Heteroaromatic compounds as vanin inhibitors

Abstract

The present invention encompasses compounds of the formula I which are suitable for the treatment of diseases related to Vanin, and processes for making these compounds, pharmaceutical preparations containing these compounds, and their methods of use.

1 . A compound of the formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         n denotes 1, 2 or 3; 
         m denotes 1, 2 or 3; 
         R 1  and R 2  are independently from each other selected from the group consisting of H, C 1-4 -alkyl optionally substituted by 1-3 F-atoms or C 1-2 -alkoxy, 6-10 membered aryl substituted by R 2.1  and 5-6 membered heteroaryl substituted by R 2.1 ,
 wherein 
 R 2.1  is selected from the group consisting of H, F, Cl, Br, —CN, NR 2.1.1 R 2.1.2 , SO 2 R 2.1.3  and OR 2.1.4 ,
 wherein 
 R 2.1.1 , R 2.1.2  independently from each other denote H, C 1-4 -alkyl or C 3-4 -cycloalkyl; 
 or 
 R 2.1.1  and R 2.1.2  together with the N-atom to which they are attached form a 4-5 membered heterocyclyl or a 6 membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N and O; 
 R 2.1.3  denotes C 1-4 -alkyl or NR 2.1.1  R 2.1.2 , 
 R 2.1.4  is selected from the group consisting of H, C 1-4 -alkyl, C 3-5 -cycloalkyl, 4-5 membered heterocyclyl containg 1 heteroatom selected from the group consisting of N and O. 
 wherein in the definition of R 2.1.1 , R 2.1.2 , R 2.1.3  and R 2.1.4  mentioned alkyl, cycloalkyl and heterocyclyl are optionally substituted by 1-3 F-atoms or one C 1-2 -alkoxy; 
 
 
         or 
         R 1  and R 2  together may form a 3-5 membered carbocycle or 4-6 membered heterocyclyl containg one heteroatom selected from the group consisting of N and O; 
         R 3  denotes NR 3.1 R 3.2 ; 
         or 
         R 3  denotes a group of formula R 3.a  or R 3.b   
       
       
         
           
           
               
               
           
         
         wherein 
         X denotes CH 2 , NR X  or O;
 wherein R X  denotes H or C 1-3 -alkyl; 
 
         R 3.1  is selected from the group consisting of C 1-4 -alkyl-CO— optionally substituted by 1-3 F-atoms, C 3-4 -cycloalkyl or C 1-2 -alkoxy, R 3.1.3 R 3.1.4 N—CO—, R 3.1.5 O—CO—, pyrimidine, pyridine, C 3-5 -cycloalkyl-CO— substituted with R 3.1.1  and R 3.1.2 , 4-6 membered heterocyclyl-CO— substituted with R 3.1.1  and R 3.1.2 , phenyl-CO— substituted with R 3.1.1  and R 3.1.2 ; 
         wherein
 R 3.1.1 , R 3.1.2  independently from each other are selected from the group consisting of H, —CH 3 , —OR 3.1.1.1 , F and —CN; 
 R 3.1.3 , R 3.1.4  independently from each other denote H, C 1-4 -alkyl or C 3-4 -cycloalkyl; 
 or 
 R 3.1.3  and R 3.1.4  together with the N-atom to which they are attached form a form a 4-5 membered heterocyclyl or a 6 membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N and O; 
 R 3.1.5  is selected from the group consisting of C 1-4 -alkyl, C 3-5 -cycloalkyl, 4-5 membered heterocyclyl and C 3-4 -cycloalkyl-CH 2 —; 
 R 3.1.1.1  denotes C 1-4 -alkyl, C 3-5 -cycloalkyl or 4-5 membered heterocyclyl; 
 wherein in the definition of R 3.1.1 , R 3.1.2 , R 3.1.3 , R 3.1.4 , R 3.1.5  and R 3.1.1.1  mentioned alkyl, cycloalkyl and heterocyclyl are optionally substituted by 1-3 F-atoms or one C 1-2 -alkoxy; 
 
         R 3.2  is selected from the group consisting of H, C 1-4 -alkyl, C 3-4 -cycloalkyl, C 3-4 -cycloalkyl-C 1-2 -alkyl- and phenyl-C 1-2 -alkyl-; 
         wherein in the definition of R 3.2  mentioned alkyl, cycloalkyl and phenyl are optionally substituted by 1-3 F-atoms or one C 1-2 -alkoxy; 
         R 4  denotes hydrogen or C 1-4 -alkyl optionally substituted with 1 to 3 F-atoms; 
         or 
         R 3  and R 4  together form a 4-6-membered heterocycle containing one oxygen atom. 
       
     
     
         2 . The compound according to  claim 1 ,
 wherein   m denotes 1,   or a pharmaceutically acceptable salt thereof.   
     
     
         3 . The compound according to  claim 1 ,
 wherein   m denotes 2,   or a pharmaceutically acceptable salt thereof.   
     
     
         4 . The compound according to  claim 1 ,
 wherein   n denotes 1 or 2,   or a pharmaceutically acceptable salt thereof.   
     
     
         5 . The compound according to  claim 1 ,
 R 1  denotes H or methyl,   or a pharmaceutically acceptable salt thereof.   
     
     
         6 . The compound according to  claim 1 ,
 R 2  denotes methyl, ethyl, pyrimidin or phenyl substituted by R 2.1 ,
 wherein 
 R 2.1  is selected from the group consisting of H, F, Cl and —CN, 
   or a pharmaceutically acceptable salt thereof.   
     
     
         7 . The compound according to  claim 1 , wherein
 R 3  denotes NR 3.1 R 3.2 ,   or   R 3  denotes a group of formula R 3.a     
       
         
           
           
               
               
           
         
         wherein 
         X denotes CH 2  or O 
         R 3.1  denotes —COCH 3 , pyrimidine, C 3-4 -cycloalkyl-CO— substituted with R 3.1.1  and R 3.1.2    
         wherein
 R 3.1.1 , R 3.1.2  independently from each other denote H, CH 3 , F or —CN 
 
         R 3.2  denotes CH 3 , 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The compound according to  claim 1 , wherein
 R 3  and R 4  together form a 6 membered heterocycle containing one oxygen atom. or a pharmaceutically acceptable salt thereof.   
     
     
         9 . The compound according to  claim 1 , wherein
 R 4  denotes hydrogen,   or a pharmaceutically acceptable salt thereof.   
     
     
         10 . The compound according to  claim 1 , wherein
 n denotes 1 or 2;   m denotes 1;   R 1  denotes methyl,   R 2  denotes methyl or phenyl substituted by R 2.1 ,
 wherein 
 R 2.1  is selected from the group consisting of H, F, Cl and —CN; 
   R 3  denotes NR 3.1 R 3.2 ;   or   R 3  denotes a group of formula R 3.a ,   
       
         
           
           
               
               
           
         
         wherein 
         X denotes CH 2  or O; 
         R 3.1  denotes —COCH 3 , pyrimidine, C 3-4 -cycloalkyl-CO— substituted with R 3.1.1  and R 3.1.2 
 wherein 
 R 3.1.1 , R 3.1.2  independently from each other denote H, —CH 3 , F or —CN; 
 
         R 3.2  denotes CH 3 , 
         R 4  denotes hydrogen; 
         or 
         R 3  and R 4  together form a 6 membered heterocycle containing one oxygen atom; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The compound according to  claim 1 ,
 wherein   n denotes 1 or 2;   m denotes 2;   R 1  denotes H or methyl;   R 2  denotes methyl, ethyl, pyrimidin or phenyl;   R 3  denotes NR 3.1 R 3.2 ;   or   R 3  denotes a group of formula R 3.a ;   
       
         
           
           
               
               
           
         
         wherein 
         X denotes CH 2  or O; 
         R 3.1  denotes —COCH 3 , pyrimidine C 3-4 -cycloalkyl-CO— substituted with R 3.1.1  and R 3.1.2 ,
 wherein 
 R 3.1.1 , R 3.1.2  independently from each other denote H, CH 3 , F or —CN; 
 
         R 3.2  denotes CH 3 , 
         R 4  denotes hydrogen, 
         or 
         R 3  and R 4  together form a 6 membered heterocycle containing one oxygen atom; or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The compound of formula I according to  claim 1 , selected from the group consisting of examples 6, 9.1, 8.2, 5.3, 2.1, 7.2, 13.3, 5.2, 13.1, 4.1, 11.10, 4.4, 11.9, 7.4, 4.3, 7.1, 8.3, 11.6, 10 and 9.3; 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I according to  claim 1  or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 
     
     
         14 . (canceled) 
     
     
         15 . A method of treating a patient suffering from Crohn's disease, ulcerative colitis, atopic dermatitis, systemic sclerosis, Non-Alcoholic Steatohepathitis (NASH), psoriasis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft versus host disease, psoriatic arthritis, Hyperlipidemia, colorectal cancer or pancreatic cancer related new onset diabetes, comprising administering to the patient the compound according to claim 
     
     
         16 . A pharmaceutical composition comprising additionally to the compound of  claim 1 , a pharmaceutically active compound selected from the group consisting of an immunomodulatory agent, anti-inflammatory agent and a chemotherapeutic agent.