Myst family histone acetyltransferase inhibitors

Abstract

The present disclosure provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

We claim: 
     
         1 . A compound of formula I′: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Z is selected from —Cy, —(C 1-3  aliphatic)-Cy, or optionally substituted C 1-4  aliphatic; 
         Cy is an optionally substituted group selected from phenyl, a 3-10 membered saturated or partially unsaturated carbocyclic ring, a 6-10 membered bridged bicyclic carbocyclic ring, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; 
         each of R 1  and R 2  is independently selected from halogen and C 1-4  aliphatic; 
         R 3  is selected from hydrogen, halogen, —CN, —NR 2 , and optionally substituted C 1-4  aliphatic; 
         each R is independently selected from hydrogen, optionally substituted C 1-4  aliphatic, and —C(O)O(C 1-4  aliphatic); 
         Ring A is an optionally substituted 5- or 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 
         each R a  is selected from halogen and optionally substituted C 1-4  aliphatic; and
 x is 0-3; 
 provided that the compound is not 
 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , wherein the compound is of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Z is selected from —Cy, —(C 1-3  aliphatic)-Cy or optionally substituted C 1-4  aliphatic; 
         Cy is an optionally substituted group selected from phenyl, a 3-10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; 
         each of R 1  and R 2  is independently selected from halogen and C 1-4  aliphatic; 
         Ring A is an optionally substituted 5- or 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 
         each R a  is selected from halogen and optionally substituted C 1-4  aliphatic; and 
         x is 0-3; 
         provided that the compound is not 
       
       
         
           
           
               
               
           
         
       
     
     
         3 - 8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein the compound is of formula I-a: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound of  claim 1 , wherein the compound is of formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Z is selected from —Cy, —(C 1-3  aliphatic)-Cy or optionally substituted C 1-4  aliphatic; 
         Cy is an optionally substituted group selected from phenyl, a 3-10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; 
         each of R 1  and R 2  is independently selected from halogen and C 1-4  aliphatic; 
         R x  is optionally substituted C 1-4  aliphatic; and 
         each of R a  and R a′  is independently selected from hydrogen, halogen and optionally substituted C 1-4  aliphatic. 
       
     
     
         11 - 15 . (canceled) 
     
     
         16 . The compound of  claim 1 , wherein the compound is of formula II-a: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The compound of  claim 1 , wherein the compound is of formula II-b: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The compound of  claim 1 , wherein the compound is of formula II-c: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The compound of  claim 1 , wherein the compound is of formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Z is selected from —Cy, —(C 1-3  aliphatic)-Cy or optionally substituted C 1-4  aliphatic; 
         Cy is an optionally substituted group selected from phenyl, a 3-10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; 
         each of R 1  and R 2  is independently selected from halogen and C 1-4  aliphatic; and 
         R x  is optionally substituted C 1-4  aliphatic. 
       
     
     
         20 - 23 . (canceled) 
     
     
         24 . The compound of  claim 1 , wherein the compound is of formula III-a: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         25 - 29 . (canceled) 
     
     
         30 . The compound of  claim 1 , wherein Z is —(C 1-3  aliphatic)-Cy. 
     
     
         31 - 32 . (canceled) 
     
     
         33 . The compound of  claim 1 , wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The compound of  claim 1 , wherein the compound is selected from Table 2, or a pharmaceutically acceptable salt thereof. 
     
     
         35 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
         36 . The composition of  claim 35 , in combination with an additional therapeutic agent. 
     
     
         37 . The composition of  claim 36 , wherein the additional therapeutic agent is a cancer therapeutic agent. 
     
     
         38 . A method of inhibiting histone acetyltransferase activity of at least one MYST family KAT, comprising administering a therapeutically effective amount of a compound of  claim 1  to a biological sample or a patient. 
     
     
         39 - 43 . (canceled) 
     
     
         44 . A method of selectively inhibiting acetyltransferase activity of KAT-7 as compared to at least one of KAT-5, KAT-6A, and KAT-8, comprising administering a therapeutically effective amount of a compound of  claim 1  a biological sample or a patient in need thereof. 
     
     
         45 . A method of treating a disease or disorder comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient. 
     
     
         46 - 51 . (canceled) 
     
     
         52 . The method of  claim 45 , wherein the disease or disorder is cancer. 
     
     
         53 . A method of treating a tumor comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient. 
     
     
         54 - 71 . (canceled)