Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Abstract

Novel benzimidazoles according to Formula I, able to inhibit JAK are disclosed, these compounds may be prepared as a pharmaceutical composition, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, allergic diseases, inflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or hypersecretion of interferons.

1 . A compound according to Formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H, or Me; 
         L 1  is —NR 2 —; —O—, or —CH2—; 
         Cy is phenyl, or 5-9 membered monocyclic or fused bicyclic heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S; 
         R 2  is H, or C14 alkyl; 
         R 3  is H, halo, C 1-4  alkyl optionally substituted with one or more halo, or C 1-4  alkoxy optionally substituted with one or more halo; 
         R 4  is H, or halo; 
         R 5  is —CN, halo, or is -L 2 -R 6 ; 
         -L 2  is absent, or is —C(=O)—, —C(=O)NR 7 —, —NR 7 C(=O)—, —SO 2 —, —SO 2 NR 7 —, or —NR 7 SO2—; 
         R 6  is H, or C 1-6  alkyl optionally substituted with one or more independently selected R 8  groups; 
         R 7  is H, or C 1-4  alkyl; 
         R 8  is OH, CN, halo, or C 1-4  alkoxy, 
         L a  is absent, or is —C(=O)—, —C(=O)O—, or —C(=O)NH—; 
         Ra is:
 H, 
 C 1-4  alkyl optionally substituted with one or more independently selected R b , 
 C 3-7  monocyclic cycloalkyl optionally substituted with one or more independently selected R c , or 
 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, and S, or 
 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, and S; 
 
         R b  is
 halo, 
 CN, 
 OH, 
 C 1-4  alkoxy, 
 C 3-7  cycloalkyl, 
 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, and S (which heterocycloalkyl is optionally substituted with one or more independently selected halo, or oxo) 
 —SO 2 —C 1-4  alkyl, or 
 —C(=O)NR b1 R b2    
 
         Rc is
 halo, 
 CN, 
 OH, 
 C 1-4  alkyl, 
 —C(=O)OH, or 
 —C(=O)NR c1i R c2 ; and 
 
         each R b1 , R b2 , R c1  and R c2  is independently selected from H, and C1 4 alkyl, or a pharmaceutically acceptable salt, or a solvate, or a solvate of the pharmaceutically acceptable salt. 
       
     
     
         2 . A compound or pharmaceutically acceptable salt according to  claim 1 , wherein R 1  is Me. 
     
     
         3 . A compound or pharmaceutically acceptable salt according to  claim 1 , wherein the compound is according to Formula IIa, IIb, or IIc: 
       
         
           
           
               
               
           
         
         wherein L 1 , R 3 , R 4 , L a , R a  and R 5  are as described in  claim 1 . 
       
     
     
         4 . A compound or pharmaceutically acceptable salt according to  claim 1 , wherein the compound is according to Formula IVa, IVb, IVc, IVd, IVe or IVf: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 3 , R 4 , R 5 , L a , and R a  are as described in  claim 1 . 
       
     
     
         5 . A compound or pharmaceutically acceptable salt according to  claim 1 , wherein the compound is according to Formula Va, Vb, Vc, Vd, Ve or Vf: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 3 , R 4 , R 5 , L a , and R a  are as described in  claim 1 . 
       
     
     
         6 . A compound or pharmaceutically acceptable salt according to  claim 1 , wherein R 4  is H, F, or Cl. 
     
     
         7 . A compound or pharmaceutically acceptable salt according to  claim 1 , wherein R 3  is H, Me, or Et. 
     
     
         8 . A compound or pharmaceutically acceptable salt according to  claim 1 , wherein R 5  is CN, F, Cl, —SO 2 Me or —SO 2 Et. 
     
     
         9 . A compound or pharmaceutically acceptable salt according  claim 1 , wherein R a  is: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound or pharmaceutically acceptable salt according to  claim 1 , wherein the compound is (1R,2R)—N-[6-[(6-cyano-4-methyl-3-pyridyl)oxy]-1-methyl-benzimidazol-4-yl]-2-fluoro-cyclopropanecarboxamide. 
     
     
         11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt according to  claim 1 . 
     
     
         12 . The pharmaceutical composition according to  claim 11 , comprising a further therapeutic agent. 
     
     
         13 . (canceled) 
     
     
         14 . A method for treating or preventing allergic diseases, inflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or hypersecretion of interferons comprising administering an effective amount of the compound or pharmaceutically acceptable according to  claim 1 . 
     
     
         15 . The pharmaceutical composition according to  claim 12 , wherein the further therapeutic agent is an agent for the treatment of allergic diseases, inflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or hypersecretion of interferons. 
     
     
         16 . A method for treating or preventing allergic diseases, inflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or hypersecretion of interferons comprising administering an effective amount of the pharmaceutical composition according to  claim 11 .