Tricyclic compounds and their use as phosphodiesterase inhibitors

Abstract

The present invention is directed to compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein the substituents A, R 1 , R 2 , R 3a , R 3b , R 4a , R 4b and n are as defined herein. The inventions also directed to pharmaceutical compositions comprising the compounds, methods of treatment using the compounds and methods of preparing the compounds.

1 - 25 . (canceled) 
     
     
         26 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Ring A is a fused (6-membered)nitrogen-containing heteroaryl ring selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl, each of which is independently optionally substituted with one to three R 8 ; 
 R 1  is selected from the group consisting of (C 3 -C 6 )cycloalkyl, (4- to 10-membered)heterocycloalkyl, (C 6 -C 10 )aryl, and (5- to 14-membered)heteroaryl, each of which is independently optionally substituted with one to three R 9 ; 
 R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (4- to 6-membered)heterocycloalkyl, and (5- to 6-membered)heteroaryl, wherein said (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (4- to 6-membered)heterocycloalkyl, and (5- to 6-membered)heteroaryl are independently optionally substituted with one to three R 8 ; 
 R 3a , where chemically permissible, is selected from the group consisting of hydrogen, halogen, oxo, cyano, hydroxy, —SF 5 , nitro, N(R 5 )(R 6 ), (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 3 -C 8 )cycloalkyl, wherein said (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 3 -C 8 )cycloalkyl are independently optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, cyano, hydroxy, —SF 5 , (C 1 -C 6 )alkylthio, nitro, —C(═O)—R 5 , and —N(R 5 )(R 6 ); 
 when present, R 3b , where chemically permissible, is selected from the group consisting of hydrogen, halogen, oxo, cyano, hydroxy, —SF 5 , nitro, N(R 5 )(R 6 ), (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 3 -C 8 )cycloalkyl, wherein said (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 3 -C 8 )cycloalkyl are independently optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, cyano, hydroxy, —SF 5 , (C 1 -C 6 )alkylthio, nitro, —C(═O)—R 5 , and —N(R 5 )(R 6 ); 
 R 4a  is hydrogen; 
 when present, R 4b  is hydrogen; 
 R 5  and R 6  at each occurrence are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl; 
 R 7  is (C 1 -C 6 )alkyl; 
 when present, R 8  at each occurrence is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, —SF 5 , nitro, N(R 5 )(R 6 ), (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy, wherein said (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy are independently optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, cyano, hydroxy, —SF 5 , (C 1 -C 6 )alkylthio, nitro, —C(═O)—R 5 , and —N(R 5 )(R 6 ). 
 when present, R 9  at each occurrence is independently selected from the group consisting of halogen, oxo, cyano, hydroxy, —SF 5 , nitro, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, N(R 5 )(R 6 ), —S(O) 2 R 7 , and —S(O) 2 N(R 5 )(R 6 ), wherein said (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy are independently optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, cyano, hydroxy, —SF 5 , (C 1 -C 6 )alkylthio, nitro, —C(═O)—R 5 , and —N(R 5 )(R 6 ); 
 ---- is absent (forming a single bond) and n is 1. 
 
       
     
     
         27 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein Ring A is a fused pyridinyl ring optionally substituted with one to three R 8 . 
     
     
         28 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 1  is phenyl optionally substituted with one to three R 9 . 
     
     
         29 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 1  is a (6-membered)nitrogen-containing heteroaryl selected from pyridinyl or pyrimidinyl optionally substituted with one to three R 9 . 
     
     
         30 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 2  is (C 1 -C 6 )alkyl optionally substituted with one to three R 8 , wherein said (C 1 -C 6 )alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, or hexyl. 
     
     
         31 . The compound of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein R 2  is ethyl optionally substituted with one to three R 8 . 
     
     
         32 . The compound of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 2  is ethyl substituted with one to three R 8 , wherein each R 8  is independently hydroxyl or methyl. 
     
     
         33 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 2  is (C 3 -C 8 )cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclooctyl. 
     
     
         34 . The compound of  claim 33 , or a pharmaceutically acceptable salt thereof, wherein R 2  is cyclopropyl. 
     
     
         35 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 3a  is hydrogen. 
     
     
         36 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 3a  is (C 1 -C 6 )alkyl optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, cyano, hydroxy, —SF 5 , (C 1 -C 6 )alkylthio, nitro, —C(═O)—R 5 , and —N(R 5 )(R 6 ), wherein said (C 1 -C 6 )alkyl is selected from methyl, ethyl, or propyl. 
     
     
         37 . The compound of  claim 36 , or a pharmaceutically acceptable salt thereof, wherein R 3a  is methyl optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, cyano, hydroxy, —SF 5 , (C 1 -C 6 )alkylthio, nitro, —C(═O)—R 5 , and —N(R 5 )(R 6 ). 
     
     
         38 . The compound of  claim 37 , or a pharmaceutically acceptable salt thereof, wherein R 3a  is methyl substituted with hydroxy. 
     
     
         39 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 3b  is hydrogen. 
     
     
         40 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 3b  is (C 1 -C 6 )alkyl optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, cyano, hydroxy, —SF 5 , (C 1 -C 6 )alkylthio, nitro, —C(═O)—R 5 , and —N(R 5 )(R 6 ), wherein said (C 1 -C 6 )alkyl is selected from methyl, ethyl, or propyl. 
     
     
         41 . The compound of  claim 40 , or a pharmaceutically acceptable salt thereof, wherein R 3b  is methyl optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, cyano, hydroxy, —SF 5 , (C 1 -C 6 )alkylthio, nitro, —C(═O)—R 5 , and —N(R 5 )(R 6 ). 
     
     
         42 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof, wherein R 3b  is methyl substituted with hydroxy. 
     
     
         43 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 8  is halogen independently selected from fluoro or chloro. 
     
     
         44 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 9  is halogen independently selected from fluoro or chloro. 
     
     
         45 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 9  is (C 1 -C 6 )alkoxy selected from methoxy, ethoxy, or propoxy. 
     
     
         46 . A pharmaceutical composition comprising a compound according to  claim 26 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         47 . A method of treating a patient suffering from a disease or condition mediated by the PDE4B isoform, comprising administering to said patient in need of said treatment a therapeutically effective amount of a compound of  claim 26 , wherein said disease or condition is selected from the group consisting of schizophrenia, depression, anxiety, Alzheimer's disease, Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease, inflammation, stroke, asthma, cerebral vascular disease, allergic conjunctivitis, psychosis, psoriatic arthritis, autoimmune and inflammatory diseases, traumatic brain injury, and behavioral disorders due to drug dependence and abuse. 
     
     
         48 . A method of treating a patient suffering from a disease or condition mediated by the PDE4B isoform, comprising administering to said patient in need of said treatment a therapeutically effective amount of a pharmaceutical composition of  claim 46 , wherein said disease or condition is selected from the group consisting of schizophrenia, depression, anxiety, Alzheimer's disease, Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease, inflammation, stroke, asthma, cerebral vascular disease, allergic conjunctivitis, psychosis, psoriatic arthritis, autoimmune and inflammatory diseases, traumatic brain injury, and behavioral disorders due to drug dependence and abuse.