Imidazopyridazines useful as inhibitors of the par-2 signaling pathway

Abstract

The present invention relates to compounds useful as inhibitors of the PAR-2 signaling pathway. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of GPCRs in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such GPCRs; and the comparative evaluation of new inhibitors of the PAR-2 signaling pathway. The compounds of this invention have formula I: wherein the variables are as defined herein.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         A is 
       
       
         
           
           
               
               
           
         
          wherein
 n is 1 or 2; 
 Z is —O—, —CH 2 —, or —NX—; 
 X is R 5 , —C(O)R 5 , or —S(O) 2 R 5 ; 
 J is CN; oxo; a C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; or a 3-7 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said J is optionally and independently substituted with 1-3 occurrences of halo or C 1-4 alkyl, wherein up to one methylene unit of said C 1-4 alkyl is optionally and independently replaced with —O—, —NR—, or —S—; 
 or two J groups on the same or different atom(s), together with the atom(s) to which they are bound, form a 3-6 membered saturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said 3-6 membered ring is optionally substituted with one occurrence of oxo; 
 p is 0-4; 
 
         R 5  is —(V) b —Y; wherein
 V is C 1-6  aliphatic wherein up to three carbon units of said C 1-6  aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; wherein V is optionally and independently substituted with 1-3 occurrences of halo or C 1-6 alkyl, wherein up to three methylene units of said C 1-6 alkyl are optionally and independently replaced with —O—, —NR—, —S—, or C(O); 
 Y is H; CN; a 3-7 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 6-10 membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-6 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein Y is optionally substituted with 1-4 occurrences of J Y ; 
 J Y  is oxo, halo, CN, —OP(═O)(OR) 2 , phenyl, or C 1-6 aliphatic, wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with O, NR, S, or C(O), wherein said C 1-6 aliphatic optionally and independently substituted with 1-3 occurrences of halo or OR; and 
 
         R 1  is H or F; 
         R 2  is —(V 2 ) a —Y 2 ; wherein
 V 2  is a C 1-4 aliphatic; 
 Y 2  is halo; C 1-6 aliphatic; or a 3-7 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein Y 2  is optionally substituted with 1-4 occurrences of J Y ; and 
 
         a and b are each independently 0 or 1; 
         R 3  is H or F; and 
         R 4  is H; halo; CN; C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; a 3-7 membered saturated, partially saturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 6-10 membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-6 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said R 4  is optionally and independently substituted with 1-3 occurrences of oxo, halo, or C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with O, NR, S or C(O); and 
         each R independently is H or C 1-4 alkyl. 
       
     
     
         2 . The compound of  claim 1 , wherein:
 J is CN; oxo; a C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; or a 3-7 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said J is optionally and independently substituted with 1-2 occurrences of halo or C 1-4 alkyl, wherein up to one methylene unit of said C 1-4 alkyl is optionally and independently replaced with —O—, —NR—, or —S—;   or two J groups on the same or different atom(s), together with the atom(s) to which they are bound, form a 3-6 membered saturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said 3-6 membered ring is optionally substituted with one occurrence of oxo; and   R 5  is —(V) b —Y; wherein
 V is C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; wherein V is optionally substituted with 1-3 occurrences of halo or C 1-4 alkyl, wherein up to two methylene units of said C 1-4 alkyl are optionally replaced with —O—, —NR—, —S—, or C(O); 
 Y is H, a 3-7 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 6-10 membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-6 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein Y is optionally substituted with 1-4 occurrences of J Y ; and 
 J Y  is oxo, halo, phenyl, or C 1-6 aliphatic, wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with O, NR, S, or C(O); and 
   R 4  is halo; CN; C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; a 3-7 membered saturated, partially saturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 6-10 membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-6 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said R 4  is optionally and independently substituted with 1-3 occurrences of oxo, halo, or C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with O, NR, S or C(O); and   R is H or C 1-4 alkyl.   
     
     
         3 . The compound of  claim 1 , wherein Z is —NX—. 
     
     
         4 .- 13 . (canceled) 
     
     
         14 . The compound of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         15 .- 29 . (canceled) 
     
     
         30 . The compound of  claim 1 , wherein R 4  is methyl, CF 3 , isopropyl, or tert-butyl. 
     
     
         31 .- 32 . (canceled) 
     
     
         33 . The compound of  claim 1 , wherein R 1  is H. 
     
     
         34 . The compound of  claim 1 , wherein R 3  is H. 
     
     
         35 .- 43 . (canceled) 
     
     
         44 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         45 . A method for treating a PAR-2 mediated disease in a patient comprising administering to the patient a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         46 . A method for treating, preventing, or reducing inflammation or nociception (pain) in a patient comprising administering to the patient a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         47 . A method for treating an inflammatory bowel disease, irritable bowel syndrome, asthma, rheumatoid arthritis, osteoarthritis, fibrosis, gingivitis, periodontitis, atopic dermatitis, psoriasis, Netherton syndrome, systemic lupus erythematosus (SLE), scleroderma, interstitial lung disease, polymyositis, dermatomyositis, uveitis, vasculitis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, inflammatory pain, post-operative incision pain, neuropathic pain, fracture pain, osteoporotic fracture pain, gout joint pain, cancer, diet-induced obesity, adipose inflammation, or metabolic dysfunction in a patient comprising administering a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The method of  claim 47 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis, and wherein the vasculitis is Wegener's granulomatosis. 
     
     
         49 . The method of  claim 47 , wherein the fibrosis is liver fibrosis, pulmonary fibrosis, cystic fibrosis, renal fibrosis, peritoneal fibrosis, pancreatic fibrosis, scleroderma, cardiac fibrosis, skin fibrosis, or intestinal fibrosis. 
     
     
         50 . The method of  claim 47 , wherein the cancer is a protease-driven cancer. 
     
     
         51 . A method of inhibiting proteolytic activation of PAR-2 in a cell comprising administering to a patient a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         52 . A method of inhibiting PAR-2 activity in a cell comprising administering to a patient a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         53 .- 55 . (canceled) 
     
     
         56 . The compound of  claim 1 , as represented by any one of the following structures or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         57 . The compound of  claim 1 , as represented by any one of the following structures or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         58 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.