N-cyclopropyl-n-piperidinyl-amides, pharmaceutical compositions containing them and uses thereof

Abstract

The present invention relates to compounds of general formula I, wherein R 1 , L P , HetAr 1 , (Het)Ar 2 and n are as defined in the application, which have valuable pharmacological properties, and in particular bind to the GPR119 receptor and modulate its activity.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is a linear or branched C 1-6 -alkyl or C 3-7 -cycloalkyl, each optionally substituted with one or more F and optionally substituted with 1 or 2 groups independently selected from H 3 C—, FH 2 C—, F 2 HC—, and F 3 C—; 
         L P  is F or C 1-3 -alkyl, wherein the alkyl group is optionally substituted with one or more F atoms; 
         n is an integer selected from 0, 1, 2, 3, or 4; 
         HetAr 1  is a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, NR N , O, and S, wherein each heteroaromatic ring is optionally substituted with 1 or more substituents L Q ; 
         L Q  is F, Cl, CN, OH, C 1-4 -alkyl, C 3-7 -cycloalkyl-, F 2 HC—, F 3 C—, C 1-4 -alkyl-O—, F 2 HC—O—, F 3 C—O—, or C 3-7 -cycloalkyl-O—; and 
         R N  is independently selected from a group consisting of H, C 1-4 -alkyl, C 1-4 -alkyl-C(═O)—, and C 1-4 -alkyl-S(═O) 2 —; 
         (Het)Ar 2  is:
 a) phenyl, tetrazolyl, pyridinonyl, or a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, NR N , O, and S, wherein each phenyl, pyridinonyl, and heteroaromatic ring thereof is optionally substituted with one or more substituents independently selected from L Ar  and each phenyl, tetrazolyl, pyridinonyl, and heteroaromatic ring thereof is optionally substituted with one group T, or 
 b) 1,2,3,6-tetrahydropyridin-4-yl substituted at the N atom with a —S(═O) 2 —C 1-6 -alkyl or —S(═O) 2 —C 3-6 -cycloalkyl group, wherein the alkyl and cycloalkyl substituents of the sulfonyl groups are optionally substituted with one or more substituents independently selected from F, Cl, CN, OH, and C 1-3 -alkyl-O—; 
 
         L Ar  is F, Cl, Br, I, CN, OH, NO 2 , C 1-4 -alkyl-, cyclopropyl, C 1-4 -alkyl-O—, (R N ) 2 N—C(═O)—, (R N ) 2 N— or C 1-4 -alkyl-S(═O) 2 —, wherein each alkyl group is optionally substituted with one or more substituents independently selected from F, Cl, CN, OH, and C 1-3 -alkyl-O—; 
         T is F, Cl, Br, I, CN, OH, NO 2 , C 3-6 -cycloalkyl, C 1-6 -alkyl-O—, —C 3-6 -cycloalkyl-O—, C 1-6 -alkyl-S—, HO—C(═O)—, C 1-6 -alkyl-O—C(═O)—, C 1-4 -alkyl-C(═O)—, C 3-6 -cycloalkyl-C(═O)—, C 1-4 -alkyl-S(═O)—, C 1-4 -alkyl-S(═O) 2 —, R NT1 R NT2 N—, R NT1 R NT2 N—C(═O)—, R NT1 R NT2 N—S(═O) 2 —, R NT1 R NT2 N—C(═O)—(R N )N—, heterocyclyl, heterocyclyl-O—, aryl, aryl-O—, heteroaryl, or heteroaryl-O—,
 wherein: each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with one or more substituents independently selected from F, Cl, CN, OH, C 1-3 -alkyl, C 3-6 -cycloalkyl, R NT1 R NT2 N—, R NT1 R NT2 N—C(═O)—, C 1-4 -alkyl-S(═O)—, C 1-4 -alkyl-S(═O) 2 —, R NT1 R NT2 N—S(═O) 2 —, aryl, heteroaryl, and heterocyclyl, 
 
         aryl is phenyl or naphthyl, 
         heteroaryl is a 5- or 6-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, NR N , O, and S,
 heterocyclyl is a 4- to 7-membered unsaturated or saturated carbocyclic ring in which 1, 2, or 3 —CH 2 — groups are independently of each other are replaced by NR N , O, —C(═O)—, S, —S(═O)—, or —S(═O) 2 —, and/or in which a —CH— group is replaced by N, and 
 each aryl, heteroaryl, and heterocyclyl group is optionally substituted with one or more substituents independently selected from L Ar ; and 
 
         R NT1  is H, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C(═O)—, C 1-6 -alkyl-S(═O) 2 —, heterocyclyl, aryl, or heteroaryl,
 wherein: each alkyl and cycloalkyl group is optionally substituted with 1 or more substituents independently selected from F, C 1-4 -alkyl, NC—, (H 3 C) 2 N—C(═O)—, HO—, C 1-4 -alkyl-O—, cyclopropyl-H 2 C—O—, F 3 C—O—, (R N ) 2 N—, C 1-4 -alkyl-S(═O) 2 —, and C 3-6 -cycloalkyl optionally substituted with 1 or 2 groups independently selected from F, H 3 C—, HO— and H 3 CO—, heterocyclyl, phenyl, and heteroaryl, 
 heterocyclyl is a C 4-7 -cycloalkyl ring in which 1 or 2 —CH 2 — groups are independently replaced by NR N , O, C(═O), S, S(═O) or S(═O) 2 , 
 heterocyclyl is optionally substituted with one or more substituents independently selected from F, C 1-4 -alkyl, (R N ) 2 N—, HO—, and C 1-4 -alkyl-O, 
 aryl is phenyl or naphthyl, 
 heteroaryl is a 5- or 6-membered aromatic ring which contains 1, 2, or 3 heteroatoms independently selected from N, NR N , O, and S; and 
 aryl, phenyl, and heteroaryl are optionally substituted with one or more substituents L Ar ; and 
 
         R NT2  is H or C 1-6 -alkyl; or 
         R NT1  and R NT2  are linked to form one group selected from a group consisting of a C 3-6 -alkylene group, wherein 1 or 2-CH 2 — groups are independently replaced by NR N , O, C(═O), S, S(═O), or S(═O) 2 , and which is optionally substituted with 1 or more substituents independently selected from F, C 1-4 -alkyl, HO—(C 1-3 -alkyl-, H 3 C—O—(C 1-3 -alkyl)-, F 3 C—, NC—, (R N ) 2 N—, HO—, C 1-4 -alkyl-O—, and 3-methyl-[1,2,4]oxadiazol-5-yl, 
         or a salt thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       or 
       
         
           
           
               
               
           
         
       
       each optionally substituted with 1 to 3 F atoms. 
     
     
         3 . The compound according to  claim 1 , wherein HetAr 1  is: 
       
         
           
           
               
               
           
         
       
       wherein each group is optionally additionally substituted with one H 3 C— group, and (Het)Ar 2 -group shows the position of the HetAr 2 -moiety within the compound of formula I. 
     
     
         4 . The compound according to  claim 1 , wherein (Het)Ar 2  is phenyl, tetrazolyl, pyridinonyl, or a heteroaromatic ring selected from pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, thienyl, or thiazolyl, and each phenyl and heteroaromatic ring is optionally substituted with one or more substituents independently selected from L Ar , each phenyl, tetrazolyl, and heteroaromatic ring is optionally substituted with one group T, and in the heteroaromatic ring, the H-atom in one NH group is optionally replaced by R N . 
     
     
         5 . The compound according to  claim 1 , wherein (Het)Ar 2  is: 
       
         
           
           
               
               
           
         
       
       and each group is optionally substituted with one group T and 1 or 2 substituents independently selected from L Ar . 
     
     
         6 . The compound according to  claim 1 , wherein n is 1 and L P  is H 3 C— or F. 
     
     
         7 . The compound according to  claim 1 , wherein n is 0 or 1 and L P  is F. 
     
     
         8 . The compound according to  claim 2 , wherein
 HetAr 1  is:   
       
         
           
           
               
               
           
         
         
           wherein each group is optionally additionally substituted with one H 3 C— group, and the (Het)Ar 2 -group shows the position of the HetAr 2 -moiety within the compound of formula I; 
         
         (Het)Ar 2  is phenyl, tetrazolyl, pyridinonyl, or a heteroaromatic ring selected from pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, thienyl, or thiazolyl, wherein the phenyl and heteroaromatic ring are optionally substituted with one or more substituents independently selected from L Ar  and the phenyl, tetrazolyl, and heteroaromatic ring are optionally substituted with one group T, and in the heteroaromatic ring, the H-atom in one NH group is optionally replaced by R N ; 
         R N  is H, H 3 C—, H 3 C—C(═O)—, or H 3 C—S(═O) 2 —; 
         T is F, Br, —CH 3 , —CH 2 CH 3 , —CH 2 —CN, —CH 2 —C(═O)—NR NT1 R NT2 , —CH 2 —NHC(═O)CH 3 , —CH 2 —OH, —CH 2 CH 2 —OH, —CN, —C(═O)—NR NT1 R NT2 , —CO 2 CH 3 , —NO 2 , —N(CH 3 ) 2 , morpholin-4-yl, —NH—S(═O) 2 —CH 3 , —O—CH 3 , —O—CH 2 CH 3 , —O—CF 3 , —S(═O) 2 —CH 3 , —S(═O) 2 —NH 2 —, or —S(═O) 2 —NHCH 3 ; 
         R NT1  is H, C 1-5 -alkyl, C 3-6 -cycloalkyl, heterocyclyl, phenyl, or heteroaryl,
 wherein each alkyl and cycloalkyl group is optionally substituted with 1 or 2 substituents independently selected from F, NC—, HO—, C 1-3 -alkyl-O—, F 3 C—O—, H 3 C—S(═O) 2 —, heterocyclyl, and heteroaryl, 
 phenyl is optionally substituted with 1 or 2 groups independently selected from F, H 3 C—, HO—(C 1-2 -alkyl)-, H 3 C—O—CH 2 —, HO—, and H 3 C—O—, 
 each heteroaryl is pyrazolyl, oxazolyl, thiazolyl, pyridyl, or pyridazinyl, optionally substituted with 1 or 2 substituents independently selected from H 3 C—, H 3 C—O—CH 2 —, cyclopropyl, HO—, and H 3 C—O—, 
 each heterocyclyl is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, optionally substituted with one H 3 C— group, and 
 R NT1 -G3 comprises the residues (H 3 C) 2 N—C(═O)—CH 2 —, cyclopropyl-CH 2 —O—CH 2 CH 2 —, 2-hydroxycyclohexyl-CH 2 —, and tetrahydropyranyl; 
 
         R NT2  is H or —CH 3 ; or 
         R NT1  and R NT2  are linked and together with the N-atom to which they are attached form a group consisting of: azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or 1,4-oxazepanyl, each optionally substituted with 1 or 2 substituents independently of each other selected from F, F 3 C—, HO—CH 2 —, H 3 CO—CH 2 —, NC—, HO—, CH 3 —O—, and 3-methyl-[1,2,4]oxadiazol-5-yl; 
         L Ar  is F or H 3 C—; 
         L P  is H 3 C— or F; and 
         n is 0 or 1. 
       
     
     
         9 . The compound according to  claim 1 , wherein:
 R 1  is   
       
         
           
           
               
               
           
         
         HetAr 1  is: 
       
       
         
           
           
               
               
           
         
         
           wherein each group is optionally additionally substituted with one H 3 C— group, and the (Het)Ar 2 -group shows the position of the HetAr 2 -moiety within the compound of formula I; 
         
         (Het)Ar 2  is: 
       
       
         
           
           
               
               
           
         
         
           wherein each group is optionally substituted with one group C 1-3 -alkyl, HO—(C 1-3 -alkyl)-, CN, (H 3 C) 2 N—, or C 1-3 -alkyl-O— and is optionally additionally substituted with one H 3 C— group; 
         
         L P  is F; and 
         n is 0 or 1. 
       
     
     
         10 . A pharmaceutically acceptable salt of the compound according to  claim 1 . 
     
     
         11 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof, and an inert carrier or diluent. 
     
     
         12 . A method for treating diseases or conditions which are mediated by activating the G-protein-coupled receptor GPR119, comprising administering to a patient in need thereof the compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A method according to  claim 12 , wherein the diseases or conditions mediated by activating the G-protein-coupled receptor GPR119 is diabetes, dislipidemia, or obesity. 
     
     
         14 .- 15 . (canceled) 
     
     
         16 . A pharmaceutical composition comprising a compound according  claim 1  or a pharmaceutically acceptable salt thereof, an additional therapeutic agents, and an inert carrier or diluents. 
     
     
         17 . (canceled)