2-heteroaryl-pyrrolo[3,4-c]pyrrole derivatives and their use as scd

Abstract

The invention relates to heterocyclic derivatives of formula I wherein R, R1, A, B, D, M, L and n are as defined herein, or their physiologically compatible salts, their pharmaceutical compositions and their uses as SCD1 inhibitors.

1 . A compound of formula I, 
       
         
           
           
               
               
           
         
         wherein: 
         R is hydrogen, (C 1 -C 16 )-alkyl, (C 1 -C 5 )-alkyloxy, (C 1 -C 5 )-alkylthio, (C 1 -C 5 )-alkylamino, di-(C 2 -C 8 )-alkylamino, (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl, (C 0 -C 4 )-alkylene-(C 5 -C 12 )-heteroaryl, (C 0 -C 4 )-alkylene-(C 3 -C 12 )-heterocyclyl, (C 0 -C 4 )-alkylene-(C 3 -C 12 )-cycloalkyl, or a bicyclic (C 8 -C 14 ) ring system, 
         wherein the aryl, heteroaryl, heterocyclyl, cycloalkyl or bicyclic (C 8 -C 14 ) ring system may be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alkylaminocarbonyl, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl or aminosulfonyl; 
         R1 is hydrogen, (C 1 -C 10 )-alkyl, (C 1 -C 10 )-alkyloxy, amino, mono-(C 1 -C 10 )-alkylamino, or di-(C 2 -C 12 )-alkylamino, 
         Wherein the alkyl may be substituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, —(C 6 -C 10 )-aryl, —(C 5 -C 12 )-heteroaryl, —(C 3 -C 12 )-heterocyclyl or —(C 3 -C 12 )-cycloalkyl, 
         Wherein the aryl, heteroaryl, heterocyclyl or cycloalkyl may be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, or di-(C 2 -C 12 )-alkylamino; 
         R2 is hydrogen, (C 1 -C 16 )-alkyl, or (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl; 
         R3 is hydrogen, (C 1 -C 6 -alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, cyano, (C 1 -C 6 )-alkylcarbonyl, halogen, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl, or aminosulfonyl; 
         A is C(R3)=C(R3); 
         B is C(R3) or N; 
         D is N; 
         n is 1 or 2; 
         L is a bond, —C(═O)—, —C(═S)—, —C(═O)—O—, —S(O) 0-2 —, —S(O) 0-2 —N(R2)-, or a mono- or bicyclic ring system in which one or more ring members may be N(R3), O, S or —C(═O)—; and 
         M is —C(═O)—N(R2)-, —N(R2)-C(═O)—, —S(O) 0-2 —, —S(O) 0-2 —N(R2)-, —N(R2)-S(O) 0-2 —, —C(═O)—O—, or —O—C(═O)—; 
         or a physiologically compatible salt thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein
 n is 1;   R1 is (C 1 -C 10 )-alkyl, (C 1 -C 10 )-alkyloxy, amino, mono-(C 1 -C 10 )-alkylamino, or di-(C 2 -C 12 )-alkylamino,   
       Wherein the alkyl may be substituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, —(C 6 -C 10 )-aryl, —(C 5 -C 12 )-heteroaryl, —(C 3 -C 12 )-heterocyclyl or —(C 3 -C 12 )-cycloalkyl, 
       Wherein the aryl, heteroaryl, heterocyclyl or cycloalkyl may each optionally be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, or di-(C 2 -C 12 )-alkylamino; 
       A is C(R3)=C(R3); 
       B is N; 
       D is N; and 
       M is —C(═O)—N(R2)-, —N(R2)-C(═O)—, —S(O) 0-2 —, —S(O) 0-2 —N(R2)-, —N(R2)-S(O) 0-2 —, or —O—C(═O)—; 
       or a physiologically compatible salt thereof. 
     
     
         3 . The compound according to  claim 1 , wherein
 n is 1;   R1 is (C 1 -C 10 )-alkyl, (C 1 -C 10 )-alkyloxy, amino, mono-(C 1 -C 10 )-alkylamino, or di-(C 2 -C 12 )-alkylamino,   Wherein the alkyl may be substituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, —(C 6 -C 10 )-aryl, —(C 5 -C 12 )-heteroaryl, —(C 3 -C 12 )-heterocyclyl or —(C 3 -C 12 )-cycloalkyl,   Wherein the aryl, heteroaryl, heterocyclyl or cycloalkyl may be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyl oxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, or di-(C 2 -C 12 )-alkylamino;   A is C(R3)=C(R3); and   M is —C(═O)—N(R2)-, —N(R2)-C(═O)—, —S(O) 0-2 —, —S(O) 0-2 —N(R2)-, —N(R2)-S(O) 0-2 —, or —O—C(═O)—;   or a physiologically compatible salt thereof.   
     
     
         4 . The compound according to  claim 1 , wherein
 n is 1;   R1 is (C 1 -C 10 )-alkyl, (C 1 -C 10 )-alkyloxy, amino, mono-(C 1 -C 10 )-alkylamino, or di-(C 2 -C 12 )-alkylamino,   
       Wherein the alkyl may be substituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, —(C 6 -C 10 )-aryl, —(C 5 -C 12 )-heteroaryl, —(C 3 -C 12 )-heterocyclyl or —(C 3 -C 12 )-cycloalkyl, 
       Wherein the aryl, heteroaryl, heterocyclyl or cycloalkyl may each optionally be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, or di-(C 2 -C 12 )-alkylamino; 
       A is C(R3)=C(R3); 
       B is C(R3); 
       D is N; and 
       M is —C(═O)—N(R2)-, —N(R2)-C(═O)—, —S(O) 0-2 —, —S(O) 0-2 —N(R2)-, —N(R2)-S(O) 0-2 —, or —O—C(═O)—; 
       or a physiologically compatible salt thereof. 
     
     
         5 . The compound according to  claim 1 , wherein
 n is 1;   R is (C 1 -C 16 )-alkyl, (C 1 -C 5 )-alkyloxy, (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl, or a bicyclic (C 8 -C 14 ) ring system,   Wherein the aryl or bicyclic (C 8 -C 14 ) ring system may be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alkyl-aminocarbonyl, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl or aminosulfonyl;   R1 is (C 1 -C 10 )-alkyl, (C 1 -C 10 )-alkyloxy, amino, mono-(C 1 -C 10 )-alkylamino, or di-(C 2 -C 12 )-alkylamino,   Wherein the alkyl may be substituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, —(C 6 -C 10 )-aryl, —(C 5 -C 12 )-heteroaryl, —(C 3 -C 12 )-heterocyclyl or —(C 3 -C 12 )-cycloalkyl,   Wherein the aryl, heteroaryl, heterocyclyl or cycloalkyl may each optionally be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, or di-(C 2 -C 12 )-alkylamino;   A is C(R3)=C(R3);   B is C(R3);   D is N;   L is a bond, or —C(═O)—; and   M is —C(═O)—N(R2)-, or —O—C(═O)—;   or a physiologically compatible salt thereof.   
     
     
         6 . The compound according to  claim 1 , wherein
 n is 1;   R is (C 1 -C 16 )-alkyl, (C 1 -C 5 )-alkyloxy, (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl, or a bicyclic (C 8 -C 14 ) ring system,   Wherein the aryl or bicyclic (C 8 -C 14 ) ring system may be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alkyl-aminocarbonyl, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl or aminosulfonyl;   R1 is (C 1 -C 10 )-alkyl, (C 1 -C 10 )-alkyloxy, amino, mono-(C 1 -C 10 )-alkylamino, or di-(C 2 -C 12 )-alkylamino,   Wherein the alkyl may be substituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, —(C 6 -C 10 )-aryl, —(C 5 -C 12 )-heteroaryl, —(C 3 -C 12 )-heterocyclyl or —(C 3 -C 12 )-cycloalkyl,   Wherein the aryl, heteroaryl, heterocyclyl or cycloalkyl may each optionally be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, or di-(C 2 -C 12 )-alkylamino;   A is C(R3)=C(R3);   B is N;   D is N;   L is a bond, or —C(═O)—; and   M is —C(═O)—N(R2)-, or —O—C(═O)—;   or a physiologically compatible salt thereof.   
     
     
         7 . The compound according to  claim 1 , which is:
 N-(3-Methylbutyl)-6-[5-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]-pyrrol-2-yl]nicotinamide;   N-Phenethyl-6-[5-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-yl]nicotinamide;   N-(2-Cyclopropylethyl)-6-[5-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo-[3,4-c]pyrrol-2-yl]nicotinamide;   N-Thiazol-2-ylmethyl-6-[5-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo-[3,4-c]pyrrol-2-yl]nicotinamide;   N-Methyl-N-thiazol-2-ylmethyl-6-[5-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinamide;   N-Cyclopropylmethyl-6-[5-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo-[3,4-c]pyrrol-2-yl]nicotinamide;   N-(3-Hydroxypentyl)-6-[5-(2-bromo-5-methoxybenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo-[3,4-c]pyrrol-2-yl]pyridazine-3-carboxamide;   N-(2-Cyclopropylethyl)-6-[5-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo-[3,4-c]pyrrol-2-yl]pyridazine-3-carboxamide;   N-Thiazol-5-ylmethyl-6-[5-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo-[3,4-c]pyrrol-2-yl]nicotinamide;   N-Cyclopentylmethyl-6-[5-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo-[3,4-c]pyrrol-2-yl]nicotinamide;   N-(2-Cyclopentylethyl)-6-[5-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo-[3,4-c]pyrrol-2-yl]nicotinamide or;   N-Thiazol-4-ylmethyl-6-[5-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo-[3,4-c]pyrrol-2-yl]nicotinamide;   or a physiologically compatible salt thereof.   
     
     
         8 . A pharmaceutical composition comprising the compound according to  claim 1  or a physiologically compatible salt thereof, in combination of a pharmacologically compatible carrier. 
     
     
         9 . A pharmaceutical composition comprising the compound according to  claim 2  or a physiologically compatible salt thereof, in combination of a pharmacologically compatible carrier. 
     
     
         10 . A pharmaceutical composition comprising the compound according to  claim 3  or a physiologically compatible salt thereof, in combination of a pharmacologically compatible carrier. 
     
     
         11 . A pharmaceutical composition comprising the compound according to  claim 4  or a physiologically compatible salt thereof, in combination of a pharmacologically compatible carrier. 
     
     
         12 . A pharmaceutical composition comprising the compound according to  claim 5  or a physiologically compatible salt thereof, in combination of a pharmacologically compatible carrier. 
     
     
         13 . A pharmaceutical composition comprising the compound according to  claim 6  or a physiologically compatible salt thereof, in combination of a pharmacologically compatible carrier. 
     
     
         14 . A pharmaceutical composition comprising the compound according to  claim 7  or a physiologically compatible salt thereof, in combination of a pharmacologically compatible carrier. 
     
     
         15 . The pharmaceutical composition according to  claim 8 , comprising as a further active ingredient selected from the group consisting of one or more antidiabetics, active hypoglycemic ingredients, HMG-CoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha agonist, PPAR gamma agonists, PPAR delta agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, MTP inhibitors, CETP inhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, active ingredients which act on the ATP-dependent potassium channel of the beta cells, glycogen phosphorylase inhibitors, glucagon receptor antagonists, activators of glucokinase, inhibitors of gluconeogenesis, inhibitors of fructose 1,6-biphosphatase, modulators of glucose transporter 4, inhibitors of glutamine:fructose-6-phosphate amidotransferase, inhibitors of dipeptidylpeptidase IV, inhibitors of 11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosine phosphatase 1B, modulators of the sodium-dependent glucose transporter 1 or 2, modulators of GPR40, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoA carboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta, endothelin-A receptor antagonists, inhibitors of I kappaB kinase, modulators of the glucocorticoid receptor, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, CB1 receptor antagonists, melanocyte-stimulating hormone agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists, lipase/amylase inhibitors, PPAR modulators, RXR modulators, TR-β-agonists and amphetamines. 
     
     
         16 . A method for treating diabetes, metabolic syndrome, insulin resistance, obesity, a cardiovascular disorder, a CNS disorder, schizophrenia, or Alzheimer's disease, or for reducing lipid, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 1  or a physiologically compatible salt thereof. 
     
     
         17 . A method for treating diabetes, metabolic syndrome, insulin resistance, obesity, a cardiovascular disorder, a CNS disorder, schizophrenia, or Alzheimer's disease, or for reducing lipid, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 2  or a physiologically compatible salt thereof. 
     
     
         18 . A method for treating diabetes, metabolic syndrome, insulin resistance, obesity, a cardiovascular disorder, a CNS disorder, schizophrenia, or Alzheimer's disease, or for reducing lipid, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 3  or a physiologically compatible salt thereof. 
     
     
         19 . A method for treating diabetes, metabolic syndrome, insulin resistance, obesity, a cardiovascular disorder, a CNS disorder, schizophrenia, or Alzheimer's disease, or for reducing lipid, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 4  or a physiologically compatible salt thereof. 
     
     
         20 . A method for treating diabetes, metabolic syndrome, insulin resistance, obesity, a cardiovascular disorder, a CNS disorder, schizophrenia, or Alzheimer's disease, or for reducing lipid, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 5  or a physiologically compatible salt thereof. 
     
     
         21 . A method for treating diabetes, metabolic syndrome, insulin resistance, obesity, a cardiovascular disorder, a CNS disorder, schizophrenia, or Alzheimer's disease, or for reducing lipid, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 6  or a physiologically compatible salt thereof. 
     
     
         22 . A method for treating diabetes, metabolic syndrome, insulin resistance, obesity, a cardiovascular disorder, a CNS disorder, schizophrenia, or Alzheimer's disease, or for reducing lipid, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 7  or a physiologically compatible salt thereof. 
     
     
         23 . A process for preparing a pharmaceutical composition comprising the compound according to  claim 1  or a physiologically compatible salt thereof, in combination of a pharmacologically compatible carrier, which comprises mixing the compound according to  claim 1  or the physiologically compatible salt thereof, with the pharmacologically compatible carrier and bringing this mixture into a form suitable for administration.