Pyrrole and pyrazole daao inhibitors

Abstract

Methods for increasing D-Serine concentration and reducing concentration of the toxic products of D-Serine oxidation, for enhancing learning, memory and/or cognition, or for treating schizophrenia, Alzheimer's disease, ataxia or neuropathic pain, or preventing loss in neuronal function characteristic of neurodegenerative diseases involve administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 and R 2 are independently selected from hydrogen, halo, nitro, alkyl, acyl, alkylaryl, and XYR 5 ; or R 1 and R 2 , taken together, form a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group; X and Y are independently selected from O, S, NH, and (CR 6 R 7 ) n ; R 3 is hydrogen, alkyl or M + ; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc ion or a mixture thereof; Z is N or CR 4 ; R 4 is from selected from hydrogen, halo, nitro, alkyl, alkylaryl, and XYR 5 ; R 5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R 6 and R 7 are independently selected from hydrogen and alkyl; n is an integer from 1 to 6; at least one of R 1 , R 2 and R 4 is other than hydrogen; and at least one of X and Y is (CR 6 R 7 ) n . D-serine or cycloserine may be coadministered along with the compound of formula I.

1 - 42 . (canceled) 
     
     
         43 . A method for increasing the concentration of D-serine and/or decreasing the concentration of toxic products of D-serine oxidation by DAAO in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of formula IA or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1a  is selected from hydrogen, nitro, and taken together with R 2a  forms a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group; 
         R 2a  is selected from halo, nitro, XYR 5 , and taken together with R 1a  forms a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group; 
         X and Y are independently selected from O, and (CR 6 R 7 ) n ; 
         R 3  is hydrogen, alkyl or M + ; 
         M is selected from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; 
         Z is N; 
         R 5  is selected from heteroaryl and substituted heteroaryl; 
         R 6  and R 7  are independently selected from hydrogen and alkyl; 
         n is an integer from 1 to 6; and 
         at least one of X and Y is (CR 6 R 7 ) n . 
       
     
     
         44 . A method for treating schizophrenia, for treating or preventing loss of memory and/or cognition associated with Alzheimer's disease, for treating ataxia, or for preventing loss of neuronal function characteristic of neurodegenerative diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula IA, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1a  is selected from hydrogen, nitro, and taken together with R 2a  forms a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group; 
         R 2a  is selected from halo, nitro, XYR 5 , and taken together with R 1a  forms a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group; 
         X and Y are independently selected from O, and (CR 6 R 7 ) n ; 
         R 3  is hydrogen, alkyl or M + ; 
         M is selected from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; 
         Z is N; 
         R 5  is selected from heteroaryl and substituted heteroaryl; 
         R 6  and R 7  are independently selected from hydrogen and alkyl; 
         n is an integer from 1 to 6; and 
       
       at least one of X and Y is (CR 6 R 7 ) n . 
     
     
         45 . A method for enhancing learning, memory and/or cognition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula IA, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1a  is selected from hydrogen, nitro, and taken together with R 2a  forms a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group; 
         R 2a  is selected from halo, nitro, XYR 5 , and taken together with R 1a  forms a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group; 
         X and Y are independently selected from O, and (CR 6 R 7 ) n ; 
         R 3  is hydrogen, alkyl or M + ; 
         M is selected from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; 
         Z is N; 
         R 5  is selected from heteroaryl and substituted heteroaryl; 
         R 6  and R 7  are independently selected from hydrogen and alkyl; 
         n is an integer from 1 to 6; and 
         at least one of X and Y is (CR 6 R 7 ) n . 
       
     
     
         46 . A method for treating neuropathic pain, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula IA, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1a  is selected from hydrogen, nitro, and taken together with R 2a  forms a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group; 
         R 2a  is selected from halo, nitro, XYR 5 , and taken together with R 1a  forms a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group; 
         X and Y are independently selected from O, and (CR 6 R 7 ) n ; 
         R 3  is hydrogen, alkyl or M + ; 
         M is selected from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; 
         Z is N; 
         R 5  is selected from heteroaryl and substituted heteroaryl; 
         R 6  and R 7  are independently selected from hydrogen and alkyl; 
         n is an integer from 1 to 6; and 
         at least one of X and Y is (CR 6 R 7 ) n . 
       
     
     
         47 . A method according to  claim 43 , wherein R 3  is hydrogen. 
     
     
         48 . A method according to  claim 44 , wherein R 3  is hydrogen. 
     
     
         49 . A method according to  claim 45 , wherein R 3  is hydrogen. 
     
     
         50 . A method according to  claim 46 , wherein R 3  is hydrogen. 
     
     
         51 . A method according to  claim 43 , wherein n is 1 or 2. 
     
     
         52 . A method according to  claim 44 , wherein n is 1 or 2. 
     
     
         53 . A method according to  claim 45 , wherein n is 1 or 2. 
     
     
         54 . A method according to  claim 46 , wherein n is 1 or 2. 
     
     
         55 . A method according to  claim 43 , wherein X and Y are (CR 6 R 7 ) n  and n is 1. 
     
     
         56 . A method according to  claim 44 , wherein X and Y are (CR 6 R 7 ) n  and n is 1. 
     
     
         57 . A method according to  claim 45 , wherein X and Y are (CR 6 R 7 ) n  and n is 1. 
     
     
         58 . A method according to  claim 46 , wherein X and Y are (CR 6 R 7 ) n  and n is 1. 
     
     
         59 . A method according to  claim 43 , wherein R 6  and R 7  are hydrogen. 
     
     
         60 . A method according to  claim 44 , wherein R 6  and R 7  are hydrogen. 
     
     
         61 . A method according to  claim 45 , wherein R 6  and R 7  are hydrogen. 
     
     
         62 . A method according to  claim 46 , wherein R 6  and R 7  are hydrogen. 
     
     
         63 . A method according to  claim 43 , wherein R 1a  is hydrogen and R 2a  is XYR 5 . 
     
     
         64 . A method according to  claim 44 , wherein R 1a  is hydrogen and R 2a  is XYR 5 . 
     
     
         65 . A method according to  claim 45 , wherein R 1a  is hydrogen and R 2a  is XYR 5 . 
     
     
         66 . A method according to  claim 46 , wherein R 1a  is hydrogen and R 2a  is XYR 5 . 
     
     
         67 . A method for
 (a) increasing the concentration of D-serine and/or decreasing the concentration of toxic products of D-serine oxidation by DAAO in a mammal;   (b) treating schizophrenia;   (c) treating or preventing loss of memory and/or cognition associated with Alzheimer's disease;   (d) treating ataxia;   (e) preventing loss of neuronal function characteristic of neurodegenerative diseases;   (f) enhancing learning, memory and/or cognition; or   (g) treating neuropathic pain,   the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from: