WO2022086882A1 - Diagnostic and therapeutic methods for treatment of cancer with a hif-2(alpha) inhibitor - Google Patents

Diagnostic and therapeutic methods for treatment of cancer with a hif-2(alpha) inhibitor Download PDF

Info

Publication number
WO2022086882A1
WO2022086882A1 PCT/US2021/055483 US2021055483W WO2022086882A1 WO 2022086882 A1 WO2022086882 A1 WO 2022086882A1 US 2021055483 W US2021055483 W US 2021055483W WO 2022086882 A1 WO2022086882 A1 WO 2022086882A1
Authority
WO
WIPO (PCT)
Prior art keywords
hif
cancer
hydroxy
gene
fluoro
Prior art date
Application number
PCT/US2021/055483
Other languages
French (fr)
Inventor
Jiping Fu
Yan Lou
Yigang He
Jing Lu
Original Assignee
Nikang Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nikang Therapeutics, Inc. filed Critical Nikang Therapeutics, Inc.
Publication of WO2022086882A1 publication Critical patent/WO2022086882A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A21—BAKING; EDIBLE DOUGHS
    • A21D—TREATMENT, e.g. PRESERVATION, OF FLOUR OR DOUGH, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS; PRESERVATION THEREOF
    • A21D13/00—Finished or partly finished bakery products
    • A21D13/04—Products made from materials other than rye or wheat flour
    • A21D13/045—Products made from materials other than rye or wheat flour from leguminous plants
    • A—HUMAN NECESSITIES
    • A21—BAKING; EDIBLE DOUGHS
    • A21D—TREATMENT, e.g. PRESERVATION, OF FLOUR OR DOUGH, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS; PRESERVATION THEREOF
    • A21D13/00—Finished or partly finished bakery products
    • A21D13/06—Products with modified nutritive value, e.g. with modified starch content
    • A—HUMAN NECESSITIES
    • A21—BAKING; EDIBLE DOUGHS
    • A21D—TREATMENT, e.g. PRESERVATION, OF FLOUR OR DOUGH, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS; PRESERVATION THEREOF
    • A21D2/00—Treatment of flour or dough by adding materials thereto before or during baking
    • A21D2/08—Treatment of flour or dough by adding materials thereto before or during baking by adding organic substances
    • A21D2/24—Organic nitrogen compounds
    • A21D2/26—Proteins
    • A21D2/264—Vegetable proteins
    • A21D2/266—Vegetable proteins from leguminous or other vegetable seeds; from press-cake or oil bearing seeds
    • A—HUMAN NECESSITIES
    • A21—BAKING; EDIBLE DOUGHS
    • A21D—TREATMENT, e.g. PRESERVATION, OF FLOUR OR DOUGH, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS; PRESERVATION THEREOF
    • A21D2/00—Treatment of flour or dough by adding materials thereto before or during baking
    • A21D2/08—Treatment of flour or dough by adding materials thereto before or during baking by adding organic substances
    • A21D2/36—Vegetable material
    • A21D2/362—Leguminous plants
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G9/00—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor
    • A23G9/32—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor characterised by the composition containing organic or inorganic compounds
    • A23G9/38—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor characterised by the composition containing organic or inorganic compounds containing peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G9/00—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor
    • A23G9/32—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor characterised by the composition containing organic or inorganic compounds
    • A23G9/42—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor characterised by the composition containing organic or inorganic compounds containing plants or parts thereof, e.g. fruits, seeds, extracts
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
    • A23J1/00—Obtaining protein compositions for foodstuffs; Bulk opening of eggs and separation of yolks from whites
    • A23J1/14—Obtaining protein compositions for foodstuffs; Bulk opening of eggs and separation of yolks from whites from leguminous or other vegetable seeds; from press-cake or oil-bearing seeds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L11/00—Pulses, i.e. fruits of leguminous plants, for production of food; Products from legumes; Preparation or treatment thereof
    • A23L11/05—Mashed or comminuted pulses or legumes; Products made therefrom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L11/00—Pulses, i.e. fruits of leguminous plants, for production of food; Products from legumes; Preparation or treatment thereof
    • A23L11/30—Removing undesirable substances, e.g. bitter substances
    • A23L11/31—Removing undesirable substances, e.g. bitter substances by heating without chemical treatment, e.g. steam treatment, cooking
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L15/00—Egg products; Preparation or treatment thereof
    • A23L15/35—Egg substitutes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A23L5/20—Removal of unwanted matter, e.g. deodorisation or detoxification
    • A23L5/21—Removal of unwanted matter, e.g. deodorisation or detoxification by heating without chemical treatment, e.g. steam treatment, cooking
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L9/00—Puddings; Cream substitutes; Preparation or treatment thereof
    • A23L9/10—Puddings; Dry powder puddings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C11/00—Milk substitutes, e.g. coffee whitener compositions
    • A23C11/02—Milk substitutes, e.g. coffee whitener compositions containing at least one non-milk component as source of fats or proteins
    • A23C11/10—Milk substitutes, e.g. coffee whitener compositions containing at least one non-milk component as source of fats or proteins containing or not lactose but no other milk components as source of fats, carbohydrates or proteins
    • A23C11/103—Milk substitutes, e.g. coffee whitener compositions containing at least one non-milk component as source of fats or proteins containing or not lactose but no other milk components as source of fats, carbohydrates or proteins containing only proteins from pulses, oilseeds or nuts, e.g. nut milk
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C20/00—Cheese substitutes
    • A23C20/02—Cheese substitutes containing neither milk components, nor caseinate, nor lactose, as sources of fats, proteins or carbohydrates
    • A23C20/025—Cheese substitutes containing neither milk components, nor caseinate, nor lactose, as sources of fats, proteins or carbohydrates mainly containing proteins from pulses or oilseeds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
    • A23J3/00—Working-up of proteins for foodstuffs
    • A23J3/22—Working-up of proteins for foodstuffs by texturising
    • A23J3/225—Texturised simulated foods with high protein content
    • A23J3/227—Meat-like textured foods

Definitions

  • the present disclosure provides diagnostic and therapeutic methods for the treatment of cancers with Hypoxia Inducible Factor 2 ⁇ (HIF-2 ⁇ ) inhibitors.
  • HIF-2 ⁇ Hypoxia Inducible Factor 2 ⁇
  • the present disclosure provides certain biomarkers for selection of patient suffering from cancer for treatment with HIF- 2 ⁇ inhibitors.
  • Background Hypoxia is characteristic of solid tumors and correlates with poor prognosis of cancer patients.
  • HIFs Hypoxia Inducible Factors
  • HIF ⁇ s are hydroxylated by prolyl hydroxylase domain (PHD) proteins, then ubiquitinated by the Von Hippel Lindau (VHL) E3 ligase complex and degraded by proteasome (Bishop, T. Ratcliffe, P. Hypoxia (Auckl).2014; 25 2:197-213).
  • PLD prolyl hydroxylase domain
  • VHL Von Hippel Lindau
  • HIF ⁇ s cannot be degraded effectively due to repressed hydroxylation with limited oxygen availability and subsequently suppressed ubiquitination-mediated degradation; thus, HIF ⁇ subunits accumulate and translocate to nucleus where they dimerize with HIF1 ⁇ and regulate transcription of downstream genes, which collectively drive the adaptation to hypoxia and cancer progression (Bishop, T.
  • HIFs regulated genes affect important cancer hallmarks including cell proliferation, apoptosis, differentiation, angiogenesis, genetic instability, tumor metabolism, tumor immune responses, invasion and metastasis, and also mediate resistance to chemo-, radiation therapy and targeted therapeutics (Wigerup, C., et al. Pharmacology & Therapeutics 164 (2016) 152–169). binding and two sequential PAS (PER ARNT SIM) domains (PAS A and PAS B) that facilitate heterodimerization with HIF-1 ⁇ /ARNT (Bersten, D.C., et al. Nat Rev Cancer, 13 (2013), pp.827- 841).
  • HIF1 ⁇ and HIF2 ⁇ are able to bind with hypoxia-response element (HRE) with core consensus sequence 5’-(A/G)CGTG-3’ on genome (Tian, H., et al. Genes Dev.1997 Jan 1; 11(1):72-82). and they share many downstream target genes, including 10 VEGFA, GLUT1, LDHA et al.
  • HIF-2 ⁇ expression is associated with numerous additional 15 cancers such as breast cancer, glioblastoma, neuroblasoma, head and neck squamous carcinoma and non-small cell lung cancer.
  • a method of treating a patient having cancer other than ccRCC wherein the cancer is characterized by at least one of: 25 (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; 30 (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene promoter; (viii) reduced function of HIF 1 ⁇ protein; the method comprising administering an effective amount of a HIF-2 ⁇ inhibitor to the patient in need thereof.
  • a method of treating a patient having cancer other than ccRCC comprising: (a) determining whether the patient has cancer that is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; 10 (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of 15 HIF-1 ⁇ gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene promoter; (vii) reduction or absence of HIF-1 ⁇ gene expression; and (viii) reduced function of HIF-1 ⁇ protein; and 20 (b) administering an effective amount of a HIF-2 ⁇ inhibitor to the patient who is
  • a method of identifying a patient having a cancer other than ccRCC who may benefit from treatment a HIF-2 ⁇ inhibitor comprising: (a) determining whether the patient has cancer that is characterized by at least one of: 25 (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; 30 (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene promoter; (viii) reduced function of HIF 1 ⁇ protein; wherein the presence at least one of: (i) absence or one or more of truncation,
  • the method further comprises administering an effective amount of a HIF-2 ⁇ inhibitor to the patient who is identified as one who may benefit from treatment with a HIF-2 ⁇ inhibitor.
  • a pharmaceutical composition comprising a HIF-2 ⁇ inhibitor for use in treatment of a patient having a cancer other than ccRCC, wherein the cancer is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, hypermethylation of VHL gene 25 promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, hypermethylation of HIF-1 ⁇ gene; 30 (vi) absence or one or more of truncation, insertion, mutation, hypermethylation of HIF-1 ⁇ gene promoter (vii) reduction or absence
  • a HIF-2 ⁇ inhibitor in the manufacture of a 5 medicament for treatment of a patient having a cancer other than ccRCC, wherein the cancer is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, hypermethylation of VHL gene (ii) absence or one or more of, truncation, insertion, mutation, hypermethylation of VHL 10 gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, hypermethylation of HIF-1 ⁇ gene; 15 (vi) absence or one or more of truncation, insertion, mutation, hypermethylation of HIF-1 ⁇ gene promoter (vii) reduction or absence of HIF-1 ⁇ gene expression; and (viii) reduced function of HIF-1 ⁇ protein.
  • the HIF-2 ⁇ inhibitor is a compound of (Formula (I): wherein: 25 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 30 together with the nitrogen atom to which they are attached form optionally substituted heterocyclyl, and each R 14 is hydrogen, alkyl, or haloal
  • the method of the first, second, and third aspects and the use of the fourth and fifth aspects above is wherein the HIF-2 ⁇ inhibitors are those disclosed in PCT application publication No. WO2015035223 in paragraphs entireties.
  • the HIF 2 ⁇ inhibitor is 3 (((1S,2S,3R) 2,3 difluoro 1 hydroxy 7 (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile.
  • the HIF-2 ⁇ inhibitor is a HIF-2 ⁇ gene-specific RNAi agent, as disclosed in PCT applications Publication Nos. WO2016196239 and WO2020146521.
  • paragraphs [0017] (i)-(iii), [0018] (i)-(iii) to [0042], [0046] to [0060], and RNAi agents disclosed in Tables 3, 4.1, 4.2, and 4.3 of WO2020146521 are incorporated herein in their entireties.
  • RNAi agents disclosed in 10 Table 1, 2A, 2B, and 3 or modified nucleotide thereof of WO2016196239 are incorporated herein in their entireties.
  • the HIF-2 ⁇ inhibitor is a compound of (II) or (III): 15 to the formulas numbered (I’) and (II), respectively, in PCT Application publication No.
  • the HIF-2 ⁇ inhibitor is a compound of Formula (IV): where Formula (IV) corresponds to formula (I) in PCT Application publication No.
  • the HIF-2 ⁇ inhibitor is Arcus AB521.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.
  • alkyl may include “alkylene” groups.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a 25 branched monovalent hydrocarbon radical of three to six carbon atoms containing a double bond, e.g., propenyl, butenyl, and the like.
  • Alkyldienyl is alkenyl as defined above that is attached via the terminal divalent carbon.
  • the alkyldienyl group is enclosed by the box which is indicated by the arrow.
  • Haloalkyldienyl is alkyldienyl that is substituted with one or two halo, each group as defined herein. branched monovalent hydrocarbon radical of three to six carbon atoms containing a triple bond, e.g., propynyl, butynyl, and the like.
  • Alkylthio means a -SR radical where R is alkyl as defined above, e.g., methylthio, 5 ethylthio, and the like.
  • Alkylsulfonyl means a –SO 2 R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • Alkylsulfoxide means a –SOR radical where R is alkyl as defined above, e.g., methylsulfoxide, ethylsulfoxide, and the like.
  • Amino means a –NH 2 .
  • Alkylamino means a -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.
  • Aminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with –NR’R” 15 where R’and R” are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkylcarbonyl, each as defined herein, e.g., aminomethyl, aminoethyl, methylaminomethyl, and the like.
  • Alkoxy means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
  • Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, such as one or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.
  • Alkoxycarbonyl means a –C(O)OR radical where R is alkyl as defined above, e.g., 25 methoxycarbonyl, ethoxycarbonyl, and the like.
  • Alkylcarbonyl means a –C(O)R radical where R is alkyl as defined herein, e.g., methylcarbonyl, ethylcarbonyl, and the like.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
  • Alkyl means a -(alkylene)-R radical where R is aryl as defined above, e.g., benzyl, phenethyl, and the like.
  • Bicyclic cycloalkyl means a fused bicyclic saturated monovalent hydrocarbon radical of six to ten carbon atoms, and is optionally substituted with one or two substituents independently decalin, octahydro 1H indene, and the like.
  • Cycloalkyl means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms optionally substituted with one or two substituents independently selected from 5 alkyl, alkyldienyl, halo, alkoxy, hydroxy, cyano, haloalkyldienyl and cyanoalkyl. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1- cyanocycloprop-1-yl, 1-cyanomethylcycloprop-1-yl, 3-fluorocyclohexyl, and the like. Cycloalkyl may include cycloalkylene as defined herein.
  • Cycloalkylalkyl means a -(alkylene)-R radical where R is cycloalkyl as defined above, 10 e.g., cyclopropylmethyl, cyclohexylmethyl, and the like.
  • Cycloalkylene means a divalent cycloalkyl, as defined above, unless stated otherwise.
  • Cycloalkenyl means a monocyclic monovalent hydrocarbon radical of three to ten carbon atoms containing one or two double bond(s) optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, cyano, and cyanoalkyl.
  • Oxocycloalkenyl means a monocyclic monovalent hydrocarbon radical of three to ten carbon atoms containing one or two double bond(s) and an oxo group, and is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, 20 cyano, and cyanoalkyl. Examples include, but are not limited to, 3-oxocyclohex-1-enyl, and the like.
  • Cyanoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with cyano e.g., cyanomethyl, cyanoethyl, and the like. 25 “Carboxy” means –COOH. “Dialkylamino” means a -NRR’ radical where R and R’ are alkyl as defined above, e.g., dimethylamino, methylethylamino, and the like.
  • “Disubstituted amino” means a –NRR’ radical where R and R’ are independently alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkylcarbonyl, each as defined herein, e.g., 30 dimethylamino, ethylmethylamino, bis-hydroxyethylamino, bis-methoxyethylamino, diethylaminoethylamino, and the like.
  • “Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
  • halogen atoms e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH 3 ) 2 , and the like.
  • halogen atoms e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH 3 ) 2 , and the like.
  • fluoroalkyl When the alkyl is substituted with only fluoro, it can be referred to in this 5 Application as fluoroalkyl.
  • Haloalkoxy means a –OR radical where R is haloalkyl as defined above e.g.,
  • R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy.
  • “Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon 10 atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2- 15 hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.
  • Heterocyclyl means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O) n , where n is an integer from 0 to 2, the remaining ring atoms being C, uless stated otherwise. Additionally, 20 one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO- group.
  • heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like.
  • heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • the 25 heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.
  • Heterocyclylalkyl or “heterocycloalkyl” means a –(alkylene)-R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
  • R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
  • Heterocyclylene means a divalent heterocyclyl, as defined above, unless stated otherwise. When heterocyclene contains 4, 5, or 6 rings atoms, it may be referred to herein as 4 to 6 membered heterocyclylene.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.
  • heteroaryl and “aryl” are mutually exclusive. When the heteroaryl ring contains 5- or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaryl.
  • Heteroarylene means a divalent heteroaryl radical as defined above.
  • Heteroaralkyl means a -(alkylene)-R radical where R is heteroaryl as defined above, 10 e.g., pyridinylmethyl, and the like.
  • heteroaryl ring in heteroaralkyl contains 5- or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaralkyl.
  • R 2 and R 9 are attached to the ring carbon atom that is meta to the ring carbon attached to R 1 ” means the R 2 and R 9 are located as indicated below: . 15
  • the term “oxo,” as used her nation, refers to (O).
  • any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkoxyalkyl means that an alkoxy group attached to the parent molecule through an alkyl group.
  • the present disclosure also includes protected derivatives of compounds of Formula (I).
  • Certain compounds of Formula (I) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, 30 Joachim M. Wiley-VHCA, Zurich, Switzerland 2003).
  • Prodrugs of the compounds of Formula (I) physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • a wide variety 5 of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • prodrug a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound of Formula (I). 10
  • a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as 15 formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 20 4-toluenesulf
  • the compounds of Formula (I) may have asymmetric centers.
  • Compounds of Formula (I) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth.
  • cyclic groups such as aryl, heteroaryl, heterocyclyl are substituted, they include all the positional isomers albeit only a few examples are set forth.
  • all 15 hydrates of a compound of Formulae (I) are within the scope of this disclosure.
  • the compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question. that differ only in the presence of one or more isotopically enriched atoms.
  • Exemplary isotopes 20 that can be incorporated into a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 1 7 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 1, respectively.
  • Isotopically labeled compounds e.g., those labeled with 3 H and 14 C
  • 25 Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • substituents such as deuterium (i.e., 2 H)
  • one or more hydrogen atoms are replaced by 2 H or 3 H, or one 30 or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C, and 15 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the reagent.
  • Certain structures provided herein are drawn with one or more floating substituents. Unless provided otherwise or otherwise clear from the context, the substituent(s) may be present on any 5 atom of the ring to which it is attached, where chemically feasible and valency rules permitting.
  • the R 7 substituent can replace any hydrogen on the benzo portion of the t ng the hydrogen of CH when X 1 is CH.
  • Optionally substituted aryl means aryl that is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, cycloalkyl, carboxy, 10 alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano.
  • Optionally substituted heteroaryl means heteroaryl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, 15 haloalkoxy, amino, alkylamino, dialkylamino, and cyano.
  • Optionally substituted heterocyclyl means heterocyclyl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl, haloalkoxy, and cyano, unless stated 20 otherwise.
  • “Optionally substituted heterocyclylene” is divalent optionally substituted heterocyclyl as defined above.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither 25 biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • “Spirocycloalkyl” means a saturated bicyclic ring having 6 to 10 ring carbon atoms 30 wherein the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ("spiro carbon").
  • the spirocycloalkyl ring is optionally and cyano.
  • Representative examples include, but are not limited to, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane (1:2:1:1), and the like.
  • “Spiroheterocyclyl” means a saturated bicyclic ring having 6 to 10 ring atoms in which 5 one, two, or three ring atoms are heteroatom selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”).
  • the spiroheterocyclyl ring is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, 10 alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl, haloalkoxy, and cyano.
  • Representative examples include, but are not limited to, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, and the like.
  • the term “about,” as used herein, is intended to qualify the numerical values which it 15 modifies, denoting such a value as variable within a margin of error.
  • disease as used herein is intended to be generally synonymous, and is used 25 interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • combination therapy means the administration of two or more therapeutic 30 agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient.
  • administering means taking a therapeutic compound and additionally means giving or dispensing a therapeutic compound to a patient which the patient takes, e.g., by infusion, inhalation, injection, application, paste, suppository, capsule, film, or tablet.
  • administering means prescribing the therapeutic compound to a patient which the patient takes. In some embodiments, including any of the foregoing embodiments, administering means dispensing the therapeutic compound to a patient which the patient takes. In some embodiments administering means supervising the taking of the therapeutic compound. 15 “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e.
  • a “therapeutically effective amount” means the amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease.
  • the “therapeutically 25 effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • inhibiting includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 30 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of HIF-2 ⁇ activity compared to normal.
  • a “mutant” or “mutants” may refer to either a polypeptide or a nucleic acid.
  • mutant may be used interchangeably with the term “variant.” Mutants include insertions, deletions, substitutions, transversions, truncations, and/or inversions at one or more locations in phrases mutant polypeptide, mutant protein, and mutant enzyme refer to a protein that has an amino acid sequence that has been modified from the amino acid sequence of a wild-type protein.
  • the mutant polypeptides include a polypeptide having a certain percent, e.g., at least 5 about 80%, 85%, 90%, 95%, or 99%, of sequence identity with the wild type polypeptide or protein.
  • Mutants may have 1, 2, 3, 4, 5, 10, 15, 20, 30, or more amino acid substitutions, additions, or deletions, or any integral value within the range of 1-100, compared to the wild-type sequence.
  • the mutant can comprise a signal peptide of another protein or a sequence designed to aid identification or purification of the expressed fusion protein, such as a His-Tag sequence.
  • the term “mutation” of a VHL gene refers to one or more changes in the nucleotide sequence of the VHL gene and the consequence may be loss of or reduced function of the VHL protein.
  • the term “mutation” of VHL gene promoter refers to one or more changes in the nucleotides sequence of the VHL gene promoter and the consequence may be the loss of or reduced expression of VHL protein.
  • mutant of HIF-1 ⁇ gene refers to one or more changes in the nucleotide 15 sequence of the HIF-1 ⁇ gene and the consequence could be loss of or reduced function of the HIF-1 ⁇ protein.
  • mutant of HIF-1 ⁇ gene promoter refers to one or more changes in the nucleotides sequence of the HIF-1 ⁇ gene promoter possibly resulting in the loss of or reduced expression of HIF-1 ⁇ protein.
  • Inserts refer to gene or protein mutations comprising the addition of one or more 20 nucleic acid or amino acid residues, respectively.
  • insertion of VHL gene means the addition of one or more nucleotide base pairs into the DNA sequence of VHL gene.
  • VHL gene promoter means the addition of one or more nucleotide base pairs into the DNA sequence of VHL gene promoter region.
  • insertion of HIF-1 ⁇ gene means the addition of one or more nucleotide base pairs into the DNA sequence of HIF-1 ⁇ gene.
  • 25 insertion of HIF-1 ⁇ gene promoter means the addition of one or more nucleotide base pairs into the DNA sequence of HIF-1 ⁇ gene promoter region.
  • absence of a gene promoter refers to the loss or nonexistence of the promoter region of the gene.
  • Cancer sample refers to a sample derived from, obtained by, generated from, provided 30 from, taken from, or removed from a patient; or from fluid or tissue from the patient.
  • Cancer samples include, but are not limited to synovial fluid, whole blood, blood serum, blood plasma, urine, sputum, tissue, saliva, tears, hair, spinal fluid, tissue section(s) obtained by biopsy, cell(s), or any combination thereof that are placed in or adapted to tissue culture, sweat, mucous, fecal material, gastric fluid, abdominal fluid, amniotic fluid, cyst fluid, peritoneal fluid, pancreatic juice, the like including derivatives, portions and combinations of the foregoing.
  • cancer samples include, but are not limited, to blood and/or plasma.
  • cancer samples include, but are not limited, to urine or stool.
  • Cancer samples include, but are not limited, 5 to saliva.
  • Cancer samples include, but are not limited, to tissue dissections and tissue biopsies. Cancer samples include, but are not limited, samples that can provide nucleic acids for analysis. Cancer samples include, but are not limited, any derivative or fraction of the aforementioned cancer samples. “Fragments" of proteins or peptides, i.e., fragments of amino acid sequences, in the context 10 of the present invention may, typically, comprise a sequence of a protein or peptide as defined herein, which is, with regard to its amino acid sequence (or its encoding nucleic acid molecule), N-terminally, C-terminally and/or intrasequentially truncated compared to the amino acid sequence of the original (native) protein (or its encoded nucleic acid molecule).
  • Such truncation may thus occur either on the amino acid level or correspondingly on the nucleic acid level.
  • a 15 sequence identity with respect to such a fragment as defined herein may therefore preferably refer to the entire protein or peptide as defined herein or to the entire (coding) nucleic acid molecule of such a protein or peptide.
  • Peptides comprising deletion at the N-terminal and/or C-terminal end of the protein are also called N-terminal and/or C-terminal truncation variants.
  • a “truncated” protein may be encoded by mature mRNA lacking one or part of an exon, or 20 more exons of the gene responsible for the full length protein, and still has, at least to some extent, the functions (particularly, functions related to altering gene expression) of the full-length protein encoded by the normal gene corresponding to the gene.
  • “Truncation” of the VHL gene refers to certain region of the VHL gene being missing and subsequently, resulting in a shorter, defective VHL protein.
  • the term “truncation” of VHL gene 25 promoter refers to a VHL promoter lacking certain region(s) resulting in the possible loss of or reduced expression of VHL protein.
  • HIF-1 ⁇ gene refers to a HIF-1 ⁇ gene missing one or more regions, subsequently resulting in a shorter, defective HIF-1 ⁇ protein.
  • Trusted” of a HIF-1 ⁇ gene promoter means that certain region(s) of the HIF-1 ⁇ gene promoter are missing, possibly leading to the loss of or reduced expression of HIF-1 ⁇ protein.
  • 30 “Hypomethylation” and “hypermethylation” of DNA are relative terms and denote less or more methylation than in some standard DNA. When applied to cancer epigenetics, that standard is normal tissue. Methylation may occur within the promoter regions of tumor suppressor genes, resulting in their silencing, and methylation within the gene itself may induce mutational events.
  • DNA methylation is an important regulator of gene transcription. Alterations in DNA methylation in non promoter region may be implicated as a cause of oncogenesis.
  • the term “hypermethylation” of VHL gene refers to an increase in the methylation of cytosine and/or adenosine nucleotides in the VHL gene, which can result in the loss of or reduced levels of VHL 5 protein.
  • the term “hypermethylation” of VHL gene promoter means an increase in the methylation of cytosine and/or adenosine nucleotides in the VHL gene promoter region, which may result in the loss of or reduced levels of VHL protein expression.
  • “Hypermethylation” of HIF-1 ⁇ gene refers to an increase in the methylation of cytosine and/or adenosine nucleotides in the HIF-1 ⁇ gene, which may result in the loss of or reduced HIF-1 ⁇ protein.
  • “Hypermethylation” 10 of a HIF-1 ⁇ gene promoter refers to an increase in the methylation of cytosine and/or adenosine nucleotides in the HIF-1 ⁇ gene promoter region, which may result in the loss of or reduced HIF- 1 ⁇ protein expression.
  • DNA methylation profiling can provide higher clinical sensitivity and dynamic range compared to somatic mutation analysis for cancer detection.
  • altered DNA 15 methylation signature has been shown to correlate with the prognosis of treatment response for certain cancers.
  • widespread and reproducible methylation changes demonstrate an important role for methylation alterations in renal cell carcinomas, colorectal cancers, and many other cancer types.
  • Gene expression refers to the tightly regulated process that allows a cell to respond to its changing environment.
  • RNA or protein acts as both an on/off switch to control when proteins are made and also a volume control that increases or decreases the amount of proteins made.
  • Gene expression is primarily controlled at the level of transcription, largely as a result of binding of proteins 25 (transcription factors) to specific sites on DNA.
  • Downregulation or upregulation of an RNA or protein may also arise by an epigenetic alteration.
  • the epigenetic alteration can be permanent or semi-permanent in a somatic cell lineage. Such an epigenetic alteration can result in expression of RNA or protein that no longer respond to an external stimulus. This occurs, for instance, in some cancers.
  • VHL gene refers to the loss or nonexistence of VHL gene.
  • absence of VHL gene promoter refers to the loss or the loss or nonexistence of HIF 1 ⁇ gene.
  • absence of HIF 1 ⁇ gene promoter refers to the loss or nonexistence of the promoter region of HIF-1 ⁇ gene.
  • Reduced gene function i.e., down regulation
  • a cell decreases the 5 quantity of a cellular component, such as RNA or protein, in response to an external stimulus.
  • the complementary process that involves increases of such components is called upregulation.
  • An example of downregulation is the cellular decrease in the expression of a specific receptor in response to its increased activation by a molecule, such as a hormone or neurotransmitter, which reduces the cell's sensitivity to the molecule.
  • wild type denotes the most common, typical phenotype in a natural healthy population.
  • wild type denotes an organism or gene locus that predominates in natural or normal populations.
  • the present disclosure includes: 15 1.
  • a method of treating a patient having cancer other than ccRCC wherein the cancer is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL 20 gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene; 25 (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene promoter; (vii) reduction or absence of HIF-1 ⁇ gene expression; and (viii) reduced function of HIF-1 ⁇ protein; the method comprising administering an effective amount of a HIF-2 ⁇ inhibitor to a
  • a method of treating a patient having cancer other than ccRCC comprising: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of 5 VHL gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene; 10 (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene promoter; (vii) reduction or absence of HIF-1 ⁇ gene expression; and (viii) reduced function of HIF-1 ⁇ protein; and (b) administering an effective amount of a HIF-2 ⁇ inhibitor to the patient who is determined to 15 have a cancer that is characterized by at least one of (a)(i)-(
  • a method of identifying a patient having a cancer other than ccRCC who may benefit from treatment a HIF-2 ⁇ inhibitor comprising: (a) determining whether the patient has cancer that is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL 20 gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; 25 (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene promoter; (vii) reduction or absence of HIF-1 ⁇ gene expression; and 30 (viii) reduced function of HIF-1 ⁇ protein; wherein the presence at least one of: (i) absence or one or more of
  • the method further comprises administering an effective amount of a HIF-2 ⁇ inhibitor to the patient who is identified as one who may benefit from treatment with a HIF-2 ⁇ inhibitor 15 4.
  • the method of embodiment 2 or 3 is wherein the presence of at least one of the following: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL 20 gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene; 25 (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1 ⁇ gene promoter; (vii) reduction or absence of HIF-1 ⁇ gene expression; and (viii) reduced function of HIF-1 ⁇ protein
  • the method of embodiment 4 is wherein the absence, truncation, insertion, mutation, hypermethylation of one or more of VHL gene, VHL gene promoter, HIF-1 ⁇ gene, and/or HIF-1 ⁇ gene promoter in the cancer sample is determined by whole genome sequencing, exome sequencing, targeted gene sequencing, methylation sequencing, or a combination thereof. insertion, mutation, hypermethylation of one or more of VHL gene, VHL gene promoter, HIF 1 ⁇ gene, and/or HIF-1 ⁇ gene promoter in the cancer sample is different from wild type VHL gene, VHL gene promoter, HIF-1 ⁇ gene, and HIF-1 ⁇ gene promoter, respectively. 5 7.
  • the method of any one of embodiments 2 to 4 is wherein the expression level of one or more of VHL gene, VHL protein, HIF-1 ⁇ gene and/or HIF-1 ⁇ protein in the cancer sample is below the reference expression level of the corresponding one or more of VHL gene, VHL protein, HIF-1 ⁇ gene and/or HIF-1 ⁇ protein.
  • the method of embodiment 6 is wherein the reference expression 10 level of the VHL gene, VHL protein, HIF-1 ⁇ gene and/or HIF-1 ⁇ protein is determined from a population of patients having the same cancer.
  • the method of embodiment 7 or 8 is wherein the expression level and the reference expression level are a nucleic acid expression level and the nucleic acid expression level is an mRNA expression level. 15 10.
  • the method of embodiment 9 is wherein the mRNA expression level is determined by RNA-seq, QuantiGene RNA Assay, Nanostring, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, or ISH, or a combination thereof.
  • the method of embodiment 7 or 8 is wherein the expression 20 level and the reference expression level are a protein expression level. 12.
  • the method of embodiment 11 is wherein the protein expression level is determined by immunohistochemistry (IHC), Western blot, enzyme-linked immunosorbent assay (ELISA), AlphaLISA immunoassay, immunoprecipitation, immunofluorescence, electrochemiluminescence detection, homogeneous time resolved 25 fluorescence (HTRF) assay, radioimmunoassay, or mass spectrometry.
  • the method of any one of embodiments 4 to 12 is wherein the cancer sample is a tissue sample, a cell sample, a whole blood sample, a plasma sample, a serum sample, or a combination thereof.
  • the method of embodiment 13 is wherein the tissue sample is a 30 tumor tissue sample. 15.
  • a pharmaceutical composition comprising a a HIF- 2 ⁇ inhibitor for use in treatment of a patient having a cancer other than ccRCC, wherein the cancer is characterized by at least one of: (i) absence, truncation, mutation, hypermethylation of VHL gene; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence, truncation, mutation, hypermethylation of HIF-1a gene; 5 (vi) absence, truncation, mutation, hypermethylation of HIF-1 ⁇ gene promoter; (vii) reduction or absence of HIF-1a gene expression; and (viii) reduced function of HIF-1a protein; and wherein the treatment comprises administration of the pharmaceutical composition to the patient having a cancer other than ccRCC.
  • a HIF-2 ⁇ inhibitor in the manufacture of a medicament for treatment of a patient having a cancer other than ccRCC, wherein the cancer is characterized by at least one of: (i) absence, truncation, mutation, hypermethylation of VHL gene (ii) absence, truncation, mutation, hypermethylation of VHL gene promoter; 15 (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence, truncation, mutation, hypermethylation of HIF-1a gene; (vi) absence, truncation, mutation, hypermethylation of HIF-1 ⁇ gene promoter; (vii) reduction or absence of HIF-1a gene expression; and 20 (viii) reduced function of HIF-1a protein.
  • a method of treating cancer other than ccRCC in a patient in need thereof comprising: (A) determining whether the patient will respond to HIF2 ⁇ inhibitor-based therapy, by measuring the expression level of at least one of: 25 (i) absence or one or more of truncation, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; 30 (iv) reduced function of VHL protein; (v) absence or at least one of truncation, mutation, and hypermethylation of HIF-1a gene; (vi) absence or at least one of truncation, mutation, and hypermethylation of HIF-1 ⁇ gene promoter; (viii) reduced function of HIF 1a protein; in a patient sample; and (B) comparing the expression level measured in the patient sample in (A) with a 5 corresponding reference expression level derived from subject(s) with
  • the reference level controls for more than one parameter (e.g. two, three, four, five, or 25 more parameters) as provided in embodiments 19-23.
  • the term “population of individuals” means one 30 or more individuals.
  • the population of individuals comprises multiple individuals.
  • the term “multiple” means at least 2 (such as at least 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 30) individuals.
  • the population of individuals comprises at least 10 individuals. individual. 25.
  • the method of any one of embodiments 1 to 24 is wherein the cancer is a solid cancer. 5 26.
  • the HIF-2 ⁇ inhibitor is according to Formula (I): wherein: 10 X 1 is CH or N; R 1 is hydroxy, halo, amino, -OP(O)(OH)2, -OCH2OP(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 15 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,
  • the method of embodiment 26, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R 3 and R 4 are independently 20 halo.
  • the method of embodiment 26 is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R 3 is halo and R 4 is hydrogen. 29.
  • the method of embodiment 26, or 27 is wherein the compound 25 of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R 1 is hydroxy.
  • the method of any one of embodiments 26 or 27, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein is R 1 is amino. 31.
  • the method of any one of embodiments 26 to 30, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R 6 is halo. 30 32.
  • the method of any one of embodiments 26 to 30, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R 6 is alkyl, preferably R 6 is methyl.
  • the method of any one of embodiments 26 to 30, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R 6 is hydrogen.
  • R is cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 35.
  • the method of any one of embodiments 26 to 34 is wherein the 5 compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R 5 is halo, preferably fluoro. 36.
  • the method of any one of embodiments 26 to 34 is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R 5 is haloalkyl, preferably R 5 is difluoromethyl or trifluoromethyl. 10 37.
  • the method of any one of embodiments 26 to 34 is wherein the compound of Formula (I)or a pharmaceutically acceptable salt thereof, is wherein R 5 is alkyl, preferably R 5 is methyl or ethyl. 38. In embodiment 38, the method of any one of embodiments 26 to 34, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R 5 is hydrogen 15 or alkoxy. 39.
  • the method of any one of embodiments 26 to 34 is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R 5 and R 6 together with the carbon to which they are attached form 3 to 6 membered cycloalkylene, preferably cyclopropylene, cyclobutylene or cyclopentylene optionally substituted with one or two 20 fluoro.
  • the method of any one of embodiments 26 to 39 is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein X 1 is CR 7 . 41.
  • the method of embodiment 26, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, has the structure of formula (IIa1) or 25 (IIb1): 42.
  • the method of embodiment 26 is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, having the structure of formula (IIa1’) 30 or (IIb1’): 43.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof has the structure of formula (IIa) or 5 (IIb): 44.
  • the compound of 10 Formula (I) or a pharmaceutically acceptable salt thereof has the structure of formula (IIa’) or (IIb’): 15 45.
  • the method of embodiment 26 is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, has the structure of formula (IVa): cycloalkylene, preferably cyclopropylene, cyclobutylene or cyclopentylene optionally substituted with one or two fluoro. 46.
  • the method of any one of embodiments 41 to 45 is wherein the 5 compound of Formulae (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, is wherein R 3 is fluoro. 47.
  • the method of any one of embodiments 41to 45 is wherein the compound of Formulae (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, is where R 3 and R 4 are fluoro. 10 48.
  • the method of any one of embodiments 26 to 47 is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, is wherein L is O, S, SO, SO 2 , or NH. 49.
  • the method of embodiment 48 is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) a pharmaceutically 15 acceptable salt thereof, is wherein L is O. 50.
  • the method of any one of embodiments 26 to 49 is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) is wherein R 8 is cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or 20 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
  • the method of any one of embodiments 26 to 49, and subembodiments contained therein is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, is 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, 30 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
  • the method of embodiment 51 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein the compound of Formulae (I), 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-methyphenyll, 3-cyanophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3-chloro-2- 5 methylphenyl, 3,5-dichlorophenyl, 3,5-dimethylphenyl, 2-chloro-6-methylphenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 4-fluoro-3-methylphen
  • R 10 is 3-cyano-5-fluorophenyl or 3-cyano-5-fluoro-2,4,6- trideuteriophenyl. 10 53.
  • the method of any one of embodiments 29 to 49 and any subembodiments contained therein is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, is wherein R 8 is cycloalkyl or cycloalkylalkyl each optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, cyano, and hydroxy.
  • the method of any one of embodiments 26 to 49 and any subembodiments contained therein is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) 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, 20 aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.
  • R 8 is heteroaryl substituted with R a , R b , and R c independently selected from hydrogen, alkyl, haloalkyl, haloalkyloxy, al
  • the method of any one of embodiments 26 to 49 is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt, thereof, is wherein R 8 is pyridin-3-yl, pyridin-2-yl, pyridazin-3- 25 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-5-yl, furan-3-yl,
  • the method of any one of embodiments 26 to 56 is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a 5 pharmaceutically acceptable salt thereof, is wherein R 2 is hydrogen, fluoro, methyl or ethyl. 58.
  • the method of any one of embodiments 26 to 57 is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIB’) and (IVa) or a pharmaceutically acceptable salt thereof, is wherein R 9 is hydrogen, alkyl, halo, hydroxy, or alkoxy. 10 59.
  • the method of any one of embodiments 26 to 57 is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, is wherein R 9 is hydrogen, methyl, methoxy, or fluoro.
  • the method of embodiment 26 to 59 is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a 15 pharmaceutically acceptable salt thereof, is wherein R 2 and R 9 are attached to the ring carbon atom that is meta to the ring carbon attached to R 1 .
  • the method of any one of embodiments 52 or 55 is wherein the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof and has the structure of formula (VIIIa1) or (VIIIb1): 20 preferably the structure of formula (VIIIb).
  • the method of embodiment 61 is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R 2 is hydrogen or deuterium, 25 R 9 is hydrogen, fluoro, or methyl and R 2a and R 9a are independently hydrogen, deuterium or fluoro. 63.
  • the method of embodiment 26, is 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- 30 cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 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; 5 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), 3-fluor
  • the method of embodiment 25, is wherein the compound of Formula (I) is selected from: 20 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; and a pharmaceutically acceptable salt thereof. 25 65.
  • the method of embodiment 26 is 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.
  • the method of embodiment 26 is wherein the compound of Formula (I) is 3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H- 30 cyclopenta[cd]inden-7-yl)oxy)-benzonitrile.
  • the method of the tenth aspect and any one of embodiments 1 to 24, is wherein the HIF-2 inhibitor is selected from the group consisting of:
  • the method of any one of embodiments 1 to 67 is wherein the 5 cancer is selected from kidney cancer of non-clear cell subtypes, 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, 10 gastric cancer, esophageal cancer, lymphoma, melanoma, mesothelioma, sarcoma, and neuroendocrine tumors.
  • the 5 cancer is selected from kidney cancer of non-clear cell subtypes, glioblastoma, neuroblastoma, paraganglio
  • the method of any one of embodiments 26 to 67 is wherein the cancer is selected from ovarian cancer, breast cancer, prostate cancer, kidney cancer of non-clear cell subtypes, colorectal cancer, uveal melanoma, pancreatic cancer, urothelial cancer, endometrial 15 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, 20 biliary tract cancer
  • the method of any one of embodiments 26 to 69 is wherein the cancer is a solid cancer.
  • the method of any one of embodiments 26 to 70, is wherein the 25 method further comprises administering one or more additional anti-cancer agents.
  • the starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, 10 chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
  • the reactions described herein take place at atmospheric pressure over a temperature range from about –78 o C to about 150 o C, such as from about 0 o C to about 125 o C and further such as at about room (or ambient) temperature, e.g., about 20 o C.
  • 2-bromo-4-fluorobenzaldehyde ethyl 2-bromo-2,2-difluoroacetate
  • ethyl 2-bromo- 2-methylpropanoate ethyl 2-bromopropanoate
  • ethyl 2-bromoacetate are commercially available.
  • the hydroxyl group in 1-c can be oxidized under oxidative conditions such as 2-iodoxybenzoic acid (IBX) or TPAP, NMO to give a ketone of formula 1-d.
  • the keto group in compound of formula 1-d can be functionalized to provide compound of formula 1-e where R 5 and R 6 are as described in the Summary by methods well known in the art.
  • a compound of formula 1-e where R 5 and R 6 are fluoro can be synthesized from 1-d by treatment with a 15 fluorinating agent such as DAST or SF 4 under conditions well known in the art.
  • Cyclization of 1-e can be achieved by treating it with alkyl lithium reagent such n-BuLi to give ketone 1-f.
  • the carbonyl group in 1-f can be reduced with reducing reagents such as NaBH 4 to provide alcohol 1- g. 1 g, followed by treating the lithio intermediate with CBr 4 .
  • Oxidation of 1 h with oxidative reagents such as IBX provides ketone of formula 1-i.
  • allyl metal reagent such as allyl magnesium bromide
  • compound of formula 1-j can be prepared from 1-f by addition of allyl metal reagent such as allyl magnesium bromide to compounds of formula 1-f illustrated below: h bromination reagent such as CBr4 or 1,2-dibromotetrafluoroethane provides compound of formula 10 1-j.
  • enantioselective synthesis of compounds of formula 1-g can be achieved by addition of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to compounds of formula 1-f in the presence of a ligand such as 1-m and a suitable base such as tBuONa in organic solvents such as MeOH, toluene as depicted below: 15 Compoun f Pd catalyst with suitable ligands such as Pd(dppf)Cl 2 CH 2 Cl 2 or Pd(PPh 3 ) 2 Cl 2 to provide compounds of formula 1-k.
  • the fluoro group in compounds of formula 1-k can be converted to a group of formula -L-R 8 where L and R 8 are as described in the Summary by treating compound 1-k with a compound of formula R 8 -LH where L is N, O, or S and R 8 is a defined in the Summary by method well known 20 in the art.
  • Compounds of formula R 8 -LH are commercially available or they can be prepared by methods well known in the art.
  • compounds of Formula (I) where with R 1 is hydroxyl, R 2 is hydrogen and R 9 is hydroxy or fluoro can be synthesized from the compounds of Formula (I) where R 9 and R 2 are combined to form oxo by further functionalizing the carbonyl group as 15 illustrated and described in Methods (i) and (ii) below.
  • Method (i) A c o form oxo can be converted to a compound of Formula (I) where R 1 is hydroxy, R 9 is hydroxy by treating it with 20 reducing reagent such as sodium borohydride under conditions well known in the art.
  • the HIF-2 ⁇ compounds can be used for the treatment of cartilage cancer(s), skin cancer(s), salivary gland cancer, gastric cancer, stomach cancer, liver cancer, endometrial cancer, bladder cancer, mesothelioma, sarcoma, esophageal cancer, lymphoma, uveal melanoma, urothelial cancer, fallopian tube cancer, primary peritoneal cancer, cholangiocarcinoma, Ewing Sarcoma, uterine leiomyosarcoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, T-cell- 15 prolymphocytic leukemia, chronic myelogenous leukemia, germ cell cancer, osteosarcoma, biliary tract cancer, soft-tissue sarcoma, rhabdomyosarcoma, mantle-cell lymphoma, and endocrine gland neoplasms.
  • the HIF-2 ⁇ inhibitors of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the therapeutically effective amount of a HIF-2 ⁇ inhibitor may range from about 0.01 to about 100 mg per kg patient body weight per day, which can be administered in single or multiple 25 doses.
  • a suitable dosage level for the HIF-2 ⁇ inhibitor may be from about 0.1 to about 50 mg/kg per day, about 0.5 to about 15 mg/kg per day.
  • compositions can be provided in the form of tablets containing about 20 to about 800 milligrams of the HIF-2 ⁇ inhibitor active ingredient, particularly about 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of HIF-2 ⁇ inhibitors, i.e., the active ingredients will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.
  • compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • oral systemic
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • the preferred manner of administration is oral using a convenient daily dosage regimen, which can be 5 adjusted according to the degree of affliction.
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • compositions are comprised of in general, a HIF-2 ⁇ inhibitors this disclosure in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the HIF- 15 2 ⁇ inhibitor.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may 20 be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • the compounds may be formulated for parenteral administration by injection, e.g., by 25 bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules 30 and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and 5 thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the 10 preparation of highly concentrated solutions.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials 15 (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials 15 for example as an emulsion in an acceptable oil
  • ion exchange resins for example, as a sparingly soluble salt.
  • the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • the level of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt. %) basis, 25 from about 0.01-99.99 wt. % of a HIF-2 ⁇ inhibitor based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the HIF-2 ⁇ inhibitor is present at a level of about 1-80 wt. %.
  • the combination therapy disclosed herein may be carried out with one or more other anti- cancer drugs that are useful in the treatment of cancers for which compounds of this disclosure 30 have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, simultaneously or sequentially with the HIF-2 ⁇ inhibitor.
  • the HIF-2 ⁇ inhibitor and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure also include those compounds of this disclosure to such other active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • anti-cancer agents include, but are not limited to, gossypol, 5 genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2’-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec TM ), geldanamycin, 17-N- Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, Taxol TM , also referred to as “paclitaxel”, 10 which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubul
  • kinases associated cell proliferative disorder. These kinases include, but not limited to, Aurora-A, BTK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, 15 Fes, Syk, Itk, Bmx, GSK3, JNK, MEK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, RAF, Rsk and SGK.
  • Aurora-A BTK
  • CDK1, CDK2, CDK3, CDK4, CDK6, CDK5, CDK7, CDK8, CDK9 ephrin receptor kinases
  • CHK1, CHK2, SRC Yes, Fyn, Lck, Fer, 15 Fes, Syk, Itk, Bmx, GSK3, JNK, MEK, PAK1, PAK2, PAK3, PAK4, PDK
  • inhibitors of CDK4/6 including abemaciclib (Verzenio), palbociclib (Ibrance) and ribociclib (Kisqali), have the potential to be synergistic with HIF-2 ⁇ inhibitors and reverse the resistance to HIF-2 ⁇ inhibition; mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, 20 wortmannin, or LY294002; Syk inhibitors; antibodies (e.g., rituxan); MET inhibitor such as foretinib, carbozantinib, or crizotinib; VEGFR inhibitor such as sunitinib, sorafenib, regorafinib, lenvatinib, vandetanib, carbozantinib, axitinib; EGFR inhibitor such as afat
  • anti-cancer agents include proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib;BET inhibitors such as INCB054329, OTX015, CPI-0610;LSD1 inhibitors such as GSK2979552, INCB059872; HDAC inhibitors such as panobinostat, vorinostat; DNA methyl transferase inhibitors such as azacytidine, decitabine, and other epigenetic protein inhibitors; HIF 2 ⁇ inhibitors such as PT2977 and PT2385; Beta catenin pathway inhibitors, notch pathway inhibitors and hedgehog pathway inhibitors; Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept.
  • LXR liver X receptor
  • AhR aryl hydrocarbon receptor
  • anti-cancer agents that can be employed in combination with the compounds of this disclosure include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; 10 aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmus
  • anti-cancer agents that can be employed in combination with the compounds of the disclosure include: 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; 15 anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-C
  • anticancer agents that can be employed in combination with the compounds of present disclosure include alkylating agents, antimetabolites, natural products, or hormones, e.g., 25 nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.).
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.
  • alkyl sulfonates e.g., busulfan
  • nitrosoureas e.g., carmustine, lomusitne, etc.
  • triazenes decarbazine, etc.
  • antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
  • natural products useful in combination with the compounds of this disclosure include but are not limited to vinca alkaloids (e.g., vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L- asparaginase), or biological response modifiers (e.g., interferon alpha).
  • vinca alkaloids e.g., vincristine
  • epipodophyllotoxins e.g., etoposide
  • antibiotics e.g., daunorubicin, doxorubicin, bleomycin
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.
  • ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
  • alkyl sulfonates e.g., busulfan
  • nitrosoureas e.g., carmustine, 5 lomusitne, semustine, streptozocin, etc.
  • triazenes decarbazine, etc.
  • antimetabolites include, but are not limited to, folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
  • folic acid analog e.g., methotrexate
  • pyrimidine analogs e.g., fluorouracil, floxuridine, cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
  • hormones and antagonists useful in combination the compounds of this 10 disclosure include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).
  • adrenocorticosteroids e.g., prednisone
  • progestins e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate
  • estrogens e
  • platinum coordination complexes e.g., cisplatin, carboblatin
  • anthracenedione e.g., mitoxantrone
  • substituted urea e.g., hydroxyurea
  • methyl hydrazine derivative e.g., procarbazine
  • adrenocortical suppressant e.g., mitotane, aminoglutethimide
  • anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and include Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as 25 Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known
  • Additional anti-cancer agents that can be used in combination with the HIF-2 ⁇ inhibitors include PARP inhibitors such as olaparib (4-[(3-[(4-cyclopropylcarbonyl)piperazin-1-yl]carbonyl) -4-fluorophenyl]methyl(2H)phthalazin-1-one), rucaparib (8-fluoro-2-(4-methyl)-1,3,4,5-30 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
  • immune checkpoint inhibitors include inhibitors (smack molecules or biologics) against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, 5 CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, SHP-2, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2.
  • inhibitors smack molecules or biologics
  • immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, 5 CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137 and STING.
  • the immune checkpoint 10 molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT and VISTA.
  • the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody.
  • the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224.
  • the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001.
  • the anti-PD1 antibody is pembrolizumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody.
  • the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C.
  • the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is ipilimumab or tremelimumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
  • the anti- LAG3 antibody is BMS-986016 or LAG525.
  • the inhibitor of an immune 30 checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody.
  • the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein.
  • OX40 e.g., an anti-OX40 antibody or OX40L fusion protein.
  • the anti-OX40 antibody is LAG525.
  • the OX40L fusion protein is MEDI6383
  • Compounds of the invention can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including 5 increasing vaccine efficacy; and to increase inflammation.
  • the compounds of the invention can be sued to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viarl vaccines, and cancer vaccines such as GVAX® (granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine).
  • GVAX® granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine.
  • Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and 10 recombinant viruses.
  • Other immune-modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists.
  • Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.

Abstract

The present disclosure provides diagnostic and therapeutic methods for the treatment of cancers with Hypoxia Inducible Factor 2α (HIF-2α) inhibitors. In particular, the present disclosure provides certain biomarkers for selection of patient suffering from cancer for treatment with HIF-2α inhibitors.

Description

DIAGNOSTIC AND THERAPEUTIC METHODS FOR TREATMENT OF CANCER WITH A HIF-2(ALPHA) INHIBITOR 5 Cross-Reference to Related Applications This Application is a PCT International Application claiming the benefit of U.S. Provisional Application No.63/094,883, filed on October 21, 2020, the entire contents of which are hereby incorporated by reference. 10 Field of the disclosure The present disclosure provides diagnostic and therapeutic methods for the treatment of cancers with Hypoxia Inducible Factor 2α (HIF-2α) inhibitors. In particular, the present disclosure provides certain biomarkers for selection of patient suffering from cancer for treatment with HIF- 2α inhibitors. 15 Background Hypoxia is characteristic of solid tumors and correlates with poor prognosis of cancer patients. The cellular response to oxygen deprivation is governed largely by a family of transcription factors known as Hypoxia Inducible Factors (HIFs), including HIF1α, HIF2α, and 20 the less well characterized HIF3α (Wang, G.L., et al. Proc Natl Acad Sci U S A.1995 Jun 6; 92(12): 5510–5514; Tian, H., et al. Genes & Dev. 1997.11: 72-82; Gu, Y.Z., et al. Gene Expr. 1998;7(3):205-13). Under physiological oxygen conditions, HIFαs are hydroxylated by prolyl hydroxylase domain (PHD) proteins, then ubiquitinated by the Von Hippel Lindau (VHL) E3 ligase complex and degraded by proteasome (Bishop, T. Ratcliffe, P. Hypoxia (Auckl).2014; 25 2:197-213). In contrast, under hypoxic conditions, HIFαs cannot be degraded effectively due to repressed hydroxylation with limited oxygen availability and subsequently suppressed ubiquitination-mediated degradation; thus, HIFα subunits accumulate and translocate to nucleus where they dimerize with HIF1β and regulate transcription of downstream genes, which collectively drive the adaptation to hypoxia and cancer progression (Bishop, T. Ratcliffe, P. 30 Hypoxia (Auckl).2014; 2:197-213). HIFs regulated genes affect important cancer hallmarks including cell proliferation, apoptosis, differentiation, angiogenesis, genetic instability, tumor metabolism, tumor immune responses, invasion and metastasis, and also mediate resistance to chemo-, radiation therapy and targeted therapeutics (Wigerup, C., et al. Pharmacology & Therapeutics 164 (2016) 152–169). binding and two sequential PAS (PER ARNT SIM) domains (PAS A and PAS B) that facilitate heterodimerization with HIF-1β/ARNT (Bersten, D.C., et al. Nat Rev Cancer, 13 (2013), pp.827- 841). There is a high degree of sequence homology between HIF1α and HIF2α with their PAS 5 domains exhibiting approximately 70% identity, their bHLH domains sharing 85% identity with the basic region consisting of almost identical sequences (Tian, H., et al. Genes Dev.1997 Jan 1; 11(1):72-82). Consequently, both HIF1α and HIF2α are able to bind with hypoxia-response element (HRE) with core consensus sequence 5’-(A/G)CGTG-3’ on genome (Tian, H., et al. Genes Dev.1997 Jan 1; 11(1):72-82). and they share many downstream target genes, including 10 VEGFA, GLUT1, LDHA et al. Pre-clinical and clinical data have demonstrated that pharmacological inhibitors of HIF-2α can efficiently combat clear cell renal carcinoma (ccRCC) growth (Wallace, E. M., et al. (2016), Cancer Res, 76(18), 5491-5500; Courtney, K. D., et al. (2018), J. Clin. Oncol., 36(9), 867-874; Choueiri, T. K., et al. (2020), ASCO). HIF-2α expression is associated with numerous additional 15 cancers such as breast cancer, glioblastoma, neuroblasoma, head and neck squamous carcinoma and non-small cell lung cancer. Although physicians have choices of therapeutics for the treatment of cancer, a patient’s response to available therapeutic agents are not always predictable. Accordingly, there exists a need for the more accurate prediction of patient response to available therapeutic agents, including20 HIF-2α inhibitors. The present disclosure fulfills this and related needs. Summary In a first aspect, provided is a method of treating a patient having cancer other than ccRCC wherein the cancer is characterized by at least one of: 25 (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; 30 (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (viii) reduced function of HIF 1α protein; the method comprising administering an effective amount of a HIF-2α inhibitor to the patient in need thereof. 5 In a second aspect, provided is a method of treating a patient having cancer other than ccRCC, the method comprising: (a) determining whether the patient has cancer that is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; 10 (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of 15 HIF-1α gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1α gene expression; and (viii) reduced function of HIF-1α protein; and 20 (b) administering an effective amount of a HIF-2α inhibitor to the patient who is determined to have a cancer that is characterized by at least one of (a)(i)-(a)(viii). In a third aspect, provided is a method of identifying a patient having a cancer other than ccRCC who may benefit from treatment a HIF-2α inhibitor, the method comprising: (a) determining whether the patient has cancer that is characterized by at least one of: 25 (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; 30 (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (viii) reduced function of HIF 1α protein; wherein the presence at least one of: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of 5 VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; 10 (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1α gene expression; and 15 (viii) reduced function of HIF-1α protein; identifies the patient as one who may benefit from treatment with a HIF-2α inhibitor. In an embodiment of the third aspect, the method further comprises administering an effective amount of a HIF-2α inhibitor to the patient who is identified as one who may benefit from treatment with a HIF-2α inhibitor. 20 In a fourth aspect, provided is a pharmaceutical composition comprising a HIF-2α inhibitor for use in treatment of a patient having a cancer other than ccRCC, wherein the cancer is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, hypermethylation of VHL gene 25 promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, hypermethylation of HIF-1α gene; 30 (vi) absence or one or more of truncation, insertion, mutation, hypermethylation of HIF-1α gene promoter (vii) reduction or absence of HIF-1α gene expression; and (viii) reduced function of HIF-1α protein; cancer other than ccRCC. In a fifth aspect, provided is a use of a HIF-2α inhibitor in the manufacture of a 5 medicament for treatment of a patient having a cancer other than ccRCC, wherein the cancer is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, hypermethylation of VHL gene (ii) absence or one or more of, truncation, insertion, mutation, hypermethylation of VHL 10 gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, hypermethylation of HIF-1α gene; 15 (vi) absence or one or more of truncation, insertion, mutation, hypermethylation of HIF-1α gene promoter (vii) reduction or absence of HIF-1α gene expression; and (viii) reduced function of HIF-1α protein. 20 In a sixth aspect, the method of the first, second, and third, aspects or use of the fourth, and fifth aspects above are wherein the HIF-2α inhibitor is a compound of (Formula (I): wherein: 25 X1 is CH or N;
Figure imgf000006_0001
R1 is hydroxy, halo, amino, -OP(O)(OH)2, -OCH2OP(O)(OH)2, -OCOR10, -OCOOR11, -OCONR12R13, –OCHR14OCOR15 or –OCHR14OCOOR15a where R10, R11, and R15 and R15a are independently alkyl or alkyl substituted with amino, carboxy or hydroxy, R12 and R13 are independently hydrogen, alkyl, or alkyl substituted with amino, carboxy or hydroxy or R12 and R13 30 together with the nitrogen atom to which they are attached form optionally substituted heterocyclyl, and each R14 is hydrogen, alkyl, or haloalkyl; R is hydrogen, halo, or deuterium; R3 and R4 are independently hydrogen, deuterium, alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl; or 5 R3 and R4 together with the carbon to which they are attached form oxo, 3 to 6 membered cycloalkylene, or 4 to 6 membered optionally substituted heterocyclylene; R5 is hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxy, or alkoxy; R6 is hydrogen, deuterium, alkyl, cycloalkyl, or halo; or R5 and R6 together with the carbon to which they are attached form oxo, alkyldienyl, 3 to 610 membered cycloalkylene, or 4 to 6 membered optionally substituted heterocyclylene; provided R5 and R6 and R3 and R4 together with the carbon to which they are attached do not form oxo, cycloalkylene or optionally substituted 4 to 6 membered heterocyclylene simultaneously; R7 is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, or haloalkoxy; L is a bond, S, SO, SO2, O, CO, or NR16 where R16 is hydrogen or alkyl; 15 R8 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 Ra, Rb, Rc, Rg and Rh wherein Ra, Rb, and Rc are 20 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 Rg and Rh are independently selected from hydrogen, deuterium, and halo; and R9 is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, haloalkoxy, 25 alkylsulfoxide, alkylsulfonyl, or heteroaryl wherein the heteroaryl is optionally substituted with Rd, Re, and Rf independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and cyano; or when R9 and R2 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; 30 R9a is hydrogen, halo, or deuterium; or a pharmaceutically acceptable salt thereof. In a seventh aspect, the method of the first, second, and third aspects and the use of the fourth and fifth aspects above (and embodiments thereof disclosed herein) is wherein the HIF-2α inhibitors are those disclosed in PCT application publication No. WO2015035223 in paragraphs entireties. In particular the HIF 2α inhibitor is 3 (((1S,2S,3R) 2,3 difluoro 1 hydroxy 7 (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile. In an eighth aspect the method of the first, second, and third aspects and the use of the 5 fourth and fifth aspects above (and embodiments thereof disclosed herein), the HIF-2α inhibitor is a HIF-2α gene-specific RNAi agent, as disclosed in PCT applications Publication Nos. WO2016196239 and WO2020146521. In particular, paragraphs [0017] (i)-(iii), [0018] (i)-(iii) to [0042], [0046] to [0060], and RNAi agents disclosed in Tables 3, 4.1, 4.2, and 4.3 of WO2020146521 are incorporated herein in their entireties. In particular, RNAi agents disclosed in 10 Table 1, 2A, 2B, and 3 or modified nucleotide thereof of WO2016196239 are incorporated herein in their entireties. In a ninth aspect, the method of the first, second, and third aspects and the use of the fourth and fifth aspects above (and embodiments thereof disclosed herein), the HIF-2α inhibitor is a compound of (II) or (III): 15
Figure imgf000008_0001
to the formulas numbered (I’) and (II), respectively, in PCT Application publication No. WO 2019/191227; and where X, Y, Z, R1, RA1, RA2, and R2 of Formula (II) and n’, Z, X’, R1, R15, R16, R17, R18, and R19 of Formula (III) are as defined in paragraphs [008], [024], and [033] to [049] of PCT Application publication No. WO 20 2019/191227, and these paragraphs are incorporated herein by reference in their entireties. Embodiments of compounds of Formula (II) and (III) are disclosed in paragraphs [[009] to [023], [025] to [026] and [0125] to [0187] and disclosed as specific compounds 1 to 833 (Table 1) and II-1 to II-60 (Table 2) of PCT Application publication No. WO 2019/191227, and these paragraphs and specific compounds are also incorporated herein by reference in their entireties. 25 In a tenth aspect, the method of the first, second, and third aspects and the use of the fourth and fifth aspects above (and embodiments thereof disclosed herein), the HIF-2α inhibitor is a compound of Formula (IV):
Figure imgf000008_0002
where Formula (IV) corresponds to formula (I) in PCT Application publication No. WO 2021/188769; and where Y1, Y2, Y3, Y4, W1, W2, W3, and R1 of Formula (IV) and embodiments thereof (i.e., compounds of formulas II, III, (IV-a) to (IV-f), and (V-a) to (V-g), as numbered in 5 WO 2021/188769) in paragraphs [0055], [0058], [0059] to [0089] and definitions of terms used in such formulae in paragraphs [0012] to [0051] are disclosed in PCT Application publication No. WO 2021/188769, and these formulae and paragraphs are incorporated herein by reference in their entireties. The specific compounds 1 to 248 disclosed in Tables 1, 2 and 3 of PCT Application publication No. WO 2021/188769, are also incorporated herein by reference in their entireties. In 10 some embodiments, the HIF-2α inhibitor is Arcus AB521. Detailed Description Definitions: Unless otherwise stated, the following terms used in the specification and claims are15 defined for the purposes of this Application and have the following meaning: “Alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like. It will be recognized by a person skilled in the art that the term “alkyl” may include “alkylene” groups. 20 “Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like. “Alkenyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a 25 branched monovalent hydrocarbon radical of three to six carbon atoms containing a double bond, e.g., propenyl, butenyl, and the like. “Alkyldienyl” is alkenyl as defined above that is attached via the terminal divalent carbon. For example, in the compound below: the alkyldienyl group is enclosed by the box which is indicated by the arrow.
Figure imgf000009_0001
30 “Haloalkyldienyl” is alkyldienyl that is substituted with one or two halo, each group as defined herein. branched monovalent hydrocarbon radical of three to six carbon atoms containing a triple bond, e.g., propynyl, butynyl, and the like. “Alkylthio” means a -SR radical where R is alkyl as defined above, e.g., methylthio, 5 ethylthio, and the like. “Alkylsulfonyl” means a –SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like. “Alkylsulfoxide” means a –SOR radical where R is alkyl as defined above, e.g., methylsulfoxide, ethylsulfoxide, and the like. 10 “Amino” means a –NH2. “Alkylamino” means a -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like. “Aminoalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with –NR’R” 15 where R’and R” are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkylcarbonyl, each as defined herein, e.g., aminomethyl, aminoethyl, methylaminomethyl, and the like. “Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like. 20 “Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, such as one or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like. “Alkoxycarbonyl” means a –C(O)OR radical where R is alkyl as defined above, e.g., 25 methoxycarbonyl, ethoxycarbonyl, and the like. “Alkylcarbonyl” means a –C(O)R radical where R is alkyl as defined herein, e.g., methylcarbonyl, ethylcarbonyl, and the like. “Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl. 30 “Aralkyl” means a -(alkylene)-R radical where R is aryl as defined above, e.g., benzyl, phenethyl, and the like. “Bicyclic cycloalkyl” means a fused bicyclic saturated monovalent hydrocarbon radical of six to ten carbon atoms, and is optionally substituted with one or two substituents independently decalin, octahydro 1H indene, and the like. “Cycloalkyl” means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms optionally substituted with one or two substituents independently selected from 5 alkyl, alkyldienyl, halo, alkoxy, hydroxy, cyano, haloalkyldienyl and cyanoalkyl. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1- cyanocycloprop-1-yl, 1-cyanomethylcycloprop-1-yl, 3-fluorocyclohexyl, and the like. Cycloalkyl may include cycloalkylene as defined herein. “Cycloalkylalkyl” means a -(alkylene)-R radical where R is cycloalkyl as defined above, 10 e.g., cyclopropylmethyl, cyclohexylmethyl, and the like. “Cycloalkylene” means a divalent cycloalkyl, as defined above, unless stated otherwise. “Cycloalkenyl” means a monocyclic monovalent hydrocarbon radical of three to ten carbon atoms containing one or two double bond(s) optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, cyano, and cyanoalkyl. 15 Examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, and the like. “Oxocycloalkenyl” means a monocyclic monovalent hydrocarbon radical of three to ten carbon atoms containing one or two double bond(s) and an oxo group, and is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, 20 cyano, and cyanoalkyl. Examples include, but are not limited to, 3-oxocyclohex-1-enyl, and the like. “Cyanoalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with cyano e.g., cyanomethyl, cyanoethyl, and the like. 25 “Carboxy” means –COOH. “Dialkylamino” means a -NRR’ radical where R and R’ are alkyl as defined above, e.g., dimethylamino, methylethylamino, and the like. “Disubstituted amino” means a –NRR’ radical where R and R’ are independently alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkylcarbonyl, each as defined herein, e.g., 30 dimethylamino, ethylmethylamino, bis-hydroxyethylamino, bis-methoxyethylamino, diethylaminoethylamino, and the like. “Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro. halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this 5 Application as fluoroalkyl. “Haloalkoxy” means a –OR radical where R is haloalkyl as defined above e.g., -OCF3, -OCHF2, and the like. When R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy. “Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon 10 atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2- 15 hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl. “Heterocyclyl” means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C, uless stated otherwise. Additionally, 20 one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO- group. More specifically the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic. When the 25 heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group. “Heterocyclylalkyl” or “heterocycloalkyl” means a –(alkylene)-R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like. 30 “Heterocyclylene” means a divalent heterocyclyl, as defined above, unless stated otherwise. When heterocyclene contains 4, 5, or 6 rings atoms, it may be referred to herein as 4 to 6 membered heterocyclylene. “Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. 5 As defined herein, the terms “heteroaryl” and “aryl” are mutually exclusive. When the heteroaryl ring contains 5- or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaryl. “Heteroarylene” means a divalent heteroaryl radical as defined above. “Heteroaralkyl” means a -(alkylene)-R radical where R is heteroaryl as defined above, 10 e.g., pyridinylmethyl, and the like. When the heteroaryl ring in heteroaralkyl contains 5- or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaralkyl. The phrase “R2 and R9 are attached to the ring carbon atom that is meta to the ring carbon attached to R1” means the R2 and R9 are located as indicated below: . 15 The term “oxo,” as used her
Figure imgf000013_0001
nation, refers to =(O). When needed, any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkoxyalkyl means that an alkoxy group attached to the parent molecule through an alkyl group. 20 The present disclosure also includes protected derivatives of compounds of Formula (I). For example, when compounds of Formula (I) contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with suitable protecting groups. A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5th Ed., John Wiley & Sons, Inc. (2014), the disclosure of 25 which is incorporated herein by reference in its entirety. The protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art. The term "prodrug" refers to a compound that is made more active in vivo. Certain compounds of Formula (I) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, 30 Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds of Formula (I) physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. A wide variety 5 of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound of Formula (I). 10 A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as 15 formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 20 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy- 2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a 25 metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, 30 which is incorporated herein by reference in its entirety. The compounds of Formula (I) may have asymmetric centers. Compounds of Formula (I) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. All chiral, diastereomeric, all mixtures of chiral or diasteromeric forms, and racemic forms 5 are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. It will also be understood by a person of ordinary skill in the art that when a compound is denoted as (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity and vice versa. Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers. All 10 possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl, heteroaryl, heterocyclyl are substituted, they include all the positional isomers albeit only a few examples are set forth. Furthermore, all 15 hydrates of a compound of Formulae (I) are within the scope of this disclosure. The compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question. that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes 20 that can be incorporated into a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 1251, respectively. Isotopically labeled compounds (e.g., those labeled with 3H and 14C) can be useful in compound or substrate tissue distribution assays. 25 Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds disclosed herein, including in Table 1 below one or more hydrogen atoms are replaced by 2H or 3H, or one 30 or more carbon atoms are replaced by 13C- or 14C-enriched carbon. Positron emitting isotopes such as 15O, 13N, 11C, and 15F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the reagent. Certain structures provided herein are drawn with one or more floating substituents. Unless provided otherwise or otherwise clear from the context, the substituent(s) may be present on any 5 atom of the ring to which it is attached, where chemically feasible and valency rules permitting. For example, in the structure , the R7 substituent can replace any hydrogen on the benzo portion of the t
Figure imgf000016_0001
ng the hydrogen of CH when X1 is CH. “Optionally substituted aryl” means aryl that is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, cycloalkyl, carboxy, 10 alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano. “Optionally substituted heteroaryl” means heteroaryl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, 15 haloalkoxy, amino, alkylamino, dialkylamino, and cyano. “Optionally substituted heterocyclyl” means heterocyclyl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl, haloalkoxy, and cyano, unless stated 20 otherwise. “Optionally substituted heterocyclylene” is divalent optionally substituted heterocyclyl as defined above. A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither 25 biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient. “Spirocycloalkyl” means a saturated bicyclic ring having 6 to 10 ring carbon atoms 30 wherein the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ("spiro carbon"). The spirocycloalkyl ring is optionally and cyano. Representative examples include, but are not limited to, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane (1:2:1:1), and the like. “Spiroheterocyclyl" means a saturated bicyclic ring having 6 to 10 ring atoms in which 5 one, two, or three ring atoms are heteroatom selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ("spiro carbon"). The spiroheterocyclyl ring is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, 10 alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl, haloalkoxy, and cyano. Representative examples include, but are not limited to, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, and the like. The term “about,” as used herein, is intended to qualify the numerical values which it 15 modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ± 10%, preferably ± 5%, the recited value and the range is included. The phrase “heteroaryl wherein the heteroaryl is optionally substituted with Rd, Re, and 20 Rf independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and cyano” in the definition of R9 in Formula (I) (and similar phrases used to define other groups in Formula (I)) is intended to cover heteroaryl that is unsubstituted and heteroaryl that is substituted with any one of Rd, Re, and Rf. The term “disease” as used herein is intended to be generally synonymous, and is used 25 interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life. The term “combination therapy” means the administration of two or more therapeutic 30 agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment disorders described herein. The term “patient” is generally synonymous with the terms “subject” and “individual,” which are used interchangeably herein, and includes all mammals including humans. Examples 5 of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human. “Administering means taking a therapeutic compound and additionally means giving or dispensing a therapeutic compound to a patient which the patient takes, e.g., by infusion, inhalation, injection, application, paste, suppository, capsule, film, or tablet. In some 10 embodiments, including any of the foregoing embodiments, administering means prescribing the therapeutic compound to a patient which the patient takes. In some embodiments, including any of the foregoing embodiments, administering means dispensing the therapeutic compound to a patient which the patient takes. In some embodiments administering means supervising the taking of the therapeutic compound. 15 “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its 20 clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. A “therapeutically effective amount” means the amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease. The “therapeutically 25 effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. The terms "inhibiting" and "reducing," or any variation of these terms in relation of HIF-2α, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 30 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of HIF-2α activity compared to normal. A “mutant” or “mutants” may refer to either a polypeptide or a nucleic acid. The term “mutant” may be used interchangeably with the term “variant.” Mutants include insertions, deletions, substitutions, transversions, truncations, and/or inversions at one or more locations in phrases mutant polypeptide, mutant protein, and mutant enzyme refer to a protein that has an amino acid sequence that has been modified from the amino acid sequence of a wild-type protein. The mutant polypeptides include a polypeptide having a certain percent, e.g., at least 5 about 80%, 85%, 90%, 95%, or 99%, of sequence identity with the wild type polypeptide or protein. Mutants may have 1, 2, 3, 4, 5, 10, 15, 20, 30, or more amino acid substitutions, additions, or deletions, or any integral value within the range of 1-100, compared to the wild-type sequence. For example, the mutant can comprise a signal peptide of another protein or a sequence designed to aid identification or purification of the expressed fusion protein, such as a His-Tag sequence. 10 The term “mutation” of a VHL gene refers to one or more changes in the nucleotide sequence of the VHL gene and the consequence may be loss of or reduced function of the VHL protein. The term “mutation” of VHL gene promoter refers to one or more changes in the nucleotides sequence of the VHL gene promoter and the consequence may be the loss of or reduced expression of VHL protein. The term “mutation” of HIF-1α gene refers to one or more changes in the nucleotide 15 sequence of the HIF-1α gene and the consequence could be loss of or reduced function of the HIF-1α protein. The term “mutation” of HIF-1α gene promoter refers to one or more changes in the nucleotides sequence of the HIF-1α gene promoter possibly resulting in the loss of or reduced expression of HIF-1α protein. “Insertions” refer to gene or protein mutations comprising the addition of one or more 20 nucleic acid or amino acid residues, respectively. The term “insertion” of VHL gene means the addition of one or more nucleotide base pairs into the DNA sequence of VHL gene. The term “insertion” of VHL gene promoter means the addition of one or more nucleotide base pairs into the DNA sequence of VHL gene promoter region. The term “insertion” of HIF-1α gene means the addition of one or more nucleotide base pairs into the DNA sequence of HIF-1α gene. The term 25 “insertion” of HIF-1α gene promoter means the addition of one or more nucleotide base pairs into the DNA sequence of HIF-1α gene promoter region. The “absence” of a gene promoter refers to the loss or nonexistence of the promoter region of the gene. “Cancer sample” refers to a sample derived from, obtained by, generated from, provided 30 from, taken from, or removed from a patient; or from fluid or tissue from the patient. Cancer samples include, but are not limited to synovial fluid, whole blood, blood serum, blood plasma, urine, sputum, tissue, saliva, tears, hair, spinal fluid, tissue section(s) obtained by biopsy, cell(s), or any combination thereof that are placed in or adapted to tissue culture, sweat, mucous, fecal material, gastric fluid, abdominal fluid, amniotic fluid, cyst fluid, peritoneal fluid, pancreatic juice, the like including derivatives, portions and combinations of the foregoing. In some embodiments, cancer samples include, but are not limited, to blood and/or plasma. In some embodiments, cancer samples include, but are not limited, to urine or stool. Cancer samples include, but are not limited, 5 to saliva. Cancer samples include, but are not limited, to tissue dissections and tissue biopsies. Cancer samples include, but are not limited, samples that can provide nucleic acids for analysis. Cancer samples include, but are not limited, any derivative or fraction of the aforementioned cancer samples. “Fragments" of proteins or peptides, i.e., fragments of amino acid sequences, in the context 10 of the present invention may, typically, comprise a sequence of a protein or peptide as defined herein, which is, with regard to its amino acid sequence (or its encoding nucleic acid molecule), N-terminally, C-terminally and/or intrasequentially truncated compared to the amino acid sequence of the original (native) protein (or its encoded nucleic acid molecule). Such truncation may thus occur either on the amino acid level or correspondingly on the nucleic acid level. A 15 sequence identity with respect to such a fragment as defined herein may therefore preferably refer to the entire protein or peptide as defined herein or to the entire (coding) nucleic acid molecule of such a protein or peptide. Peptides comprising deletion at the N-terminal and/or C-terminal end of the protein are also called N-terminal and/or C-terminal truncation variants. A “truncated” protein may be encoded by mature mRNA lacking one or part of an exon, or 20 more exons of the gene responsible for the full length protein, and still has, at least to some extent, the functions (particularly, functions related to altering gene expression) of the full-length protein encoded by the normal gene corresponding to the gene. “Truncation” of the VHL gene refers to certain region of the VHL gene being missing and subsequently, resulting in a shorter, defective VHL protein. The term “truncation” of VHL gene 25 promoter refers to a VHL promoter lacking certain region(s) resulting in the possible loss of or reduced expression of VHL protein. The term “truncation” of HIF-1α gene refers to a HIF-1α gene missing one or more regions, subsequently resulting in a shorter, defective HIF-1α protein. “Truncation” of a HIF-1α gene promoter means that certain region(s) of the HIF-1α gene promoter are missing, possibly leading to the loss of or reduced expression of HIF-1α protein. 30 “Hypomethylation” and “hypermethylation” of DNA are relative terms and denote less or more methylation than in some standard DNA. When applied to cancer epigenetics, that standard is normal tissue. Methylation may occur within the promoter regions of tumor suppressor genes, resulting in their silencing, and methylation within the gene itself may induce mutational events. DNA methylation is an important regulator of gene transcription. Alterations in DNA methylation in non promoter region may be implicated as a cause of oncogenesis. The term “hypermethylation” of VHL gene refers to an increase in the methylation of cytosine and/or adenosine nucleotides in the VHL gene, which can result in the loss of or reduced levels of VHL 5 protein. The term “hypermethylation” of VHL gene promoter means an increase in the methylation of cytosine and/or adenosine nucleotides in the VHL gene promoter region, which may result in the loss of or reduced levels of VHL protein expression. “Hypermethylation” of HIF-1α gene refers to an increase in the methylation of cytosine and/or adenosine nucleotides in the HIF-1α gene, which may result in the loss of or reduced HIF-1α protein. “Hypermethylation” 10 of a HIF-1α gene promoter refers to an increase in the methylation of cytosine and/or adenosine nucleotides in the HIF-1α gene promoter region, which may result in the loss of or reduced HIF- 1α protein expression. DNA methylation profiling can provide higher clinical sensitivity and dynamic range compared to somatic mutation analysis for cancer detection. In other instances, altered DNA 15 methylation signature has been shown to correlate with the prognosis of treatment response for certain cancers. For example, widespread and reproducible methylation changes demonstrate an important role for methylation alterations in renal cell carcinomas, colorectal cancers, and many other cancer types. (Lasseigne and Brooks, Mol. Diagn. Ther. (2018) 22(4):431-442; Ashktorab, H and Brim, H. Curr Colorectal Cancer Rep.2014 Dec 1; 10(4): 425–430; McMahon, K.W., et al. 20 Cancer J.2017 Sep-Oct; 23(5): 257–261). Gene expression refers to the tightly regulated process that allows a cell to respond to its changing environment. It acts as both an on/off switch to control when proteins are made and also a volume control that increases or decreases the amount of proteins made. Gene expression is primarily controlled at the level of transcription, largely as a result of binding of proteins 25 (transcription factors) to specific sites on DNA. Downregulation or upregulation of an RNA or protein may also arise by an epigenetic alteration. The epigenetic alteration can be permanent or semi-permanent in a somatic cell lineage. Such an epigenetic alteration can result in expression of RNA or protein that no longer respond to an external stimulus. This occurs, for instance, in some cancers. 30 Absence of gene expression occurs due to failure to produce mRNA by the enzyme RNA polymerase, or the failure of the expressed mRNA to drive translation (i.e., protein synthesis), and/or post translational processing. Gene silencing refers to regulation of gene expression in cell or tissue to prevent expression of a certain gene. The term “absence” of VHL gene refers to the loss or nonexistence of VHL gene. The term “absence” of VHL gene promoter refers to the loss or the loss or nonexistence of HIF 1α gene. The term absence of HIF 1α gene promoter refers to the loss or nonexistence of the promoter region of HIF-1α gene. Reduced gene function, i.e., down regulation, is the process by which a cell decreases the 5 quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary process that involves increases of such components is called upregulation. An example of downregulation is the cellular decrease in the expression of a specific receptor in response to its increased activation by a molecule, such as a hormone or neurotransmitter, which reduces the cell's sensitivity to the molecule. 10 In some embodiments, the term “wild type” denotes the most common, typical phenotype in a natural healthy population. In some embodiments, the term “wild type” denotes an organism or gene locus that predominates in natural or normal populations. Embodiments: In further embodiments 1-70 below, the present disclosure includes: 15 1. In embodiment 1, provided is a method of treating a patient having cancer other than ccRCC wherein the cancer is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL 20 gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; 25 (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1α gene expression; and (viii) reduced function of HIF-1α protein; the method comprising administering an effective amount of a HIF-2α inhibitor to a patient in 30 need thereof. 2. In embodiment 2, provided is a method of treating a patient having cancer other than ccRCC, the method comprising: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of 5 VHL gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; 10 (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1α gene expression; and (viii) reduced function of HIF-1α protein; and (b) administering an effective amount of a HIF-2α inhibitor to the patient who is determined to 15 have a cancer that is characterized by at least one of (a)(i)-(a)(viii). 3. In embodiment 3, provided is a method of identifying a patient having a cancer other than ccRCC who may benefit from treatment a HIF-2α inhibitor, the method comprising: (a) determining whether the patient has cancer that is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL 20 gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; 25 (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1α gene expression; and 30 (viii) reduced function of HIF-1α protein; wherein the presence at least one of: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; 5 (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1α gene expression; and 10 (viii) reduced function of HIF-1α protein; identifies the patient as one who may benefit from treatment with a HIF-2α inhibitor. In a sub-embodiment of embodiment 3, the method further comprises administering an effective amount of a HIF-2α inhibitor to the patient who is identified as one who may benefit from treatment with a HIF-2α inhibitor 15 4. In embodiment 4, the method of embodiment 2 or 3, is wherein the presence of at least one of the following: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL 20 gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; 25 (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1α gene expression; and (viii) reduced function of HIF-1α protein; is assessed by histological and/or genetic analysis of a cancer sample obtained from the patient. 30 5. In embodiment 5, the method of embodiment 4 is wherein the absence, truncation, insertion, mutation, hypermethylation of one or more of VHL gene, VHL gene promoter, HIF-1α gene, and/or HIF-1α gene promoter in the cancer sample is determined by whole genome sequencing, exome sequencing, targeted gene sequencing, methylation sequencing, or a combination thereof. insertion, mutation, hypermethylation of one or more of VHL gene, VHL gene promoter, HIF 1α gene, and/or HIF-1α gene promoter in the cancer sample is different from wild type VHL gene, VHL gene promoter, HIF-1α gene, and HIF-1α gene promoter, respectively. 5 7. In embodiment 7, the method of any one of embodiments 2 to 4 is wherein the expression level of one or more of VHL gene, VHL protein, HIF-1α gene and/or HIF-1α protein in the cancer sample is below the reference expression level of the corresponding one or more of VHL gene, VHL protein, HIF-1α gene and/or HIF-1α protein. 8. In embodiment 8, the method of embodiment 6 is wherein the reference expression 10 level of the VHL gene, VHL protein, HIF-1α gene and/or HIF-1α protein is determined from a population of patients having the same cancer. 9. In embodiment 9, the method of embodiment 7 or 8 is wherein the expression level and the reference expression level are a nucleic acid expression level and the nucleic acid expression level is an mRNA expression level. 15 10. In embodiment 10, the method of embodiment 9 is wherein the mRNA expression level is determined by RNA-seq, QuantiGene RNA Assay, Nanostring, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, or ISH, or a combination thereof. 11. In embodiment 11, the method of embodiment 7 or 8 is wherein the expression 20 level and the reference expression level are a protein expression level. 12. In embodiment 12, the method of embodiment 11 is wherein the protein expression level is determined by immunohistochemistry (IHC), Western blot, enzyme-linked immunosorbent assay (ELISA), AlphaLISA immunoassay, immunoprecipitation, immunofluorescence, electrochemiluminescence detection, homogeneous time resolved 25 fluorescence (HTRF) assay, radioimmunoassay, or mass spectrometry. 13. In embodiment 13, the method of any one of embodiments 4 to 12 is wherein the cancer sample is a tissue sample, a cell sample, a whole blood sample, a plasma sample, a serum sample, or a combination thereof. 14. In embodiment 14, the method of embodiment 13 is wherein the tissue sample is a 30 tumor tissue sample. 15. In embodiment 15, provided is a pharmaceutical composition comprising a a HIF- 2α inhibitor for use in treatment of a patient having a cancer other than ccRCC, wherein the cancer is characterized by at least one of: (i) absence, truncation, mutation, hypermethylation of VHL gene; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence, truncation, mutation, hypermethylation of HIF-1a gene; 5 (vi) absence, truncation, mutation, hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1a gene expression; and (viii) reduced function of HIF-1a protein; and wherein the treatment comprises administration of the pharmaceutical composition to the patient having a cancer other than ccRCC. 10 16. In embodiment 16, provided is a use of a HIF-2α inhibitor in the manufacture of a medicament for treatment of a patient having a cancer other than ccRCC, wherein the cancer is characterized by at least one of: (i) absence, truncation, mutation, hypermethylation of VHL gene (ii) absence, truncation, mutation, hypermethylation of VHL gene promoter; 15 (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence, truncation, mutation, hypermethylation of HIF-1a gene; (vi) absence, truncation, mutation, hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1a gene expression; and 20 (viii) reduced function of HIF-1a protein. 17. In embodiment 17, provided is a method of treating cancer other than ccRCC in a patient in need thereof, comprising: (A) determining whether the patient will respond to HIF2α inhibitor-based therapy, by measuring the expression level of at least one of: 25 (i) absence or one or more of truncation, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; 30 (iv) reduced function of VHL protein; (v) absence or at least one of truncation, mutation, and hypermethylation of HIF-1a gene; (vi) absence or at least one of truncation, mutation, and hypermethylation of HIF-1α gene promoter; (viii) reduced function of HIF 1a protein; in a patient sample; and (B) comparing the expression level measured in the patient sample in (A) with a 5 corresponding reference expression level derived from subject(s) with cancer who are responsive to the treatment; or (C) comparing the expression level measured in the patient sample in (A) with a corresponding reference expression level derived from cancer-free subject(s); and (D) administering to the patient an effective amount of a HIF-2α inhibitor when the expression 10 level measured in the patient sample in (A) and the corresponding reference expression level in (B) are similar or when the expression level measured in the patient sample in (A) is lower than the corresponding reference expression level in (C). 18. In embodiment 18, provided is the method or use of any one of embodiments 2 to 17, wherein a plurality of (A)(i)-(A)(viii) are measured. 15 19. In embodiment 19, provided is a method or use of any one of embodiments 7-11, 16, and 18, wherein the reference level is an age-matched reference level. 20. In embodiment 20, provided is a method or use of any one of embodiments 7-11, 16, and 18, wherein the reference level is a BMI-matched reference level. 21. In embodiment 21, provided is a method or use of any one of embodiments 7-11, 20 16, and 18, wherein the reference level is a sex-matched reference level. 22. In embodiment 22, provided is a method of any one of embodiments 7-11, 16, and 18, wherein the reference level is a smoking/non-smoking matched reference level. 23. In embodiment 23, provided is a method of any one of embodiments 7-11, 16, and 18, wherein the reference level controls for more than one parameter (e.g. two, three, four, five, or 25 more parameters) as provided in embodiments 19-23. 24. In embodiment 24, provided is a method of any one of embodiments 7-11, 16, and 18-23, wherein the reference level is determined by measuring the level in a population of individuals. In a first embodiment of embodiment 24, the term “population of individuals” means one 30 or more individuals. In a second embodiment of embodiment 24, the population of individuals comprises multiple individuals. In another embodiment, the term “multiple” means at least 2 (such as at least 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 30) individuals. In another embodiment, the population of individuals comprises at least 10 individuals. individual. 25. In embodiment 25, the method of any one of embodiments 1 to 24 is wherein the cancer is a solid cancer. 5 26. In embodiment 26, the method of any one of embodiments 1-24, and embodiments thereof, is wherein the HIF-2α inhibitor is according to Formula (I): wherein: 10 X1 is CH or N;
Figure imgf000028_0001
R1 is hydroxy, halo, amino, -OP(O)(OH)2, -OCH2OP(O)(OH)2, -OCOR10, -OCOOR11, -OCONR12R13, –OCHR14OCOR15 or –OCHR14OCOOR15a where R10, R11, and R15 and R15a are independently alkyl or alkyl substituted with amino, carboxy or hydroxy, R12 and R13 are independently hydrogen, alkyl, or alkyl substituted with amino, carboxy or hydroxy or R12 and R13 15 together with the nitrogen atom to which they are attached form optionally substituted heterocyclyl, and each R14 is hydrogen, alkyl, or haloalkyl; R2 is hydrogen, deuterium, alkyl, halo, haloalkyl, alkenyl, or alkynyl; R2a is hydrogen, halo, or deuterium; R3 and R4 are independently hydrogen, deuterium, alkyl, cycloalkyl, halo, haloalkyl, 20 hydroxyalkyl, or alkoxyalkyl; or R3 and R4 together with the carbon to which they are attached form oxo, 3 to 6 membered cycloalkylene, or 4 to 6 membered optionally substituted heterocyclylene; R5 is hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxy, or alkoxy; R6 is hydrogen, deuterium, alkyl, cycloalkyl, or halo; or 25 R5 and R6 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 R5 and R6 and R3 and R4 together with the carbon to which they are attached do not form oxo, cycloalkylene or optionally substituted 4 to 6 membered heterocyclylene simultaneously; R7 is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, or haloalkoxy; 30 L is a bond, S, SO, SO2, O, CO, or NR16 where R16 is hydrogen or alkyl; 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 5 heterocyclylalkyl is substituted with Ra, Rb, Rc, Rg and Rh wherein Ra, Rb, and Rc 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 Rg and Rh are independently selected from hydrogen, deuterium, and halo; and 10 R9 is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, haloalkoxy, alkylsulfoxide, alkylsulfonyl, or heteroaryl wherein the heteroaryl is optionally substituted with Rd, Re, and Rf independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and cyano; or when R9 and R2 are attached to the same carbon atom, they can combine to form oxo, 15 alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to 6-membered heterocyclylene; R9a is hydrogen, halo, or deuterium; or a pharmaceutically acceptable salt thereof. 27. In embodiment 27, the method of embodiment 26, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R3 and R4 are independently 20 halo. 28. In embodiment 28, the method of embodiment 26, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R3 is halo and R4 is hydrogen. 29. In embodiment 29, the method of embodiment 26, or 27, is wherein the compound 25 of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R1 is hydroxy. 30. In embodiment 30, the method of any one of embodiments 26 or 27, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein is R1 is amino. 31. In embodiment 31, the method of any one of embodiments 26 to 30, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R6 is halo. 30 32. In embodiment 32, the method of any one of embodiments 26 to 30, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R6 is alkyl, preferably R6 is methyl. 33. In embodiment 33, the method of any one of embodiments 26 to 30, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R6 is hydrogen. compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R is cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 35. In embodiment 35, the method of any one of embodiments 26 to 34, is wherein the 5 compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R5 is halo, preferably fluoro. 36. In embodiment 36, the method of any one of embodiments 26 to 34, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R5 is haloalkyl, preferably R5 is difluoromethyl or trifluoromethyl. 10 37. In embodiment 37, the method of any one of embodiments 26 to 34, is wherein the compound of Formula (I)or a pharmaceutically acceptable salt thereof, is wherein R5 is alkyl, preferably R5 is methyl or ethyl. 38. In embodiment 38, the method of any one of embodiments 26 to 34, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R5 is hydrogen 15 or alkoxy. 39. In embodiment 39, the method of any one of embodiments 26 to 34, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R5 and R6 together with the carbon to which they are attached form 3 to 6 membered cycloalkylene, preferably cyclopropylene, cyclobutylene or cyclopentylene optionally substituted with one or two 20 fluoro. 40. In embodiment 40, the method of any one of embodiments 26 to 39, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein X1 is CR7. 41. In embodiment 41, the method of embodiment 26, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, has the structure of formula (IIa1) or 25 (IIb1):
Figure imgf000030_0001
42. In embodiment 42, the method of embodiment 26, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, having the structure of formula (IIa1’) 30 or (IIb1’): 43. In embodi
Figure imgf000031_0001
herein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, has the structure of formula (IIa) or 5 (IIb): 44. In embodime
Figure imgf000031_0002
ein the compound of 10 Formula (I) or a pharmaceutically acceptable salt thereof, has the structure of formula (IIa’) or (IIb’): 15
Figure imgf000031_0003
45. In embodiment 45, the method of embodiment 26, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, has the structure of formula (IVa):
Figure imgf000031_0004
cycloalkylene, preferably cyclopropylene, cyclobutylene or cyclopentylene optionally substituted with one or two fluoro. 46. In embodiment 46, the method of any one of embodiments 41 to 45, is wherein the 5 compound of Formulae (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, is wherein R3 is fluoro. 47. In embodiment 47, the method of any one of embodiments 41to 45, is wherein the compound of Formulae (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, is where R3 and R4 are fluoro. 10 48. In embodiment 48, the method of any one of embodiments 26 to 47, is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, is wherein L is O, S, SO, SO2, or NH. 49. In embodiment 49, the method of embodiment 48, is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) a pharmaceutically 15 acceptable salt thereof, is wherein L is O. 50. In embodiment 50, the method of any one of embodiments 26 to 49, is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) is wherein R8 is cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or 20 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 Ra, Rb, and Rc 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. 25 51. In embodiment 51, the method of any one of embodiments 26 to 49, and subembodiments contained therein, is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, is wherein R8 is phenyl substituted with Ra, Rb, Rc, Rg and Rh wherein Ra, Rb, and Rc are independently selected from hydrogen, deuterium, alkyl, haloalkyl, haloalkyloxy, alkoxy, 30 hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl and Rg and Rh are independently selected from hydrogen, and halo. 52. In embodiment 52, the method of embodiment 51 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, is wherein the compound of Formulae (I), 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-methyphenyll, 3-cyanophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3-chloro-2- 5 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. In a first subembodiment of embodiment 52, R10 is 3-cyano-5-fluorophenyl or 3-cyano-5-fluoro-2,4,6- trideuteriophenyl. 10 53. In embodiment 53, the method of any one of embodiments 29 to 49 and any subembodiments contained therein, is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, is wherein R8 is cycloalkyl or cycloalkylalkyl each optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, cyano, and hydroxy. 15 54. In embodiment 54, the method of any one of embodiments 26 to 49 and any subembodiments contained therein, is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, wherein R8 is heteroaryl substituted with Ra, Rb, and Rc independently selected from hydrogen, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, 20 aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl. 55. In embodiment 55, the method of any one of embodiments 26 to 49, is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt, thereof, is wherein R8 is pyridin-3-yl, pyridin-2-yl, pyridazin-3- 25 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 Ra, Rb, and Rc wherein Ra and Rb are independently selected from hydrogen, methyl, methoxy, hydroxy, chloro, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy and Rc is selected from 30 hydrogen, methyl, cyano, chloro, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy. 56. In embodiment 56, the method of any one of embodiments 26 to 55, wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a fluoro, trifluoromethyl, or trifluoromethoxy, preferably R is hydrogen. 57. In embodiment 57 the method of any one of embodiments 26 to 56, is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a 5 pharmaceutically acceptable salt thereof, is wherein R2 is hydrogen, fluoro, methyl or ethyl. 58. In embodiment 58, the method of any one of embodiments 26 to 57, is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIB’) and (IVa) or a pharmaceutically acceptable salt thereof, is wherein R9 is hydrogen, alkyl, halo, hydroxy, or alkoxy. 10 59. In embodiment 59, the method of any one of embodiments 26 to 57 is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a pharmaceutically acceptable salt thereof, is wherein R9 is hydrogen, methyl, methoxy, or fluoro. 60 In embodiment 60, the method of embodiment 26 to 59, is wherein the compound of Formulae (I), (IIa1), (IIb1), (IIa1’), (IIb1’), (IIa), (IIb), (IIa’), (IIb’) and (IVa) or a 15 pharmaceutically acceptable salt thereof, is wherein R2 and R9 are attached to the ring carbon atom that is meta to the ring carbon attached to R1. 61. In embodiment 61, the method of any one of embodiments 52 or 55, is wherein the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof and has the structure of formula (VIIIa1) or (VIIIb1): 20
Figure imgf000034_0001
preferably the structure of formula (VIIIb). 62. In embodiment 62, the method of embodiment 61, is wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein R2 is hydrogen or deuterium, 25 R9 is hydrogen, fluoro, or methyl and R2a and R9a are independently hydrogen, deuterium or fluoro. 63. In embodiment 63, the method of embodiment 26, is 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- 30 cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 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; 5 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- 10 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; 15 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- 20 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; 25 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- 30 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; 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; 5 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- 10 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-(((2aS,3S,4R)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H- cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 15 3-fluoro-5-(((2aS,4R,4R)-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. 64. In embodiment 64, the method of embodiment 25, is wherein the compound of Formula (I) is selected from: 20 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; and a pharmaceutically acceptable salt thereof. 25 65. In embodiment 65, the method of embodiment 26, is 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. 66. In embodiment 66, the method of embodiment 26, is wherein the compound of Formula (I) is 3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H- 30 cyclopenta[cd]inden-7-yl)oxy)-benzonitrile. 67. In embodiment 67, the method of the tenth aspect and any one of embodiments 1 to 24, is wherein the HIF-2 inhibitor is selected from the group consisting of:
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0002
Figure imgf000045_0001
68. In embodiment 68, the method of any one of embodiments 1 to 67, is wherein the 5 cancer is selected from kidney cancer of non-clear cell subtypes, 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, 10 gastric cancer, esophageal cancer, lymphoma, melanoma, mesothelioma, sarcoma, and neuroendocrine tumors. 69. In embodiment 68, the method of any one of embodiments 26 to 67, is wherein the cancer is selected from ovarian cancer, breast cancer, prostate cancer, kidney cancer of non-clear cell subtypes, colorectal cancer, uveal melanoma, pancreatic cancer, urothelial cancer, endometrial 15 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, 20 biliary tract cancer, soft-tissue sarcoma, rhabdomyosarcoma, mantle-cell lymphoma, and endocrine gland neoplasms. 70. In embodiment 70, the method of any one of embodiments 26 to 69 is wherein the cancer is a solid cancer. 71. In embodiment 71, the method of any one of embodiments 26 to 70, is wherein the 25 method further comprises administering one or more additional anti-cancer agents. Table I Compound Structure Name #
Figure imgf000046_0001
-
Figure imgf000047_0001
Figure imgf000048_0001
-
Figure imgf000049_0001
Synthesis of compounds 1 to 23 are disclosed in PCT International Application No. PCT/US2020/028579, published as WO 2020/214853 on October 22, 2020. 5 General Synthetic Scheme Compounds of this disclosure can be made by the methods depicted in the reaction schemes shown below. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, 10 Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Volumes 15 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers 5 Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this disclosure can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art reading this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, 10 chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about –78 oC to about 150 oC, such as from about 0 oC to about 125 oC and further such as at about room (or ambient) temperature, e.g., about 20 oC. 15 Compounds of Formula (I) where X1 is CH, R1 is hydroxyl, R3, R4, R5, R6, R7, and R8 are as defined in the Summary (or any embodiments thereof), and R9 and R2 are combined to form alkyldienyl, can be prepared as illustrated and described in Scheme 1 below.
Figure imgf000051_0001
he Summary or a precursor group thereof and a compound of formula 1-b where X1 is halide and R3 5 is as defined, e.g., independently hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl, mediated by zinc metal provides a compound of formula 1-c. Compounds of formula 1-a and 1-b are commercially available or they can be prepared by methods well known in the art. For example, 2-bromo-4-fluorobenzaldehyde, ethyl 2-bromo-2,2-difluoroacetate, ethyl 2-bromo- 2-methylpropanoate, ethyl 2-bromopropanoate, ethyl 2-bromoacetate are commercially available. 10 The hydroxyl group in 1-c can be oxidized under oxidative conditions such as 2-iodoxybenzoic acid (IBX) or TPAP, NMO to give a ketone of formula 1-d. The keto group in compound of formula 1-d can be functionalized to provide compound of formula 1-e where R5 and R6 are as described in the Summary by methods well known in the art. For example, a compound of formula 1-e where R5 and R6 are fluoro can be synthesized from 1-d by treatment with a 15 fluorinating agent such as DAST or SF4 under conditions well known in the art. Cyclization of 1-e can be achieved by treating it with alkyl lithium reagent such n-BuLi to give ketone 1-f. The carbonyl group in 1-f can be reduced with reducing reagents such as NaBH4 to provide alcohol 1- g. 1 g, followed by treating the lithio intermediate with CBr4. Oxidation of 1 h with oxidative reagents such as IBX provides ketone of formula 1-i. Addition of allyl metal reagent such as allyl magnesium bromide to compounds of formula 1-i provides compounds of formula 1-j. 5 Alternatively, compound of formula 1-j can be prepared from 1-f by addition of allyl metal reagent such as allyl magnesium bromide to compounds of formula 1-f illustrated below:
Figure imgf000052_0001
h bromination reagent such as CBr4 or 1,2-dibromotetrafluoroethane provides compound of formula 10 1-j. If desired, enantioselective synthesis of compounds of formula 1-g can be achieved by addition of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to compounds of formula 1-f in the presence of a ligand such as 1-m and a suitable base such as tBuONa in organic solvents such as MeOH, toluene as depicted below: 15 Compoun
Figure imgf000052_0002
f Pd catalyst with suitable ligands such as Pd(dppf)Cl2 CH2Cl2 or Pd(PPh3)2Cl2 to provide compounds of formula 1-k. The fluoro group in compounds of formula 1-k can be converted to a group of formula -L-R8 where L and R8 are as described in the Summary by treating compound 1-k with a compound of formula R8-LH where L is N, O, or S and R8 is a defined in the Summary by method well known 20 in the art. Compounds of formula R8-LH are commercially available or they can be prepared by methods well known in the art. For example, 3-fluoro-5-hydroxybenzonitrile, 3,5-difluorophenol, 3-chloro-5-fluorophenol, 3-chloro-5-hydroxy-benzonitrile, 5-fluoropyridin-3-ol, 5-chloropyridin- 3-ol, 5-hydroxynicotinonitrile, 3-fluoro-5-mercaptobenzonitrile, 3-amino-5-fluorobenzonitrile, 3,3-difluorocyclobutan-1-ol, 3-amino-5-fluorobenzonitrile, 3-fluoro-5-mercaptobenzonitrile, 25 3-chloro-5-mercaptobenzonitrile, 3-amino-5-chlorobenzonitrile are commercially available. in the Summary (or any embodiments thereof), and R and R are combined to form oxo can be prepared as illustrated and described in Scheme 2 below. Scheme 2 5
Figure imgf000053_0001
ng it with an oxidative cleavage reagent such as NaIO4 and RuCl3 hydrate under conditions well known in the art. The fluoro group in compounds of Formula 1-l can be converted to a group of formula -L-R8 where L and R8 are as described in the Summary by treating compound 1-l with a 10 compound of formula R8-LH. Compounds of Formula (I) can be coverted to other compounds of Formula (I) by methods well known in the art. For example, compounds of Formula (I) where with R1 is hydroxyl, R2 is hydrogen and R9 is hydroxy or fluoro can be synthesized from the compounds of Formula (I) where R9 and R2 are combined to form oxo by further functionalizing the carbonyl group as 15 illustrated and described in Methods (i) and (ii) below. Method (i) A c
Figure imgf000053_0002
o form oxo can be converted to a compound of Formula (I) where R1 is hydroxy, R9 is hydroxy by treating it with 20 reducing reagent such as sodium borohydride under conditions well known in the art. Method (ii)
Figure imgf000053_0003
to a compound of Formula (I) where R is hydroxy, R is fluoro by treating it with fluorination reagent such as DAST under conditions well known in the art. 5 Utility HIF-2α plays an important role in the initiation and progression of many human cancers. Many extensive studies have demonstrated the critical role of increased HIF-2α activity in driving clear cell renal cell carcinoma (ccRCC) (see review by Shen and Kaelin, Seminars in Cancer Biology 23: 18-25, 2013). 10 The HIF-2α compounds can be used for the treatment of cartilage cancer(s), skin cancer(s), salivary gland cancer, gastric cancer, stomach cancer, liver cancer, endometrial cancer, bladder cancer, mesothelioma, sarcoma, esophageal cancer, lymphoma, uveal melanoma, urothelial cancer, fallopian tube cancer, primary peritoneal cancer, cholangiocarcinoma, Ewing Sarcoma, uterine leiomyosarcoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, T-cell- 15 prolymphocytic leukemia, chronic myelogenous leukemia, germ cell cancer, osteosarcoma, biliary tract cancer, soft-tissue sarcoma, rhabdomyosarcoma, mantle-cell lymphoma, and endocrine gland neoplasms. 20 Pharmaceutical Compositions In general, the HIF-2α inhibitors of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The therapeutically effective amount of a HIF-2α inhibitor may range from about 0.01 to about 100 mg per kg patient body weight per day, which can be administered in single or multiple 25 doses. A suitable dosage level for the HIF-2α inhibitor may be from about 0.1 to about 50 mg/kg per day, about 0.5 to about 15 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 20 to about 800 milligrams of the HIF-2α inhibitor active ingredient, particularly about 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. 30 The actual amount of HIF-2α inhibitors, i.e., the active ingredients, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors. compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be 5 adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, 10 including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance. The compositions are comprised of in general, a HIF-2α inhibitors this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the HIF- 15 2αinhibitor. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may 20 be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. The compounds may be formulated for parenteral administration by injection, e.g., by 25 bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules 30 and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and 5 thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the 10 preparation of highly concentrated solutions. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials 15 (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth. 20 The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides. The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, 25 from about 0.01-99.99 wt. % of a HIF-2α inhibitor based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the HIF-2α inhibitor is present at a level of about 1-80 wt. %. The combination therapy disclosed herein may be carried out with one or more other anti- cancer drugs that are useful in the treatment of cancers for which compounds of this disclosure 30 have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, simultaneously or sequentially with the HIF-2α inhibitor. It is also contemplated that when used in combination with such one or more other active ingredients, the HIF-2α inhibitor and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure also include those compounds of this disclosure to such other active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Examples of such other anti-cancer agents include, but are not limited to, gossypol, 5 genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2’-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (GleevecTM), geldanamycin, 17-N- Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, TaxolTM, also referred to as “paclitaxel”, 10 which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of TaxolTM., such as TaxotereTM. Other anti-cancer agents include inhibitors of kinases associated cell proliferative disorder. These kinases include, but not limited to, Aurora-A, BTK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, 15 Fes, Syk, Itk, Bmx, GSK3, JNK, MEK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, RAF, Rsk and SGK. In particular, inhibitors of CDK4/6, including abemaciclib (Verzenio), palbociclib (Ibrance) and ribociclib (Kisqali), have the potential to be synergistic with HIF-2α inhibitors and reverse the resistance to HIF-2α inhibition; mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, 20 wortmannin, or LY294002; Syk inhibitors; antibodies (e.g., rituxan); MET inhibitor such as foretinib, carbozantinib, or crizotinib; VEGFR inhibitor such as sunitinib, sorafenib, regorafinib, lenvatinib, vandetanib, carbozantinib, axitinib; EGFR inhibitor such as afatinib, brivanib, carbozatinib, erlotinib, gefitinib, neratinib, lapatinib; PI3K inhibitor such as XL147, XL765, BKM120 (buparlisib), GDC-0941, BYL719, IPI145, BAY80-6946, BEX235 (dactolisib), 25 CAL101 (idelalisib), GSK2636771, TG100-115; MTOR inhibitor such as rapamycin (sirolimus), temsirolimus, everolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, GDC0349; MEK inhibitor such as AZD6244, trametinib, PD184352, pimasertinib, GDC-0973, AZD8330; CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155, etc); TGF beta receptor kinase inhibitor such as LY2157299; BTK inhibitor such as 30 ibrutinib. Other anti-cancer agents include proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib;BET inhibitors such as INCB054329, OTX015, CPI-0610;LSD1 inhibitors such as GSK2979552, INCB059872; HDAC inhibitors such as panobinostat, vorinostat; DNA methyl transferase inhibitors such as azacytidine, decitabine, and other epigenetic protein inhibitors; HIF 2α inhibitors such as PT2977 and PT2385; Beta catenin pathway inhibitors, notch pathway inhibitors and hedgehog pathway inhibitors; Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept. 5 Other anti-cancer agents/drugs that can be used in combination with the compounds of the invention include, but are not limited to, liver X receptor (LXR) modulators, including LXR agonists and LXR beta-selective agonists; aryl hydrocarbon receptor (AhR) inhibitors. Other anti-cancer agents that can be employed in combination with the compounds of this disclosure include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; 10 aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin 15 hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; 20 epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including 25 recombinant interleukin II, or Ril2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; 30 methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; 5 teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; 10 zeniplatin; zinostatin; zorubicin hydrochloride. Other anti-cancer agents that can be employed in combination with the compounds of the disclosure include: 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; 15 anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; 20 azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; Bfgf inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; 25 CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis- porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; 30 cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; 5 galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; 10 isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; 15 loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; 20 molgramostim; monoclonal antibody, human chorionic gonadotrophin; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric 25 oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; 30 phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis- acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; R.sub.11 retinamide; rogletimide; rohitukine; romurtide; 5 roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; 10 stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin 15 mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; 20 variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Yet other anticancer agents that can be employed in combination with the compounds of present disclosure include alkylating agents, antimetabolites, natural products, or hormones, e.g., 25 nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). 30 Examples of natural products useful in combination with the compounds of this disclosure include but are not limited to vinca alkaloids (e.g., vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L- asparaginase), or biological response modifiers (e.g., interferon alpha). disclosure include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, 5 lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin. Examples of hormones and antagonists useful in combination the compounds of this 10 disclosure include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide). Other agents that can be used in the methods and compositions described 15 herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide). Other anti-cancer agents that can be employed in combination with the compounds of the 20 disclosure include: anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and include Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as 25 Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU- 103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone30 A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21- hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 KAR 2 (Hungarian Academy of Sciences), BSF 223651 (BASF, also known as ILX 651 and LU 223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 5 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS- 39.HCl), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC- 106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 10 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of 15 Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, 20 Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317 25 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi). Additional anti-cancer agents that can be used in combination with the HIF-2α inhibitors include PARP inhibitors such as olaparib (4-[(3-[(4-cyclopropylcarbonyl)piperazin-1-yl]carbonyl) -4-fluorophenyl]methyl(2H)phthalazin-1-one), rucaparib (8-fluoro-2-(4-methyl)-1,3,4,5-30 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), and pamiparib ((2R)-14-fluoro-2- methyl-6,9,10,19-tetrazapentacyclo[14.2.1.02,6.08,18.012,17]nonadeca-1(18),8,12(17),13,15-pentaen- 11-one; trihydrate). compound as described herein for treatment of HIF 2α associated diseases, disorders or conditions. Exemplary immune checkpoint inhibitors include inhibitors (smack molecules or biologics) against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, 5 CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, SHP-2, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137 and STING. In some embodiments, the immune checkpoint 10 molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors. 15 In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab. 20 In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab). 25 In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti- LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune 30 checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is LAG525. In some embodiments, the OX40L fusion protein is MEDI6383 Compounds of the invention can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including 5 increasing vaccine efficacy; and to increase inflammation. In some embodiments, the compounds of the invention can be sued to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viarl vaccines, and cancer vaccines such as GVAX® (granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine). Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and 10 recombinant viruses. Other immune-modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists. Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer. Compounds of this application may be effective in 15 combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation Examples The following preparations of compounds of Formula /(I) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be 20 considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof. Example 1 Synthesis of 3-fluoro-5-(((2aS,3S,4R)-1,1,2,2,3,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-25 1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile [24a] and 3-fluoro-5-(((2aS,3R,4R)-1,1,2,2,3,4- hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile [24b]
Figure imgf000065_0001
cyclopenta[cd]inden 5 yl)oxy) 5 fluorobenzonitrile A solution of (R)-3-fluoro-
Figure imgf000066_0001
, , , -hydroxy-4-oxo-2,2a,3,4-tetrahydro- 5 1H-cyclopenta[cd] inden-5-yl)oxy)benzonitrile (700 mg, 1.84 mmol, 1.0 equiv., ~80% ee), TFA (42 mg, 0.37 mmol, 0.2 equiv.) and butylamine (1343 mg, 18.36 mmol, 10.0 equiv.) in toluene (15 mL) was stirred for 16 h at 100 oC under N2 atmosphere. The resulting mixture was concentrated under vacuum to afford the title compound (1.0 g, crude) as a light brown oil, which was used for next step directly. MS (ES, m/z): [M+1]+= 437.2. 10 Step 2: 3-fluoro-5-(((2aS,3R)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H- cyclopenta[cd]inden-5-yl)oxy)benzonitrile and 3-fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a- hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd] inden-5-yl)oxy)benzonitrile A mixture of
Figure imgf000066_0002
, , , y-2,2a,3,4-tetrahydro- 15 1H-cyclopenta [cd]inden-5-yl)oxy)-5-fluorobenzonitrile (1.0 g crude, 1.84 mmol, 1.0 equiv.), sodium sulfate (651 mg, 4.58 mmol, 2.5 equiv.) and Selectfluor (1.05 g, 2.96 mmol, 1.6 equiv.) in MeCN (15 mL) was stirred for 4 h at 60 oC under N2 atmosphere. The crude product was purified by Prep-HPLC to afford 150 mg of 3-fluoro-5-(((2aS,3R)-1,1,2,2,3-pentafluoro-2a-hydroxy-4- oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (94% purity) and 300 mg20 of 3-fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H- cyclopenta[cd]inden-5-yl)oxy)benzonitrile (31% purity, contaminated with 60% of (R)-3-fluoro- 5-((1,1,2,2-tetrafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd] inden-5- yl)oxy)benzonitrile). MS (ES, m/z): [M-1]-= 397.9. cyclopenta[cd] inden 5 yl)oxy)benzonitrile To a s
Figure imgf000067_0001
, , , , , p y y-4-oxo- 5 2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (100 mg, 0.25 mmol, 1.0 equiv) in MeOH (2 mL) was added NaBH4 (19 mg, 0.50 mmol, 2.0 equiv) in portions at 0 oC under N2 atmosphere. The resulting mixture was stirred for 1h at room temperature under N2 atmosphere and then quenched with saturated NH4Cl solution (2 mL) at rt. The resulting mixture was extracted with EtOAc. The combined organic layer was washed with brine (2 x 2 mL), dried 10 over anhydrous Na2SO4, and concentrated to afford the title compound (90 mg, 90% crude yield, contained 36% desired product by HPLC). MS (ES, m/z): [2M-1]-= 801.2 Step 4: 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 [24b] 15 T
Figure imgf000067_0002
, , , , , , , hydroxy- 2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (70 mg, 0.17 mmol, 1.0 equiv) in DCM (2 mL) was added DAST (42 mg, 0.26 mmol, 1.5 equiv) dropwise at -40 oC under N2 atmosphere and the resulting mixture was stirred for 2 h at -40 oC under N2 atmosphere. The reaction was quenched with saturated NH4Cl solution (2 mL) at room temperature, and the 20 resulting mixture was extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC to afford the title compound (17 mg, 24.3 % yield) as a light- yellow solid. MS (ES, m/z): [M-1]-= 402.0 cyclopenta[cd] inden 5 yl)oxy)benzonitrile To a s
Figure imgf000068_0001
, , , , , p y y-4-oxo- 5 2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (250 mg crude, 0.63 mmol, 1.0 equiv) in MeOH (3 mL) was added NaBH4 (47 mg, 1.25 mmol, 2.0 equiv) in portions at 0 oC under N2 atmosphere. The resulting mixture was stirred for 1.0 hour at room temperature under N2 atmosphere. The reaction was quenched with saturated NH4Cl solution (2 mL) at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layer was 10 washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC to afford the title compound (90 mg). MS (ES, m/z): [M-1]-= 400.0 Step 6: 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 [24a] 15
Figure imgf000068_0002
To a stirred solution of 3-fluoro-5-(((2aS,3R,4S)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy- 2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (70 mg, 0.17 mmol, 1.00 equiv) in DCM (2 mL) was added DAST (42 mg, 0.26 mmol, 1.5 equiv) dropwise at -40 oC under N2 atmosphere. The resulting mixture was stirred for 2 h at -40 oC under N2 atmosphere. The 20 reaction was quenched with saturated NH4Cl solution (2 mL) at room temperature. The resulting mixture was extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give the title compound (18 mg). MS (ES, m/z): [M-1]-= 402.1

Claims

1. A method of treating a patient having cancer other than ccRCC wherein the cancer is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of 5 VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; 10 (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1α gene expression; and 15 (viii) reduced function of HIF-1α protein; the method comprising administering an effective amount of a HIF-2α inhibitor to the patient in need thereof.
2. A method of treating a patient having cancer other than ccRCC, the method comprising: 20 (a) determining whether the patient has cancer that is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; 25 (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of 30 HIF-1α gene promoter; (vii) reduction or absence of HIF-1α gene expression; and (viii) reduced function of HIF-1α protein; and (b) administering an effective amount of a HIF-2α inhibitor to the patient who is determined to have a cancer that is characterized by at least one of (a)(i)-(a)(viii). benefit from treatment a HIF 2α inhibitor, the method comprising: (a) determining whether the patient has cancer that is characterized by at least one of: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of 5 VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; 10 (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1α gene expression; and 15 (viii) reduced function of HIF-1α protein; wherein the presence at least one of: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of 20 VHL gene promoter; (iii) reduction or absence of VHL gene expression; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; 25 (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1α gene expression; and (viii) reduced function of HIF-1α protein; identifies the patient as one who may benefit from treatment with a HIF-2α inhibitor. 30 4. The method of claim 2 or 3, wherein the presence of at least one of the following: (i) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene; (ii) absence or one or more of truncation, insertion, mutation, and hypermethylation of VHL gene promoter; (iv) reduced function of VHL protein; (v) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene; 5 (vi) absence or one or more of truncation, insertion, mutation, and hypermethylation of HIF-1α gene promoter; (vii) reduction or absence of HIF-1α gene expression; and (viii) reduced function of HIF-1α protein; is assessed by histological and/or genetic analysis of a cancer sample obtained from the 10 patient. 5. The method of claim 4, wherein the absence, truncation, insertion, mutation, hypermethylation of one or more of VHL gene, VHL gene promoter, HIF-1α gene, and/or HIF-1α gene promoter in the cancer sample is determined by whole genome sequencing, exome sequencing, targeted gene sequencing, methylation sequencing, or a combination thereof. 15 6. The method of claim 4 or 5, wherein the truncation, insertion, mutation, hypermethylation of one or more of VHL gene, VHL gene promoter, HIF-1α gene, and/or HIF-1α gene promoter in the cancer sample is different from wild type VHL gene, VHL gene promoter, HIF-1α gene, and HIF-1α gene promoter, respectively. 7. The method of any one of claims 2 to 4, wherein the expression level of one or 20 more of VHL gene, VHL protein, HIF-1α gene and/or HIF-1α protein in the cancer sample is below the reference expression level of the corresponding one or more of VHL gene, VHL protein, HIF-1α gene and/or HIF-1α protein. 8. The method of claim 6, wherein the reference expression level of the VHL gene, VHL protein, HIF-1α gene and/or HIF-1α protein is determined from a population of patients 25 having the same cancer. 9. The method of claim 7 or 8, wherein the expression level and the reference expression level are a nucleic acid expression level and the nucleic acid expression level is an mRNA expression level. 10. The method of claim 9, wherein the mRNA expression level is determined by 30 RNA-seq, QuantiGene RNA Assay, Nanostring, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, or ISH, or a combination thereof. 11. The method of claim 7 or 8, wherein the expression level and the reference expression level are a protein expression level. 12. The method of claim 11, wherein the protein expression level is determined by AlphaLISA immunoassay, immunoprecipitation, immunofluorescence, electrochemiluminescence detection, homogeneous time resolved fluorescence (HTRF) assay, radioimmunoassay, or mass spectrometry. 5 13. The method of any one of claims 4 to 12, wherein the cancer sample is a tissue sample, a cell sample, a whole blood sample, a plasma sample, a serum sample, or a combination thereof. 14. The method of claim 13, wherein the tissue sample is a tumor tissue sample. 15. The method of any one of claims 1 to 14 wherein the HIF-2α inhibitor is a 10 compound of Formula (I): wherein: X1 is CH or N;
Figure imgf000072_0001
15 R1 is hydroxy, halo, amino, -OP(O)(OH)2, -OCH2OP(O)(OH)2, -OCOR10, -OCOOR11, -OCONR12R13, –OCHR14OCOR15 or –OCHR14OCOOR15a where R10, R11, and R15 and R15a are independently alkyl or alkyl substituted with amino, carboxy or hydroxy, R12 and R13 are independently hydrogen, alkyl, or alkyl substituted with amino, carboxy or hydroxy or R12 and R13 together with the nitrogen atom to which they are attached form optionally substituted 20 heterocyclyl, and each R14 is hydrogen, alkyl, or haloalkyl; R2 is hydrogen, deuterium, alkyl, halo, haloalkyl, alkenyl, or alkynyl; R2a is hydrogen, halo, or deuterium; R3 and R4 are independently hydrogen, deuterium, alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl; or 25 R3 and R4 together with the carbon to which they are attached form oxo, 3 to 6 membered cycloalkylene, or 4 to 6 membered optionally substituted heterocyclylene; R5 is hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxy, or alkoxy; R6 is hydrogen, deuterium, alkyl, cycloalkyl, or halo; or R5 and R6 together with the carbon to which they are attached form oxo, alkyldienyl, 3 to 630 membered cycloalkylene, or 4 to 6 membered optionally substituted heterocyclylene; provided R5 cycloalkylene or optionally substituted 4 to 6 membered heterocyclylene simultaneously; R7 is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, or haloalkoxy; L is a bond, S, SO, SO2, O, CO, or NR16 where R16 is hydrogen or alkyl; 5 R8 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 Ra, Rb, Rc, Rg and Rh wherein Ra, Rb, and Rc are 10 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 Rg and Rh are independently selected from hydrogen, deuterium, and halo; and R9 is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, haloalkoxy, 15 alkylsulfoxide, alkylsulfonyl, or heteroaryl wherein the heteroaryl is optionally substituted with Rd, Re, and Rf independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and cyano; or when R9 and R2 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; 20 R9a is hydrogen, halo, or deuterium; or a pharmaceutically acceptable salt thereof. 16. The method of claim 15, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is where R1 is hydroxy. 17. The method of claim 15, wherein the compound of Formula (I) or a 25 pharmaceutically acceptable salt thereof, has the structure of formula (IIa1) or (IIb1):
Figure imgf000073_0001
pharmaceutically acceptable salt thereof, has the structure of formula (IIa1 ) or (IIb1 ):
Figure imgf000074_0001
5 19. The method of any one of claims 15 to 18, wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1’) or (IIb1’), or a pharmaceutically acceptable salt thereof, is where R3 is fluoro. 20. The method of any one of claims 15 to 18, wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1’) or (IIb1’), or a pharmaceutically acceptable salt thereof, is where R3 and R4 are fluoro. 10 21. The method of any one of claims 15 to 20, wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1’) or (IIb1’), or a pharmaceutically acceptable salt thereof, is where L is O. 21. The method of any one of claims 15 to 20, wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1’) or (IIb1’), or a pharmaceutically acceptable salt thereof, is where R8 is phenyl substituted with Ra, Rb, Rc, Rg and Rh and wherein Ra, Rb, and Rc are independently selected from 15 hydrogen, deuterium, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl and Rg and Rh are independently selected from hydrogen, deuterium, and halo. 22. The method of claim 21, wherein the compound of Formula (I), (IIa1), (IIb1),20 (IIa1’) or (IIb1’), or a pharmaceutically acceptable salt thereof, is where R8 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, 2,6-25 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. 23. The method of any one of claims 15 to 22, wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1’) or (IIb1’), or a pharmaceutically acceptable salt thereof, is where R7 is hydrogen, methyl, ethyl, methoxy, fluoro, trifluoromethyl, or trifluoromethoxy. 30 24. The method of any one of claims 15 to 23, wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1’) or (IIb1’), or a pharmaceutically acceptable salt thereof, is where R2 is and R and R are attached to the ring carbon atom that is meta to the ring carbon attached to R . 25. The method of claim 22, wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1’) or (IIb1’), or a pharmaceutically acceptable salt thereof has the structure of formula (VIIIa) 5 or (VIIIb):
Figure imgf000075_0001
26. The method of claim 25, wherein the compound of Formula (VIIIa) or (VIIIb), or a pharmaceutically acceptable salt thereof, is where R2 is hydrogen or deuterium, R9 is hydrogen, 10 fluoro, or methyl and R2a and R9a are independently hydrogen, deuterium or fluoro. 27. The method of 15, 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- 15 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; 20 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- 25 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; 30 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; 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; 5 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- 10 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; 15 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- 20 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; 25 (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-(((2aS,3S,4R)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H- 30 cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 3-fluoro-5-(((2aS,3R,4R)-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. 28. The method of claim 15, wherein the compound of Formula (I) is selected from: [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; and 5 a pharmaceutically acceptable salt thereof. 29. The method of claim 15, 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. 30. The method of claim 15, wherein the compound of Formula (I) is 3-fluoro-5-10 ((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)- benzonitrile. 31. The method of any one of claims 1 to 30, wherein the cancer is selected from kidney cancer of non-clear cell subtypes, glioblastoma, neuroblastoma, paraganglioma, pheochromocytoma, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors, 15 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. 32. The method of any one of claims 1 to 31, wherein the cancer is a solid cancer. 20 33. The method of any one of claims 1 to 32, wherein the method further comprises administering one or more additional anti-cancer agents.
PCT/US2021/055483 2020-10-21 2021-10-18 Diagnostic and therapeutic methods for treatment of cancer with a hif-2(alpha) inhibitor WO2022086882A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063094883P 2020-10-21 2020-10-21
US63/094,883 2020-10-21

Publications (1)

Publication Number Publication Date
WO2022086882A1 true WO2022086882A1 (en) 2022-04-28

Family

ID=78622027

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/055483 WO2022086882A1 (en) 2020-10-21 2021-10-18 Diagnostic and therapeutic methods for treatment of cancer with a hif-2(alpha) inhibitor

Country Status (1)

Country Link
WO (1) WO2022086882A1 (en)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015035223A1 (en) 2013-09-09 2015-03-12 Peloton Therapeutics, Inc. Aryl ethers and uses thereof
WO2016196239A1 (en) 2015-05-29 2016-12-08 Arrowhead Pharmaceuticals, Inc. Compositions and methods for inhibiting gene expression of hif2alpha
US20160362390A1 (en) * 2015-06-12 2016-12-15 Peloton Therapeutics, Inc. Tricyclic inhibitors of hif-2-alpha and uses thereof
WO2019191227A1 (en) 2018-03-28 2019-10-03 Peloton Therapeutics, Inc. Methods of reducing inflammation of the digestive system with inhibitors of hif-2-alpha
WO2020055883A1 (en) * 2018-09-11 2020-03-19 Nikang Therapeutics, Inc. 2,3-DIHYDROBENZO[b]THIOPHENE DERIVATIVES AS HYPOXIA INDUCIBLE FACTOR-2(ALPHA) INHIBITORS
WO2020081695A1 (en) * 2018-10-17 2020-04-23 Nikang Therapeutics, Inc. Indane derivatives as hypoxia inducible factor-2(alpha) inhibitors
WO2020146521A2 (en) 2019-01-09 2020-07-16 Arrowhead Pharmaceuticals, Inc. Rnai agents for inhibiting expression of hif-2 alpha (epas1), compositions thereof, and methods of use
WO2020214853A1 (en) 2019-04-18 2020-10-22 Nikang Therapeutics, Inc. Tetrahydro-1h-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2(alpha) inhibitors
WO2021188769A1 (en) 2020-03-19 2021-09-23 Arcus Biosciences, Inc. Tetralin and tetrahydroquinoline compounds as inhibitors of hif-2alpha
WO2021212062A1 (en) * 2020-04-16 2021-10-21 Nikang Therapeutics, Inc. Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015035223A1 (en) 2013-09-09 2015-03-12 Peloton Therapeutics, Inc. Aryl ethers and uses thereof
WO2016196239A1 (en) 2015-05-29 2016-12-08 Arrowhead Pharmaceuticals, Inc. Compositions and methods for inhibiting gene expression of hif2alpha
US20160362390A1 (en) * 2015-06-12 2016-12-15 Peloton Therapeutics, Inc. Tricyclic inhibitors of hif-2-alpha and uses thereof
WO2019191227A1 (en) 2018-03-28 2019-10-03 Peloton Therapeutics, Inc. Methods of reducing inflammation of the digestive system with inhibitors of hif-2-alpha
WO2020055883A1 (en) * 2018-09-11 2020-03-19 Nikang Therapeutics, Inc. 2,3-DIHYDROBENZO[b]THIOPHENE DERIVATIVES AS HYPOXIA INDUCIBLE FACTOR-2(ALPHA) INHIBITORS
WO2020081695A1 (en) * 2018-10-17 2020-04-23 Nikang Therapeutics, Inc. Indane derivatives as hypoxia inducible factor-2(alpha) inhibitors
WO2020146521A2 (en) 2019-01-09 2020-07-16 Arrowhead Pharmaceuticals, Inc. Rnai agents for inhibiting expression of hif-2 alpha (epas1), compositions thereof, and methods of use
WO2020214853A1 (en) 2019-04-18 2020-10-22 Nikang Therapeutics, Inc. Tetrahydro-1h-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2(alpha) inhibitors
WO2021188769A1 (en) 2020-03-19 2021-09-23 Arcus Biosciences, Inc. Tetralin and tetrahydroquinoline compounds as inhibitors of hif-2alpha
WO2021212062A1 (en) * 2020-04-16 2021-10-21 Nikang Therapeutics, Inc. Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
"Fieser and Fieser's Reagents for Organic Synthesis", vol. 1-40, 1991, JOHN WILEY AND SONS
"Larock's Comprehensive Organic Transformations", vol. 1-5, 1989, ELSEVIER SCIENCE PUBLISHERS
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
ASHKTORAB, HBRIM, H, CURR COLORECTAL CANCER REP, vol. 10, no. 4, 1 December 2014 (2014-12-01), pages 425 - 430
BERNARDMAYERJOACHIM M.: "Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology", 2003, WILEY-VHCA
BERSTEN, D.C. ET AL., NAT REV CANCER, vol. 13, 2013, pages 827 - 841
BISHOP, T.RATCLIFFE, P., HYPOXIA (AUCKL, vol. 2, 2014, pages 197 - 213
COURTNEY, K. D. ET AL., J. CLIN. ONCOL., vol. 36, no. 9, 2018, pages 867 - 874
GU, Y.Z. ET AL., GENE EXPR, vol. 7, no. 3, 1998, pages 205 - 13
HAASE VOLKER: "The VHL Tumor Suppressor: Master Regulator of HIF", CURRENT PHARMACEUTICAL DESIGN, vol. 15, no. 33, 1 November 2009 (2009-11-01), NL, pages 3895 - 3903, XP055884957, ISSN: 1381-6128, DOI: 10.2174/138161209789649394 *
KAPITSINOU P P ET AL: "The VHL tumor suppressor and HIF: insights from genetic studies in mice", CELL DEATH & DIFFERENTIATION, vol. 15, no. 4, 1 April 2008 (2008-04-01), GB, pages 650 - 659, XP055884956, ISSN: 1350-9047, Retrieved from the Internet <URL:https://www.nature.com/articles/4402313.pdf> DOI: 10.1038/sj.cdd.4402313 *
LASSEIGNEBROOKS, MOL. DIAGN. THER., vol. 22, no. 4, 2018, pages 431 - 442
MCMAHON, K.W. ET AL., CANCER J, vol. 23, no. 5, September 2017 (2017-09-01), pages 257 - 261
SHENKAELIN, SEMINARS IN CANCER BIOLOGY, vol. 23, 2013, pages 18 - 25
T.W. GREENE: "Protective Groups in Organic Synthesis", 2014, JOHN WILEY & SONS, INC.
TIAN, H. ET AL., GENES & DEV., vol. 11, 1997, pages 72 - 82
TIAN, H. ET AL., GENES DEV, vol. 11, no. 1, 1 January 1997 (1997-01-01), pages 72 - 82
WALLACE, E. M. ET AL., CANCER RES, vol. 76, no. 18, 2016, pages 5491 - 5500
WANG, G.L. ET AL., PROC NATL ACAD SCI USA., vol. 92, no. 12, 6 June 1995 (1995-06-06), pages 5510 - 5514
WIGERUP, C. ET AL., PHARMACOLOGY & THERAPEUTICS, vol. 164, 2016, pages 152 - 169

Similar Documents

Publication Publication Date Title
US11753366B2 (en) Tetrahydro-1H-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2(alpha) inhibitors
EP3866927A1 (en) Indane derivatives as hypoxia inducible factor-2(alpha) inhibitors
WO2021016280A1 (en) Tricyclic derivatives as hypoxia inducible factor-2(alpha) inhibitors
CA3179508A1 (en) Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases
US11254651B2 (en) Histone methyltransferase inhibitors
WO2020140001A1 (en) Quinazoline derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors
KR20150085068A (en) Azaindole derivatives as jak3 inhibitors
US20220054451A1 (en) 2,3-DIHYDROBENZO[b]THIOPHENE DERIVATIVES AS HYPOXIA INDUCIBLE FACTOR-2(ALPHA) INHIBITORS
WO2022086882A1 (en) Diagnostic and therapeutic methods for treatment of cancer with a hif-2(alpha) inhibitor
US11420936B2 (en) Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases
WO2023060458A1 (en) Processes of making 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 and polymorphs thereof
US20230115881A1 (en) PROCESSES OF MAKING 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 AND POLYMORPHS THEREOF
WO2023070483A1 (en) PROCESSES OF MAKING 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 POLYMORPHS THEREOF
US11578079B2 (en) SUMO inhibitor compounds and uses thereof
CA3235013A1 (en) Hypoxia inducible factor-2(alpha) inhibitors for the treatment of bladder cancer
WO2023069372A1 (en) Hypoxia inducible factor-2(alpha) inhibitors for the treatment of bladder cancer
WO2022197734A1 (en) Bicyclic heteroaryl boronate derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21807374

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21807374

Country of ref document: EP

Kind code of ref document: A1