Non-imidazole heterocyclic compounds

Abstract

Certain non-imidazole heterocyclic compounds are histamine H 3 modulators useful in the treatment of histamine H 3 receptor mediated diseases.

1 .- 44 . (canceled) 
   
   
       45 . A method for the treatment or prevention of a CNS disorder selected from the group consisting of: neurologic disorders including sleep/wake and arousal/vigilance disorders (e.g. insomnia and jet lag), attention deficit hyperactivity disorders (ADHD), learning and memory disorders, cognitive dysfunction, migraine, neurogenic inflammation, dementia, mild cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy with or without associated cataplexy, cataplexy, disorders of sleep/wake homeostasis, idiopathic somnolence, excessive daytime sleepiness (EDS), circadian rhythm disorders, sleep/fatigue disorders, fatigue, drowsiness associated with sleep apnea, sleep impairment due to perimenopausal hormonal shifts, Parkinson's-related fatigue, MS-related fatigue, depression-related fatigue, chemotherapy-induced fatigue, eating disorders, obesity, motion sickness, vertigo, schizophrenia, substance abuse, bipolar disorders, manic disorders and depression in mammals, comprising the step of administering to a mammal suffering there from a therapeutically effective amount of compound having histamine H3 receptor modulator activity of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 in the A- and B-containing ring,
 I) A, B 1  and B 2  are CH; 
 II) A is CH, one of B 1  and B 2  is N, and the other of B 1  and B 2  is CH; or 
 III) A is absent, B 1  is CH, and B 2  is O; 
 
 L is —C 1-4 alkylene- or a covalent bond; 
 Q is —(CH 2 ) m O—, —(CH 2 ) n C—C— (where the O— and —C≡C— portions are directly attached to the ring), carbonyl, or thiocarbonyl; 
 m is 2, 3, or 4; 
 n is 1, 2, 3, or 4; 
 R 1 , optionally mono- or di-substituted with R p , is independently selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; 
 R 2 , optionally mono- or di-substituted with R p , is independently selected from the group consisting of —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; 
 
     or, alternatively,
 R 1  and R 2  may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of:
 i) a 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents Rq; and 
 ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents R q ; 
 R p  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-4 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, or —COOC 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , and —COOC 1-4 alkyl, and —COOH; 
 R q  is independently selected from the group consisting of —C 1-6 alkyl, halo, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —CF 3 , and —COOC 1-4 alkyl, 
 R 3 , optionally mono- or di-substituted with R 5 , is independently selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; and 
 R 4 , optionally mono- or di-substituted with R s , is independently selected from the group consisting of —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; 
 R s  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-4 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, or —COOC 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , —COOC 1-4 alkyl, and —COOH; 
 or, alternatively 
 R 3  and R 4  may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of:
 i) a 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents Rt; and 
 ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents Rt; 
 
 R t  is independently selected from the group consisting of is independently selected from the group consisting of —C 1-6 alkyl, halo, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —CF 3 , and —COOC 1-4 alkyl; 
 
 and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
 
   
   
       46 . A method for the treatment or prevention of a histamine H 3  receptor mediated disorder selected from the group consisting of upper airway allergic response, asthma, itch, nasal congestion and allergic rhinitis in mammals, comprising the step of administering to a mammal suffering there from a therapeutically effective amount of compound having histamine H 3  receptor modulator activity of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 in the A- and B-containing ring,
 I) A, B 1  and B 2  are CH; 
 II) A is CH, one of B 1  and B 2  is N, and the other of B 1  and B 2  is CH; or 
 III) A is absent, B 1  is CH, and B 2  is O; 
 
 L is —C 1-4 alkylene- or a covalent bond; 
 Q is —(CH 2 ) m O—, —(CH 2 ) n C≡C— (where the —O— and —C≡C— portions are directly attached to the ring), carbonyl, or thiocarbonyl; 
 m is 2, 3, or 4; 
 n is 1, 2, 3, or 4; 
 R 1 , optionally mono- or di-substituted with R p , is independently selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; 
 R 2 , optionally mono- or di-substituted with R p , is independently selected from the group consisting of —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; 
 
     or, alternatively,
 R 1  and R 2  may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of:
 i) a 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents R q ; and 
 ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents R q ; 
 R p  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-4 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, or —COOC 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , and —COOC 1-4 alkyl, and —COOH; 
 R q  is independently selected from the group consisting of —C 1-6 alkyl, halo, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —CF 3 , and —COOC 1-4 alkyl, 
 
 R 3 , optionally mono- or di-substituted with KS, is independently selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; and 
 R 4 , optionally mono- or di-substituted with R s , is independently selected from the group consisting of —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds;
 R s  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-4 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, or —COOC 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , —COOC 1-4 alkyl, and —COOH; 
 
 
     or, alternatively
 R 3  and R 4  may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of:
 i) a 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents Rt; and 
 ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents R t ; 
 R t  is independently selected from the group consisting of is independently selected from the group consisting of —C 1-6 alkyl, halo, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —CF 3 , and —COOC 1-4 alkyl; 
 
 and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
 
   
   
       47 .- 48 . (canceled) 
   
   
       49 . A method for treating allergic rhinitis, nasal congestion, or allergic congestion, comprising
 (a) administering to the subject a jointly effective amount of a compound of formula (1)   
     
       
         
         
             
             
         
       
     
     wherein
 in the A- and B-containing ring,
 I) A, B 1  and B 2  are CH; 
 II) A is CH, one of B 1  and B 2  is N, and the other of B 1  and B 2  is CH; or 
 III) A is absent B 1  is CH, and B 2  is O; 
 
 L is —C 1-4 alkylene- or a covalent bond; 
 Q is —(CH 2 ) m O—, —(CH 2 ) n C≡C— (where the —O— and —C≡C— portions are directly attached to the ring) carbonyl or thiocarbonyl: 
 m is 2, 3, or 4; 
 n is 1, 2, 3, or 4; 
 R 1 , optionally mono- or di-substituted with R p , is independently selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl having 0, 1, or 2 double bonds; 
 R 2 , optionally mono- or di-substituted with R p , is independently selected from the group consisting of —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; 
 
     or, alternatively
 R 1  and R 2  may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of:
 i) a 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents R q ; and 
 ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl having 0 or 1 additional double bonds having 0, 1, or 2 carbon members which is a carbonyl and having 0, 1, or 2 substituents R q ; 
 R p  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —C 3-6 cycloalkyl —Ophenyl, —Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-4 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, or —COOC 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , and —COOC 1-4 alkyl, and —COOH; 
 R q  is independently selected from the group consisting of —C 1-6 alkyl, halo, —OH —OC 1-6 alkyl, —CN, —NO 2 , —CF 3 , and —COOC 1-4 alkyl, 
 
 R 3 , optionally mono- or di-substituted with R s , is independently selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl having 0, 1, or 2 double bonds; and 
 R 4 , optionally mono- or di-substituted with R s , is independently selected from the group consisting of —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl having 0, 1, or 2 double bonds;
 R s  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-4 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, or —COOC 1-4 alkyl), —(C═O)N(R y )R z , —(C═OC 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , —COOC 1-14 alkyl, and —COOH; 
 
 
     or, alternatively
 R 3  and R 4  may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of:
 i) a 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents R t ; and 
 ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl and having 0, 1, or 2 substituents R t ; 
 R t  is independently selected from the group consisting of is independently selected from the group consisting of —C 1-6 alkyl, halo, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —CF 3 , and —COOC 1-4 alkyl; 
 
 and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof; and 
 (b) administering to the subject a jointly effective amount of a histamine H 1  antagonist. 
 
   
   
       50 . A method for treating depression, mood disorders, or schizophrenia, comprising
 (a) administering to the subject a jointly effective amount of a compound of formula (1)   
     
       
         
         
             
             
         
       
     
     wherein
 in the A- and B-containing ring,
 I) A, B 1  and B 2  are CH; 
 II) A is CH, one of B 1  and B 2  is N, and the other of B 1  and B 2  is CH; or 
 III) A is absent B 1  is CH, and B 2  is O; 
 
 L is —C 1-4 alkylene- or a covalent bond; 
 Q is —(CH 2 ) m O—, —(CH 2 ) n C≡C— (where the —O— and —C≡C— portions are directly attached to the ring), carbonyl or thiocarbonyl; 
 m is 2, 3, or 4; 
 n is 1, 2, 3, or 4; 
 R 1 , optionally mono- or di-substituted with R p , is independently selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; 
 R 2 , optionally mono- or di-substituted with R p , is independently selected from the group consisting of —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl having 0, 1, or 2 double bonds; 
 
     or, alternatively
 R 1  and R 2  may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of:
 i) a 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds having 0, 1, or 2 carbon members which is a carbonyl having 0, 1, or 2 substituents R q ; and 
 ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents R q ; 
 R p  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-4 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, or —COOC 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , and —COOC 1-4 alkyl, and —COOH; 
 R q  is independently selected from the group consisting of —C 1-6 alkyl, halo, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —CF 3 , and —COOC 1-4 alkyl, 
 
 R 3 , optionally mono- or di-substituted with R s , is independently selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; and 
 R 4 , optionally mono- or di-substituted with R s , is independently selected from the group consisting of —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds;
 R s  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-4 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, or —COOC 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)CO 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , —COOC 1-4 alkyl, and —COOH; 
 
 
     or, alternatively
 R 3  and R 4  may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of:
 i) a 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents R t ; and 
 ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents R t : 
 R t  is independently selected from the group consisting of is independently selected from the group consisting of —C 1-6 alkyl, halo, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —CF 3 , and —COOC 1-4 alkyl; 
 
 and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof; and 
 (b) administering to the subject a jointly effective amount of a selective serotonin re-uptake inhibitor. 
 
   
   
       51 . A method for treating narcolepsy, excessive daytime sleepiness (EDS), Alzheimer's disease, depression, attention deficit disorders, MS-related fatigue, post-anesthesia grogginess, cognitive impairment, schizophrenia, spasticity associated with cerebral palsy, age-related memory decline, idiopathic somnolence, or jet-lag, comprising
 (a) administering to the subject a jointly effective amount of a compound of formula (1)   
     
       
         
         
             
             
         
       
     
     wherein
 in the A- and B-containing ring
 I) A, B 1  and B 2  are CH; 
 II) A is CH, one of B 1  and B 2  is N, and the other of B 1  and B 2  is CH; or 
 III) A is absent B 1  is CH, and B 2  is O; 
 
 L is —C 1-4 alkylene- or a covalent bond; 
 O is —(CH 2 ) m O—, —(CH 2 ) n C≡C— (where the —O— and —C≡C— portions are directly attached to the ring) carbonyl or thiocarbonyl; 
 m is 2, 3, or 4; 
 n is 1, 2, 3, or 4; 
 R 1 , optionally mono- or di-substituted with R p , is independently selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; 
 R 2 , optionally mono- or di-substituted with R p , is independently selected from the group consisting of —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; 
 
     or, alternatively
 R 1  and R 2  may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of:
 i) a 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds having 0, 1, or 2 carbon members which is a carbonyl having 0, 1, or 2 substituents R q ; and 
 ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0 or 1 additional double bonds having 0, 1, or 2 carbon members which is a carbonyl and having 0, 1, or 2 substituents R q ; 
 R p  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-4 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, or —COOC 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , and —COOC 1-4 alkyl, and —COOH; 
 R q  is independently selected from the group consisting of —C 1-6 alkyl, halo, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —CF 3 , and —COOC 1-4 alkyl, 
 
 R 3 , optionally mono- or di-substituted with R s , is independently selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; and 
 R 4 , optionally mono- or di-substituted with R s , is independently selected from the group consisting of —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds;
 R s  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-4 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, or —COOC 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —SCF 3 , —OFC 3 , —CF 3 , —COOC 1-4 alkyl, and —COOH; 
 
 
     or, alternatively
 R 3  and R 4  may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of:
 i) a 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds having 0, 1, or 2 carbon members which is a carbonyl having 0, 1, or 2 substituents R t ; and 
 ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0 or 1 additional double bonds having 0, 1, or 2 carbon members which is a carbonyl and having 0, 1, or 2 substituents R t ; 
 R t  is independently selected from the group consisting of is independently selected from the group consisting of —C 1-6 alkyl, halo, —OH, —OC 1-6 alkyl, —CF 3 , and —COOC 1-4 alkyl; 
 
 and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof; and 
 (b) administering to the subject a jointly effective amount of modafinil.