WO2023076532A1 - Processus de fabrication de 3-fluoro-5-(((1r,2s,2as)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tétrahydro-1h-cyclopenta[cd]inden-7-yl)-oxy)-benzonitrile et de polymorphes de celui-ci - Google Patents

Processus de fabrication de 3-fluoro-5-(((1r,2s,2as)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tétrahydro-1h-cyclopenta[cd]inden-7-yl)-oxy)-benzonitrile et de polymorphes de celui-ci Download PDF

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WO2023076532A1
WO2023076532A1 PCT/US2022/048111 US2022048111W WO2023076532A1 WO 2023076532 A1 WO2023076532 A1 WO 2023076532A1 US 2022048111 W US2022048111 W US 2022048111W WO 2023076532 A1 WO2023076532 A1 WO 2023076532A1
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inden
tetrahydro
cyclopenta
oxy
benzonitrile
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PCT/US2022/048111
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English (en)
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Rongzhen Chen
Charles M. Cook
Yan Dong
Jiping Fu
Bo Gao
Yigang He
Yan Lou
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Nikang Therapeutics, Inc.
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Publication of WO2023076532A1 publication Critical patent/WO2023076532A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings

Definitions

  • the present disclosure provides certain processes of making 3-fluoro-5-(((lR,2S,2aS)- 1,2, 3,3,4, 4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-lH-cyclopenta[cd]inden-7-yl)oxy)- benzonitrile according to the following structure:
  • compositions comprising a crystalline polymorph form of Compound (I) and processes for preparing such polymorph forms.
  • Compound (I) is a hypoxia inducible factor-2a (HIF-2a) inhibitor and is being developed for the treatment of pulmonary artery hypertension (PAH) and is also useful for the treatment of additional diseases such as, including cancer, such as renal cancer, glioblastoma, neuroblastoma, pheochromocytomas, paragangliomas, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors (GIST), pituitary tumors, leiomyomas, leiomyosarcomas, polycythaemia, and retinal tumors, and non-cancer diseases such as, reflux esophagitis, hepatic steatosis, NASH, inflammatory disease (such as inflammatory bowel disease), autoimmune disease (such as Graft- versus-Host-Disease), and iron overload.
  • cancer such as renal cancer, glioblastoma, neuroblastoma, pheochromocytomas, paragan
  • Compound (I) is disclosed in Example 24, as compound No. 24al, of PCT Application No. Publication No. WO 2020/214853.
  • the published process may be unsuitable for large scale synthesis of Compound (I) as fluorination of (R)-3-((4-(butylimino)-l,l,2,2-tetrafluoro-2a- hydroxy-2,2a,3,4-tetrahydro-lH-cyclopenta [cd]inden-5-yl)oxy)-5-fluorobenzonitrile with Selectfluor gives a mixture of (2aS,3S) and (2aS,3R) diastereomers of 3-fluoro-5-(l,l,2,2,3- pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-lH-cyclopenta[cd]inden-5-yloxy)- benzonitrile.
  • the polymorphic behavior of small molecule drugs can be critical in pharmacology since the same small molecule can have different physical properties as a result of the arrangement of molecules in the crystal lattice. These different properties can affect pharmaceutical parameters such as storage stability, compressibility, density, hygroscopy, dissolution rates, and bioavailability. It is known that one polymorph can convert into another polymorph, and in some cases this happens spontaneously. Accordingly, there is a need to find a thermodynamically stable polymorph of a small molecule drug. The present disclosure fulfills these and related needs.
  • R 1 is hydrogen and R 2 is C2-C12 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-Ci-6 alkyl;
  • R 1 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-Ci-6 alkyl and
  • R 2 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-Ci-6 alkyl; or
  • R 1 and R 2 together with the nitrogen atom to which they are attached form cyclylamine; or
  • R 1 is hydrogen and R 2 is C2-C12 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-Ci-6 alkyl;
  • R 1 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-Ci-6 alkyl and
  • R 2 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-Ci-6 alkyl; or
  • R 1 and R 2 together with the nitrogen atom to which they are attached form cyclylamine; or
  • a process of preparing crystalline Form A polymorph of Compound (I) (as defined in Embodiment Al to All), from a di ethylamine solvate of Compound (I), comprising:
  • a process of preparing crystalline Form A polymorph of Compound (I) comprising: a4) crystallizing or recrystallizing Compound (I) from one or more suitable organic solvents; b4) optionally adding one or more anti-solvents to the mixture of Step (a4); c4) optionally adding a solid crystalline seed of Compound (I) to the mixture of Step (a4) and/or (b4); and d4) isolating the crystalline Form A polymorph of Compound (I) from the mixture.
  • a seventh aspect provided is a process of preparing compound (5): with an inorganic base, organic amine, amine N-oxide, or cyclylamine N-oxide in a suitable organic or aqueous organic solvent;
  • a pharmaceutical composition comprising crystalline Form A of Compound (I) as defined in the first aspect above or any one of embodiments thereof disclosed herein; and a pharmaceutically acceptable excipient.
  • a method of treating a disease treatable by inhibition of HIF-2a in a patient preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of crystalline Form A polymorph of Compound (I) as defined in the first aspect above or any one of embodiments thereof disclosed herein in a pharmaceutical composition comprising a pharmaceutically acceptable excipient.
  • the disease includes VHL (von Hippel-Lindau) disease (see Oncotarget, 2015, 6, 23036-23037), PAH (pulmonary artery hypertension) (see Mol. Cell. Biol. 2016, 36, 1584-1594), esophagitis, reflux esophagitis (see Current Opinion in Pharmacology 2017, 37: 93-99), hepatic steatosis (see Nature Medicine 2017, 23, 1298-1308), NASH, inflammatory disease such as inflammatory bowel disease (see Nature Reviews gastroenterology & Hepatology 2017, 14, 596), autoimmune disease such as Graft-versus-Host- Disease (see Blood, 2015, 126, 1865), and iron overload.
  • VHL von Hippel-Lindau
  • the disease is cancer, such as renal cancer, clear cell renal cell carcinoma, liver cancer, hepatocellular carcinoma (HCC), pancreatic cancer, pancreatic neuroendocrine tumor, gastric cancer, ovarian cancer, non-small cell lung cancer, colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer (BTC), glioblastoma (see PNAS 2017, 114, E6137-E6146), neuroblastoma, pheochromocytomas and paragangliomas (see European Journal of Cancer 2017, 86, 1-4), somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors (GIST), pituitary tumors, leiomyomas, leiomyosarcomas, polycythaemia, retinal tumors, cancers with one or more EPAS1/HIF2A mutations such as uterine cancer, pheochromocyto
  • a pharmaceutical composition prepared with crystalline Form A polymorph of Compound (I) as defined in the first aspect above or any one of embodiments thereof disclosed herein; and a pharmaceutically acceptable excipient.
  • a method of inhibiting HIF2a comprises contacting HIF2a with crystalline Form A polymorph of Compound (I) as defined in the first aspect above or any one of embodiments thereof disclosed herein; or contacting HIF2a with a pharmaceutical composition comprising crystalline Form A polymorph of Compound (I) as defined in the first aspect above or any one of embodiments thereof disclosed herein, and a pharmaceutically acceptable excipient.
  • the diseases are those disclosed herein including those disclosed in the first and second embodiments of the ninth aspect.
  • any of the aforementioned aspects involving the treatment of cancer provided are further embodiments comprising administering crystalline Form A polymorph of Compound (I) as defined in the first aspect above or any one of embodiments thereof, in combination with at least one additional anticancer agent such as an EGFR inhibitor gefitinib, erlotinib, afatinib, icotinib, neratnib, rociletinib, cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab.
  • additional anticancer agent such as an EGFR inhibitor gefitinib, erlotinib, afatinib, icotinib, neratnib, rociletinib, cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab.
  • the crystalline Form A polymorph of Compound (I) as defined in the first aspect above or any one of embodiments thereof is administered in combination with a HER2/neu inhibitor including lapatinib, trastuzumab, and pertuzumab.
  • the crystalline Form A polymorph of Compound (I) as defined in the first aspect above or any one of embodiments thereof is administered in combination with a PI3k/mTOR inhibitor including idelalisib, buparlisib, BYL719, and LY3023414.
  • the crystalline Form A polymorph of Compound (I) as defined in the first aspect above or any one of embodiments thereof is administered in combination with a VEGF inhibitor such as bevacizumab, and/or a multi-tyrosine kinase inhibitors such as sorafenib, sunitinib, pazopanib, and cabozantinib.
  • a VEGF inhibitor such as bevacizumab
  • a multi-tyrosine kinase inhibitors such as sorafenib, sunitinib, pazopanib, and cabozantinib.
  • the crystalline Form A polymorph of Compound (I) as defined in the first aspect above or any one of embodiments thereof is administered in combination with an immunotherapeutic agents such as PD-1 and PD-L1 inhibitors, CTLA4 inhibitors, IDO inhibitors, TDO inhibitors, A2A agonists, A2B agonists, STING agonists, RIG-1 agonists, Tyro/Axl/Mer inhibitors, glutaminase inhibitors, arginase inhibitors, CD73 inhibitors, CD39 inhibitors, TGF-P inhibitors, IL-2, interferon, PI3K-y inhibitors, CSF-1R inhibitors, GITR agonists, 0X40 agonists, TIM-3 antagonists, LAG-3 antagonists, CAR-T therapies, and therapeutic vaccines.
  • an immunotherapeutic agents such as PD-1 and PD-L1 inhibitors, CTLA4 inhibitors, IDO inhibitors, TDO inhibitors, A2A agonists, A2B agonists, STING
  • Fig. 1 depicts a representative XRPD diffractogram of crystalline Form A polymorph of Compound (I).
  • Fig. 2 depicts a representative TGA thermogram of crystalline Form A polymorph of Compound (I).
  • Fig. 3 depicts a representative DSC thermogram of crystalline Form A polymorph of Compound (I).
  • Fig. 4 depicts a representative XRPD diffractogram of crystalline Form B polymorph of a diethylamine solvate of Compound (I).
  • Alkyl means a linear or branched saturated monovalent hydrocarbon radical of one to six carbon atoms i.e., Ci-Ce alkyl, unless stated otherwise e.g., C1-C12 alkyl or C2-C12 alkyl means an alkyl radical as defined above that contains 1 to 12 carbon atoms and 2 to 12 carbon atoms respectively. Examples include, but are not limited to, methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.
  • Ci-Ce alkylene means a linear or branched saturated divalent hydrocarbon radical of one to six carbon atoms.
  • Examples include, but are not limited to, methylene, -CH2CH2-, -CH2CH2CH2-, -CH 2 CH(CH 3 )-, -CH2CH2CH2CH2- (and isomers hereof), -CH2CH2CH2CH2CH2- (and isomers thereol), and the like.
  • C2-C6 alkenyl means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a single double bond. Examples include, but are not limited to, vinyl, allyl, and the like.
  • C2-C6 alkynyl means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a single triple bond. Examples include, but are not limited to, ethynyl, propargyl, and the like.
  • Anti-solvent as used herein means a solvent in which Compound (I) or a diethylamine solvate of Compound (I) is less soluble.
  • an antisolvent is a solvent in which Compound (I) has a solubility of less than about 25 mg/mL.
  • “Amine N-oxide” is a compound of formula R a R b R c N-*O (where R a and R b are alkyl and R c is Ci-C 12 alkyl), or is a six or ten-membered, monocyclic or bicyclic, aromatic heteroaryl ring containing a nitrogen atom that is bound to oxygen atom (e.g., pyridine N-oxide, quinoline N-oxide, isoquinoline N-oxide) wherein each ring is optionally substituted with one or two alkyl as defined herein.
  • Organic amine is a compound of formula R a R b R c N (where R a and R b are alkyl and R c is C1-C12 alkyl, or 4-pyridyl), pyridine, l,8-diazabicyclo[5.4.0]undec-7-ene, cyclylamine, or bridged cyclylamine, each term as defined herein.
  • “Bridged cyclylamine” means a saturated monocyclic ring of 6 to 8 ring atoms in which one ring atom is nitrogen and an additional ring atom can be a heteroatom independently selected from N, O, and S(O) n , where n is an integer selected from 0 to 2, the remaining ring atoms being C and further wherein two non-adjacent ring atoms are linked by a (CRR’)nl group where nl is 1 to 3, and R and R’ are independently H or methyl (also may be referred to herein as “bridging” group).
  • the bridged cyclylamine may be substituted with one or two alkyl as defined herein. Representative examples include, but is not limited to, l,4-diazabicyclo[2.2. 2]octane, l-azabicyclo[2.2. 2]octane, and the like.
  • C3-C7 cycloalkyl means a monocyclic saturated monovalent hydrocarbon radical of three to seven carbon atoms optionally substituted with one or two alkyl. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • C3-C7 cycloalkyl-Ci-6 alkyl means a -C1-6 alkylene-R group where C1-6 alkylene is as defined above and R is C3-C7 cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, cyclohexylmethyl, and the like.
  • Cyclylamine means a saturated monocyclic ring of 4 to 8 ring atoms in which one ring atom is nitrogen and an additional ring atom can be a heteroatom independently selected from N, O, and S(O) n , where n is an integer selected from 0 to 2, the remaining ring atoms being C.
  • the cyclylamine may be substituted with one, two, three, or four alkyl as defined herein. Representative examples include, but is not limited to, pyrrolidine, piperidine, homopiperidine, morpholine, piperazine, thiomorpholine, and the like.
  • Cyclylamine N-oxide means cyclylamine as defined above, wherein one of the ring nitrogen is bound to oxygen atom.
  • Representative examples include, but is not limited to, pyrrolidine N-oxide, piperidine N-oxide, homopiperidine N-oxide, morpholine N-oxide, N-methylmorpholine N-oxide, piperazine N-oxide, and the like.
  • solvate refers to forms of a compound where the compound is associated by a non-covalent bond to a solvent molecule. This physical association may include hydrogen bonding.
  • an amine solvate of Compound (I) refers to forms of Compound (I) that are associated with an amine NHR 1 R 2 or R 3 R 4 N-(CH2) n -NR 5 R 6 , each as defined herein and includes both stoichiometric solvates and non-stoichiometric solvates.
  • the amine solvate of Compound (I) are isolable, for example, when an amine molecule is incorporated in the crystal lattice of a crystalline solid of Compound (I).
  • the amine solvate of Compound (I) are present in situ.
  • An amine solvate of Compound (I) thus includes both isolable and in situ solvates.
  • An amine solvate of Compound (I) present in situ are also referred to herein as adducts.
  • the present disclosure includes a polymorphic form of Compound (I) or a di ethylamine solvate of Compound (I).
  • Polymorphs are crystalline forms of a compound that differ in arrangements of the molecules of that compound in a crystal lattice. Therefore, a single compound may give rise to a variety of polymorphic forms.
  • the polymorphs of a compound usually have different melting points, solubilities, densities, and optical properties.
  • Polymorphic forms of a compound can be distinguished by a number of techniques well known in the art such as X-ray diffractometry, IR or Raman spectroscopy.
  • XRPD means X-ray powder diffraction, an analytical technique which measures the diffraction of X-rays in the presence of a solid component. Materials which are crystalline and have regular repeating arrays of atoms generate a distinctive powder pattern. “Substantially free” as used herein refers to crystalline Form A polymorph of Compound (I) (i.e.
  • crystalline Form A polymorph of Compound (I) has less than about 8% by weight the (lS,2R,2aR) enantiomer. In another embodiment, crystalline Form A polymorph of Compound (I) has less than about 7% by weight the (lS,2R,2aR) enantiomer. In yet another embodiment, crystalline Form A polymorph of Compound (I) has less than about 6% by weight the (lS,2R,2aR) enantiomer. In yet another embodiment, crystalline Form A polymorph of Compound (I) has less than about 5% by weight the (lS,2R,2aR) enantiomer.
  • crystalline Form A polymorph of Compound (I) has less than about 4% by weight the (lS,2R,2aR) enantiomer. In yet another embodiment, crystalline Form A polymorph of Compound (I) has less than about 3% by weight the (lS,2R,2aR) enantiomer. In yet another crystalline Form A polymorph of Compound (I) has less than about 2% by weight the (lS,2R,2aR) enantiomer. In yet another embodiment, crystalline Form A polymorph of Compound (I) has less than about 1% by weight the (!S,2R,2aR) enantiomer.
  • crystalline Form A polymorph of Compound (I) has less than about 0.8% by weight the (!S,2R,2aR) enantiomer. In yet another embodiment, crystalline Form A polymorph of Compound (I) has less than about 0.7% by weight the (!S,2R,2aR) enantiomer. In yet another embodiment, crystalline Form A polymorph of Compound (I) has less than about 0.6% by weight the (!S,2R,2aR) enantiomer. In yet another embodiment, crystalline Form A polymorph of Compound (I) has less than about 0.5% by weight the (!S,2R,2aR) enantiomer.
  • crystalline Form A polymorph of Compound (I) has less than about 0.4% by weight the (!S,2R,2aR) enantiomer. In yet another embodiment, crystalline Form A polymorph of Compound (I) has less than about 0.3% by weight the (!S,2R,2aR) enantiomer. In yet another embodiment, crystalline Form A polymorph of Compound (I) has less than about 0.2% by weight the (!S,2R,2aR) enantiomer. In yet another embodiment, crystalline Form A polymorph of Compound (I) has less than about 0.1% by weight the (!S,2R,2aR) enantiomer. In yet another embodiment, crystalline Form A polymorph of Compound (I) has less than about 0.05% by weight the (!S,2R,2aR) enantiomer.
  • substantially pure refers to a solid-state form of Compound (I) that contain less than about 5% by weight total impurities.
  • crystalline Form A polymorph is substantially pure means that Form A polymorph of Compound (I) that contain less than about 5% by weight total impurities or less than about 5% of total impurities as measured by HPLC or less than about 5% of total impurities as measured by HPLC.
  • crystalline Form A polymorph of Compound (I) that contain less than about 3% by weight total impurities or less than about 3% of total impurities as measured by HPLC. In yet another embodiment, crystalline Form A polymorph of Compound (I) that contain less than about 2% by weight total impurities or less than about 2% of total impurities as measured by HPLC. In yet another embodiment, crystalline Form A polymorph of Compound (I) that contain less than about 1% by weight total impurities or less than about 1% of total impurities as measured by HPLC. In yet another embodiment, crystalline Form A polymorph of Compound (I) that contain less than about 0.9% by weight total impurities or less than about 0.9% of total impurities as measured by HPLC.
  • crystalline Form A polymorph of Compound (I) that contain less than about 0.8% by weight total impurities or less than about 0.8% of total impurities as measured by HPLC. In yet another embodiment, crystalline Form A polymorph of Compound (I) that contain less than about 0.7% by weight total impurities or less than about 0.7% of total impurities as measured by HPLC. In yet another embodiment, crystalline Form A polymorph of Compound (I) that contain less than about 0.6% by weight total impurities or less than about 0.6% of total impurities as measured by HPLC. In yet another embodiment, crystalline Form A polymorph of Compound (I) that contain less than about 0.5% by weight total impurities or less than about 0.5% of total impurities as measured by HPLC.
  • crystalline Form A polymorph of Compound (I) that contain less than about 0.4% by weight total impurities or less than about 0.4% of total impurities as measured by HPLC. In yet another embodiment, crystalline Form A polymorph of Compound (I) that contain less than about 0.3% by weight total impurities or less than about 0.3% of total impurities as measured by HPLC. In yet another embodiment, crystalline Form A polymorph of Compound (I) that contain less than about 0.2% by weight total impurities or less than about 0.2% of total impurities as measured by HPLC. In yet another embodiment, crystalline Form A polymorph of Compound (I) that contain less than about 0. 1% by weight total impurities or less than about 0.1% of total impurities as measured by HPLC. Impurities include, but are not limited to, synthesis by-products, residual starting materials, reagents, residual organic solvent, and the like.
  • substantially identical refers to measured physical characteristics that are comparable in value or data traces that are comparable in peak position and amplitude or intensity within the scope of variations that are typically associated with sample positioning or handling or the identity of the instrument employed to acquire the traces or physical characteristics or due to other variations or fluctuations normally encountered within or between laboratory environments or analytical instrumentation.
  • reacting when describing a certain process is used as known in the art and generally refers to the bringing together of chemical reagents in such a manner so as to allow their interaction at the molecular level to achieve a chemical or physical transformation.
  • the reacting steps of the processes described herein can be conducted for a time and under conditions suitable for preparing the identified product.
  • Suitable organic solvent or “first suitable organic solvent” refers to an organic solvent which, under the reaction conditions of the processes disclosed herein, does not enter into any appreciable reaction with either the reactants, intermediates and/or the products at the temperatures at which the reactions are carried out.
  • a given reaction disclosed herein can be carried out in one organic solvent or a mixture of two or more organic solvents.
  • suitable organic solvents that can be used in the reactions described herein include polar (protic and/or aprotic) and nonpolar organic solvents e.g., halogenated alkanes such as carbon tetrachloride, chloroform, di chloromethane, 1,2-di chloroethane, and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, diisopropyl ether, methyl t-butyl ether, and the like; alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, tert-butyl alcohol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, and the like; esters such as ethyl acetate, isopropyl acetate
  • Additional organic solvents that can be used in the reactions described herein include polar organic solvents including, but not limited to, acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, ethyl acetate, alcohols, and the like.
  • polar organic solvents e.g., alcohols, acetonitrile, DMF, N-methylpyrrolidinone, nitromethane
  • solvents that are suitable for the particular reaction step can be readily selected by a person skilled in the art.
  • the processes described herein can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., J H or 13 C), infrared spectroscopy, spectrophotometry, or mass spectrometry; or by chromatography such as high -performance liquid chromatography (HPLC) or thin layer chromatography.
  • HPLC high -performance liquid chromatography
  • the compounds obtained by the reactions can be purified by any suitable method known in the art. For example, chromatography (medium pressure) on a suitable adsorbent (e.g., silica gel, alumina and the like), HPLC, or preparative thin layer chromatography; distillation; sublimation, trituration, or recrystallization.
  • the purity of the compounds in general, are determined by physical methods such as measuring the melting point (in case of a solid), obtaining an NMR spectrum, or performing a HPLC separation.
  • Alcohol refers to an aliphatic hydrocarbon compound that carries one or more such as 1 or 2 hydroxy group. Representative examples include, but are not limited to, methanol, ethanol, propanol, butanol, 1,2-propanediol, and the like.
  • 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 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, benzenesul
  • 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 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.
  • a when used in reference to “a solid crystalline seed” means one or more solid crystalline seeds.
  • disease as used herein is intended to be generally synonymous, and is used 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 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 regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • patient is generally synonymous with the term “subject” and includes all mammals including humans. Examples 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.
  • Treating” or “treatment” of a disease includes:
  • inhibiting the disease i.e., arresting (i.e., stabilizing) or reducing the development 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 effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • a numerical range of embodiments may refer to a numbering range of another embodiments.
  • process embodiments D47-D54 refer to numerical range of embodiments C2 to C9 respectively, of composition of matter Embodiment C
  • embodiments D60-69 refer to numerical range of embodiments A2 to All, respectively, of composition of matter Embodiment A.
  • process embodiments D47-D54 produce, respectively, the product embodiments C2-C9, namely process embodiment D47 produces the product according to embodiment C2, process embodiment C48 produces the product according to embodiment C3, etc.
  • process embodiment D60 produces the product according to embodiment A2
  • process embodiment D69 produces the product according to embodiment A1E
  • the present disclosure includes:
  • the crystalline Form A polymorph of embodiment Al is wherein the Form A X-ray powder diffraction pattern further comprises a peak at angular position 16.0, wherein the angular positions may vary by ⁇ 0.2° 20.
  • the crystalline Form A polymorph of embodiment Al is wherein the Form A X-ray powder diffraction pattern further comprises peaks at angular positions 14.5 and 16.0, wherein the angular positions may vary by ⁇ 0.2° 20.
  • the crystalline Form A polymorph of embodiment Al is wherein the Form A X-ray powder diffraction pattern further comprises peaks at angular positions 14.5, 16.0, and 19.8, wherein the angular positions may vary by ⁇ 0.2° 20.
  • the crystalline Form A polymorph of embodiment Al is wherein the Form A X-ray powder diffraction pattern further comprises peaks at angular positions 14.5, 16.0, 19.6, and 19.8, wherein the angular positions may vary by + 0.2° 20.
  • a crystalline Form A polymorph of Compound (I) having an X-ray powder diffraction pattern comprising at least two, at least three, at least four, at least five, at least six peaks, at least seven peaks, or at least eight peaks at angular positions selected from Table 1 in Synthetic Example 1, wherein the angular positions may vary by + 0.2° 20.
  • the crystalline Form A polymorph of embodiment A6 is wherein the at least two, at least three, at least four, at least five, or at least six peaks are selected from 8.3, 14.5, 16.0, 19.6, 19.8, 20.7, and 21.9 wherein the angular positions may vary by + 0.2° 20.
  • embodiment A8 provided is a crystalline Form A polymorph of Compound (I) having an X-ray powder diffraction pattern substantially identical as shown in Fig 1.
  • the crystalline Form A polymorph of any one of Al to A8, are wherein the angular positions of the X-ray diffraction peaks denoted therein may vary by + 0.1° 20.
  • the crystalline Form A polymorph of any one of Al to A9 is substantially pure.
  • Al l the crystalline Form A polymorph of any one of Al to A10 is substantially free of 3-fluoro-5-(((lS,2R,2aR)-l,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4- tetrahydro-lH-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile enantiomer of Compound (I).
  • the crystalline Form A polymorph of any one of Al to Al 1 is wherein the amount of 3-fluoro-5-(((lS,2R,2aR)-l,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4- tetrahydro-lH-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile enantiomer of Compound (I) is less than about 5% w/w of Compound (I), preferably less than 3% w/w of Compound (I).
  • the amine solvate of embodiment Bl is wherein the amine is NHR’ R 2 .
  • the amine solvate of embodiment Bl is wherein the amine is R 3 R 4 -N-(CH 2 ) n -NR 5 R 6 .
  • the amine solvate of embodiment Bl or B2 is wherein R 1 is hydrogen and R 2 is C2-C12 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-Ci-6 alkyl.
  • the amine solvate of embodiment Bl, B2, or B4 is wherein R 1 is hydrogen and R 2 is C2-C12 alkyl.
  • the amine solvate of embodiment Bl, B2, or B4 is wherein R 1 is hydrogen and R 2 is C3-C7 cycloalkyl.
  • the amine solvate of embodiment Bl, B2, or B4 is wherein R 1 is hydrogen and R 2 is C3-C7 cycloalkyl-Ci-6 alkyl.
  • the amine solvate of embodiment Bl or B2 is wherein R 1 is Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl and R 2 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-Ci-6 alkyl.
  • the amine solvate of embodiment Bl, B2, or B7 is wherein R 1 is Ci-Ce alkyl and R 2 is Ci-Ce alkyl.
  • the amine solvate of embodiment Bl, B2, or B7 is wherein R 1 is Ci-Ce alkyl and R 2 is C3-C7 cycloalkyl.
  • the amine solvate of embodiment Bl, B2, or B7 is wherein R 1 is Ci-Ce alkyl and R 2 is C3-C7 cycloalkyl-Ci-6 alkyl.
  • the amine solvate of embodiment Bl or B2 is wherein R 1 and R 2 are independently C3-C7 cycloalkyl-Ci-6 alkyl.
  • the amine solvate of embodiment Bl or B2 is wherein R 1 and R 2 together with the nitrogen atom to which they are attached form cyclylamine.
  • n is selected from 2 to 5. In a first embodiment of B12, n is 3 to 5. In a second embodiment of B12, n is 4 or 5.
  • n is selected from 2 to 4. In a first embodiment of Bl 3, n is 3 or 4. In a second embodiment of Bl 3, n is 3.
  • the amine solvate of embodiment Bl or B3 is wherein n is 2 or 3.
  • the amine solvate of any one of embodiments Bl, B2, and B4 to B6A is wherein the amine is ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, tert-butylamine, n-pentylamine, sec-pentylamine, pentyl-3 -amine, neopentylamine, n-hexylamine, 2-hexylamine, 3-hexylamine, isohexylamine,
  • the amine solvate of any one of embodiments Bl, B2, B4, and B5 is wherein the amine is ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, tert-butylamine, n-pentylamine, sec-pentylamine, pentyl-3 -amine, neopentylamine, n-hexylamine, 2-hexylamine, 3-hexylamine, isohexylamine, 1 -methylpentylamine, 2-ethylbutyl-amine, 2-butylamine, 2-methylpentylamine, 1,1 -dimethylbutylamine, 1,3-dimethylbutylamine, 3,3-dimethylbutylamine, 2-methyl-3- pentylamine, 3-methylpentylamine, 3 -methyl-3 -pentylamine, 3-methyl-2-pentylamine, 3 -
  • the amine solvate of any one of embodiments Bl, B2, B4, and B6 is wherein the amine is cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, 2-methylcyclopropylamine, 2-methylcyclopentylamine, 3-methyl- cyclopentylamine, or 2-ethylcyclopropylamine.
  • the amine solvate of any one of embodiments Bl, B2, and B7 to B9 is wherein the amine is N-methylethylamine, di ethylamine, N-methyl-n-propylamine, N-methylisopropylamine, N-allylmethylamine, N-methylpropargylamine, N-ethyl-n- propylamine, N-ethylisopropylamine, N-methylbutylamine, N-methyl-2 -butylamine, N-tert- butyl-methyl-amine, N-methyl-cyclobutylamine, N-ethylcyclopropylamine, 1-cyclopropyl-N- methylmethanamine, N-ethyl-prop-2-yn-l -amine, N-ethylallylamine, N-methylpentylamine, N-methyl-2-pentylamine, N-methyl-3-pentylamine, N,3-di
  • the amine solvate of any one of embodiments Bl, B2, B7, and B8 is wherein the amine is N-methylethylamine, diethylamine, N-methyl-n-propylamine, N-methyl-isopropylamine, N-ethyl-n-propyl amine, N-ethyl-isopropylamine, N-methylbutylamine, N-methyl-2-butylamine, N-zc/V-butyl-methyl-amine.
  • N-methylpentyl-1- amine N-methyl-2-pentylamine, N-methyl-3-pentylamine, N,3-dimethylbutane-2-amine, N,2-dimethylbutane-2-amine, N,3-dimethylbutane-2-amine, N-ethyl-1 -butylamine, N-ethyl-2 - butylamine, N-ethyl-2 -methyl-2 -propylamine, N-ethyl-2 -methylpropylamine, di-n-propylamine, di-isopropylamine, or N-isopropylpropylamine.
  • the amine solvate of any one of embodiments Bl, B2, B7, and B9 is wherein the amine is N-methylcyclobutylamine, N-ethylcyclopropylamine, N-methylcyclopentylamine, or N-ethylcyclobutylamine.
  • the amine solvate of any one of embodiments Bl, B2, and Bl 1 is wherein the amine is azetidine, pyrrolidine, piperidine, piperazine, morpholine, azepane, or azocane.
  • B12 to B16, B19, B20, B22, B23, and B25 is wherein the amine is ethylenendiamine, propane- 1,3-diamine, butane- 1,4-diamine, pentane-l,5-diamine, hexane-l,6-diamine, N ⁇ -dimethylethane-l ⁇ -diamine, or N'.N 2 -di ethylethane- 1,2-diamine.
  • the amine solvate of embodiment Bl is wherein the amine is N-methylethylamine, diethylamine, N-methyl-n-propylamine, N-methyl-isopropylamine, N-ethyl-n-propylamine, N-ethyl-isopropylamine, azetidine, pyrrolidine, piperidine, morpholine, 1-methylpiperzaine, azepane, or thiomorpholine.
  • the amine solvate of embodiment Bl or B36 is wherein the amine is diethylamine.
  • the amine solvate of embodiment B37 is wherein the stoichiometric ratio of diethylamine to Compound (I) in the diethylamine solvate of Compound (I) is 1:1.
  • the amine solvate of any one of embodiments Bl to B38 is wherein the amine solvate of Compound (I) is a solid.
  • the amine solvate of embodiment B37 or B38 is wherein the amine solvate of Compound (I) is a crystalline solid.
  • the amine solvate of any one of embodiments Bl to B38 is wherein the amine solvate of Compound (I) is present in situ.
  • the amine solvate of embodiment B40 is wherein the amine solvate of Compound (I) is present in a mixture comprising, one or more suitable organic solvents, Compound (I), and the amine.
  • the amine solvate of embodiment B37 is wherein the diethylamine solvate of Compound (I) is present in a mixture comprising, one or more suitable organic solvent, Compound (I), and diethylamine.
  • the amine solvate of any one of embodiments B40 to B42 is wherein the one or more suitable organic solvents are independently selected from ethers, alcohols, esters, halogenated alkanes, ketones, dimethylformamide, dimethylacetamide, acetonitrile, nitromethane, n-methyl pyrrolidinone, toluene, and xylene.
  • the one or more suitable organic solvents are independently selected from ethers, alcohols, esters, halogenated alkanes, ketones, dimethylformamide, dimethylacetamide, acetonitrile, nitromethane, n-methyl pyrrolidinone, toluene, and xylene.
  • the amine solvate of embodiment B43 is wherein the one or more suitable organic solvents are independently selected from n-pentanol, methanol (MeOH), ethanol, n-propanol, isopropanol (IP A), n-butanol, 1,2-propanediol, methylene di chloride, chloroform, 1,2-di chloroethane, diethyl ether, diisopropyl ether, diglyme, triglyme, methyl tert- butyl ether (MTBE), methyl /c/7-am l ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propylacetate, isopropylacetate (IP Ac), butyl acetate, n-methyl pyrrolidinone (NMP), dimethyl formamide (DMF), dimethyl acetamide (DMAC), tetrahydrofuran (MeOH), ethanol,
  • the amine solvate of embodiment B43 is wherein the suitable organic solvent is methyl tert-butyl ether.
  • the crystalline Form B of embodiment Cl is wherein the Form B X-ray powder diffraction pattern further comprises a peak at angular position 23.2, wherein the angular positions may vary by ⁇ 0.2° 20.
  • the crystalline Form B of embodiment Cl is wherein the Form B X-ray powder diffraction pattern further comprises peaks at angular positions 8.4 and
  • the crystalline Form B of embodiment Cl is wherein the Form B X-ray powder diffraction pattern further comprises peaks at angular positions 8.4, 18.2, and 23.2, wherein the angular positions may vary by ⁇ 0.2° 20.
  • the crystalline Form B of embodiment Cl is wherein the Form B X-ray powder diffraction pattern further comprises peaks at angular positions 8.4, 18.2,
  • the crystalline Form B of embodiment C6 is wherein the at least two, at least three, at least four, at least five, or six peaks are selected from 8.4, 9.1, 13.5,
  • DI provided is a process of preparing an amine solvate of Compound (I) as described in the fourth aspect of the Summary.
  • embodiment D2 the process of embodiment DI is wherein Compound (I) is contacted with the amine by adding Compound (I) to the amine or by adding the amine to a mixture of Compound (I) in one or more suitable organic solvents in Step (al).
  • embodiment D3 the process of embodiment DI or D2 is wherein the amine is added to a mixture of Compound (I) in one or more suitable organic solvents in Step (al).
  • the process of any one of embodiments DI to D3 is wherein the amine is R 3 R 4 -N-(CH2) n -NR 5 R 6 .
  • any one of embodiments DI to D4 is wherein R 1 is hydrogen and R 2 is C2-C12 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-Ci-6 alkyl.
  • D7A the process of any one of embodiments DI to D4 and D5A is wherein R 1 is hydrogen and R 2 is C3-C7 cycloalkyl-Ci-6 alkyl.
  • any one of embodiments DI to D4 is wherein R 1 is Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl and R 2 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-Ci-6 alkyl.
  • process of any one of embodiments DI to D4, and D7B is wherein R 1 is Ci-Ce alkyl and R 2 is C3-C7 cycloalkyl-Ci-6 alkyl.
  • the process of any one of embodiments DI to D4 is wherein R 1 and R 2 together with the nitrogen atom to which they are attached form cyclylamine.
  • D12 the process of any one of embodiments DI to D3 and D5 is wherein n is selected from 2 to 5. In a first embodiment of DI 2, n is 3 to 5. In a second embodiment of DI 2, n is 4 or 5.
  • n is selected from 2 to 4. In a first embodiment of DI 3, n is 3 or 4. In a second embodiment of DI 3, n is 3.
  • DI 8 the process of any one of embodiments DI to D3 and D12 to DI 5 and subembodiments contained therein is wherein R 3 is C3-C7 cycloalkyl.
  • D27 the process of any one of embodiments DI to D3 and D12 to D24 and subembodiments contained therein is wherein R 6 is C3-C7 cycloalkyl.
  • D28 the process of any one of embodiments DI to D4 and D5A to D7A is wherein the amine is ethylamine, n-propylamine, isopropylamine, n-butylamine, secbutylamine, tert-butylamine, n-pentyl amine, sec-pentylamine, pentyl-3-amine, neopentyl amine, n-hexylamine, 2-hexylamine, 3-hexylamine, isohexylamine, 1 -methylpentylamine, 2-ethylbutylamine, 2-methylpentylamine, 1,1 -dimethylbutylamine, 1,3-dimethylbutylamine, 3,3-
  • the process of any one of embodiments DI to D4, D5A and D6 is wherein the amine is ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, tert-butylamine, n-pentylamine, sec-pentylamine, pentyl-3 -amine, neopentylamine, n-hexylamine, 2-hexylamine, 3-hexylamine, isohexylamine,
  • the process of any one of embodiments DI to D4, D5A and D7 is wherein the amine is cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, 2-methylcyclopropylamine, 2-methylcyclopentylamine, 3-methylcyclopentylamine, or 2-ethylcyclopropylamine.
  • the process of any one of embodiments DI to D4, and D7B to D9 is wherein the amine is N-methylethylamine, diethylamine, N-methyl-n-propylamine, N- methylisopropylamine, N-allylmethylamine, N-methylpropargylamine, N-ethyl-n-propylamine, N-ethylisopropylamine, N-methylbutylamine, N-methyl-2 -butylamine, N-/c/7-butyl-methyl- amine, N-methyl-cyclobutylamine, N-ethylcyclopropylamine, 1-cyclopropyl-N- methylmethanamine, N-ethyl-prop-2-yn-l -amine, N-ethylallylamine, N-methylpentylamine, N-methyl-2-pentylamine, N-methyl-3-pentylamine, N,3-dimethylbutan
  • the process of any one of embodiments DI to D4, D7B, and D9 is wherein the amine is N-methylethylamine, diethylamine, N-methyl-n-propylamine, N-methyl-isopropylamine, N-ethyl-n-propyl amine, N-ethyl-isopropylamine, N-methylbutylamine, N-methyl-2-butylamine, N-zc/V-butyl-methyl-amine.
  • N-methylpentyl-1- amine N-methyl-2-pentylamine, N-methyl-3-pentylamine, N,3-dimethylbutane-2-amine, N,2-dimethylbutane-2-amine, N,3-dimethylbutane-2-amine, N-ethyl-1 -butylamine, N-ethyl-2- butylamine, N-ethyl-2-methyl-2 -propylamine, N-ethyl-2 -methylpropylamine, di-n-propylamine, di-isopropylamine, or N-isopropylpropylamine.
  • the process of any one of embodiments DI to D4, D7B, and D9 is wherein the amine is N-methylcyclobutylamine, N-ethylcyclopropylamine, N-methylcyclopentylamine, or N-ethylcyclobutylamine.
  • the process of any one of embodiments DI to D4, and Dll is wherein the amine is azetidine, pyrrolidine, piperidine, piperazine, morpholine, azepane, or azocane.
  • the process of any one of embodiments DI to D3, D5, and D12 to D16, D19, D20, D22, D23, and D25 is wherein the amine is ethylenendiamine, propane- 1,3-diamine, butane- 1,4-diamine, pentane-l,5-diamine, hexane-l,6-diamine, N 1 , ⁇ -dimethylethane- 1,2-diamine, or N ’.N 2 -di ethylethane- 1,2-diamine.
  • the process of embodiment DI to D4 is wherein the amine is N-methylethylamine, diethylamine, N-methyl-n-propylamine, N-methyl-isopropylamine, N-ethyl-n-propylamine, N-ethyl-isopropylamine, azetidine, pyrrolidine, piperidine, or morpholine.
  • the process of embodiment DI to D4, or D36 is wherein the amine is diethylamine. In one embodiment, the process of embodiment D37, is wherein the molar ratio of diethylamine to Compound (I) in the mixture is at least about 1:0.8.
  • any one of embodiments DI to D37 is wherein one or more anti-solvents are added to the mixture of Step (al) to obtain a solid amine solvate of Compound (I).
  • the process of embodiment D38 or D39A is wherein the one or more anti-solvents in Step (bl) are independently selected from alkanes and water.
  • the one or more anti-solvents are independently selected from the group consisting of heptanes, hexanes, n-heptane, n-hexane, isooctane, pentane, cyclohexane, and cyclopentane.
  • any one of embodiments D2 to D41 is wherein the one or more suitable organic solvents of Step (al) are independently selected from the group consisting of alcohols, ethers, toluene, ketones, esters, halogenated alkanes, nitromethane, N-methylpyrrolidinone, acetonitrile, dimethylformamide, and dimethylacetamide.
  • the one or more suitable organic solvents of Step (al) are independently selected from the group consisting of alcohols, ethers, toluene, ketones, esters, halogenated alkanes, nitromethane, N-methylpyrrolidinone, acetonitrile, dimethylformamide, and dimethylacetamide.
  • any one of embodiments D2 to D41 is wherein the one or more suitable organic solvents of Step (al) are independently selected from the group consisting of n-pentanol, methanol, ethanol, n-propanol, isopropanol, n-butanol, 1,2-propanediol, methylene di chloride, chloroform, 1,2-di chloroethane, diethyl ether, diisopropyl ether, diglyme, triglyme, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propylacetate, isopropylacetate (IP Ac), butyl acetate, n-methyl pyrrolidinone (NMP), dimethyl formamide (DMF), dimethylacetamide (DMAc), te
  • the process of embodiment D45 is wherein the diethylamine solvate of Compound (I) is crystalline Form B polymorph having an X-ray powder diffraction pattern as described in the Summary. D47-D54. In embodiments D47 to D54, the process of embodiment D46 is wherein the crystalline Form B has an X-ray powder diffraction pattern as described in above embodiments C2 to C9, respectively.
  • any one of embodiments DI to D55 is wherein the amine solvate of Compound (I) is converted to Compound (I) by heating the amine solvate to remove the amine from the amine solvate.
  • the amine solvate of Compound (I) is heated at about 65 °C to about 70 °C.
  • any one of embodiments DI to D55 is wherein the amine solvate of Compound (I) is converted to Compound (I) by partitioning the amine solvate between one or more suitable organic solvents and an aqueous acidic solution.
  • D57A the process of D57 is wherein the aqueous acidic solution of hydrochloric acid.
  • embodiment D58 the process of embodiment D57 is wherein the one or more suitable organic solvents containing Compound (I) is isolated and concentrated to provide a solid form of Compound (I).
  • embodiment D59 the process of embodiment D56 or D58 is wherein the crystalline Form A polymorph Compound (I) has an X-ray powder diffraction pattern as described in the Summary is produced.
  • embodiment D60-D69A the process of embodiment D59 is wherein crystalline Form A polymorph of Compound (I) has an X-ray powder diffraction pattern as described in above embodiments A2 to A12, respectively is produced.
  • any one of embodiments DI to D69 further comprises preparing the Compound (I) of Step (al), by steps comprising:
  • the process of embodiment D70 is wherein the deoxyfluorination agent is bis(2 -methoxy ethyl)aminosulphur trifluoride (BAST, Deoxo-Fluor), diethylaminosulfur trifluoride (DAST), N-tosyl-4-chlorobenzenesulfonimidoyl fluoride (SulfoxFluor), Sulfur tetrafluoride (SF4), (diethylamino)difluorosulfonium tetrafluoroborate (XtalFluor-E), difluoro(morpholino)sulfonium tetrafluoroborate (XtalFluor-M), 4-/c/7-butyl-2.6- dimethylphenylsulfur trifluoride (Fluolead), A i ethyl- 1 , 1 ,2,3,3,3-hexafluoropropyl
  • BAST bis(2
  • embodiment D72 the process of embodiment D70 or D71 is wherein the suitable organic solvent is a halogenated alkane, ether, or acetate.
  • embodiment D72A the process of embodiment D70 or D71 is wherein the suitable organic solvent is dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, or ethyl acetate.
  • the suitable organic solvent is dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, or ethyl acetate.
  • embodiment D74 the process of embodiment D73 or 73A is wherein the deoxyfluorination agent is bis(2 -methoxy ethyl)aminosulphur trifluoride.
  • the process of any one of embodiments D70 to D74 further comprises preparing compound (6): comprising reducing the keto of 3-fluoro-5-(((2aS,3S)-l,l,2,2,3-pentafluoro-2a-hydroxy- 4-oxo-2,2a,3,4-tetrahydro-lH-cyclopenta[cd]inden-5-yl)oxy)benzonitrile according to structure (i.e. compound 5): with a suitable reducing agent in one or more suitable organic solvents and optionally in the presence of an organic acid.
  • the process of embodiment D75 is wherein the reducing agent is sodium borohydride, lithium borohydride, sodium triacetoxy borohydride, zinc borohydride, tetrabutylammonium borohydride, sodium cyanoborohydride, (R)-methyl-CBS oxazaborolidine, (S)-methyl-CBS oxazaborolidine, L-selectride, RuCl(p-cymene)[(S,S)-Ts- DPEN], RuCl(p-cymene)[(R,R)-Ts-DPEN], or tetramethylammonium triacetoxyborohydride.
  • the reducing agent is sodium borohydride, lithium borohydride, sodium triacetoxy borohydride, zinc borohydride, tetrabutylammonium borohydride, sodium cyanoborohydride, (R)-methyl-CBS oxazaborolidine, (S)-methyl-CBS o
  • embodiment D76A the process of embodiment D76 is wherein the one or more suitable organic solvents are selected from ether and halogenated alkane.
  • the process of embodiment D75 or 76 is wherein the reduction of the keto group of compound (5) is carried out with sodium borohydride in tetrahydrofuran, 2-methyltetrahydrofuran, a mixture of tetrahydrofuran or 2- methyltetrahydrofuran and methanol, tetrahydrofuran containing acetic acid or trifluoroacetic acid, 2-methyltetrahydrofuran containing acetic acid or trifluoroacetic acid, or methanol containing acetic acid or trifluoroacetic acid.
  • embodiment D78 the process of embodiment D75 or 76 is wherein the reduction of the keto group of compound (5) is carried out with sodium acetoxy borohydride in ethyl acetate and the reaction is carried out at about -20 °C to about 35 °C.
  • the process of any one of embodiments D75 to D78 further comprises preparing compound (5): by treating 3-fluoro-5-(((2aS)-l, 1,2,2, 3-pentafluoro-2a-hydroxy-4-oxo-2, 2a, 3,4- tetrahydro-lH-cyclopenta[cd]inden-5-yl)oxy)benzonitrile according to structure (i.e.
  • compound 4 or 3-fluoro-5-(((2aS, 3R)-1, 1,2,2, 3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro- lH-cyclopenta[cd]inden-5-yl)oxy)benzonitrile according to structure (i. e. , compound 4a): with an inorganic base, organic amine, amine N-oxide, or cyclylamine N-oxide in a suitable organic or aqueous organic solvent.
  • embodiment D82 the process of embodiment D79 is wherein an amine N-oxide is used.
  • embodiment D82A the process of embodiment D79 is wherein a cyclylamine N-oxide is used.
  • the process of embodiment D79 is wherein sodium fluoride, potassium fluoride, tetrabutylammonium fluoride, sodium acetate, potassium acetate, triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, 2, 2,6,6- tetramethyl-piperidine, azabicyclo[2.2. 2]octane, l,4-diazabicyclo[2.2. 2]octane, trimethylamine N-oxide, pyridine-N-oxide, or N-methylmorpholine N-oxide is used.
  • embodiment D85 the process of embodiment D79 or D84 is wherein N-methylmorpholine N-oxide is used and the reaction is carried out in aqueous acetonitrile at about 20 °C to about 85 °C.
  • embodiments E2 to E10 the process of embodiment El is wherein the diethylamine solvate of Compound (I) is crystalline Form B polymorph having an X-ray powder diffraction pattern as described in above embodiments Cl to C9, respectively.
  • the process of any one of embodiments El to E10 is wherein the diethylamine is removed from the diethylamine solvate of Compound (I) by heating the diethylamine solvate of Compound (I).
  • the process of any one of embodiments El to El 1 is wherein the diethylamine is removed from the diethylamine solvate of Compound (I) by partitioning the diethylamine solvate of Compound (I) between one or more suitable organic solvents and an aqueous acidic solution.
  • the acid is hydrochloric acid.
  • embodiment El 3 the process of embodiment E12 is wherein the one or more suitable organic solvents are isolated and concentrated to provide crystalline Form A polymorph of Compound (I) having an X-ray powder diffraction pattern as described in any one of embodiments Al to Al 1 above.
  • the process of embodiment E14 is wherein the crystalline Form A polymorph of Compound (I) is dissolved in one or more suitable organic solvents independently selected from the group consisting of alcohols, ethers, toluene, ketones, esters, halogenated alkanes, nitromethane, N-methylpyrrolidinone, acetonitrile, dimethylacetamide and dimethylformamide.
  • suitable organic solvents independently selected from the group consisting of alcohols, ethers, toluene, ketones, esters, halogenated alkanes, nitromethane, N-methylpyrrolidinone, acetonitrile, dimethylacetamide and dimethylformamide.
  • the process of embodiment E15 is wherein the one or more suitable organic solvents are selected from the group consisting n-pentanol, methanol, ethanol, n-propanol, isopropanol, n-butanol, 1,2-propanediol, methylene di chloride, chloroform, 1,2-di chloroethane, diethyl ether, diisopropyl ether, diglyme, triglyme, methyl /c/7-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propylacetate, isopropylacetate (IP Ac), butyl acetate, n-methyl pyrrolidinone (NMP), dimethyl formamide (DMF), dimethyl acetamide (DMAc), tetrahydrofuran (THF), 2-methyl THF
  • embodiment E17 the process of embodiment E15, E16, or E16A is wherein one or more anti-solvents and/or solid crystalline seed of Compound (I) are added.
  • the process of embodiment 17 is wherein the one or more anti-solvents are independently selected from alkanes and water.
  • the process of embodiment El 8 is wherein the one or more anti-solvents are independently selected from the group consisting of water, n-heptane, n-hexane, isooctane, pentane, cyclohexane, and cyclopentane.
  • embodiment E21 the process of embodiment E14 is wherein the crystalline Form A polymorph of Compound (I) is recrystallized from isopropyl acetate, isopropyl alcohol, or toluene.
  • the process of embodiment Fl is wherein the one or more suitable organic solvents are independently selected from the group consisting of alcohols, ethers, toluene, ketones, esters, halogenated alkanes, nitromethane, N-methylpyrrolidinone, acetonitrile, dimethylacetamide, and dimethylformamide.
  • the one or more suitable organic solvents are independently selected from the group consisting of alcohols, ethers, toluene, ketones, esters, halogenated alkanes, nitromethane, N-methylpyrrolidinone, acetonitrile, dimethylacetamide, and dimethylformamide.
  • the process of embodiment F2 is wherein the one or more suitable organic solvents are selected from the group consisting n-pentanol, methanol, ethanol, n-propanol, isopropanol, n-butanol, 1,2-propanediol, methylene di chloride, chloroform, 1,2-di chloroethane, diethyl ether, diisopropyl ether, diglyme, triglyme, methyl /c/7-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propylacetate, isopropylacetate (IP Ac), butyl acetate, n-methyl pyrrolidinone (NMP), dimethyl formamide (DMF), dimethyl acetamide (DMAc), tetrahydrofuran (THF), 2-methyl THF (2-
  • the process of embodiment F4 is wherein the one or more anti-solvents is independently selected from alkanes and water.
  • the process of embodiment F5 is wherein the one or more anti-solvents is independently selected from the group consisting of water, n-heptane, n-hexane, isooctane, pentane, cyclohexane, and cyclopentane.
  • embodiment F7 the process of embodiment F6 is wherein the one or more anti-solvents is n-heptane.
  • the process of any one of embodiments Fl to F7 is wherein the process is carried out at about 0 °C to about 70 °C.
  • embodiment F9 the process of embodiment Fl is wherein Compound (I) is crystallized or recrystallized from IP Ac, IP A, or toluene.
  • Gl In embodiment Gl, provided is a process of preparing compound (5) as described in the seventh aspect of the Summary.
  • embodiment G2 the process of embodiment Gl is wherein an organic amine is used.
  • embodiment G4 the process of embodiment Gl is wherein an amine oxide is used.
  • embodiment G4A the process of embodiment Gl is wherein a cyclylamine N- oxide is used.
  • the process of embodiment Gl is wherein sodium fluoride, potassium fluoride, tetrabutylammonium fluoride, sodium acetate, potassium acetate, triethylamine, diisopropylethylamine, dimethylaminopyridine, 2,2,6,6-tetramethyl-piperidine, l,4-diazabicyclo[2.2.2]octane, trimethylamine N-oxide, or N-methylmorpholine N-oxide is used.
  • G6 In embodiment G6, the process of embodiment Gl or G4a is wherein N-methylmorpholine N-oxide is used.
  • G7 In embodiment G7, the process of embodiment G1 or G4a is wherein N-methylmorpholine N-oxide is used and the reaction is carried out in aqueous acetonitrile at about 20 °C to about 85 °C.
  • any one of embodiments G1 to G7 optionally further comprises converting compound (5): to compound (6): comprising treating compound (5) with a suitable reducing agent in one or more suitable organic solvents and optionally in the presence of an organic acid.
  • the process of embodiment G8 is wherein the reducing agent is sodium borohydride, lithium borohydride, sodium triacetoxy borohydride, zinc borohydride, tetrabutylammonium borohydride, sodium cyanoborohydride, (R)-methyl-CBS oxazaborolidine, (S)-methyl-CBS oxazaborolidine, L-selectride, RuCl(p-cymene)[(S,S)-Ts-DPEN], RuCl(p- cymene)[(R,R)-Ts-DPEN], or tetramethylammonium triacetoxyborohydride.
  • the reducing agent is sodium borohydride, lithium borohydride, sodium triacetoxy borohydride, zinc borohydride, tetrabutylammonium borohydride, sodium cyanoborohydride, (R)-methyl-CBS oxazaborolidine, (S)-methyl-CBS
  • embodiment G9A the process of embodiment G8 or G9 is wherein the one or more suitable organic solvents are selected from ethers and halogenated alkanes.
  • the process of embodiment G8 or G9 is wherein the reduction is carried out with sodium borohydride in tetrahydrofuran, 2-methyltetrahydrofuran, a mixture of tetrahydrofuran or 2-methyltetrahydrofuran and methanol, tetrahydrofuran containing acetic acid or trifluoroacetic acid, 2-methyltetrahydrofuran containing acetic acid or trifluoroacetic acid, or methanol containing acetic acid or trifluoroacetic acid.
  • the process of embodiment G8 or G9 is wherein the reduction is carried out with sodium acetoxy borohydride in ethyl acetate and the reaction is carried out at about -20 °C to about 35 °C.
  • the process of any one of embodiments G8 to G11 optionally further comprises converting compound (6) to Compound (I), comprising treating compound (6): with a deoxyfluorination agent in a suitable organic solvent.
  • Compound (I) is optionally recrystallized as described in the sixth aspect (and embodiment thereof disclosed herein).
  • Compound (I) is useful for the treatment of HIF-2a mediated diseases, which include but are not limited to, various types of cancer, liver disease such as nonalcoholic steatohepatitis (NASH), inflammatory disease such as inflammatory bowel disease (IBD), pulmonary diseases such as pulmonary arterial hypertension (PAH), and iron load disorders.
  • liver disease such as nonalcoholic steatohepatitis (NASH)
  • inflammatory disease such as inflammatory bowel disease (IBD)
  • pulmonary diseases such as pulmonary arterial hypertension (PAH)
  • iron load disorders include iron load disorders.
  • HIF-2a plays an important role in the initiation and progression of many human cancers. Many extensive studies have demonstrated the critical role of increased HIF-2a activity in driving clear cell renal cell carcinoma (ccRCC) (see review by Shen and Kaelin, Seminars in Cancer Biology 23: 18-25, 2013). Abnormal HIF-2a activity is largely due to loss of function of a tumor suppressor, VHL. It is known that over eighty percent of ccRCC have defective VHL either through deletion, mutation or disturbed post-translational modification. Defective VHL leads to constitutively active HIF-a proteins regardless of oxygen level.
  • HIF-2a is the key oncogenic substrate of VHL (see Kondo, et al. Cancer Cell 1: 237-246, 2002; Kondo, et al. PLoS Biology 1: 439-444, 2002; Maranchi, et al. Cancer Cell 1: 247-255, 2002; Zimmer, et al. Mol. Cancer Res 2: 89-95, 2004).
  • knockdown of HIF-2a in VHL-null tumors inhibited tumor formation; while reintroduction of VHL and overexpression of HIF-2a overcame the tumor suppressive role of VHL.
  • single nucleotide polymorphism in HIF-2a is associated with resistant to PHD-mediated degradation, has been linked to an increased risk of developing RCC.
  • the VHL-HIF-2a axis has also been implicated in ccRCC tumor metastasis through its downstream CXCR4 and CYTIP (see Vanharanta et al. Nature Medicine 19: 50-59, 2013; Peter Staller et al. Nature. 2003 Sep 18;425(6955):307-l l).
  • VHL Defective VHL not only predisposes patients to kidney cancer (with a70% lifetime risk), but also to hemangioblastomas, pheochromocytoma, endolymphatic sac tumors, and pancreatic neuroendocrine tumors. Tumors derived from defective VHL are frequently driven by the constitutively active downstream HIF-a proteins, with the majority of these dependent on HIF- 2a activity (see Maher, et al. Eur. J. Hum. Genet. 19: 617-623, 2011). Both genetic and epigenetic mechanisms can lead to the loss of function in VHL.
  • HIF-a has been found in many cancers including RCC, multiple myeloma, retinoblastoma, NSCLC, pancreatic endocrine tumors, squamous cell carcinoma, acute myeloid leukemia, myelodysplastic syndrome, and esophageal squamous cell carcinoma (see reviewed in Nguyen, et al. Arch. Phann. Res 36: 252-263, 2013).
  • HIF-2a has also been linked to cancers of the retina, adrenal gland and pancreas through both loss of function in VHL and activating mutations in HIF-2a.
  • HIF-2a target gene products e.g., VEGF, PDGF, and cyclin DI
  • VEGF vascular endothelial growth factor
  • PDGF vascular endothelial growth factor
  • cyclin DI vascular endothelial growth factor
  • HIF-2a targeted therapy could be beneficial for the above cancers when driven by these signaling events downstream of abnormal HIF-2a pathway activation.
  • HIF-a proteins are also frequently upregulated in the intratumor environment of rapidly growing tumors, due to the hypoxic condition resulting from poor vascularization in large tumors.
  • the activated HIF-a pathways in turn, further promotes tumor cell survival and proliferation by transcriptionally upregulating various essential factors.
  • HIF-2a has been demonstrated to augment the growth of APC mutant colorectal cancer through its regulation of genes involved in proliferation, iron utilization and inflammation (see Xue, et al.
  • HCC hepatocellular carcinoma
  • HIF-2a activity has been linked to the progression of chronic obstructive pulmonary disease (COPD), in addition to lung cancer, in mouse models (see Karoor, et al. Cancer Prev. Res. 5: 1061-1071, 2012). HIF-2a activity has also been demonstrated to be important in cancers of the central nervous system (see Holmquist-Mengelbier, et al. Cancer Cell 10: 413-423, 2006 and Li, et al. Cancer Cell 15: 501-513, 2009). HIF-2a knockdown reduced tumor growth in preclinical animal models of neuroblastoma, Conversely, increased level of HIF-2a correlated with advanced disease, poor prognosis and higher VEGF levels, which likely contribute to the poor clinical outcome.
  • COPD chronic obstructive pulmonary disease
  • HIF-2a expression has been correlated with a poor survival in glioma.
  • inhibition of HIF -2a in glioma stem cells reduced cell proliferation and survival in vitro and tumor initiation in vivo.
  • HIF-la is expressed in both neural progenitors and brain tumor stem cells, HIF-2a is found exclusively in the latter.
  • survival of glioma patients correlates to with HIF-2a, but not HIF-la level.
  • HIF-2a effector is cyclin D, an essential partner for the activation of CDK4 and CDK6. Therefore, administration of a HIF-2a inhibitor with CDK4/6 inhibitors, including abemaciclib (Verzenio®), palbociclib (Ibrance®) and riboci clib (Kisqali®) should result in downregulation of cyclin D, thereby increasing antiproliferative effects of CDK4/6 inhibitors.
  • abemaciclib Verzenio®
  • palbociclib Ibrance®
  • riboci clib Kisqali®
  • Somatostatinomas are somatostatin-producing neuroendocrine tumors that are rare, but often malignant. It has been found that HIF-2a mutations lead to the disruption of the prolyl hydroxylation domain (PHD) of HIF-2a, thus abolish the modification by PHDs, and subsequently reduce HIF-2a degradation mediated by VHL (see Yang, et al. Blood. 121: 2563- 2566, 2013). The stabilized HIF-2a can then translocate to the nucleus, driving increased expression of hypoxia-related genes to contribute to somatostatinoma. Thus, aHIF-2a inhibitor will provide an alternative approach in treating somatostatinoma.
  • PHD prolyl hydroxylation domain
  • Polycythaemia is a hematologic disorder characterized by elevated hematocrit (the volume percentage of red blood cells in the blood), also known as erythrocytosis.
  • Gain-of- function mutations in HIF-2a are associated with autosomal dominant erythrocytosis (see Percy, et al. N. Engl. J. Med. 358: 162-8, 2008 and Wilson et al. Case Rep Hematol. 6373706, 2016).
  • mutations in PHD of HIF-2a which is responsible in signaling HIF-2a for ubiquitination and degradation by VHL, have also been found to drive polycythaemia.
  • HIF-2a n which is stabilized either by gain of function HIF-2a mutations or by loss of function mutations in PHD, VHL
  • an HIF-2a inhibitor should be able to suppress HIF-2a downstream genes, such as EPO and thereby reducing hematocrit of polycythaemia.
  • Pheochromocytomas and paragangliomas are rare neuroendocrine tumors that often develop on a background of predisposing genetic mutations, including loss of function in VHL or PHD2 or activating mutations of HIF-2a , all of which result in highly expressed HIF-2a protein and subsequently downstream genes to promote oncogenic progression (see Dahia, Nat Rev Cancer. 14:108-19, 2014). Furthermore, germline heterozygous mutations in genes encoding succinate dehydrogenase (SDH) subunits and the SDH complex assembly factor 2 protein (SDHAF2) have been described in patients with hereditary phaeochromocytoma and paraganglioma (PPGL).
  • SDH succinate dehydrogenase
  • SDHAF2 SDH complex assembly factor 2 protein
  • HIF-2a Loss-of-function mutations of fumarate hydratase (FH) predispose patients to the autosomal dominant syndrome of both cutaneous and uterine leiomyomatosis. It has been suggested that activation ofHIF proteins contributes to FH-associated tumor development by activation of hypoxia pathways, (see O'Flaherty, et al. Hum Mol Genet. 19: 3844-3851, 2010 and Wei, et al. J Med Genet. 43:18-27, 2006). Furthermore, high expression of HIF-2a is found in leiomyosarcomas, a rare neoplasm of smooth-muscle origin (see Mayer, et al. Cancer Res. 68: 4719, 2008) Thus, inhibition of HIF-2a could be beneficial in treating both leiomyomas and leiomyosarcomas.
  • Retinal capillary hemangioblastomas can be the ocular manifestations of VHL diseases, which are caused by loss of tumor suppressor VHL. Upregulation of HIF-2a upon loss of VHL has been detected in retinal hemangioblastoma patients and is indicated to contribute to the aggressive course of retinal hemangioblastomas, resulting in the resistance to multiple anti-VEGF and radiation therapies (see Wang, et al. Graefes Arch. Clin. Exp. Ophthalmol. 252: 1319-1327, 2014). Moreover, uncontrolled blood vessel growth is a central pathological component of many human blindness disorders, including diabetic retinopathy, age-related macular degeneration, glaucoma, and retinopathy of prematurity.
  • HIF-2a may have potential utility in treating various diseases of blindness.
  • systemic reduction of HIF-2a expression with a hypomorphic Hif-2a allele caused marked decreases in retinal neovascularization that was accompanied by defects in EPO expression (see Morita, et al. EMBO J. 22: 1134-46, 2003).
  • a direct role in promoting the initiation, progression and metastasis of tumor cells e.g.
  • HIF-2a also indirectly contributes to tumorigenesis through augmenting the immunosuppressive effect of hypoxia within the tumor microenvironment.
  • Expression of HIF-2a has been detected in cells of the myeloid lineage (see Talks KL, et dal. Am J Pathol. 2000; 157(2): 411-421).
  • HIF-2a is shown to favor the polarization of macrophages to the immunosuppressive M2 phenotype and enhances migration and invasion of tumor- associated macrophages (see Imtiyaz HZ et al. J Clin Invest. 2010;120(8):2699-2714).
  • HIF-2a can indirectly promote additional immunosuppressive pathways (e.g. adenosine and arginase etc.) by modulating the expression of key signaling regulators such as adenosine A2B/A2A receptors and arginase.
  • additional immunosuppressive pathways e.g. adenosine and arginase etc.
  • key signaling regulators such as adenosine A2B/A2A receptors and arginase.
  • HIF- 2a proteins Due to the key roles of HIF- 2a proteins in regulating physiological response to the fluctuation of oxygen levels, they have been causally associated with many hypoxia-related pathological processes in addition to cancer.
  • PAH a debilitating and life- threatening disease with very poor prognosis.
  • HIF-2a contributes to the process of hypoxic pulmonary vascular remodeling, reduced plasticity of the vascular bed, and ultimately, debilitating PAH (see Andrew S., et al. Proc Natl Acad Sci U S A. 2016 Aug 2; 113(31): 8801-8806, Tang H, et al. Am J Physiol. Lung Cell Mol Physiol. 2018 Feb 1;314(2):L256-L275.).
  • hypoxia-related pathological processes is IBD, a chronic relapsing inflammatory disease of the intestine. It is found that intestinal inflammation and subsequently IBD arose when a dysregulated epithelial oxygen tension occurs and intensifies across epithelial villi in the intestine (see Shah Y.M., Molecular and Cellular Pediatrics, 2016 Dec; 3(1): 1). HIF-2a activation contributes to IBD, while HIF-la in intestinal epithelial cells is considered as a major protective factor in IBD (see Karhausen J, et al.
  • HIF-2a activation not only leads to the upregulation of pro-inflammatory cytokines which promotes IBD directly, but also results in loss of intestine barrier integrity, thus indirectly contributes to the manifestation of IBD.
  • HIF-2a inhibitor holds the promise of reverting the pro-inflammatory condition and increasing the intestinal barrier integrity, thus alleviate the symptoms of IBD.
  • HIF-2a inhibitor also represents a novel therapeutic approach in NASH, for which limited therapeutic options are available.
  • a recent study showed that an intestine-specific disruption of HIF-2a led to a significant reduction of hepatic steatosis and obesity induced by high-fat-diet.
  • intestine HIF-2a positively regulates the gene encoding neuraminidase 3, thus regulates ceramide metabolism which contributes to the development of NASH (see Xie C, et al. Nat Med. 2017 Nov;23(ll): 1298-1308.). Therefore, a HIF-2a inhibitor should have preventive and therapeutic effects on metabolic disorders, such as NASH.
  • HIF-2a HIF-2a
  • HIF-la HIF-2a
  • the present disclosure provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or over activation of HIF-2a is implicated in the disease state.
  • the present disclosure provides a method of treating renal cell carcinoma of a subject with Compound (I).
  • HIF-2a inhibitors also have therapeutic potentials for a broad range of non-cancer indications including but not limited to NASH, IBD, PAH, and iron overload.
  • Form A polymorph of Compound (I) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Therapeutically effective amounts of Form A polymorph of Compound (I) may range from about 10 mg/per day to about 500 mg/per day or 200 mg/per day to about 1000 mg/per day, which can be administered in single or multiple doses.
  • the compositions can be provided in the form of tablets containing about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of Form A polymorph of Compound (I) 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.
  • Form A polymorph of Compound (I) will be administered as pharmaceutical 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.
  • 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 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.
  • formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred.
  • compositions are comprised of in general, Form A polymorph of Compound (I) 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 Form A polymorph of Compound (I).
  • 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 be independently 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.
  • Form A polymorph of Compound (I) may be formulated for parenteral administration by injection, e.g., by 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 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.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of Form A polymorph of Compound (I) 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 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 Form A polymorph of Compound (I) to allow for the preparation of highly concentrated solutions.
  • Form A polymorph of Compound (I) 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.
  • Form A polymorph of Compound (I) may be formulated with suitable polymeric or hydrophobic materials (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.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise Form A polymorph of Compound (I) in a flavored basis such as sucrose and acacia or tragacanth.
  • the level of Form A polymorph of Compound (I) 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, from about 0.01-99.99 wt. % of Form A polymorph of Compound (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %.
  • Form A polymorph of Compound (I) may be used in combination with one or more other drugs in the treatment of diseases or conditions for which Form A polymorph of Compound (I) or the other drugs may have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with Form A polymorph of Compound (I).
  • a pharmaceutical composition in unit dosage form containing such other drugs and Form A polymorph of Compound (I) is preferred.
  • the combination therapy may also include therapies in which Form A polymorph of Compound (I) and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, Form A polymorph of Compound (I) and the other active ingredients may be used in lower doses than when each is used singly.
  • compositions of the present disclosure also include those that contain one or more other drugs, in addition to Form A polymorph of Compound (I).
  • the above combinations include combinations of Form A polymorph of Compound (I) not only with one other drug, but also with two or more other active drugs.
  • Form A polymorph of Compound (I) may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which Form A polymorph of Compound (I) is useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with Form A polymorph of Compound (I).
  • a pharmaceutical composition containing such other drugs in addition to Form A polymorph of Compound (I) can be used.
  • compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to Form A polymorph of Compound (I).
  • the weight ratio of Form A polymorph of Compound (I) to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the subject in need is suffering from or at risk of suffering from cancer
  • the subject can be treated with Form A polymorph of Compound (I) in any combination with one or more other anti-cancer agents.
  • one or more of the anti-cancer agents are proapoptotic agents.
  • anti-cancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2’- deoxy cytidine, 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”, which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule
  • Suitable anti-cancer agents also include inhibitors of kinases associated cell proliferative disorder.
  • 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, Lek, Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, MEK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, RAF, Rsk and SGK.
  • inhibitors of CDK4/6 including abemaciclib (Verzenio), palbociclib (Ibrance) and ribociclib (Kisqali), have the potential to be synergistic with HIF-2a inhibitors and reverse the resistance to HIF-2a inhibition; mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, 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 afatin
  • BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771, TGI 00-115; 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 ibrutinib.
  • MTOR inhibitor such as rapamycin (sirolimus), temsirolimus, everolimus, XL388, XL765,
  • anti-cancer agents include proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib;BET inhibitors such as INCB054329, OTX015, CPI-0610;LSDl inhibitors such as GSK2979552, INCB059872; HDAC inhibitors such as panobinostat, vorinostat;DNA methyl transferase inhibitors such as azacytidine, decitabine), and other epigenetic modulator; SHP-2 inhibitor such as TNO155; Bcl2 inhibitor ABT- 199, and other Bcl- 2 family protein inhibitors; HIF-2a 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.
  • BET inhibitors such as INCB054329, OTX015, CPI-0610
  • LXR liver X receptor
  • AhR aryl hydrocarbon receptor
  • anti-cancer agents that can be employed in combination with Form A polymorph of Compound (I) include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; 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; carbop
  • anti-cancer agents that can be employed in combination with Form A polymorph of Compound (I) include: 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; 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
  • anticancer agents that can be employed in combination with Form A polymorph of Compound (I) include alkylating agents, antimetabolites, natural products, or hormones, e.g., 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).
  • folic acid analog e.g., methotrexate
  • pyrimidine analogs e.g., cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
  • Examples of natural products useful in combination with Form A polymorph of Compound (I) 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
  • enzymes e.g., L-asparaginase
  • biological response modifiers e.g., interferon alpha
  • alkylating agents examples include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethly melamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.).
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.
  • ethylenimine and methylmelamines e.g., hexamethly melamine, thiotepa
  • alkyl sulfonates e
  • 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 with Form A polymorph of Compound (I) 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
  • 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 that can be employed in combination with Form A polymorph of Compound (I) 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 Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride
  • immune checkpoint inhibitors can be used in combination with Form A polymorph of Compound (I) for treatment of HIF-2a -associated diseases, disorders, or conditions.
  • exemplary immune checkpoint inhibitors include inhibitors (smack molecules or biologies) against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, 0X40, 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.
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, 0X40, GITR, CD137 and STING.
  • the immune checkpoint 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-PDl antibody is pembrolizumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody.
  • the anti-PD-Ll monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C.
  • the anti-PD-Ll 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 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 0X40, e.g., an anti-OX40 antibody or OX40L fusion protein.
  • the anti-OX40 antibody is MEDI0562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF- 04518600 or LAG525.
  • the OX40L fusion protein is MEDI6383.
  • Form A polymorph of Compound (I) can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including 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 GV AX® (granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine).
  • GV AX® granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine.
  • Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and 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.
  • anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.
  • Form A polymorph of Compound (I) may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation.
  • Step 1 ethyl 3 -(2-bromo-4-fluorophenyl)-2,2-difluoro-3 -hydroxy propanoate
  • the resulting mixture was further stirred at 25 °C for 2 h under N2 atmosphere, then was filtered through silica gel pad and the pad cake was washed with MTBE.
  • the combined filtrate was washed with 1.0 M aqueous HC1.
  • the combined aqueous phase was extracted with MTBE.
  • the combined MTBE organic phase was washed with H2O, filtered through a silica gel pad and the pad cake was washed with MTBE.
  • the combined filtrate was concentrated to give the title compound (561.0 g, 95.1% yield) as a yellow oil, which was used for next step without further purification.
  • Step 3 ethyl 3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropanoate
  • Step 1 (R)- 1 -ally 1-2,2, 3 ,3 ,6-pentafluoro-2,3 -dihydro- IH-inden- 1 -ol
  • 2-allyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane 94.57 g, 562.78 mmol, 1.21 eq.
  • (S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethyl- butanamide 36.51 g, 119.14 mmol, 0.26 eq.
  • t-BuONa (4.33 g, 45.06 mmol, 0.097 eq.
  • toluene 900 mL
  • MeOH 28.8 g, 898.88 mmol, 1.94 eq.
  • the mixture was stirred at 20 °C under nitrogen atmosphere until a clear solution formed.
  • the reaction mixture was heated to 60 °C, and a solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-lH-inden-l-one (103.09 g, 464.14 mmol, 1.00 eq.) in toluene (100 mL) was added slowly over 2 h at 60 °C.
  • the resulting mixture was stirred continually for 16 h at 60 °C, then cooled to room temperature, quenched with water, and extracted with MTBE.
  • Step 2 (R)-l-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-lH-inden-l-ol
  • Step 3 (R)-3, 3,4,4, 7-pentafluoro-l -methylene- 1, 2,3, 4-tetrahydro-2aH-cy cl openta[cd]inden-2a- ol
  • Step 4 (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-lH-cyclopenta[cd]inden-l- one
  • Step 1 (R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-l-oxo-2,2a,3,4-tetrahydro-lH- cyclopenta[cd]inden-7-yl)oxy)benzonitrile
  • Step 1 3-fluoro-5-(((2aS,3S,4R)-l,l,2,2,3,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-lH- cyclopenta[cd]inden-5-yl)oxy)benzonitrile and 3-fluoro-5-(((2aR,3R,4S)-l,l,2,2,3,4-hexafluoro- 2a-hydroxy-2,2a,3,4-tetrahydro-lH-cyclopenta[cd]inden-5-yl)oxy)benzonitrile
  • the resulting mixture was stirred for 2 h at -20 °C under nitrogen atmosphere and then quenched with saturated Na2COs (aq.) at -20 °C.
  • the resulting mixture was diluted with H2O and extracted with DCM.
  • the combined organic layers were washed with 10% Na2SC>4 solution, dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure.
  • XRPD patterns were obtained with an X-ray diffractometer (PANanalytical Aeris) using an incident beam of Cu Ka (1.5418 A), from a generator operating at 40kV and 7.5 mA. The system was equipped with PIXcellD-Medipix3 detector. A sample of Compound (I) were scanned from 3 to 40° 20, at a step size 0.02° 20. Data was analyzed using HighScore Version 4.7a. The X-ray powder diffraction was determined at an ambient temperature
  • TGA was carried out on a Discovery TGA 55 or Q500 (TA Instruments, US).
  • a sample of Compound (I) was placed into an open tared aluminum pan, automatically weighed, and inserted into the TGA furnace. The sample was heated at a rate of 10 °C/min from ambient temperature to 300 °C.
  • Crystalline Form A polymorph of Compound (I) showed 0.3 % wt loss from RT- 150 °C.
  • DSC was performed using a Discovery DSC 250 or Q200 (TA Instruments, US).
  • a sample of Compound (I) was placed into an aluminum pin-hole hermetic pan and the weight was accurately recorded. The sample was heated at a rate of 10 °C/min from 25 °C to 300 °C.
  • Crystalline Form A polymorph of Compound (I) showed endotherm onset T(AH) at 155 °C (72 J/g).
  • Evaporative crystallization was performed in a 96-well plate using binary solvents according to the solvent matrix in Tables 2A and 2B below. For example, “1/1” means only methanol was used, and “2/13” means that a mixture of ethanol and water was used.
  • the filtrates were distributed into 96-well plate. Each well contained 200 pL of Compound (I) solutions in different solvents with the ratio of 1:1 (v:v). The plate was covered by film with a pin hole and then placed at ambient conditions for slow evaporation.
  • Crystalline solid was obtained from most of solvent systems. A quarter of obtained solids were characterized by XRPD, and XRPD patterns were the same as that obtained in (A) above.
  • SCR single crystal
  • CR crystal
  • GL glassy solid
  • NA too little or no solid
  • the deoxyfluorination step was also conducted under following conditions: AlkyFluor/CsF in toluene at 0 °C;
  • Step 1 3-fluoro-5-(((2aS,3S)-l,l,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-lH- cyclopenta[cd]inden-5-yl)oxy)benzonitrile
  • the reaction mixture was cooled and distilled in vacuo under 40 °C to about 8.5 L, diluted with EtOAc, followed by addition of water. The layers were separated and the organic layer was washed with water, 10% brine, and then decolorized with activated charcoal. The organic solution was concentrated in vacuo below 40 °C to about 8.5 L. The residual solution was swapped two times with EtOAc to obtain a solution of the title compound in EtOAc (24.50 kg, 12.67% assay).
  • Step 2 3-fluoro-5-(((2aS,3R,4S)-l,l,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-lH- cyclopenta[cd]inden-5-yl)oxy)benzonitrile
  • the reaction mixture was quenched with 17% aqueous Na2COs (10.76 kg), followed by the addition of water. After layer separation, the organic layer was washed twice with water. The organic layer was concentrated in vacuo below 40 °C to about 7.4 L. The residual solution was swapped twice with DCM. The obtained residual solution then was dissolved in DCM to give a solution of the title compound in DCM (49.05 kg, 6.62% assay).
  • Step 3 3-fluoro-5-(((2aS,3S,4R)-l,l,2,2,3,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-lH- cyclopenta[cd]inden-5-yl)oxy)benzonitrile
  • the resulting mixture was stirred at -25 °C to -15 °C for 9 h, and then quenched with 15% aqueous Na2COs (9.21 kg) slowly at -25 °C to -15 °C.
  • the resulting mixture was warmed to 20 - 30 °C, followed by the addition of water.
  • the organic layer was separated and concentrated in vacuo to about 7.8 kg DCM solution.
  • the aqueous layer was extracted with MTBE and the organic layers were combined with the 7.8 Kg DCM solution.
  • the resulting organic solution was washed with water and then passed through a silica gel pad.
  • the silica gel pad was rinsed with MTBE.
  • the filtrate was concentrated in vacuo and the residual solution was swapped one time with MTBE.
  • the reaction mixture was quenched with 15% aqueous Na2COs slowly at -20 °C, warmed to 20 to 30 °C, followed by the addition of water.
  • the organic layer was separated and then concentrated.
  • the aqueous layer was extracted with MTBE and the organic layer was combined with the residue from DCM solution concentration.
  • the resulting organic solution was washed with water, 0.5 M aqueous HC1 and then water.
  • the organic layer was concentrated and the residual solution was swapped twice with MTBE.
  • Step 1 was also carried out under following conditions: ethane- l,2-diol/H 2 O/Py HF at 100 °C ethane-l,2-diol/H 2 O/(C 2 H 5 ) 3 N • 3HF at 100 °C ethane- l,2-diol/H 2 O/LiF at 100 °C ethane-l,2-diol/H 2 O/NaF at 100 °C ethane- l,2-diol/H 2 O/KF at 100 °C ethane- l,2-diol/H 2 O/CsF at 100 °C ethane- l,2-diol/H 2 O/AgF at 100 °C ethane-l,2-diol/H 2 O/CaF 2 at 100 °C ethane- l,2-diol/H 2 O/TBAF at 100 °C ethane
  • Step 2 Me-THF or THF or DMSO or acetone, acetonitrile, or dioxane/water/NMO at 60-80 °C Step 2 was also carried out under following conditions:
  • the XRPD pattern of DEA solvate of Compound (I) (shown in Fig. 4) was obtained with an X-ray diffractometer (Bruker D8 Focus), using an incident beam of Cu Ka (1.5406 A), from a generator operating at 40kV and 40 mA. The system was equipped with
  • LYNXEYE detector Sample of di ethylamine solvate of Compound (I) was scanned from 3 to 42° 20, at a step size 0.02° 20 at 23.8 °C. Data was analyzed using DIFFRAC.EVA software.
  • Ingredient Quantity per tablet (mg) compound of this disclosure 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5
  • Capsule Formulation The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
  • a pharmaceutical composition for inhalation delivery 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.
  • an inhalation delivery unit such as a nebulizer
  • a pharmaceutical topical gel composition 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxy propyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
  • a pharmaceutical ophthalmic solution composition 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
  • a pharmaceutical nasal spray solution 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 pL of spray for each application.
  • a 0.05M phosphate buffer solution pH 4.4

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Abstract

La présente divulgation concerne certains processus de fabrication de 3-fluoro-5-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tétrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile et de certains polymorphes de celui-ci. La divulgation concerne également des compositions pharmaceutiques comprenant une forme polymorphe cristalline du composé (I) et des processus de préparation de telles formes polymorphes.
PCT/US2022/048111 2021-10-29 2022-10-27 Processus de fabrication de 3-fluoro-5-(((1r,2s,2as)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tétrahydro-1h-cyclopenta[cd]inden-7-yl)-oxy)-benzonitrile et de polymorphes de celui-ci WO2023076532A1 (fr)

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PCT/US2022/048111 WO2023076532A1 (fr) 2021-10-29 2022-10-27 Processus de fabrication de 3-fluoro-5-(((1r,2s,2as)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tétrahydro-1h-cyclopenta[cd]inden-7-yl)-oxy)-benzonitrile et de polymorphes de celui-ci

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