Hetero-halo inhibitors of histone deacetylase

Abstract

This invention provides compounds that are inhibitors of HDAC2. The compounds (e.g., compounds according to Formula I, II or any of Compounds 100-128 or any of those in Tables 2 or 3) accordingly are useful for treating, alleviating, or preventing a condition in a subject such as a neurological disorder, memory or cognitive function disorder or impairment, extinction learning disorder, fungal disease or infection, inflammatory disease, hematological disease, or neoplastic disease, or for improving memory or treating, alleviating, or preventing memory loss or impairment.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: ring A is selected from 
       
         
           
           
               
               
           
         
         R 1  is an optionally substituted monocyclic or bicyclic heterocyclyl; 
         R 2  is selected from optionally substituted C 2 -C 6  alkenyl, optionally substituted heteroaryl, optionally substituted partially unsaturated heterocyclyl, optionally substituted partially unsaturated carbocyclyl, and para-substituted phenyl wherein said phenyl can be optionally further substituted, and when ring A comprises two nitrogen atoms, R 2  is additionally selected from unsubstituted phenyl, 
         wherein any two substituents on adjacent ring atoms in R 2  are optionally taken together with the adjacent ring atoms to form a ring that is an aryl, a carbocyclyl, a heteroaryl, or a heterocyclyl ring; 
         R 3 , when present, is selected from chloro, fluoro, —CF 3  and —CHF 2 ; 
         n is 0 or 1; 
         “1” represents a point of attachment between ring A and —NH—C(O)—R 1 ; 
         “2” represents a point of attachment between ring A and R 2 ; 
         “3” represents a point of attachment between ring A and —NH 2 ; and wherein the compound is other than 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein n is 0. 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . The compound of  claim 1 , wherein ring A is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 3 , wherein R 1  is selected from 5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl, pyrrolidin-1-yl, 1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-2H-pyran-4-yl, hexahydrocyclopenta[c]pyrrol-2(1H)-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, isoindolin-2-yl, 4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, and 2-oxa-6-azaspiro[3.4]octan-6-yl, wherein R 1  is optionally substituted with up to 3 independently selected substituents. 
     
     
         8 . The compound of  claim 7 , wherein R 1  is selected from 5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl, pyrrolidin-1-yl, 1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-2H-pyran-4-yl, hexahydrocyclopenta[c]pyrrol-2(1H)-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, isoindolin-2-yl, 4,6-difluoroisoindolin-2-yl, 4,7-difluoroisoindolin-2-yl, 4-fluoroisoindolin-2-yl, 5-fluoroisoindolin-2-yl, 4-chlorolisoindolin-2-yl, 4-methoxyisoindolin-2-yl, 5-methoxyisoindolin-2-yl, 5-chloroisoindolin-2-yl, 4-trifluoromethylisoindolin-2-yl, 5,6-difluoroisoindolin-2-yl, 5-trifluoromethylisoindolin-2-yl, 5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl, 3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl, 5-(cyclopropylmethyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl, 4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, and 34(4-methylpiperazin-1-yl)methyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl. 
     
     
         9 . The compound of  claim 7 , wherein R 2  is selected from —C 2 -C 4  alkenyl, unsubstituted phenyl, 4-substituted phenyl, pyridin-4-yl, isoxazol-5-yl, oxazol-5-yl, isothiazol-5-yl, thiazol-5-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, furan-3-yl, furan-2-yl, cyclopent-1-ene-1-yl, and 2,5-dihydrofuran-3-yl. 
     
     
         10 . The compound of  claim 9 , wherein R 2  is selected from —C(CH 3 )═CH 2 , phenyl, 4-fluorophenyl, 4-difluoromethoxyphenyl, 4-methylphenyl, 3,4-difluorophenyl, pyridin-4-yl, isoxazol-5-yl, oxazol-5-yl, isothiazol-5-yl, thiazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 1-(2-methylpropyl)-1H-pyrazol-4-yl, 1-trifluoromethyl-1H-pyrazol-4-yl, 1,5-dimethyl-1H-pyrazol-4-yl, 1-cyclobutyl-1H-pyrazol-4-yl, 1-cyclopentyl-1H-pyrazol-4-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, furan-3-yl, furan-2-yl, 5-methylfuran-2-yl, 5-methylfuran-3-yl, cyclopent-1-ene-1-yl, and 2,5-dihydrofuran-3-yl. 
     
     
         11 . The compound of  claim 1 , wherein the compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A compound having the Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 ring A′B′ is a fused bicyclic ring system containing at least two nitrogen atoms, wherein ring A′ is a 6-membered heterocyclyl and ring B′ is a 5-membered heteroaryl; 
 X 1  is carbon or nitrogen; 
 R 3 ′ and R 4  are each independently halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, or halo(C 1 -C 4 )alkoxy; 
 R 5  is halo, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, monocyclic heterocyclyl, or (C 1 -C 4 )alkyl optionally substituted with monocyclic heterocyclyl, wherein each of said heterocyclyl are optionally and independently substituted with 1 to 2 groups selected from halo, (C 1 -C 4 )alkyl, and halo(C 1 -C 4 )alkyl; 
 n′ is 0 or 1; and 
 p and t are each independently 0, 1, or 2. 
 
     
     
         13 . The compound of  claim 12 , wherein the compound is of the Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The compound of  claim 13 , wherein the compound is of the Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The compound of  claim 14 , wherein ring A′B′ is selected from 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 15 , wherein ring A′B′ is selected from 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 16 , wherein p is 0 or 1. 
     
     
         18 . The compound of  claim 17 , wherein R 4 , if present, is halo. 
     
     
         19 . The compound of  claim 18 , wherein t is 0 or 1. 
     
     
         20 . The compound of  claim 19 , wherein R 5 , if present, is selected from halo(C 1 -C 4 )alkyl and (C 1 -C 4 )alkyl. 
     
     
         21 . The compound of  claim 20 , wherein ring A′B′ and (R 5 ) t  taken together are selected from 
       
         
           
           
               
               
           
         
       
     
     
         22 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         23 . (canceled) 
     
     
         24 . A method of treating a condition in a subject selected from a neurological disorder, memory or cognitive function disorder or impairment, extinction learning disorder, fungal disease or infection, inflammatory disease, hematological disease, and neoplastic disease, comprising administering to the subject in need thereof an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         25 . A method of improving memory in a normal subject or treating, alleviating, or preventing memory loss or impairment in a subject comprising administering to the subject in need thereof an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method of  claim 25 , wherein the condition is:
 a. a cognitive function disorder or impairment associated with Alzheimer's disease, Huntington's disease, seizure induced memory loss, schizophrenia, Rubinstein Taybi syndrome, Rett Syndrome, Fragile X, Lewy body dementia, vascular dementia, frontotemporal dementia, ADHD, dyslexia, bipolar disorder and social, cognitive and learning disorders associated with autism, traumatic head injury, attention deficit disorder, anxiety disorder, conditioned fear response, panic disorder, obsessive compulsive disorder, posttraumatic stress disorder (PTSD), phobia, social anxiety disorder, substance dependence recovery, Age Associated Memory Impairment (AAMI), Age Related Cognitive Decline (ARCD), ataxia, or Parkinson's disease; or   b. a hematological disease selected from acute myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, myelodysplastic syndromes, and sickle cell anemia; or   c. a neoplastic disease; or   
       an extinction learning disorder selected from fear extinction and post-traumatic stress disorder. 
     
     
         27 . The method of  claim 26 , wherein the condition is Alzheimer's disease, Huntington's disease, frontotemporal dementia, Freidreich's ataxia, post-traumatic stress disorder (PTSD), Parkinson's disease, or substance dependence recovery. 
     
     
         28 . The method of  claim 27 , wherein the method is a combination therapy further comprising: administering to the subject an effective amount of a pharmaceutically active ingredient; and/or exposing the subject to cognitive behavioral therapy (CBT), psychotherapy, behavioral exposure treatments, virtual reality exposure (VRE) and/or cognitive remediation therapy. 
     
     
         29 . The method of  claim 28 , wherein the method is a combination therapy for treating, alleviating, and/or preventing post-traumatic stress disorder or Alzheimer's disease and the pharmaceutically active ingredient administered is selected from Aricept® (donepezil), memantine, galantamine and Excelon® (rivastigmine). 
     
     
         30 - 33 . (canceled)