Mast-cell modulators and uses thereof

Abstract

Provided are novel compounds of Formula I pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of diseases and disorders associated with mast cells. Also provided are pharmaceutical compositions comprising the novel compounds of Formula I and methods for their use in treating one or more diseases and disorders associated with mast cells.

1 . A compound having the Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, polymorph, or solvate thereof, wherein
 Z is CH or N; 
 X is CO and Y is NH, or X is NH and Y is CO; 
 Cy is phenyl or pyridyl; 
 R 1  and R 2  are each halo; and 
 p and s are each independently 1, 2, or 3; provided the compound is not 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein the compound is of the Formula II or III: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 1 , wherein the compound is of the Formula IV or V: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound of  claim 1 , wherein p is 2. 
     
     
         5 . The compound of  claim 1 , wherein s is 1 or 2. 
     
     
         6 . The compound of  claim 1 , wherein R 2  is fluoro. 
     
     
         7 . The compound of  claim 1 , wherein R 1  is chloro. 
     
     
         8 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A pharmaceutical composition comprising the compound of any  claim 1 , or a pharmaceutically acceptable salt thereof, polymorph, or solvate thereof; and a pharmaceutically acceptable carrier. 
     
     
         10 . A method of delaying the onset of, reversing, or reducing the risk of acquiring peripheral neuropathy (PN) in a subject having diabetes, comprising administering to the subject an effective amount of a compound having the Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, polymorph, or solvate thereof, wherein
 Z is CR 3  or N; 
 X is CO and Y is NH, or X is NH and Y is CO; 
 Cy is phenyl or monocyclic heteroaryl; 
 R 1  and R 2  are each independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halo, and cyano; 
 R 3  is hydrogen or (C 1 -C 4 )alkyl; and 
 p and s are each independently 0, 1, 2, 3, or 4. 
 
     
     
         11 . A method of delaying the onset of, reversing, or reducing the risk of acquiring peripheral diabetic neuropathy (PN) in a subject in need thereof, comprising administering to the subject an effective amount of a compound having the Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, polymorph, or solvate thereof, wherein
 Z is CR 3  or N; 
 X is CO and Y is NH, or X is NH and Y is CO; 
 Cy is phenyl or monocyclic heteroaryl; 
 R 1  and R 2  are each independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halo, and cyano; 
 R 3  is hydrogen or (C 1 -C 4 )alkyl; and 
 p and s are each independently 0, 1, 2, 3, or 4. 
 
     
     
         12 . A method of delaying the onset of, reducing the risk of developing, or accelerating the healing of a wound in a subject having diabetes, comprising administering to the subject an effective amount of a compound having the Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, polymorph, or solvate thereof, wherein
 Z is CR 3  or N; 
 X is CO and Y is NH, or X is NH and Y is CO; 
 Cy is phenyl or monocyclic heteroaryl; 
 R 1  and R 2  are each independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halo, and cyano; 
 R 3  is hydrogen or (C 1 -C 4 )alkyl; and 
 p and s are each independently 0, 1, 2, 3, or 4. 
 
     
     
         13 . A method of altering the M1/M2 macrophage ratio in a wound on a subject having diabetes, comprising administering to the subject an effective amount of a compound having the Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, polymorph, or solvate thereof, wherein
 Z is CR 3  or N; 
 X is CO and Y is NH, or X is NH and Y is CO; 
 Cy is phenyl or monocyclic heteroaryl; 
 R 1  and R 2  are each independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halo, and cyano; 
 R 3  is hydrogen or (C 1 -C 4 )alkyl; and 
 p and s are each independently 0, 1, 2, 3, or 4. 
 
     
     
         14 . A method of preventing the increase of matrix metallopeptidase 9 (MMP-9), in a subject having diabetes, comprising administering to the subject an effective amount of a compound having the Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, polymorph, or solvate thereof, wherein
 Z is CR 3  or N; 
 X is CO and Y is NH, or X is NH and Y is CO; 
 Cy is phenyl or monocyclic heteroaryl; 
 R 1  and R 2  are each independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halo, and cyano; 
 R 3  is hydrogen or (C 1 -C 4 )alkyl; and 
 p and s are each independently 0, 1, 2, 3, or 4. 
 
     
     
         15 . The method of  claim 10 , wherein, Cy is phenyl or pyridyl. 
     
     
         16 . The method of  claim 10 , wherein R 1  and R 2  are each halo. 
     
     
         17 . The method of  claim 10 , wherein p and s are each independently 1, 2, or 3. 
     
     
         18 . The method of  claim 10 , wherein p is 2. 
     
     
         19 . The method of  claim 10 , wherein s is 1 or 2. 
     
     
         20 . The method of  claim 10 , wherein R 2  is fluoro. 
     
     
         21 . The method of  claim 10 , wherein R 1  is chloro. 
     
     
         22 . The method of  claim 10 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.