Fused Bicycloheterocycle Substituted Azabicyclic Alkane Derivatives

Abstract

The invention relates to fused bicycloheterocycle substituted azabicyclic alkane derivatives, compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.

1 . The compound of formula (I), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein
 n is 1, 2 or 3; 
 A is N or N + -0 − ; 
 R is hydrogen, alkyl, cycloalkylalkyl and arylalkyl; 
 L is selected from the group consisting of O, S, and —N(R a )—; 
 Ar 1  is a 6-membered aryl or 6-membered heteroaryl ring; and 
 Ar 2  is a bicyclic heteroaryl; and 
 R a  is selected from the group consisting of hydrogen, alkyl and alkylcarbonyl; 
 provided that if Ar 1  is 
 
       
         
           
           
               
               
           
         
       
       then L is O or S. 
     
     
         2 . The compound of  claim 1 , wherein Ar 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4  and R 5  are independently selected from the group consisting of acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl, alkynyl, amino, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto, nitro, thioalkoxy, —NR 8 R j , (NR 8 R j )alkyl, (NR 8 R j )alkoxy, (NR 8 R j )carbonyl, and (NR 8 R j )sulfonyl; 
         R 8  and R j  are each independently selected from the group consisting of hydrogen and alkyl. 
       
     
     
         3 . The compound of  claim 1 , wherein Ar 2  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein Z 1 , Z 2 , Z 3  and Z 4  are each independently nitrogen or are carbon, wherein the carbon atom is optionally substituted with a substituent selected from the group consisting of hydrogen, halogen, alkyl, —OR c , -alkyl-OR c , —NR d R e , and -alkyl-NR d R e ; 
         R b  is selected from the group consisting of hydrogen, alkyl and alkylcarbonyl; 
         R c  is alkyl; 
         R d  and R e  are each independently selected from the group consisting of hydrogen and alkyl, 
         R 6  and R 7  are each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydrogen, hydroxy, hydroxyalkyl, mercapto, nitro, thio alkoxy, —NR 8 R j , (NR 8 R j )alkyl, (NR 8 R j )alkoxy, (NR 8 R j )carbonyl, and (NR 8 R j )sulfonyl; R 8  and R j  are each independently selected from the group consisting of hydrogen and alkyl. 
       
     
     
         4 . The compound of  claim 2 , wherein
 A is N; R is methyl or hydrogen; L is O; n is 2; and Ar 2  is selected from the group of consisting of:   
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 2 , wherein
 A is N; R is methyl or hydrogen; L is O; n is 2; Ar 1  is   
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 2 , wherein
 A is N; R is methyl or hydrogen; L is O; n is 2; Ar 1  is   
       
         
           
           
               
               
           
         
       
       and
 Ar 2  is 
 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , selected from the group consisting of:
 5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-indole;   (endo)-3-(6-benzo[b]thiophen-5-yl-pyridazin-3-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane;   (endo)-3-[6-(benzofuran-5-yl)-pyridazin-3-yloxy]-8-methyl-8-aza-bicyclo[3.2.1]octane;   6-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-indole;   5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-indazole;   1-methyl-5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-indole;   5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-2-trifluoromethyl-1H-indole;   5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-indole;   5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-indole;   (endo)-3-(6-benzo[b]thiophen-5-yl-pyridin-3-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane;   5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-indole;   (exo)-3-[6-(benzofuran-5-yl)-pyridin-3-yloxy]-8-methyl-8-aza-bicyclo[3.2.1]loctane;   5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-indazole;   5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-2-trifluoromethyl-1H-indole;   4-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-indole;   5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-indole;   (endo)-3-(5-benzo[b]thiophen-5-yl-pyridin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane;   5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-indole;   [6-(1H-indol-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine;   [6-(benzofuran-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine;   [(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-[6-(2-trifluoromethyl-1H-indol-5-yl)-pyridin-3-yl]-amine;   [6-(1H-indazol-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine;   [6-(1H-indol-4-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine;   [(endo)-8-aza-bicyclo[3.2.1]oct-3-yl]-[6-(1H-indol-5-yl)-pyridin-3-yl]amine;   [4-(1H-indol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine;   [4-(1H-indazol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine;   [(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-[4-(1-methyl-1H-indol-5-yl)-phenyl]-amine;   (4-benzo[b]thiophen-5-yl-phenyl)-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine;   [4-(benzofuran-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine;   [4-(1H-indol-4-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine;   [3-(1H-indol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine;   [3-(1H-indol-4-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine;   5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-2-trifluoromethyl-1H-indole;   4-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-indole;   5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-indole;   5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-2-trifluoromethyl-1H-indole;   4-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-indole;   6-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-indole;   5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-indole;   4-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H}-indole;   6-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-indole;   [6-(1H-indol-6-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine;   5-{6-[(endo)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yloxy]pyridazin-3-yl}-1H-indole;   (endo)-3-[6-(benzo[b]thiophen-5-yl)pyridazin-3-yloxy]-9-methyl-9-azabicyclo[3.3.1]nonane;   5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-pyrrolo[2,3-b]pyridine;   5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-pyrrolo[2,3-b]pyridine;   5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-indole;   5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-indole;   4-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-indole;   6-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-indole.   (endo)-N-(5-(1H-Indol-5-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine   (endo)-N-(5-(1H-Indol-4-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine   (endo)-N-(5-(1H-Indol-6-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine   (endo)-N-{5-[2-(trifluoromethyl)-1H-indol-5-yl]pyridin-3-yl}-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine;   5-{5-[(endo)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-pyrrolo[2,3-b]pyridine;   5-{5-[(endo)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}indolin-2-one;   5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;   (1R,3r,5S,8s)-3-(6-(1H-Indol-5-yl)pyridin-3-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane8-oxide;   (1R,3r,5S,8r)-3-(6-(1H-Indol-5-yl)pyridin-3-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane 8-oxide;   4-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;   5-{5-[(exo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;   5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}indolin-2-one;   5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-pyrrolo[2,3-b]pyridine;   5-{5-[(exo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-pyrrolo[2,3-b]pyridine.   
     
     
         8 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with a pharmaceutically acceptable carrier. 
     
     
         9 . A method of selectively modulating the effects of α7 nicotinic acetylcholine receptors, α4β2 nicotinic acetylcholine receptors, or both α7 and α4β2 nicotinic acetylcholine receptors in a mammal comprising administering an effective amount of a compound of  claim 1 . 
     
     
         10 . A method of treating or preventing a condition or disorder selected from the group consisting of attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment, senile dementia, AIDS dementia, Pick's Disease, dementia associated with Lewy bodies, dementia associated with Down's syndrome, amyotrophic lateral sclerosis, Huntington's disease, diminished CNS function associated with traumatic brain injury, acute pain, post-surgical pain, chronic pain, inflammation, inflammatory pain, neuropathic pain, infertility, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, septic shock, toxic shock syndrome, sepsis syndrome, depression, and rheumatoid spondylitis, comprising the step of administering a compound of  claim 1 . 
     
     
         11 . The method according to  claim 10 , wherein the condition or disorder is selected from the group consisting of a cognitive disorder, neurodegeneration, and schizophrenia. 
     
     
         12 . The method according to  claim 10 , further comprising administering a compound of  claim 1  in combination with an atypical antipsychotic. 
     
     
         13 . The method according to  claim 10 , further comprising administering a compound of  claim 1  in combination with a medication used in the treatment of attention deficit hyperactivity disorders and other cognitive disorders such as Alzheimer's disease.