Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases

Abstract

The present disclosure is directed certain Hypoxia Inducible Factor 2α (HIF-2α) inhibitors and their use in the treatment of diseases mediated by HIF-2α such as cancer. Also provided is the use of HIF-2α inhibitors in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. In particular, the present disclosure is directed to methods for the treatment of cancers using a HIF-2α inhibitor in combination with a PARP inhibitor and pharmaceutical compositions comprising the same.

1 . A compound of Formula (IA): 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is hydrogen or deuterium; 
         R 9  is fluoro; 
         R 7  is hydrogen; 
         R 8  is phenyl substituted with R a , R b , R c , R g  and R h  wherein R a , R b , and R 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; 
         R 2a  is hydrogen, deuterium, or fluoro; and 
         R 9a  is fluoro; or 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, having a structure according to Formula (IA′): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt thereof, wherein R a , R b , and R c  are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano. 
     
     
         4 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt thereof, is wherein R a , R b , and R c  are independently selected from hydrogen, deuterium, methyl, methoxy, hydroxy, chloro, fluoro, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy and R g  and R h  are independently hydrogen or deuterium. 
     
     
         5 . The compound of  claim 1  or  2 , 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-methylphenyl, 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. 
     
     
         6 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt thereof, wherein R 8  is 3-cyano-5-fluorophenyl or 3-cyano-5-fluoro-2,4,6-trideuteriophenyl. 
     
     
         7 . The compound of  claim 2 , wherein the compound is selected from:
 3-fluoro-5-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd] inden-7-yl)oxy)benzonitrile; and   3-fluoro-5-(((1R,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.   
     
     
         8 . The compound of  claim 7 , wherein the compound is 3-fluoro-5-(((1R,2S,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.   
     
     
         9 . The compound of  claim 8 , wherein the compound is 3-fluoro-5-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile. 
     
     
         10 . A pharmaceutical composition comprising a compound of any one of  claims 1  to  9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         11 . The pharmaceutical composition of  claim 10  wherein the compound is 3-fluoro-5-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile. 
     
     
         12 . A method of inhibiting HIF-2α which method comprises contacting HIF-2α with a compound of any one of  claims 1  to  9 , or a pharmaceutically acceptable salt thereof. 
     
     
         13 . 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 need thereof, a therapeutically effective amount of a compound of any one of  claims 1  to  9 , or a pharmaceutically acceptable salt thereof in a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         14 . The method of  claim 13 , wherein the disease is cancer and the compound of  claim 1  to  9 , or a pharmaceutically acceptable salt thereof, is optionally administered in combination with at least one other anticancer agent. 
     
     
         15 . The method of  claim 13  or  14 , wherein the disease is cancer selected from renal cancer, breast cancer, cervical cancer, colorectal cancer, glioblastoma, glioma, head and neck cancer, liver cancer, non-small cell lung cancer, melanoma, neuroblastoma, ovarian cancer, and prostate cancer. 
     
     
         16 . The method of  claim 13 , wherein the disease is pulmonary artery hypertension. 
     
     
         17 . A method of treating cancer in a patient, comprising administering to the patient a HIF-2α inhibitor of Formula (I): 
       
         
           
           
               
               
           
         
       
       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; or 
 a pharmaceutically acceptable salt thereof, 
 in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof. 
 
     
     
         18 . The method of  claim 17 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is where R 1  is hydroxy. 
     
     
         19 . The method of  claim 17 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is where R 1  is amino. 
     
     
         20 . The method of any one of  claims 17  to  19 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is where R 6  is halo. 
     
     
         21 . The method of any one of  claims 17  to  20 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is where R 5  is halo. 
     
     
         22 . The method of any one of  claims 17  to  21 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is where X 1  is CR 7 . 
     
     
         23 . The method of  claim 17 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, has the structure of formula (IIa1) or (IIb1): 
       
         
           
           
               
               
           
         
       
     
     
         24 . The method of  claim 17 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, has the structure of formula (IIa1′) or (IIb1′): 
       
         
           
           
               
               
           
         
       
     
     
         25 . The method of any one of  claims 17  to  24 , wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′) or (IIb1′), or a pharmaceutically acceptable salt thereof, is where R 3  is fluoro. 
     
     
         26 . The method of any one of  claims 17  to  24 , wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′) or (IIb1′), or a pharmaceutically acceptable salt thereof, is where R 3  and R 4  are fluoro. 
     
     
         27 . The method of any one of  claims 17  to  26 , wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′) or (IIb1′), or a pharmaceutically acceptable salt thereof, is where L is O, S, SO, SO 2 , or NH. 
     
     
         28 . The method of  claim 27 , wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′) or (IIb1′), or a pharmaceutically acceptable salt thereof, is where L is O. 
     
     
         29 . The method of any one of  claims 17  to  28 , wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′) or (IIb1′), or a pharmaceutically acceptable salt thereof, is where 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. 
     
     
         30 . The method of any one of  claims 17  to  28 , wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′) or (IIb1′), or a pharmaceutically acceptable salt thereof, is where R 8  is phenyl substituted with R a , R b , R, R and R h  and 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. 
     
     
         31 . The method of  claim 30 , wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′) or (IIb1′), or a pharmaceutically acceptable salt thereof, is where R′ 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-methylphenyl, 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. 
     
     
         32 . The method of  claim 29 , wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′) or (IIb1′), or a pharmaceutically acceptable salt thereof, is where R′ 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. 
     
     
         33 . The method of  claim 29 , wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′) or (IIb1′), or a pharmaceutically acceptable salt, thereof, is where 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 each of the aforementioned rings 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. 
     
     
         34 . The method of any one of  claims 17  to  33 , wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′) or (IIb1′), or a pharmaceutically acceptable salt thereof, is where R 7  is hydrogen, methyl, ethyl, methoxy, fluoro, trifluoromethyl, or trifluoromethoxy. 
     
     
         35 . The method of any one of  claims 17  to  34 , wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′) or (IIb1′), or a pharmaceutically acceptable salt thereof, is where R 2  is hydrogen, deuterium, fluoro, methyl, or ethyl and R 9  is hydrogen, alkyl, halo, hydroxy, or alkoxy, and R 2  and R 9  are attached to the ring carbon atom that is meta to the ring carbon attached to R 1 . 
     
     
         36 . The method of  claim 31  or  33 , wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′) or (IIb1′), or a pharmaceutically acceptable salt thereof has the structure of formula (VIIIa) or (VIIIb): 
       
         
           
           
               
               
           
         
       
     
     
         37 . The method of  claim 36 , wherein the compound of Formula (VIIIa) or (VIIIb), or a pharmaceutically acceptable salt thereof, is where R 2  is hydrogen or deuterium, R 9  is hydrogen, fluoro, or methyl and R 2a  and R 9a  are independently hydrogen, deuterium or fluoro. 
     
     
         38 . The method of  claim 17 , wherein the compound of Formula (I) is 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-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd] inden-7-yl)oxy)benzonitrile; and   3-fluoro-5-(((1R,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.   
     
     
         39 . The method of  claim 17 , wherein the compound of Formula (I) is 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.   
     
     
         40 . The method of  claim 17 , wherein the compound of Formula (I) 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 . The method of  claim 17 , wherein the compound of Formula (I) 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. 
     
     
         42 . The method of any one  claims 17  to  41 , wherein the PARP inhibitor is olaparib (4-[(3-[(4-cyclopropylcarbonyl)piperazin-1-yl]carbonyl)-4-fluorophenyl]methyl(2H)phthalazin-1-one), rucaparib (8-fluoro-2-{[(4-methylamino)-methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one), nirparib (2-[4-[(3S)-3-piperidyl]phenyl]indazole-7-carboxamide), talazoparib ((8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one), or pamiparib ((2R)-14-fluoro-2-methyl-6,9,10,19-tetrazapentacyclo[14.2.1.0 2,6 .0 8,18 .0 12,17 ]nonadeca-1(18),8,12(17),13,15-pentaen-11-one; trihydrate). 
     
     
         43 . The method of any one of  claims 17  to  42 , wherein the cancer is selected from renal cancer, glioblastoma, neuroblastoma, paraganglioma, pheochromocytoma, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors, pituitary tumors, leiomyomas, leiomyosarcomas, polycythaemia, retinal cancers, lung cancer, pancreatic cancer, liver cancer, ovarian cancer, breast cancer, prostate cancer, colorectal cancer, head and neck cancer, cervical cancer, endometrial cancer, bladder cancer, gastric cancer, esophageal cancer, lymphoma, melanoma, mesothelioma, sarcoma and neuroendocrine tumors. 
     
     
         44 . The method of  claim 43 , wherein the cancer is clear cell renal cancer. 
     
     
         45 . The method of any one of  claims 17  to  42  wherein the cancer is selected from ovarian cancer, breast cancer, prostate cancer, renal cancer, colorectal cancer, uveal melanoma, pancreatic cancer, urothelial cancer, endometrial cancer, lung cancer, lymphoma, head and neck cancer, fallopian tube cancer, primary peritoneal cancer, cervical cancer, melanoma, esophageal cancer, gastric cancer, mesothelioma, cholangiocarcinoma, glioblastoma, Ewing Sarcoma, uterine leiomyosarcoma, chronic lymphocytic leukemia, T-cell-prolymphocytic leukemia, multiple myeloma, acute myeloid leukemia, chronic myelogenous leukemia, germ cell cancer, bladder cancer, neuroendocrine tumors, osteosarcoma, biliary tract cancer, soft-tissue sarcoma, rhabdomyosarcoma, mantle-cell lymphoma, and endocrine gland neoplasms. 
     
     
         46 . The method of any one of  claims 17  to  45 , wherein the compound of Formula (I) and the PARP inhibitor are administered sequentially, optionally within 1 to 30 minutes of each other, or simultaneously. 
     
     
         47 . The method of any one of  claims 17  to  46 , wherein the combination is a synergistic combination. 
     
     
         48 . The method of any one of  claims 17  to  47 , wherein the method further comprises administering one or more additional anti-cancer agents.