
         each R x  is independently —R, optionally substituted alkylidenyl, oxo, -halo, —NO 2 , —CN, —OR, —SR, —N(R′) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R′) 2 , —S(O) 2 N(R′) 2 , —OC(O)R, —N(R′)C(O)R, —N(R′)N(R′) 2 , —N(R′)OR, —N(R′)C(═NR′)N(R′), —C(═NR′)N(R′) 2 , —C═NOR, —N(R′)C(O)N(R′), —N(R′)S(O) 2 N(R′) 2 , —N(R′)S(O) 2 R, or —OC(O)N(R′) 2 ; 
         each R is independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         each R′ is independently —R, or two R′ groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         L 3  is C 1-4  alkylene optionally substituted with methyl or ethyl; 
         Ring A 3  is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         Ring A 4  is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any substitutable carbon on Ring A 4  is optionally substituted with R 3 , R 4 , or R 5 , and any substitutable nitrogen on Ring A 4  is optionally substituted with R 6 ; 
         each of R 3 , R 4 , and R 5  is independently —R, -halo, —NO 2 , —CN, —OR, —SR, —N(R′) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R′), —S(O) 2 N(R′) 2 , —OC(O)R, —N(R′)C(O)R, —N(R′)N(R′), —N(R′)OR, —N(R′)C(═NR′)N(R′) 2 , —C(═NR′)N(R′) 2 , —C═NOR, —N(R′)C(O)N(R′) 2 , —N(R′)S(O) 2 N(R′) 2 , —N(R′)S(O) 2 R, or —OC(O)N(R′) or,
 R 3  and R 4  or R 4  and R 5  are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 
 each R 6  is independently —R, —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R′) 2 , or —S(O) 2 N(R′) 2  or, 
 R 3  and R 6  are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, an sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
 
       
     
     
         2 . The compound of  claim 1 , wherein Ring A 4  is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 .- 8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein R 3  is hydrogen, —Cl, or —CF 3 . 
     
     
         10 . The compound of  claim 1 , wherein R 4  is halo, —NH 2 , —CN, —NO 2 , —SC 1-4 alkyl, —S(O)C 1-4  alkyl, —S(O) 2 C 1-4  alkyl, —S(O)N(R′), —CF 3 , —OCH 3 , —OCHCH 3 , benzyloxy, —C(O)N(R′) 2 , or —NHC(O)C 1-4 alkyl. 
     
     
         11 . (canceled) 
     
     
         12 . The compound of  claim 1 , wherein Ring A 4  is: 
       
         
           
           
               
               
           
         
         wherein: 
         R 3  is hydrogen, —Cl, or —CF 3 ; 
         R 4  is —CN, —NO 2 , —NH 2 , —NHC(O)C 1-4 alkyl, —COH, —CO 2 C 1-4 alkyl, —C(O)N(R′) 2 , —NHS(O)C 1-6 alkyl, —NHS(O) 2 C 1-6 alkyl, —SC 1-6 alkyl, —S(O)C 1-6 alkyl, —S(O) 2 C 1-6 alkyl, —S(O)N(R′) 2 , —S(O) 2 N(R′) 2 , —CF 3 , —OCH 3 , —OCH 2 CH 3 , or benzyloxy; 
         R 5  is hydrogen, —OCH 3 , or —NH 2 ; 
         R 6  is hydrogen or an optionally substituted group selected from C 1-4  alkyl, phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; and 
         each R′ is independently hydrogen or C 1-4  alkyl, or two R′ groups on the same nitrogen are taken together with the intervening nitrogen to form an optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
       
     
     
         13 . The compound of  claim 1 , wherein L 3  is unsubstituted methylene or methylene substituted with methyl or ethyl. 
     
     
         14 .- 15 . (canceled) 
     
     
         16 . The compound of  claim 1 , wherein Ring A 3  is phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, n sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein Ring A 3  is optionally substituted with one or more halo or alkyl groups. 
     
     
         17 . (canceled) 
     
     
         18 . The compound of  claim 1 , wherein L 1  is optionally substituted C 1-3  alkylene. 
     
     
         19 .- 22 . (canceled) 
     
     
         23 . The compound of  claim 1 , wherein A 1  is an optionally substituted bivalent ring selected from phenylene or an 8-10 membered bicyclic arylene. 
     
     
         24 . The compound of  claim 23 , wherein A 1  is 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 1 , wherein L 2  is a covalent bond or an optionally substituted methylene. 
     
     
         26 . The compound of  claim 1 , wherein Ring A 2  is optionally substituted with 1-4 R x  groups and is selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         27 . (canceled) 
     
     
         28 . The compound of  claim 1 , wherein Ring A 2  is 
       
         
           
           
               
               
           
         
       
     
     
         29 .- 31 . (canceled) 
     
     
         32 . The compound of  claim 1 , wherein the compound is of formula II or formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         33 . (canceled) 
     
     
         34 . The compound of  claim 32 , wherein:
 R 3  is hydrogen, —Cl, or —CF 3 ;   R 4  is —CN, —NO 2 , —SC 1-4 alkyl, —S(O)C 1-4  alkyl, —S(O) 2 C 1-4  alkyl, —S(O)N(R′), —S(O) 2 N(R′) 2 , —CF 3 , —OCH 3 , —OCH 2 CH 3 , or benzyloxy or,
 R 3  and R 4  are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially saturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
   each R′ is independently hydrogen or C 1-4 alkyl; and   R 5  is hydrogen, —OCH 3 , or —NH 2 .   
     
     
         35 .- 45 . (canceled) 
     
     
         46 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         47 . A pharmaceutical composition containing a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         48 . A pharmaceutical composition containing a compound of  claim 46  and a pharmaceutically acceptable excipient. 
     
     
         49 . A method of treating cancer in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of  claim 1  or a composition of  claim 47 . 
     
     
         50 . (canceled) 
     
     
         51 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.