Mercaptoamidine derivatives and methods of use

Abstract

Compounds of formula (I) are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions of compounds of formula (I), methods for using such compounds and compositions, and a process for preparing the compounds.

What is claimed is: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, amide, or radiolabelled form thereof, wherein: 
         R 1  is hydrogen or C 1 -C 4 -alkyl; 
         R 2 , at each occurrence, is independently hydrogen or C 1 -C 4 -alkyl; 
         R 3 , at each occurrence, is independently hydrogen or methyl; 
         R 4 , at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, cyano, cyanoalkyl, halogen, haloalkyl, —OR x , —OC(O)R x . —OC(O)N(R x )(R y ), —SR y , —S(O)R w , —S(O) 2 R w , —S(O) 2 N(R x )(R y ), —C(O)R w , —C(O)OR y , —C(O)N(R x )(R y ), —N(R x )(R y ), —N(R x )C(O)R w , —N(R x )C(O)O(R v ), or —N(R x )S(O) 2 (R w ); 
         R v , R w , R x , and R y , at each occurrence, are independently hydrogen, alkyl, or haloalkyl; 
         L 1  is O or S; 
         G 1  is phenyl or monocyclic heteroaryl, wherein G 1  is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl or fluoro; 
         G 2  is selected from (i) or (ii), 
       
       
         
           
           
               
               
           
         
         wherein, R 5 , R 6 , R 7  and R 8  are, at each occurrence, independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, fluoroalkyl, and hydroxyalkyl; 
         R 9  and R 10  are, at each occurrence, independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylamino, dialkylamino, fluoro, hydroxy, and hydroxyalkyl; 
         R 11 , R 12 , R 13  and R 14  are, at each occurrence, independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, and hydroxyalkyl; 
         Q is selected from the group consisting of a bond, O, S, and NR 15 ; wherein 
         R 15  is hydrogen, alkyl, —C(O)R w , or —C(O)N(R x )(R y ); 
         m is 2, 3, 4, 5 or 6; 
         n is 1, 2, 3, 4, or 5; and 
         p is 0 and q is 0; or p is 1 and q is 1; or p is 1 and q is 0. 
       
     
     
         2 . The compound of  claim 1 , wherein G 1  is (iii); 
       
         
           
           
               
               
           
         
         wherein 1 of X 5 , X 6 , X 7 , X 8  and X 9  is —C-L 1 [—C(R 3 ) 2 ] m-G   2 ; 0, 1, or 2 of X 5 , X 6 , X 7 , X 8  and X 9  are N and the others of X 5 , X 6 , X 7 , X 8  and X 9  are CR 16 ; and 
         R 16 , at each occurrence, is independently hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl or fluoro. 
       
     
     
         3 . The compound of  claim 1 , wherein G 1  is (iv); 
       
         
           
           
               
               
           
         
         X 5 , X 6 , X 8  and X 9  are N or CR 16 ; wherein 0, 1, or 2 of X 5 , X 6 , X 8  and X 9  are N and the others of X 5 , X 6 , X 8  and X 9  are CR 16 ; and 
         R 16 , at each occurrence, is independently hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl or fluoro. 
       
     
     
         4 . The compound of  claim 3 , wherein
 L 1  is O;   R 3 , at each occurrence, is hydrogen;   G 2  is (i); and   
       
         
           
           
               
               
           
         
         m is 2, 3 or 4. 
       
     
     
         5 . The compound of  claim 3 , wherein
 L 1  is O;   R 3 , at each occurrence, is hydrogen;   G 2  is (ii); and   
       
         
           
           
               
               
           
         
         m is 2, 3 or 4. 
       
     
     
         6 . The compound of  claim 1 , wherein
 p is 0 or 1;   q is 0;   R 2  at each occurrence is hydrogen; and   R 4  is hydrogen.   
     
     
         7 . The compound of  claim 1 , wherein
 p is 1;   q is 1; and   R 2  at each occurrence is hydrogen; and   R 4  is hydrogen.   
     
     
         8 . The compound of  claim 7 , wherein
 R 1  is C 1 -C 4 -alkyl;   R 3 , at each occurrence, is hydrogen;   L 1  is O;   G 1  is (iv);   
       
         
           
           
               
               
           
         
         X 5 , X 6 , X 8  and X 9  are each CR 16 ; 
         R 16 , at each occurrence, is independently hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl or fluoro; 
         G 2  is (i); 
       
       
         
           
           
               
               
           
         
         R 5  is hydrogen, alkyl, or hydroxyalkyl; 
         R 6 , R 7 , and R 8  are each hydrogen; 
         R 9  and R 10 , at each occurrence, are hydrogen; 
         m is 3; and 
         n is 1, 2, or 3. 
       
     
     
         9 . The compound of  claim 7 , wherein
 R 1  is C 1 -C 4 -alkyl;   R 3 , at each occurrence, is hydrogen;   L 1  is O;   G 1  is (iv);   
       
         
           
           
               
               
           
         
         X 5 , X 6 , X 8  and X 9  are each CR 16 ; 
         R 16 , at each occurrence, is independently hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl or fluoro; 
         G 2  is (ii); 
       
       
         
           
           
               
               
           
         
         R 5  is hydrogen, alkyl, or hydroxyalkyl; 
         R 6 , R 7 , and R 8  are each hydrogen; 
         R 11 , R 12 , R 13 , and R 14  are each hydrogen; 
         Q is O or S; and 
         m is 3. 
       
     
     
         10 . The compound of  claim 1 , selected from:
 ((2S)-1-{3-[4-(3-methyl-5,10-dihydro[1,3]thiazolo[3,2-b][2,4]benzodiazepin-2-yl)phenoxy]propyl}pyrrolidin-2-yl)methanol;   3-methyl-2-[4-(3-piperidin-1-ylpropoxy)phenyl]-5,10-dihydro[1,3]thiazolo[3,2-b][2,4]benzodiazepine;   3-methyl-2-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-5,10-dihydro[1,3]thiazolo[3,2-b][2,4]benzodiazepine; and   3-methyl-2-[4-(3-morpholin-4-ylpropoxy)phenyl]5,10-dihydro[1,3]thiazolo[3,2-b][2,4]benzodiazepine.   
     
     
         11 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with a pharmaceutically acceptable carrier. 
     
     
         12 . A method of selectively modulating the effects of histamine-3 receptors in a mammal comprising administering an effective amount of a compound of  claim 1 . 
     
     
         13 . A method of treating a condition or disorder modulated by the histamine-3 receptors in a mammal comprising administering an effective amount of a compound of  claim 1 . 
     
     
         14 . The method according to  claim 13 , wherein the condition or disorder is selected from the group consisting of acute myocardial infarction, Alzheimer's disease, asthma, attention-deficit hyperactivity disorder, bipolar disorder, cognitive dysfunction, cognitive deficits in psychiatric disorders, deficits of memory, deficits of learning, dementia, cutaneous carcinoma, drug abuse, diabetes, type II diabetes, depression, epilepsy, gastrointestinal disorders, inflammation, insulin resistance syndrome, jet lag, medullary thyroid carcinoma, melanoma, Meniere's disease, metabolic syndrome, mild cognitive impairment, migraine, mood and attention alteration, motion sickness, narcolepsy, neurogenic inflammation, obesity, obsessive compulsive disorder, pain, neuropathic pain, osteoarthritis pain, Parkinson's disease, polycystic ovary syndrome, schizophrenia, cognitive deficits of schizophrenia, seizures, septic shock, Syndrome X, Tourette's syndrome, vertigo, and sleep disorders. 
     
     
         15 . The method according to  claim 13 , wherein the condition or disorder is selected from the group consisting of attention-deficit hyperactivity disorder, Alzheimer's disease, deficits of memory, deficits of learning, dementia, mild cognitive impairment, schizophrenia, cognitive deficits of schizophrenia, narcolepsy, sleep disorders, pain, neuropathic pain, and osteoarthritis pain.