Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity

Abstract

This invention relates to substituted bicyclic dihydropyrimidinones of formula 1 and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other autoimmune and allergic disorders, allograft rejection, and oncological diseases.

What we claim: 
     
         1 . A compound of formula 1 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is phenyl or a five- or six-membered heteroaryl, wherein one, two or three elements are replaced by an element independently selected from the group consisting of N, O or S; each ring optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, O 2 N—, NC—, H 2 N—, HO—, R 1.1 , R 1.1 O—, R 1.2 , R 1.3 S—, R 1.3 (O)S— and R 1.3 (O) 2 S—;
 R 1.1  is independently selected from the group consisting of C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -haloalkyl- and C 3-6 -halocycloalkyl; 
 R 1.2  is HO—C 1-6 -alkyl- or R 1.1 —O—C 1-6 -alkyl-; 
 R 1.3  is independently selected from the group consisting of H, HO—, R 1.1  and R 1.2 ; 
 
         R 2  is phenyl or a five- or six-membered heteroaryl, wherein one or two elements are replaced by an element independently selected from the group consisting of N, O or S; each ring optionally substituted with a substituent independently selected from the group consisting of halogen, C 1-4 -alkyl-, C 1-4 -haloalkyl- and C 1-4 -alkyl-O—; 
         R 3  is a residue independently selected from the group consisting of
 R 3.1 —; 
 R 3.2 (O)C—; 
 R 3.2 O(O)C—; 
 R 3.2 O(O)C-A-; 
 R 3.2 S—; R 3.2 (O)S—; R 3.2 (O) 2 S—; 
 (R 3.2 ) 2 N(O)C and 
 (R 3.2 ) 2 N(O)C-A-; 
 R 3.1  is independently selected from the group consisting of H, R 3.3 , R 3.4 , C 1-6 -alkyl-C 3-6 -cycloalkyl- and C 3-6 -cycloalkyl-C 1-6 -alkyl-, each optionally substituted with one or two substituents independently selected from R 3.1.1 —;
 R 3.1.1  is selected from the group consisting of HO—, halogen, NC—, R 3.3 O—, R 3.5 , R 3.6  and R 3.7  or 
 R 3.1.1  denotes a ring independently selected from phenyl and a four-membered heterocyclic ring containing one element independently selected from among N, O, S, S(O) and S(O) 2 ; 
 R 3.1.1  denotes a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from among N, O, S, S(O) and S(O) 2 ;
 each of the rings optionally substituted with one or two substituents independently selected from among HO—, O═, halogen, NC—, R 3.3 , R 3.3 O—, R 3.3 —(O)C—, R 3.4 , R 3.5 , R 3.6  and R 3.7  or two substituents are together R 3.8 ; 
 
 
 R 3.2  is independently selected from among R 3.1 , phenyl and a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from among N, O, S, S(O) and S(O) 2 ; each ring optionally substituted with one or two substituents independently selected from among HO—, O═, NC—, halogen, R 3.3 , R 3.3 O—, R 3.3 —(O)C—, R 3.4 , R 3.5 , R 3.6  and R 3.7  or two substituents are together R 3.8 ;
 or two R 3.2  are together a three-, four-, five- or six-membered monocyclic or a six-, seven-, eight-, nine- or ten-membered bicyclic heterocyclic or heteroaryl ring optionally containing additional to the nitrogen one or two elements independently selected from among N, O, S, S(O) and S(O) 2 ; optionally substituted with one or two substituents, independently selected from among HO—, F, O═, NC—, R 3.3 , R 3.3 O—, R 3.3 —(O)C—, R 3.4 , R 3.5 , R 3.6 , R 3.7 , phenyl and a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from among N, O, S, S(O) and S(O) 2 ; or two substituents are together R 3.8 ; 
 
 R 3.3  is independently selected from the group consisting of C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -haloalkyl- and C 3-6 -halocycloalkyl; 
 R 3.4  is HO—C 1-6 -alkyl- or R 3.3 —O—C 1-6 -alkyl-; 
 R 3.5  is independently selected from the group consisting of H 2 N—, R 3.3 —HN—, (R 3.3 ) 2 N—, R 3.3 —(O)C—HN— and R 3.3 —(O)C—(R 3.3 )N—; 
 R 3.6  is independently selected from the group consisting of R 3.3 —(O)S—, R 3.3 —(O) 2 S—, R 3.3 (HN)S—, R 3.3 (HN)(O)S—, R 3.3 (R 3.3 N)S—, R 3.3 (R 3.3 N)(O)S—, R 3.3 (R 3.4 N)S—, R 3.3 (R 3.4 N)(O)S—; R 3.3 (NC—N)S and R 3.3 (NC—N)(O)S—; 
 R 3.7  is independently selected from the group consisting of HO(O)C—, H 2 N(O)C—, R 3.3 —O—(O)C—, R 3.3 —NH—(O)C— and (R 3.3 ) 2 N—(O)C—; 
 R 3.8  is independently selected from the group consisting of C 1-6 -alkylene and C 1-6 -haloalkylene, wherein optionally one or two CH 2 -groups are replaced by —HN—, —(R 3.3 )N—, —(R 3.4 )N—, —(R 3.3 (O)C—)N—, —(R 3.4 (O)C—)N—, —O—, —S—, —S(O)— or —S(O) 2 —; 
 A is —CH 2 —, —CH 2 —CH 2 — or —CH 2 —CH 2 —CH 2 —; optionally substituted with one or two substituents independently selected from the group consisting of halogen, R 3.3 , R 3.3 O— and R 3.4  or two substituents together are R 3.8 ; 
 
         R 4  is independently selected from the group consisting of halogen, C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -haloalkyl- and C 3-6 -halocycloalkyl; or two R 4  are together C 1-6 -alkylene or C 1-6 -haloalkylene; 
         m is 0, 1 or 2; 
         or a salt thereof. 
       
     
     
         2 . A compound of formula 1, according to  claim 1 , wherein R 1  is R 1.c  and R 1.c  is phenyl or pyridinyl; each ring optionally substituted by one, two or three residues independently selected from the group consisting of F, Cl, Br—, NC—, R 1.1 , R 1.3 (O)S— and R 1.3 (O) 2 S—;
 R 1.1  is independently selected from the group consisting of C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -haloalkyl- and C 3-6 -halocycloalkyl; 
 R 1.2  is HO—C 1-6 -alkyl- or R 1.1 —O—C 1-6 -alkyl-; 
 R 1.3  is independently selected from the group consisting of H, HO—, R 1.1  and R 1.2 ; 
 
       or a salt thereof. 
     
     
         3 . A compound of formula 1, according to  claim 1 , wherein R 1  is R 1.e  and R 1.e  is phenyl or pyridinyl; each ring optionally substituted by one or two residues independently selected from the group consisting of NC—, Me(O)S—, Me(O) 2 S and Et(O) 2 S; or a salt thereof. 
     
     
         4 . A compound of formula 1, according to one of the  claim 1 , wherein R 2  is R 2.b  and R 2.b  is phenyl or a six-membered heteroaryl; wherein one or two elements are replaced by N; each ring optionally substituted with a substituent independently selected from the group consisting of halogen, C 1-4 -alkyl- and C 1-4 -haloalkyl-; or a salt thereof. 
     
     
         5 . A compound of formula 1, according to one of the  claim 1 , wherein R 2  is R 2.f  and R 2.f  is pyridinyl, optionally substituted with a substituent independently selected from the group consisting of F 3 C— and F 2 HC—, or a salt thereof. 
     
     
         6 . A compound of formula 1, according to one of the  claim 1 , wherein A is A b  and A b  is —CH 2 —, optionally substituted with one or two substituents independently selected from the group consisting of F, Me, Et, i-Pr, MeO, EtO, HOCH 2 O— and MeOCH 2 —; or a salt thereof. 
     
     
         7 . A compound of formula 1, according to one of the  claim 1 , wherein R 4  is R 4.a  and R 4.a  is selected from the group consisting of halogen, C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -haloalkyl- and C 3-6 -halocycloalkyl; or a salt thereof. 
     
     
         8 . A compound of formula 1, according to one of the  claim 1 , wherein R 3  is a residue independently selected from the group consisting of
 R 3.1 —;   R 3.2 O(O)C— or R 3.2 O(O)C—CH 2 —;   R 3.2 (O) 2 S— and   (R 3.2 ) 2 N(O)C— or (R 3.2 ) 2 N(O)C—CH 2 —;   R 3.1  is independently selected from the group consisting of H, R 3.3 , R 3.4 , C 1-6 -alkyl-C 3-6 -cycloalkyl- and C 3-6 -cycloalkyl-C 1-6 -alkyl-, each optionally substituted with one or two substituents independently selected from R 3.1.1 —;
 R 3.1.1  is selected from the group consisting of HO—, halogen, NC—, R 3.3 O—, R 3.5 , R 3.6  and R 3.7  or 
 R 3.1.1  is selected from the group consisting of a ring independently selected from phenyl and a four-membered heterocyclic ring containing one element independently selected from among N, O, S, S(O) and S(O) 2 ; or 
 R 3.1.1  denotes a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from among N, O, S, S(O) and S(O) 2 ; each of the rings optionally substituted with one or two substituents independently selected from among HO—, O═, halogen, R 3.3 , R 3.3 O—, R 3.3 —(O)C—, R 3.4 , R 3.5 , R 3.6  and R 3.7  or two substituents are together R 3.8 ; 
   R 3.2  is independently selected from R 3.1 , phenyl or a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from among N, O, S, S(O) and S(O) 2 ; each ring optionally substituted with one or two substituents independently selected from HO—, O═, NC—, halogen, R 3.3 , R 3.3 O—, R 3.3 —(O)C—, R 3.4 , R 3.5 , R 3.6  and R 3.7  or two substituents are together R 3.8 ;
 or two R 3.2  are together a five- or six-membered monocyclic or a eight-, nine- or ten-membered bicyclic heterocyclic or heteroaryl ring optionally containing additional to the nitrogen one or two elements independently selected from among N, O, S, S(O) and S(O) 2 ; optionally substituted with one or two substituents, independently selected from HO—, F, O═, R 3.3 , R 3.3 O—, R 3.3 —(O)C—, R 3.4 , R 3.5 , R 3.7  and R 3.6  or two substituents are together R 3.8 ; 
   R 3.3  is independently selected from the group consisting of C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -haloalkyl- and C 3-6 -halocycloalkyl;   R 3.4  is HO—C 1-6 -alkyl- or R 3.3 —O—C 1-6 -alkyl-;   R 3.5  is independently selected from the group consisting of H 2 N—, R 3.3 —HN—, (R 3.3 ) 2 N— and R 3.3 —(O)C—HN—;   R 3.6  is independently selected from the group consisting of R 3.3 —(O)S—, R 3.3 —(O) 2 S—, R 3.3 (HN)S—, R 3.3 (HN)(O)S—R 3.3 (R 3.3 N)S—, R 3.3 (R 3.3 N)(O)S—, R 3.3 (R 3.4 N)S— and R 3.3 (R 3.4 N)(O)S—;   R 3.7  is independently selected from the group consisting of HO(O)C—, H 2 N(O)C—, R 3.3 —O—(O)C—, R 3.3 —NH—(O)C— and (R 3.3 ) 2 N—(O)C—;   R 3.8  is independently selected from the group consisting of C 1-6 -alkylene or C 1-6 -haloalkylene, wherein optionally one or two CH 2 -groups are replaced by —HN—, —(R 3.3 )N—, —(R 3.4 )N—, —(R 3.3 (O)C—)N—, —(R 3.4 (O)C—)N—, —O—, —S—, —S(O)— and —S(O) 2 —;   
       or a salt thereof. 
     
     
         9 . A compound of formula 1, according to one of the  claim 1 , wherein R 3  is independently selected from the group consisting of HO(O)C—H 2 C—, MeO(O)C—H 2 C—, H 2 N(O)C—H 2 C—, MeHN(O)C—H 2 C—, Me 2 N(O)C—H 2 C—, morpholinyl-(O)C—H 2 C—, azetidinyl-(O)C—H 2 C—, pyrrolidinyl-(O)C—H 2 C—, MeHN(O)C—, EtHN(O)C—, HO(CH 2 ) 2 HN(O)C—, HO(CMe 2 )(CH 2 )HN(O)C—, HO(CH 2 ) 3 HN(O)C—, Me(O)S(CH 2 ) 2 HN(O)C—, Me(O) 2 S(CH 2 ) 2 HN(O)C—, Et(O) 2 S— and Me(O) 2 S—; or a salt thereof. 
     
     
         10 . A compound of formula I.a to I.s, according to  claim 1   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         11 . A compound according to one of the  claim 1 , wherein the configuration of formula 1 is formula 1′ 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         12 . A method for the treatment of a condition selected from the group consisting of asthma, allergic diseases, gastrointestinal inflammatory diseases, eosinophilic diseases, chronic obstructive pulmonary disease, infection by pathogenic microbes and rheumatoid arthritis, which method comprising administering to a host suffering from one of said conditions a therapeutically effective amount of a compound of formula 1 according  claim 1 . 
     
     
         13 . A pharmaceutical composition comprising a compound of formula 1 according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.