Bicyclic pyrazolyl and imidazolyl compounds and uses thereof

Abstract

Compounds of Formula (I) are described herein. The compounds have been shown to act as cannabinoid receptor ligands and are therefore useful in the treatment of diseases linked to the mediation of the cannabinoid receptors in animals.

1 - 181 . (canceled)  
     
     
         182 . A pharmaceutical composition comprising (1) a compound of Formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 A is nitrogen and B is carbon, or A is carbon and B is nitrogen;  
 R 0  is an aryl optionally substituted with one or more substituents, or a heteroaryl optionally substituted with one or more substituents;  
 R 1  is aryl optionally substituted with one or more substituents, heteroaryl optionally substituted with one or more substituents, —CH═CH—R 1a , or —CH 2 CH 2 —R 1a , where R 1a  is hydrogen or a chemical moiety selected from (C 1 -C 8 )alkyl, 3- to 8-membered partially or fully saturated carbocyclic ring(s), 3- to 6-membered partially or fully saturated heterocycle, aryl, or heteroaryl, where the chemical moiety is optionally substituted with one or more substituents;  
 X is O, S, SO, SO 2 , —N(R 2a )— or —C(R 2b )(R 2c )—, where R 2a , R 2b  and R 2c  are each independently hydrogen, (C 1 -C 4 )alkyl, halo-substituted (C 1 -C 4 )alkyl or (C 1 -C 5 )acyl;  
 R 3a  and R 3b  are each independently hydrogen, (C 1 -C 6 )alkyl, or halo-substituted C 1 -C 6 )alkyl,  
 or either R 3a  or R 3b  taken together with R 4  forms a fully or partially saturated 5- to 6-membered heterocyclic ring, where the heterocyclic ring optionally contains an additional heteroatom selected from oxygen, nitrogen or sulfur and is optionally substituted with one or more substituents; and  
 R 4  is a chemical moiety selected from the group consisting of (C 1 -C 8 )alkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, a 3- to 8-membered partially or fully saturated carbocyclic ring(s), heteroaryl(C 1 -C 3 )alkyl, 5-6 membered lactone, 5- to 6-membered lactam, and a 3- to 8-membered partially or fully saturated heterocycle, where said chemical moiety is optionally substituted with one or more substituents,  
 or R 4  taken together with either R 3a  or R 3b  forms a fully or partially saturated 5- to 6-membered heterocyclic ring, where the heterocyclic ring optionally contains an additional heteroatom selected from oxygen, nitrogen or sulfur and is optionally substituted with one or more substituents;  
 a pharmaceutically acceptable salt thereof, or a solvate or hydrate of said compound or said salt;  
 (2) a pharmaceutically acceptable excipient, diluent, or carrier; and  
 (3) at least one additional pharmaceutical agent.  
 
     
     
         183 . The composition of  claim 182  wherein said additional pharmaceutical agent is a nicotine receptor partial agonist, an opioid antagonist, a dopaminergic agent, an attention deficit disorder agent, or an anti-obesity agent.  
     
     
         184 . The composition of  claim 183  wherein said anti-obesity agent is selected from the group consisting of an apo-B/MTP inhibitor, a 11β-hydroxy steroid dehydrogenase-1 inhibitor, peptide YY 3-36  or an analog thereof, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β 3  adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2c receptor agonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent, dehydroepiandrosterone or analog thereof, a glucocorticoid receptor antagonist, an orexin receptor antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human agouti-related protein antagonist, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or inverse agonist, and a neuromedin U receptor agonist.  
     
     
         185 . A method for treating a disease, condition or disorder which is modulated by a cannabinoid receptor antagonist in animals comprising the step of administering to an animal in need of such treatment a therapeutically effective amount of a compound of Formula (I)  
       
         
           
           
               
               
           
         
       
       where 
 A is nitrogen and B is carbon, or A is carbon and B is nitrogen;  
 R 0  is an aryl optionally substituted with one or more substituents, or a heteroaryl optionally substituted with one or more substituents;  
 R 1  is aryl optionally substituted with one or more substituents, heteroaryl optionally substituted with one or more substituents, —CH═CH—R 1a , or CH 2 CH 2 —R 1a , where R 1a  is hydrogen or a chemical moiety selected from (C 1 -C 8 )alkyl, 3- to 8-membered partially or fully saturated carbocyclic ring(s), 3- to 6-membered partially or fully saturated heterocycle, aryl, or heteroaryl, where the chemical moiety is optionally substituted with one or more substituents;  
 X is O, S, SO, SO 2 , —N(R 2a )— or —C(R 2b )(R 2c )—, where R 2a , R 2b  and R 2c  are each independently hydrogen, (C 1 -C 4 )alkyl, halo-substituted (C 1 -C 4 )alkyl or (C 1 -C 5 )acyl;  
 R 3a  and R 3b  are each independently hydrogen, (C 1 -C 6 )alkyl, or halo-substituted (C 1 -C 6 )alkyl,  
 or either R 3a  or R 3b  taken together with R 4  forms a fully or partially saturated 5- to 6-membered heterocyclic ring, where the heterocyclic ring optionally contains an additional heteroatom selected from oxygen, nitrogen or sulfur and is optionally substituted with one or more substituents; and  
 R 4  is a chemical moiety selected from the group consisting of (C 1 -C 8 )alkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, a 3- to 8-membered partially or fully saturated carbocyclic ring(s), heteroaryl(C 1 -C 3 )alkyl, 5-6 membered lactone, 5- to 6-membered lactam, and a 3- to 8-membered partially or fully saturated heterocycle, where said chemical moiety is optionally substituted with one or more substituents,  
 or R 4  taken together with either R 3a  or R 3b  forms a fully or partially saturated 5- to 6-membered heterocyclic ring, where the heterocyclic ring optionally contains an additional heteroatom selected from oxygen, nitrogen or sulfur and is optionally substituted with one or more substituents;  
 a pharmaceutically acceptable salt thereof, or a solvate or hydrate of said compound or said salt,  
 wherein said compound is administered in combination with a nicotine receptor partial agonist, an opioid antagonist, a dopaminergic agent, an attention deficit disorder agent, or an anti-obesity agent.  
 
     
     
         186 . (canceled)  
     
     
         187 . The method of  claim 186  wherein said anti-obesity agent is selected from the group consisting of an apo-B/MTP inhibitor, a 11β-hydroxy steroid dehydrogenase-1 inhibitor, peptide YY 3-36  or an analog thereof, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a 3 adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2c receptor agonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent, dehydroepiandrosterone or analog thereof, a glucocorticoid receptor antagonist, an orexin receptor antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human agouti-related protein antagonist, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or inverse agonist, and a neuromedin U receptor agonist.  
     
     
         188 - 189 . (canceled)  
     
     
         190 . A method for treating a disease, condition or disorder modulated by a cannabinoid receptor antagonist comprising the step of administering a pharmaceutical composition of  claim 182 .  
     
     
         191 . (canceled)  
     
     
         192 . The method of  claim 190  wherein said additional pharmaceutical agent is a nicotine partial agonist, an opioid antagonist, a dopaminergic agent, an attention deficit disorder agent, or an anti-obesity agent.  
     
     
         193 . The method of  claim 192  wherein said anti-obesity agent is selected from the group consisting of an apo-B/MTP inhibitor, a 11β-hydroxy steroid dehydrogenase-1 inhibitor, peptide YY 3-36  or an analog thereof, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β 3  adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2c receptor agonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent, dehydroepiandrosterone or analog thereof, a glucocorticoid receptor antagonist, an orexin receptor antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human agouti-related protein antagonist, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or inverse agonist, and a neuromedin U receptor agonist.  
     
     
         194 . The method of  claim 190 ,  192  or  193  wherein said disease, condition or disorder modulated by a cannabinoid receptor antagonist is obesity, bulimia, attention deficit disorder, Parkinson's disease, dementia, alcoholism, or tobacco abuse.  
     
     
         195 . A method for treating a disease, condition or disorder modulated by a cannabinoid receptor antagonist in animals comprising the step of administering to an animal in need of such treatment two separate pharmaceutical compositions comprising 
 (i) a first composition comprising a compound of Formula (I)                          wherein    A is nitrogen and B is carbon, or A is carbon and B is nitrogen;    R 0  is an aryl optionally substituted with one or more substituents, or a heteroaryl optionally substituted with one or more substituents;    R 1  is aryl optionally substituted with one or more substituents, heteroaryl optionally substituted with one or more substituents, —CH═CH—R 1a , or —CH 2 CH 2 —R 1a , where R 1a  is hydrogen or a chemical moiety selected from (C 1 -C 8 )alkyl, 3- to 8-membered partially or fully saturated carbocyclic ring(s), 3- to 6-membered partially or fully saturated heterocycle, aryl, or heteroaryl, where the chemical moiety is optionally substituted with one or more substituents;    X is O, S, SO, SO 2 , —N(R 2a )— or —C(R 2b )(R 2c )—, where R 2a , R 2b  and R 2c  are each independently hydrogen, (C 1 -C 4 )alkyl, halo-substituted (C 1 -C 4 )alkyl or (C 1 -C 5  acyl;    R 3a  and R 3b  are each independently hydrogen, (C 1 -C 6 )alkyl, or halo-substituted or either R 3a  or R 3b  taken together with R 4  forms a fully or partially saturated 5- to 6-membered heterocyclic ring, where the heterocyclic ring optionally contains an additional heteroatom selected from oxygen, nitrogen or sulfur and is optionally substituted with one or more substituents; and    R 4  is a chemical moiety selected from the group consisting of (C 1-8 )alkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, a 3- to 8-membered partially or fully saturated carbocyclic ring(s), heteroaryl(C 1 -C 3 )alkyl, 5-6 membered lactone, 5- to 6-membered lactam, and a 3- to 8-membered partially or fully saturated heterocycle, where said chemical moiety is optionally substituted with one or more substituents,    or R 4  taken together with either R 3a  or R 3b  forms a fully or partially saturated 5- to 6-membered heterocyclic ring, where the heterocyclic ring optionally contains an additional heteroatom selected from oxygen, nitrogen or sulfur and is optionally substituted with one or more substituents;    or a pharmaceutically acceptable salt thereof or a solvate or hydrate of said compound or said salt, and a pharmaceutically acceptable excipient, diluent, or carrier, and    (ii) a second composition comprising at least one additional pharmaceutical agent and a pharmaceutically acceptable excipient, diluent, or carrier.    
     
     
         196 . The method of  claim 195  wherein said at least one additional pharmaceutical agent is a nicotine partial agonist, an opioid antagonist, a dopaminergic agent, an attention deficit disorder agent, or an anti-obesity agent.  
     
     
         197 . The method of  claim 196  wherein said anti-obesity agent is selected from the group consisting of an apo-B/MTP inhibitor, a 11β-hydroxy steroid dehydrogenase-1 inhibitor, peptide YY 3-36  or an analog thereof, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β 3  adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2c receptor agonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent, dehydroepiandrosterone or analog thereof a glucocorticoid receptor antagonist, an orexin receptor antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human agouti-related protein antagonist, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or inverse agonist, and a neuromedin U receptor agonist.  
     
     
         198 . The method of  claim 195  wherein said first composition and said second composition are administered simultaneously.  
     
     
         199 . The method of  claim 195  wherein said first composition and said second composition are administered sequentially and in any order.  
     
     
         200 . The composition of  claim 182  wherein said additional pharmaceutical agent is a cognitive impairment agent.  
     
     
         201 . The composition of  claim 200  wherein said cognitive impairment agent is donepezil hydrochloride.