Tetrahydro-1h-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2(alpha) inhibitors

Abstract

The present disclosure provides certain tetrahydro-1H-cyclopenta[cd]indene compounds that are Hypoxia Inducible Factor 2α (HIF-2α) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of HIF-2α. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

What is claimed: 
     
         1 . A compound of Formula (IA): 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1  is CH or N; 
 R 1  is hydroxy, halo, amino, —OP(O)(OH) 2 , —OCH 2 OP(O)(OH) 2 , —OCOR 10 , —OCOOR 11 , —OCONR 12 R 13 , —OCHR 14 OCOR 15  or —OCHR 14 OCOOR 15a  where R 10 , R 11 , and R 15  and R 15a  are independently alkyl or alkyl substituted with amino, carboxy or hydroxy, R 12  and R 13  are independently hydrogen, alkyl, or alkyl substituted with amino, carboxy or hydroxy or R 12  and R 13  together with the nitrogen atom to which they are attached form optionally substituted heterocyclyl, and each R 14  is hydrogen, alkyl, or haloalkyl; 
 R 2  is hydrogen, deuterium, alkyl, halo, haloalkyl, alkenyl, or alkynyl; 
 R 2a  is hydrogen, halo, or deuterium; 
 R 3  and R 4  are independently hydrogen, deuterium, alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl; or 
 R 3  and R 4  together with the carbon to which they are attached form oxo, 3 to 6 membered cycloalkylene, or 4 to 6 membered optionally substituted heterocyclylene; 
 R 5  is hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxy, or alkoxy; 
 R 6  is hydrogen, deuterium, alkyl, cycloalkyl, or halo; or 
 R 5  and R 6  together with the carbon to which they are attached form oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to 6 membered optionally substituted heterocyclylene; provided R 5  and R 6  and R 3  and R 4  together with the carbon to which they are attached do not form oxo, cycloalkylene or optionally substituted 4 to 6 membered heterocyclylene simultaneously; 
 R 7  is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, or haloalkoxy; 
 L is a bond, S, SO, SO 2 , O, CO, or NR 16  where R 16  is hydrogen or alkyl; 
 R 8  is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl wherein aryl or heteroaryl, each by itself or as part of aralkyl or heteroaralkyl, or heterocyclyl by itself or as part of heterocyclylalkyl is substituted with R a , R b , R c , R g  and R h  wherein R a , R b , and R c  are independently selected from hydrogen, deuterium, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl and R g  and R h  are independently selected from hydrogen, deuterium, and halo; and 
 R 9  is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, haloalkoxy, alkylsulfoxide, alkylsulfonyl, or heteroaryl wherein the heteroaryl is optionally substituted with R d , R e , and R f  independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and cyano; or 
 when R 9  and R 2  are attached to the same carbon atom, they can combine to form oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to 6-membered heterocyclylene; 
 R 9a  is hydrogen, halo, or deuterium; 
 a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof wherein R 2a  is hydrogen or deuterium and R 9a  is hydrogen or deuterium. 
     
     
         3 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein
 having a structure of Formula (I):   
       
         
           
           
               
               
           
         
       
       wherein:
 R 8  is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl wherein aryl or heteroaryl, each by itself or as part of aralkyl or heteroaralkyl, or heterocyclyl by itself or as part of heterocyclylalkyl is substituted with R a , R b , and R c  independently selected from hydrogen, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl. 
 
     
     
         4 . The compound of  claim 1 ,  2 , or  3 , or a pharmaceutically acceptable salt thereof, wherein R 3  and R 4  are independently halo. 
     
     
         5 . The compound of  claim 1 ,  2 , or  3 , or a pharmaceutically acceptable salt thereof, wherein R 3  is halo and R 4  is hydrogen. 
     
     
         6 . The compound of any one of  claims 1  to  5 , or a pharmaceutically acceptable salt thereof, wherein R 1  is hydroxy. 
     
     
         7 . The compound of any one of  claims 1  to  5 , or a pharmaceutically acceptable salt thereof, is wherein R 1  is amino. 
     
     
         8 . The compound of any one of  claims 1  to  7 , or a pharmaceutically acceptable salt thereof, wherein R 6  is halo. 
     
     
         9 . The compound of any one of  claims 1  to  7 , or a pharmaceutically acceptable salt thereof, wherein R 6  is alkyl, hydrogen, or deuterium. 
     
     
         10 . The compound of any one of  claims 1  to  9 , or a pharmaceutically acceptable salt thereof, wherein R 5  is halo. 
     
     
         11 . The compound of any one of  claims 1  to  9 , or a pharmaceutically acceptable salt thereof, wherein R 5  is alkyl, hydrogen, or alkoxy. 
     
     
         12 . The compound of any one of  claims 1  to  7 , or a pharmaceutically acceptable salt thereof, wherein R 5  and R 6  together with the carbon to which they are attached form 3 to 6 membered cycloalkylene. 
     
     
         13 . The compound of any one of  claims 1  to  12 , or a pharmaceutically acceptable salt thereof, wherein X 1  is CR 7 . 
     
     
         14 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of formula (IIa1) or (IIb1): 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of formula (IIa1) or (IIb1): 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof, having the structure of formula (IIa) or (IIb): 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof, having the structure of formula (IIa′) or (IIb′): 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of any one of  claims 1  to  17 , or a pharmaceutically acceptable salt thereof, wherein R 3  is fluoro. 
     
     
         19 . The compound of any one of  claims 1  to  17 , or a pharmaceutically acceptable salt thereof, wherein R 3  and R 4  are fluoro. 
     
     
         20 . The compound of any one of  claims 1  to  19 , or a pharmaceutically acceptable salt thereof, wherein L is O, S, SO, SO 2 , or NH. 
     
     
         21 . The compound of  claim 20 , or a pharmaceutically acceptable salt thereof, wherein L is O. 
     
     
         22 . The compound of any one of  claims 3  to  13  and  16  to  21 , or a pharmaceutically acceptable salt thereof, wherein R 8  is cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl wherein aryl or heteroaryl, each by itself or as part of aralkyl or heteroaralkyl, or heterocyclyl by itself or as part of heterocyclylalkyl is substituted with R a , R b , and R c  independently selected from hydrogen, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl. 
     
     
         23 . The compound of any one of  claims 1 ,  2 ,  4  to  15  and  18  to  21 , or a pharmaceutically acceptable salt thereof, wherein R 8  is phenyl substituted with R a , R b , R c , R g  and R h  wherein R a , R b , and R c  are independently selected from hydrogen, deuterium, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl and R g  and R h  are independently selected from hydrogen, deuterium, and halo. 
     
     
         24 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 8  is 3-chloro-5-fluorophenyl, 3,5-difluorophenyl, 3-fluoro-5-methoxyphenyl, 3-cyano-5-fluorophenyl, 3-chloro-5-cyanophenyl, 3-cyano-5-methylphenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-fluoro-5-methyl, 3-cyanophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3-chloro-2-methylphenyl, 3,5-dichlorophenyl, 3,5-dimethylphenyl, 2-chloro-6-methylphenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 4-fluoro-3-methylphenyl, 3-cyano-4-fluorophenyl, 3-cyano-5-difluoromethylphenyl or 3-cyano-5-fluoro-2,4,6-trideuteriophenyl. 
     
     
         25 . The compound of  claim 22 , or a pharmaceutically acceptable salt, thereof, wherein R 8  is phenyl substituted with R a , R b , and R 0  independently selected from hydrogen, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl. 
     
     
         26 . The compound of  claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 8  is 3-chloro-5-fluorophenyl, 3,5-difluorophenyl, 3-fluoro-5-methoxyphenyl, 3-cyano-5-fluorophenyl, 3-chloro-5-cyanophenyl, 3-cyano-5-methylphenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-fluoro-5-methyl, 3-cyanophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3-chloro-2-methylphenyl, 3,5-dichlorophenyl, 3,5-dimethylphenyl, 2-chloro-6-methylphenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 4-fluoro-3-methylphenyl, 3-cyano-4-fluorophenyl, or 3-cyano-5-difluoromethylphenyl. 
     
     
         27 . The compound of  claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 8  is heteroaryl substituted with R a , R b , and R c  independently selected from hydrogen, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl. 
     
     
         28 . The compound of  claim 22 , or a pharmaceutically acceptable salt, thereof, wherein R 8  is 5- or 6-membered heteroaryl substituted with R a , R b , and R c  wherein R a  and R b  are independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano and R c  is selected from hydrogen, alkyl, halo, haloalkyl, and haloalkoxy. 
     
     
         29 . The compound of  claim 22 , or a pharmaceutically acceptable salt, thereof, wherein R 8  is pyridin-3-yl, pyridin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, pyrimidin-2-yl, thien-2-yl, furan-2-yl, thiazol-5-yl, oxazol-5-yl, imidazol-5-yl, furan-3-yl thien-3-yl, thiazol-4-yl, pyridin-4-yl, oxazol-2-yl, imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, or thiazol-2-yl, and is substituted with R a , R b , and R c  wherein R a  and R b  are independently selected from hydrogen, methyl, methoxy, hydroxy, chloro, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy and R c  is selected from hydrogen, methyl, cyano, chloro, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy. 
     
     
         30 . The compound of any one of  claims 1  to  29 , or a pharmaceutically acceptable salt thereof, wherein R 7  is hydrogen, methyl, ethyl, methoxy, fluoro, trifluoromethyl, or trifluoromethoxy. 
     
     
         31 . The compound of any one of  claims 1  to  30 , or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen, fluoro, methyl or ethyl and R 9  is hydrogen, alkyl, halo, hydroxy, or alkoxy. 
     
     
         32 . The compound of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein wherein R 2  and R 9  are attached to the same carbon atom. 
     
     
         33 . The compound of  claim 32 , or a pharmaceutically acceptable salt thereof, wherein R 2  and R 9  are attached to the ring carbon atom that is meta to the ring carbon attached to R 1 . 
     
     
         34 . The compound of any one of  claims 1  to  30 , or a pharmaceutically acceptable salt thereof, wherein R 2  and R 9  are attached to the same carbon atom and together with the carbon atom to which they are attached form oxo and are attached to the ring carbon atom that is meta to the ring carbon attached to R 1 . 
     
     
         35 . The compound of any one of  claims 17  to  22  and  25  to  34 , or a pharmaceutically acceptable salt thereof having the structure of formula (VIIIa) or (VIIIb): 
       
         
           
           
               
               
           
         
       
     
     
         36 . The compound of  claim 35 , or a pharmaceutically acceptable salt thereof having a structure of formula (VIIIb) wherein R 2  is hydrogen and R 9  is hydrogen, fluoro, or methyl. 
     
     
         37 . The compound of  claim 1 , selected from:
 3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-fluoro-5-(((1R,2aS)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-fluoro-5-(((1R,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   1,3,3,4,4-pentafluoro-7-((5-fluoropyridin-3-yl)oxy)-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol;   3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydrospiro[cyclopenta[cd]-indene-1,1′-cyclopropan]-7-yl)oxy)benzonitrile;   3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-((2a-amino-1,3,3,4,4-pentafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile;   3-fluoro-5-((1,1,2a,3,3,4,4-heptafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-((3,3-difluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile;   3-((3,3-difluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile;   3-((3,3-difluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile;   3-fluoro-5-((1,3,3-trifluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile;   3-fluoro-5-((1,2,2,3,3,4,4-heptafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile;   3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d3;   (R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   (S)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-fluoro-5-(((2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   3-fluoro-5-(((2R,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; or   a pharmaceutically acceptable salt thereof.   
     
     
         38 . The compound of  claim 1 , selected from:
 3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta-[cd]inden-7-yl)oxy)benzonitrile; and   3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;   or a pharmaceutically acceptable salt thereof.   
     
     
         39 . The compound of  claim 1 , wherein the compound is 3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile. 
     
     
         40 . The compound of  claim 1 , wherein the compound is 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile. 
     
     
         41 . A pharmaceutical composition comprising a compound of any one of  claims 1  to  38  or a pharmaceutically acceptable salt thereof or the compound of  claim 39  or  40 ; and a pharmaceutically acceptable excipient. 
     
     
         42 . A method of inhibiting HIF2α which method comprises contacting HIF2α with a compound of any one of  claims 1  to  38 , or a pharmaceutically acceptable salt thereof or the compound of  claim 39  or  40 . 
     
     
         43 . A method of treating cancer, inflammatory disease, liver disease, iron overload, or pulmonary disease in a patient which method comprises administering to the patient in recognized need thereof (a) a therapeutically effective amount of a compound of any one of  claims 1  to  38 , or a pharmaceutically acceptable salt thereof or the compound of  claim 39  or  40 ; or (b) a pharmaceutical composition comprising a compound of any one of  claims 1 - 38 , or a pharmaceutically acceptable salt thereof or the compound of  claim 39  or  40 , and a pharmaceutically acceptable excipient in a therapeutically effective amount. 
     
     
         44 . The method of  claim 43 , wherein the disease is cancer and the compound of  claim 1  to  38 , or a pharmaceutically acceptable salt thereof, or the compound of  claim 39  or  40 , optionally administered in combination with at least one other anticancer agent. 
     
     
         45 . The method of  claim 43  or  44 , wherein the disease is cancer selected from renal cancer, glioblastoma neuroblastoma, paraganglioma, pheochromocytoma, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors, pituitary tumors, leiomyomas, leiomyosarcomas, polycythaemia, and retinal cancers. 
     
     
         46 . The method of  claim 43 , wherein the disease is NASH, pulmonary artery hypertension, inflammatory bowel disease or iron overload.