Nociceptin analogs

Abstract

A compound of the having the general formula (I) or general formula (II): wherein Z, A, B, C, R 1 , R 2 , Q, W, and n are as described herein.

1 - 32 . (canceled) 
   
   
       33 . A compound of the formula (II): 
     
       
         
         
             
             
         
       
       wherein W is hydrogen, C 1-10  alkyl, C 3-12  cycloalkyl, C 3-12  cycloalkylC 1-4 alkyl-, C 1-10  alkoxy, C 3-12  cycloalkoxy-, C 1-10  alkyl substituted with 1-3 halogen, C 3-12  cycloalkyl substituted with 1-3, halogen, C 3-12  cycloalkylC 1-4 alkyl-substituted with 1-3 halogen, C 1-10  alkoxy substituted with 1-3 halogen, C 3-12  cycloalkoxy- substituted with 1-3 halogen, —COOV 1 , —C 1-4 COOV 1 , —CH 2 OH, —SO 2 N(V 1 ) 2 , hydroxyC 1-10 alkyl-, hydroxyC 3-10 cycloalkyl-, cyanoC 1-10 alkyl-, cyanoC 3-10 cycloalkyl-, —CON(V 1 ) 2 , NH 2 SO 2 C 1-4 alkyl-, NH 2 SOC 1-4 alkyl-, sulfonylaminoC 1-10 alkyl-, diaminoalkyl-, -sulfonylC 1-4 alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocyclicC 1-4 alkyl-, a 6-membered heteroaromaticC 1-4 alkyl-, a 6-membered aromatic ring, a 6-membered aromaticC 1-4  alkyl-, a 5-membered heterocyclic ring optionally substituted with an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclicC 1-4 alkyl- optionally substituted with an oxo or thio, a 5-membered heteroaromaticC 1-4 alkyl-, —C 1-5 (═O)W 1 , —C 0-5 (═NH)W 1 , —C 1-5 NHC(═O)W 1 , —C 1-5 NHS(═O) 2 W 1 , —C 1-5 NHS(═O)W 1 , wherein W 1  is hydrogen, C 1-10  alkyl, C 3-12  cycloalkyl, C 1-10 alkoxy, C 3-12  cycloalkoxy, —CH 2 OH, amino, C 1-4 alkylamino-, diC 1-4 alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl; 
       wherein each V 1  is independently selected from 1, C 1-6  alkyl, C 3-6  cycloalkyl, benzyl and phenyl; 
       Q is a 6 membered aromatic group; 
       n is an integer from 0 to 3, 
       A, B and C are independently hydrogen, C 1-10  alkyl, C 3-12  cycloalkyl, C 1-10 alkoxy, C 3-12  cycloalkoxy, —CH 2 OH, —NHSO 2 , hydroxyC 1-10 alkyl-, aminocarbonyl-, C 1-4 alkylaminocarbonyl-, diC 1-4 alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC 1-10 alkyl-, or A-B can together form a C 2-6  bridge, or B-C can together form a C 3-7  bridge, or A-C can together form a C 1-5  bridge; 
       Z is selected from the group consisting of a bond, straight or branched C 1-6  alkylene, —NH—, —CH 2 O—, —CH 2 NH—, —CH 2 N(CH 3 )—, —NHCH 2 —, —CH 2 CONH—, —NHCH 2 CO—, —CH 2 CO—, —COCH 2 —, —CH 2 COCH 2 —, —CH(CH 3 )—, —CH═, —O— and —HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group; 
       R 1  is selected from the group consisting of hydrogen, C 1-10 alkyl, C 3-12 cycloalkyl, C 2-10 alkenyl, amino, C 1-10 alkylamino-, C 3-12 cycloalkylamino-, —COOV 1 , —C 1-4 COOV 1 , cyano, cyanoC 1-10 alkyl-, cyanoC 3-10 cycloalkyl-, NH 2 SO 2 —, NH 2 SO 2 C 1-4 alkyl-, NH 2 SOC 1-4 alkyl-, aminocarbonyl-, C 1-4 alkylaminocarbonyl-, diC 1-4 alkylaminocarbonyl-, benzyl, C 3-12  cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (III): 
     
     
       
         
         
             
             
         
       
       wherein X 1  and X 2  are independently selected from the group consisting of NH, O, S and CH 2 ; 
       wherein said allyl, cycloalkyl, alkenyl, C 1-10 alkylamino-, C 3-12 cycloalkylamino-, or benzyl of R 1  is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C 1-10  alkyl, C 1-10  alkoxy, nitro, trifluoromethyl-, cyano, —COOV 1 , —C 1-4 COOV 1 , cyanoC 1-10 alkyl-, —C 1-5 (═O)W 1 , —C 1-5 NHS(═O) 2 W 1 , —C 1-5 NHS(═O)W 1 , a 5-membered heteroaromaticC 0-4 alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10  alkyl-, C 1-10  alkoxy-, and cyano; and wherein said C 3-12  cycloalkyl, C 3-12  cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula (III) is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10  alkyl, C 1-10  alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10  alkyl, C 1-10  alkoxy, and cyano; 
       R 2  is selected from the group consisting of hydrogen, C 1-10  alkyl, C 3-12  cycloalkyl and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group; 
       or a pharmaceutically acceptable salt thereof or solvate thereof. 
     
   
   
       34 . (canceled) 
   
   
       35 . The compound of  claim 33 , wherein W is selected from the group consisting of —CH 2 C(═O)NH 2 , —C(NH)NH 2 , pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, —C(O)CH 3 , —CH 2 CH 2 NHC═OCH 3 , —SO 2 CH 3 , CH 2 CH 2 NHSO 2 CH 3 , furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyano methyl-, oxo-oxazolemethyl-, and diazolemethyl-. 
   
   
       36 . The compound of  claim 33 , wherein ZR 1  is selected from the group consisting of cyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazoylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, and oxocanylpropyl-. 
   
   
       37 . The compound of  claim 33 , wherein at least one of ZR 1  or W is selected from the group consisting of CH 2 COOV 1 , tetrazolylmethyl-, cyanomethyl-, NH 2 SO 2 methyl-, NH 2 SOmethyl-, aminocarbonylmethyl-, C 1-4 alKylaminocarbonylmethyl-, and diC 1-4 alkylaminocarbonylmethyl-. 
   
   
       38 . The compound of  claim 33 , wherein ZR 1  is 3,3 diphenylpropyl optionally substituted at the 3 carbon of the propyl with —COOH, —COOV 1 , tetrazolylC 0-4 alkyl-, cyano-, aminocarbonyl-, C 1-4 alkylaminocarbonyl-, or diC 1-4 alkylaminocarbonyl-. 
   
   
       39 . A compound of the formula (IIA): 
     
       
         
         
             
             
         
       
       wherein 
       n is an integer from 0 to 3; 
       Z is selected from the group consisting of a bond, —CH 2 —, —NH—, —CH 2 O—, —CH 2 CH 2 —, —CH 2 NH—, —CH 2 N(CH 3 )—, —NHCH 2 —, —CH 2 CONH—, —NHCH 2 CO—, —CH 2 CO—, —COCH 2 —, —CH 2 COCH 2 —, —CH(CH 3 )—, —CH═, and —HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy or alkoxy group; 
       R 1  is selected from the group consisting of hydrogen, C 1-10 alkyl, C 3-12 cycloalkyl, C 2-10 alkenyl, amino, C 1-10 alkylamino, C 3-12 cycloalkylamino, benzyl, C 3-12  cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (III): 
     
     
       
         
         
             
             
         
       
       wherein X 1  and X 2  are independently selected from the group consisting of NH, O, S and CH 2 ; 
       wherein said alkyl, cycloalkyl, alkenyl, C 1-10  alkylamino, C 3-12 cycloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10  alkyl, C 1-10  alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10  alkyl, C 1-10  alkoxy, and cyano; 
       wherein said C 3-12  cycloalkyl, C 3-12  cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, and spiro ring system of the formula (II) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10  alkyl, C 1-10  alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10  alkyl, C 1-10  alkoxy, and cyano; 
       R 2  is selected from the group consisting of hydrogen, C 1-10  alkyl, C 3-12  cycloalkyl and halogen, said alkyl optionally substituted with an oxo group; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       40 . A compound of  claim 39 , wherein R 1  is alkyl selected from the group consisting; of methyl, ethyl, propyl, butyl, pentyl and hexyl. 
   
   
       41 . A compound of  claim 39 , wherein R 1  is cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and norbornyl. 
   
   
       42 . A compound of  claim 39 , wherein R 1  is tetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl. 
   
   
       43 . A compound of  claim 39 , wherein R 1  is phenyl or benzyl. 
   
   
       44 . A compound of  claim 39 , wherein R 1  is a bicyclic aromatic ring. 
   
   
       45 . A compound of  claim 44 , wherein said bicyclic aromatic ring is indenyl, quinoline or naphthyl. 
   
   
       46 . A compound of  claim 39 , wherein Z is a bond, methyl, or ethyl. 
   
   
       47 . A compound of  claim 39 , wherein n is 0. 
   
   
       48 . A compound of  claim 39 , wherein X 1  and X 2  are both O. 
   
   
       49 . A compound selected from the group consisting of: 
     1,2,3,4-tetrahydro-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-(p-phenylbenzyl)-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-quinolin-2-one; 
     1, 2,3,4-tetrahydro-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-(4-propyl-cyclohexyl)-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-(norbornan-2-yl)-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-(10,11-dihydro-5H-dibenzo[a.d]-cyclohepten-5-yl)-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-(3,3-diphenylpropyl)-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-(cyclooctyl)-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-quinolin-2-one; 
     1,2,3,4-tetrahydro-1-[1-(cyclooctylmethyl)-4-piperidinyl]-quinolin-2-one; 
     and pharmaceutically acceptable salts thereof. 
   
   
       50 . A pharmaceutical composition comprising a compound of  claim 33  and at least one pharmaceutically acceptable excipient. 
   
   
       51 . A method of treating pain comprising administering to a patient in need thereof, an effective amount of an analgesic compound according to  claim 33 . 
   
   
       52 . A method of modulating a pharmacological response from the ORL1 receptor comprising administering to a patient in need thereof, an effective amount of a compound according to  claim 33 . 
   
   
       53 . A pharmaceutical composition comprising a compound of  claim 39  and at least one pharmaceutically acceptable excipient. 
   
   
       54 . A method of treating pain comprising administering to a patient in need thereof, an effective amount of an analgesic compound according to  claim 39 . 
   
   
       55 . A method of modulating a pharmacological response from the ORL1 receptor comprising administering to a patient in need thereof an effective amount of a compound according to  claim 39 . 
   
   
       56 . A compound of the formula (IIA): 
     
       
         
         
             
             
         
       
       wherein 
       R 2  is selected from the group consisting of hydrogen, C 1-10  alkyl, C 3-12  cycloalkyl and halogen, said alkyl is optionally substituted with an oxo group; 
       n is an integer from 0 to 3; 
       and ZR 1  is 
     
     
       
         
         
             
             
         
       
       wherein Y 1  is R 3 —(C 1 -C 12 )alkyl, R 4 -aryl, R 5 -heteroaryl, R 6 —(C 3 -C 12 )cyano-alkyl, R 7 —(C 3 -C 7 ) heterocycloalkyl, —CO 2 (C 1 -C 6 )alkyl, CN or —C(O)NR 8 R 9 ; Y 2  is hydrogen or Y; Y 3  is hydrogen or (C 1 -C 6 )alkyl; or Y 1 , Y 2  and Y 3 , together with the carbon to which they are attached, form one of the following structures: 
     
     
       
         
         
             
             
         
       
       wherein r is 0 to 3; c and d are independently 1 or 2; s is 1 to 5; and ring E is a fused R 4 -phenyl or R 5 -heteroaryl ring; 
       R 10  is 1 to 3 substituents independently selected from the-group consisting of H, (C 1 -C 6 )alkyl, —OR 9 , —(C 1 -C 6 )alkyl-OR 8 , —NR 8 R 9  and —(C 1 -C 6 )allyl-NR 8 R 9 ; 
       R 11  is 1 to 3 substituents independently selected from the group consisting of R 10 , —CF 3 , —OCF 3 , NO 2  and halo, or R 11  substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring; 
       R 8  and R 9  are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 12 ) cycloalkyl, aryl and aryl(C 1 -C 6 )alkyl; 
       R 3  is 1 to 3 substituents independently selected from the group consisting of H, R 4 -aryl, R 6 —(C 3 -C 12 ) cycloalkyl, R 5 -heteroaryl, R 7 —(C 3 -C 7 )heterocycloalkyl, —NR 8 R 9 , —OR 12  and —S(O) 0-2 R 12 , 
       R 6  is 1 to 3 substituents independently selected from the group consisting of H, (C 1 -C 6 )alkyl, R 4 -aryl, —NR 8 R 9 , —OR 12  and —SR 12 ; 
       R 4  is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C 1 -C 6 )alkyl, R 13 -aryl, (C 3 -C 12 )cycloalkyl, —CN, —CF 3 , —OR 8 , —(C 1 -C 6 )alkyl-OR 8 , —OCF 3 , NR 8 R 9 , —(C 1 -C 6 )alkyl-NR 8 R 9 , —NHSO 2 R 8 , —SO 2 N(R 14 ) 2 , —SO 2 R 5 , —SOR 9 , —SR 5 , —NO 2 , —CONR 8 R 9 , —NR 9 COR 8 , —COR 8 , —COCF 3 , —OCOR 8 , —OCO 2 R 8 , —COOR 8 , —(C 1 -C 6 )allyl-NHCOOC(CH 3 ) 3 , —(C 1 -C 6 )alkyl-NHCOCF 3 , —(C 1 -C 6 )alkyl-NHSO 2 —(C 1 -C 6 ) alkyl, —(C 1 -C 6 )alkyl-NHCONH—(C 1 -C 6 )-alkyl and 
     
     
       
         
         
             
             
         
       
       wherein f is 0 to 6; or R 4  substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring; 
       R 5  is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C 1 -C 6 )alkyl, R 13 -aryl, (C 3 -C 12 )cycloalkyl, —CN, —CF 3 , —OR 9 , —(C 1 -C 6 )alkyl-OR 8 , —OCF 3 , —NR 8 R 9 , —(C 1 -C 6 )alkyl-NR 8 R 9 , —NHSO 2 R 8 , —SO 2 N(R 14 ) 2 , —NO 2 , —CONR 8 R 9 , —NR 9 COR 8 , —COR 8 , —OCOR 8 , —OCO 2 R 8  and —COOR 8 ; 
       R 7  is H, (C 1 -C 6 )alkyl, —OR 8 , —(C 1 -C 6 )alkyl-OR 8 , —NR 8 R 9  or —(C 1 -C 6 )alkyl-NR 8 R 9 ; 
       R 12  is H-1, (C 1 -C 6 )alkyl, R 4 -aryl, —(C 1 -C 6 )alkyl-OR 9 , —(C 1 -C 6 )alkyl-NR 8 R 9 , —(C 1 -C 6 )alkyl-SR 8 , or aryl(C 1 -C 6 ) alkyl; 
       R 13  is 1-3 substituents independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 1 -C 6 ) alkoxy and halo; 
       R 14  is independently selected from the group consisting of H, (C 1 -C 6 )alkyl and R 13 —C 6 H 4 —CH 2 —; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       57 . A pharmaceutical composition comprising a compound of  claim 56  and at least one pharmaceutically acceptable excipient. 
   
   
       58 . A method of treating pain comprising administering to a patient in need thereof, an effective amount of an analgesic compound according to  claim 56 . 
   
   
       59 . A method of modulating a pharmacological response from the ORL1 receptor comprising administering to a patient in need thereof, an effective amount of a compound according to  claim 56 . 
   
   
       60 . A method of modulating a pharmacological response from an opioid receptor comprising administering to a patient in need thereof, an effective amount of a compound according to  claim 33 . 
   
   
       61 . A method of modulating a pharmacological response from an opioid receptor comprising administering to a patient in need thereof, an effective amount of a compound according to  claim 39 . 
   
   
       62 . A method of modulating a pharmacological response from an opioid receptor comprising administering to a patient in need thereof, an effective amount of a compound according to  claim 56 .