Aza-substituted spiro derivatives

Abstract

A compound of the following formula (I) or its pharmaceutically-acceptable salt is provided: [wherein X, Y, Z and W each independently represent a methine group or a nitrogen atom, provided that a case where all of X, Y, Z and W are methine group; A represents —O— or the like, B represents —C(O)— or the like, D represent —(CH 2 )m 2 -, —O— or the like, and m2 represents 0 or 1; Q represents a methine group or a nitrogen atom; and R represents a group represented by the following formula (II-1) (wherein R 6 , R 7 and R 8 independently represent a lower alkyl group or the like].

1 - 22 . (canceled) 
     
     
         23 . A method for the treatment of a disease or disorder selected from the group consisting of:
 a metabolic system disease, obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, a circulatory system disease, stenocardia, acute/congestive cardiac insufficiency, cardiac infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte disorder, a sleep disorder, a disease accompanied by sleep disorder, idiopathic hypersomnia, repetitive hypersomnia, true hypersomnia, narcolepsy, sleep periodic acromotion disorder, sleep apnea syndrome, circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder, senile insomnia, night workers' sleep insanitation, idiopathic insomnia, repetitive insomnia, true insomnia, a central nervous system disease, a peripheral nervous system disease, bulimia, emotional disorder, depression, anxiety, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, memory disorder, Alzheimer's disease, Parkinson's disease, cognition disorder, motion disorder, paresthesia, dysosmia, epilepsy, morphine resistance, drug dependency and alcoholism, in a mammalian patient in need thereof which comprises:   administering to the patient a therapeutically effective amount of a compound of the formula (I):   
       
         
           
           
               
               
           
         
       
       wherein:
 X, Y, Z and W each independently are selected from: 
 a methine group optionally having substituents selected from a substituent group α; and a nitrogen atom; 
 
       provided that where X, Y, Z and W all represent a methine group optionally having substituents selected from a substituent group α is excluded;
 A is —(C(R 3 )(R 4 )) m1 —, —C(O)—, —O— or —N(R 5 )—; 
 B is —N(SO 2 R 1 )—, —N(COR 2 )—, —N(R 50 )—, —O— or —C(O)—; 
 D is —(C(R 30 )(R 40 )) m2 —, —O—, —N(R 51 )— or —C(O)—; 
 m1 and m2 each independently are 0 or 1; 
 R 1 , R 2  and R 5  are independently selected from: a hydrogen atom, a lower alkyl group, an aralkyl group, and an aryl group; 
 R 3 , R 4 , R 30  and R 40  are independently selected from: a hydrogen atom, a hydroxyl group, a lower alkyl group, an aralkyl group, and an aryl group; 
 R 50  and R 51  are independently selected from: a hydrogen atom and a lower alkyl group; 
 Q is selected from: a methine group and a nitrogen atom; 
 R is selected from the following formula (II): 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 6  represents a hydrogen atom or a lower alkyl group; 
 R 7  and R 8  each independently represent a lower alkyl group, a cycloalkyl group, an aralkyl group, a heteroarylalkyl group; 
 or R 7  and R 8  together with the nitrogen atom to which they bond form a 4- to 8-membered nitrogen-containing aliphatic heterocyclic group; 
 or R 7 , taken together with C a  and the nitrogen atom to which it bonds, forms a 4- to 8-membered nitrogen-containing aliphatic heterocyclic group; 
 
       wherein in the formulae (II-2), (II-4) and (II-5) the group of the formula: 
       
         
           
           
               
               
           
         
       
       represent a 4- to 8-membered nitrogen-containing aliphatic heterocyclic group; 
       r indicates 0 to 2; t indicates 0 or 1; u indicates 0 or 1; with the proviso that t+u=1; 
       and any hydrogen atom in the formula (II) may have a substituent selected from a group consisting of a lower alkyl group (the lower alkyl group may be substituted with a halogen atom, an oxo group or an alkoxy group), a cycloalkyl group, a hydroxy group, an alkoxy group (the alkoxy group may be substituted with a halogen atom) and a halogen atom;
 substituent group α is selected from the group consisting of: 
 
       a halogen atom, a hydroxyl group, a lower alkyl group (the group may be substituted with a halogen atom, a hydroxyl group or an alkoxy group), a cycloalkyl group (the group may be substituted with a halogen atom, a hydroxyl group or an alkoxy group), an alkoxy group (the group may be substituted with a cycloalkyl group, a halogen atom or a hydroxyl group), an amino group, a cyano group, a mono- or di-lower alkylamino group, a formyl group, an alkanoyl group, a mono- or di-lower alkylcarbamoyl group, an arylcarbamoyl group, a heteroarylcarbamoyl group, an arylalkylcarbamoyl group, a heteroarylalkylcarbamoyl group, a lower alkylsulfonyl group, a lower alkylthio group, an aryloxycarbonylamino group, an arylalkyloxycarbonylamino group, an alkoxycarbonylamino group, an alkanoylamino group, an arylcarbonylamino group, an arylalkylcarbonyl group, a lower alkylsulfonylamino group, an arylsulfonylamino group, a lower alkylsulfamoyl group, an arylsulfamoyl group, an aryl group, an aryloxy group, a heteroaryl group, an aralkyl group and an aralkyloxy group; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The method of  claim 23  wherein the compound 1 of X, Y, Z and W is a nitrogen atom. 
     
     
         25 . The method of  claim 23  wherein the compound Q is a methane group. 
     
     
         26 . The method of  claim 23  wherein the compound:
 A is —O— or —N(R 5 )—, 
 B is —C(O)—, 
 D is —(C(R 30 (R 40 )) m2 —, and 
 m2 is 0 or 1. 
 
     
     
         27 . The compound of  claim 23  wherein the compound:
 A is —C(O)—, 
 B is —O— or —N(R 50 )—, 
 D is —(C(R 30 (R 40 ) m2 —, and 
 m2 is 0 or 1. 
 
     
     
         28 . The method of  claim 23  wherein the compound:
 A is —(C(R 3 )(R 4 )) m1 —, 
 B is —O—, 
 D is —(C(R 30 (R 40 )) m2 —, 
 m1 is 0, and 
 m2 is 1. 
 
     
     
         29 . The method of  claim 23  wherein the compound:
 A is —(C(R 3 )(R 4 )) m1 —, 
 B is —C(O)—, 
 D is —O—, —N(R 51 )— or)))—(C(R 30 (R 40 )) m2 —, 
 m1 is 0 or 1, and 
 m2 is 0. 
 
     
     
         30 . The method of  claim 23  wherein the compound R is of the formula (II-1), (II-4) or (II-5), and R 6  is a lower alkyl group. 
     
     
         31 . The method of  claim 30  wherein the compound R is of the formula (II-1). 
     
     
         32 . The method of  claim 31  wherein the compound R 7  and R 8 , taken together, form a 4- to 8-membered nitrogen-containing aliphatic heterocyclic group optionally having substituents selected from a group consisting of a lower alkyl group (which may be substituted with a halogen atom, an oxo group or an alkoxy group), a cycloalkyl group, a hydroxy group, an alkoxy group (which may be substituted with a halogen atom) and a halogen atom. 
     
     
         33 . The method of  claim 23  wherein the selected from the group consisting of:
 trans-5′-chloro-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-chloro-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-6′-azaisobenzofuran]-4-carboxamide, 
 trans-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-7′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-fluoro-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-6′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-ethoxy-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-methoxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-ethoxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-methoxy-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-propoxy-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(morpholin-4-yl)-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(dimethylamino)-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(piperidin-1-yl)-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(piperidin-1-yl)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-phenoxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(pyridin-3-yloxy)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-phenyl-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-phenyl-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(4-fluorophenyl)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(pyrimidin-5-yl)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(6-methoxypyridin-3-yl)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-[4-(methylsulfonyl)phenyl]-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(6-methoxypyridin-3-yl)-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(1-methyl-1H-pyrazol-4-yl)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(2,4-dimethoxypyrimidin-5-yl)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-ethyl-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 N-methyl-7′-oxo-N-(2-piperidin-1-ylethyl)-7′H-spiro[cyclohexane-1,5′-furo[3,4-b]pyridine]-4-carboxamide, 
 trans-4′-chloro-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-chloro-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-methoxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-methoxy-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-ethoxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-ethoxy-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-isopropoxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-isopropoxy-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-cyclopropylmethoxy-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-methyl-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-ethyl-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-phenyl-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-(4-fluorophenyl)-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-(1-methyl-1H-pyrazol-4-yl)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-phenoxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-(4-fluorophenoxy)-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-(pyrrolidin-1-yl)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-(piperidin-1-yl)-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-(pyrrolidin-1-yl)-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-4′-(morpholin-4-yl)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(pyridin-3-yl)-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-(pyridin-3-yl)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-pyrazinyl-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-benzyloxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 trans-5′-hydroxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, and 
 trans-6′-bromo-5′-methoxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The method of  claim 23  wherein the compound is selected from the group consisting of:
 trans-5′-methoxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide; 
 trans-5′-methoxy-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide; 
 trans-4′-methoxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide; 
 trans-4′-methyl-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide; 
 trans-4′-(1-methyl-1H-pyrazol-4-yl)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide; 
 trans-5′-pyrazinyl-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The method of  claim 34  wherein the compound is selected from the group consisting of:
 trans-5′-methoxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-Spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         36 . The method of  claim 34  wherein the compound is selected from the group consisting of:
 trans-5′-methoxy-3′-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The method of  claim 34  wherein the compound is selected from the group consisting of: trans-4′-methoxy-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         38 . The method of  claim 34  wherein the compound is selected from the group consisting of:
 trans-4′-methyl-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The method of  claim 34  wherein the compound is selected from the group consisting of:
 trans-4′-(1-methyl-1H-pyrazol-4-yl)-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-5′-azaisobenzofuran]-4-carboxamide; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         40 . The method of  claim 34  wherein the compound is selected from the group consisting of:
 trans-5′-pyrazinyl-3′-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1′-(3′H)-4′-azaisobenzofuran]-4-carboxamide; 
 
       or a pharmaceutically acceptable salt thereof.