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, or:
 R 1  and a substituent on Ring A 4  are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         X is —C(O)— or —S(O) 2 —, 
         L 1  is a covalent bond or an optionally substituted bivalent group selected from C 1-4  alkylene, C 2-4  alkenylene, or C 2-4  alkynylene wherein one or more methylene units of L 1  are optionally and independently replaced by -Cy 1 -, —O—, —S—, —N(R 2 )—, —C(O)—, —C(O)N(R 2 )—, —N(R 2 )C(O)N(R 2 )—, —N(R 2 )C(O)—, —N(R 2 )C(O)O—, —OC(O)N(R 2 )—, —S(O) 2 —, —S(O) 2 N(R 2 )—, —N(R 2 )S(O) 2 —, —OC(O)—, or —C(O)O; 
         Cy 1  is an optionally substituted bivalent ring selected from phenylene, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         each R 2  is hydrogen or optionally substituted C 1-6  aliphatic; 
         A 1  is a covalent bond or 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, or sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenylene, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         L 2  is a covalent bond, alkylidenylene, or an optionally substituted alkylene chain wherein one or more methylene units of L 2  are optionally and independently replaced by —O—, —S—, —N(R 2 )—, —C(O)—, —C(O)N(R 2 )—, —N(R 2 )C(O)N(R 2 )—, —N(R 2 )C(O)—, —N(R 2 )C(O)O—, —OC(O)N(R 2 )—, —S(O) 2 —, —S(O) 2 N(R 2 )—, —N(R 2 )S(O) 2 —, —OC(O)—, or —C(O)O—; 
         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, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A 2  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′) 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′) 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, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur; 
         L 3  is a covalent bond or an optionally substituted C 1-4  alkylene chain wherein one or more methylene units of L 3  are optionally and independently replaced by —O—, —S—, —N(R 2 )—, —C(O)—, —C(O)N(R 2 )—, —N(R 2 )C(O)N(R 2 )—, —N(R 2 )C(O)—, —N(R 2 )C(O)O—, —OC(O)N(R 2 )—, —S(O) 2 —, —S(O) 2 N(R 2 )—, —N(R 2 )S(O) 2 —, —OC(O)—, or —C(O)O—; 
         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, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         Ring A 4  is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or 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′) 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′) 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′) 2 ; 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, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 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, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         provided that: 
         when A 1  is a bivalent monocyclic ring and L 1  is a covalent bond, L 2  is not —O—; 
         when A 1  is a bivalent monocyclic or bicyclic ring, L 1  and L 2  are not simultaneously a covalent bond; and 
         L 1 , A 1 , and L 2  are not simultaneously a covalent bond. 
       
     
     
         2 . The compound of  claim 1 , wherein Ring A 4  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein Ring A 4  is of formula: 
       
         
           
           
               
               
           
         
         wherein 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 saturated or partially unsaturated carbocyclic ring, phenyl, a 5-6 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         4 . The compound of  claim 1 , wherein Ring A 4  is of formula: 
       
         
           
           
               
               
           
         
         wherein R 4  and R 5  are taken together with their intervening atoms to form an optionally substituted 5-membered heteroaryl fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         5 . The compound of  claim 1 , wherein Ring A 4  is of formula: 
       
         
           
           
               
               
           
         
         wherein R 3  and R 4  are taken together with their intervening atoms to form an optionally substituted 5-membered heteroaryl fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         6 . The compound of  claim 2 , wherein R 1  and R 5  are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         7 . The compound of  claim 2 , wherein 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 unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         8 . The compound of  claim 2 , wherein R 6  is hydrogen, methyl, phenyl, or pyridyl. 
     
     
         9 . The compound of  claim 2 , wherein R 3  is hydrogen, —Cl, or —CF 3 . 
     
     
         10 . The compound of  claim 2 , 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′) 2 , —CF 3 , —OCH 3 , —OCH 2 CH 3 , benzyloxy, —C(O)N(R′) 2 , or —NHC(O)C 1-4 alkyl. 
     
     
         11 . The compound of  claim 2 , wherein R 5  is hydrogen, —OCH 3 , or —NH 2 . 
     
     
         12 . The compound of  claim 1 , wherein Ring A 4  is selected from: 
       
         
           
           
               
               
           
         
         wherein: 
         R 3  is hydrogen, —Cl, or —CF 3 ; 
         R 4  is —CN, —NO 2 , —NH 2 , —NHC(O)C 1-6 alkyl, —CO 2 H, —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, or 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, or sulfur. 
       
     
     
         13 .- 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, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms selected from nitrogen, oxygen, or 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 bivalent group selected from —O—C 1-3  alkylene, C 1-3  alkylene, C 2-3  alkenylene, or C 2-3  alkynylene. 
     
     
         19 .- 22 . (canceled) 
     
     
         23 . The compound of  claim 1 , wherein A 1  is a covalent bond or a optionally substituted bivalent ring selected from phenylene, an 8-10 membered bicyclic arylene, a 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         24 . The compound of  claim 23 , wherein A 1  is an optionally substituted group selected from: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 1 , wherein L 2  is a covalent bond or an optionally substituted methylene. 
     
     
         26 .- 45 . (canceled) 
     
     
         46 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         47 . A pharmaceutical composition containing a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         48 . (canceled) 
     
     
         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)