Mst1 kinase inhibitors and methods of their use

Abstract

Compounds for the inhibition of mammalian Ste20-like kinase 1 (MST1) are disclosed, along with compositions comprising them and methods of their use in the treatment, management or prevention of an inflammatory or autoimmune diseases or disorders.

1 . A method of treating an inflammatory or autoimmune disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is aryl or 4-7-membered heterocycle; 
 D is a 4-7-membered heterocycle; 
 X is N or CH; 
 Y 1  and Y 2  are each independently S, N or CH, provided that at least one of Y 1  and Y 2  is N or CH; 
 each R 1  is independently R 1A , —(R 1B ) n SO p R 1C , —(R 1B ) n SO p N(R 1C ) 2 , —(R 1B ) n NR 1C SO p R 1C , —(R 1B ) n C(O)N(R 1C ) 2 , or —(R 1B ) n NR 1C C(O)R 1C , or optionally substituted C 1-12  hydrocarbyl or 2-12-membered heterocarbyl, which optional substitution is with one or more of R 1A ; 
 each R 1A  is independently amino, alkoxyl, carboxyl, cyano, halo, or hydroxyl; 
 each R 1B  is independently C 1-12  hydrocarbyl optionally substituted with one or more of amino, alkoxyl, carboxyl, cyano, halo, or hydroxyl; 
 each R 1C  is independently hydrogen or optionally substituted C 1-12  hydrocarbyl or 2-12-membered heterocarbyl, which optional substitution is with one or more of amino, alkoxyl, carboxyl, cyano, halo, or hydroxyl; 
 each R 3A  is independently amino, alkoxyl, carboxyl, cyano, halo, or hydroxyl; 
 m is 0-3; 
 n is 0 or 1; 
 p is 0-2; and 
 Q is 0-2. 
 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein Z is N or CR 1 . 
     
     
         6 . The method of  claim 5 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein Y 1  and Y 2  are each independently N or CH. 
     
     
         7 . The method of  claim 5 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 5 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 5 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 4  is hydrogen or alkyl; and 
 r is 1 or 2. 
 
     
     
         10 . The method of  claim 5 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein X is N. 
     
     
         14 . The method of  claim 1 , wherein Y 1  is CH. 
     
     
         15 . The method of  claim 1 , wherein Y 2  is CH. 
     
     
         16 . The method of  claim 5 , wherein Z is N. 
     
     
         17 . The method of  claim 5 , wherein Z is CR 1 . 
     
     
         18 . The method of  claim 1 , wherein R 1  is —(R 1B ) n SO p R 1C , —(R 1B ) n SO p N(R 1C ) 2 , —(R 1B ) n NR 1C SO p R 1C , —(R 1B ) n C(O)N(R 1C ) 2 , or —(R 1B ) n NR 1C C(O)R 1C . 
     
     
         19 . The method of  claim 18 , wherein n=0. 
     
     
         20 . The method of  claim 18 , wherein p=2. 
     
     
         21 . The method of  claim 20 , which is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         22 - 24 . (canceled) 
     
     
         25 . The use of  claim 1 , wherein the autoimmune disease or disorder is achlorhydra autoimmune, Addison's Disease, ankylosing spondylitis, anti-phospholipid syndrome, asthma (e.g., bronchial asthma), atopic dermatitis, autoimmune atrophic gastritis, Behest's disease, Celiac Disease, Crohn's Disease, Cushing's Syndrome, dermatomyositis, Goodpasture's Syndrome, graft-vs-host disease, Grave's Disease, Hashimoto's thyroiditis, hepatitis (e.g., inflammatory and alcohol-induced), idiopathic adrenal atrophy, idiopathic thrombocytopenia, Kawasaki syndrome, Lambert-Eaton Syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigoid, pemphigus vulgaris, pernicious anemia, pollinosis, polyarteritis nodosa, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, Raynauds, Reiter's Syndrome, relapsing polychondritis, rheumatoid arthritis, Schmidt's Syndrome, scleroderma, Sjogren's Syndrome sympathetic ophthalmia, Takayasu's Arteritis, temporal arteritis, thyrotoxicosis, transplant rejection (e.g., of organ, cell or bone marrow), type 1 diabetes, ulcerative colitis, uveitis, and Wegener's granulomatosis. 
     
     
         26 . The use of  claim 25 , wherein the autoimmune disease or disorder is Crohn's disease, graft-versus-host disease, psoriasis, rheumatoid arthritis, or ulcerative colitis.