Process for making 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[CD]inden-7-yl)oxy)-benzonitrile and polymorphs thereof

Abstract

The present disclosure provides certain processes for making 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile (Compound 1) and certain polymorphs thereof. Pharmaceutical compositions containing crystalline polymorphs of Compound 1 and processes for preparing such polymorphs are also provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. non-provisional application that claims the benefit of International Application No. PCT / CN2021 / 123248, filed October 12, 2021, and PCT / CN2021 / 123407, filed October 13, 2021, the entire contents of each of which are hereby incorporated by reference in their entirety.

[0002] The present disclosure provides a compound having the following structure: [ka] In accordance with the present invention, there are provided certain processes for making 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (referred to herein as "Compound 1"), and certain polymorphs thereof. Pharmaceutical compositions comprising crystalline polymorphs of Compound 1 and processes for preparing such polymorphs are also provided. [Background technology]

[0003] Compound 1 is a hypoxia-inducible factor-2α (HIF-2α) inhibitor and is being developed to treat a variety of diseases, including cancers such as renal carcinoma, glioblastoma, neuroblastoma, pheochromocytoma, paraganglioma, somatostatinoma, hemangioblastoma, gastrointestinal stromal tumor (GIST), pituitary tumor, leiomyoma, leiomyosarcoma, polycythemia, and retinal tumor, as well as non-cancer diseases such as pulmonary arterial hypertension (PAH), gastroesophageal reflux disease, hepatic steatosis, NASH, inflammatory diseases (such as inflammatory bowel disease), autoimmune diseases (such as graft-versus-host disease), and iron overload.

[0004] Compound 1 is disclosed in PCT Application Publication No. WO 2020 / 214853, Table 1, as Compound No. 5. The disclosed process for making Compound 1 generates impurities and requires purification of Compound 1 by column chromatography. From a cost and operational standpoint, the use of column chromatography for large-scale manufacturing of drug substances is inappropriate. Thus, there is a need to identify a scalable process that meets regulatory and other purity requirements and can produce Compound 1 on a large scale, such as a commercial scale, in a cost-effective manner.

[0005] The polymorphic behavior of small molecule drugs can be extremely important in pharmacology, because 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 drug parameters, such as storage stability, compressibility, density, hygroscopicity, dissolution rate, and bioavailability. One polymorph can change into another polymorph, and in some cases, this is known to occur spontaneously. Therefore, there is a need to find thermodynamically stable polymorphs of small molecule drugs. The present disclosure meets these and related needs. Summary of the Invention [Means for solving the problem]

[0006] Among the various aspects of the present disclosure may be noted the provision of a process for the synthesis of Compound 1 that is suitable for large-scale synthesis of Compound 1 in a cost-effective manner. The process is based, in part, on the discovery by applicants that Compound 1 can form amine solvates with certain organic amines. The formation of such amine solvates with Compound 1 allows for the removal of certain impurities generated in the synthesis of Compound 1, providing Compound 1 in high purity without the need for column chromatography.

[0007] In a first aspect, there is provided a crystalline form of Compound 1, designated as the A polymorph, having an X-ray powder diffraction pattern comprising peaks at angular positions 15.8 and 18.6, where the angular positions may vary by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength (Cu Kα) of 1.5418 Å. In an embodiment of the first aspect, the X-ray powder diffraction pattern is measured at about 23° C. to about 25° C.

[0008] In a second embodiment, there is provided an amine solvate of Compound 1, wherein the amine is (i) NHR 1 R 2 (In the formula, (1)R 1 is hydrogen and R 2 is C2~C 12 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C 1~6 (2) R is alkyl; 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C 1~6 is alkyl, R 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C 1~6 or (3) R 1 and R 2 together with the nitrogen atom to which they are attached form a cyclylamine; or (ii)R 3 R 4 N-(CH2) n -NR 5 R 6 (In the formula, n is an integer selected from 1 to 6, and R 3 , R 4 , R 5 , and R 6 are independently H, C1-C6 alkyl, or C3-C7 cycloalkyl.

[0023] An amine solvate is provided,

[0009] In a third aspect, there is provided a crystalline form of the diethylamine solvate of Compound 1, designated as the Form B polymorph, having an X-ray powder diffraction pattern comprising peaks at angular positions 13.8 and 21.3, where the angular positions may vary by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength (Cu Kα) of 1.5406 Å. In an embodiment of the third aspect, the X-ray powder diffraction pattern is measured at about 23° C. to about 25° C.

[0010] In a fourth embodiment, there is provided a process for preparing an amine solvate of Compound 1, the amine being (i) NHR 1 R 2 (In the formula, (1)R 1 is hydrogen and R 2 is C2~C 12 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C 1~6 (2) R is alkyl; 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C 1~6 is alkyl, R 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C 1~6 or (3) R 1 and R 2 together with the nitrogen atom to which they are attached form a cyclylamine; or (ii)R 3 R 4 N-(CH2) n -NR 5 R 6 (wherein n is an integer selected from 1 to 6, and R 3 , R 4 , R 5 , R 6 are independently H, C1-C6 alkyl, or C3-C7 cycloalkyl. and (a1) reacting compound 1 with an amine NHR in the presence or absence of one or more suitable organic solvents. 1 R 2 or R 3 R 4 -N-(CH2) n -R 5 R 6 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 and n is as defined in (i) and (ii), respectively; (b1) optionally adding (i) one or more anti-solvents and / or (ii) solid crystalline seeds of Compound 1, or solid crystalline seeds of an amine solvate of Compound 1, or a combination thereof, to the mixture of step (a1) to precipitate an amine solvate of Compound 1; (c1) isolating the solid of step (b1) to obtain a solid amine solvate of compound 1; (d1) optionally converting an amine solvate of compound 1 from any one of steps (a1)-(c1) to compound 1; A process is provided that includes:

[0011] The process of the fourth aspect, further comprising the step of preparing compound 1 in step (a1): (a) treating 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile with a deoxyfluorinating agent in a suitable organic solvent and optionally in the presence of triethylamine trihydrofluoride (EtN·3HF) with or without a base; (b) purifying the mixture from step (a) to obtain compound 1; A process is provided that includes:

[0012] In a fifth aspect, there is provided a process for preparing the crystalline Form B polymorph of the diethylamine solvate of Compound 1 as described in embodiments C1-C9 (disclosed herein below), comprising: (a2) contacting 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (compound 1) with diethylamine in the presence or absence of one or more suitable organic solvents; (b2) optionally adding (i) one or more anti-solvents and / or (ii) solid crystalline seeds of Compound 1, or an amine solvate of Compound 1, or a combination thereof, to the mixture of step (a2) to precipitate the crystalline Form B polymorph of the diethylamine solvate of Compound 1; (c2) isolating the crystalline Form B polymorph of the diethylamine solvate of Compound 1; (d2) optionally converting the crystalline Form B polymorph of the diethylamine solvate of Compound 1 to Compound 1; A process is provided that includes:

[0013] In a sixth aspect, there is provided a process for preparing the crystalline Form A polymorph of Compound 1 (as defined herein below in embodiments A1-A11) from a diethylamine solvate of Compound 1, comprising: (a3) removing diethylamine from the diethylamine solvate of compound 1; (b3) optionally recrystallizing the crystalline form A polymorph of Compound 1 obtained from step (a3); A process is provided that includes:

[0014] In a seventh aspect, there is provided a process for making the crystalline Form A polymorph of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (Compound 1), comprising: (a4) contacting a solution of compound 1 in one or more suitable organic solvents with one or more anti-solvents; (b4) optionally adding solid crystalline seeds of Compound 1; (c4) isolating the crystalline form A polymorph of compound 1 from the mixture; A process is provided that includes:

[0015] In an eighth embodiment, there is provided a process for making compound 1 from 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, comprising: (a5) treating 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile with perfluorobutanesulfonyl fluoride (PBSF) and EtN·3HF in the presence of an organic base in one or more suitable organic solvents; (b5) purifying the mixture from step (a5) to obtain compound 1; (c5) optionally converting compound 1 from step (b5) to an amine solvate of the second aspect or any embodiment thereof disclosed herein below; (d5) optionally converting the amine solvate of Compound 1 obtained from step (c5) into the crystalline Form A polymorph of Compound 1 as disclosed in the first aspect or any embodiment thereof disclosed herein below. A process is provided that includes:

[0016] In a ninth aspect, there is provided a solid composition comprising a diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile and 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, wherein the 3-fluoro-5-(((1S,2aR In one embodiment, the percent weight ratio of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (DEA solvate of Compound 1) to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (Compound 1) is about 1 part DEA solvate to no more than 9 parts Compound 1. In an embodiment of the ninth aspect, there is provided a solid composition comprising a diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile and 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, Compositions are provided in which the percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is from about 1:9 to about 1:0.001.

[0017] In a tenth aspect, there is provided a method of treating a disease treatable by inhibition of HIF-2α in a patient, preferably a patient in need of such treatment, the method comprising administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of the crystalline Form A polymorph of Compound 1 as defined in the first aspect above, or any one of its embodiments disclosed herein, in a pharmaceutical composition comprising a pharma- ceutically acceptable excipient.

[0018] In one embodiment of the tenth aspect, the disease is selected from the group consisting of renal cancer, clear cell renal cell carcinoma, liver cancer, hepatocellular carcinoma (HCC), pancreatic cancer, pancreatic neuroendocrine tumors, 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, pheochromocytoma and paraganglioma (European Journal of Cancer 2017,86,1-4), somatostatin-producing tumors, hemangioblastomas, gastrointestinal stromal tumors (GISTs), pituitary tumors, leiomyomas, leiomyosarcoma, polycythemia, retinal tumors, uterine cancer, pheochromocytoma / paraganglioma, melanoma, gastric cancer, lung adenocarcinoma, esophageal cancer, squamous cell lung cancer, ovarian cancer, cervical cancer, head and neck cancer, liver cancer, colorectal cancer, breast cancer, renal cell carcinoma, diffuse large B-cell lymphoma, glioblastoma, thymoma, prostate cancer, pancreatic cancer, sarcoma, and low-grade glioma; and cancers with one or more EPAS1 / HIF2A mutations such as prostate cancer, uterine cancer, liver cancer, breast cancer, pancreatic cancer, ovarian cancer, lung adenocarcinoma, head and neck cancer, gastric cancer, sarcoma cancer, colorectal cancer, squamous cell lung cancer, esophageal cancer, diffuse large B-cell lymphoma, melanoma, renal cell carcinoma, cervical cancer, pheochromocytoma / paraganglioma, adenoid cystic carcinoma, acute myeloid leukemia, glioblastoma, and low-grade glioma.

[0019] In another embodiment, non-cancerous diseases that may benefit from Hif-2α inhibition include VHL (von Hippel-Lindau) disease (see Oncotarget, 2015, 6, 23036-23037), PAH (pulmonary arterial hypertension) (see Mol. Cell. Biol. 2016, 36, 1584-1594), esophagitis, reflux esophagitis (see Current Opinion in Pharmacology 2017, 37:93-99), fatty liver (see Nature Medicine 2017, 23, 1298-1308), inflammatory diseases such as NASH, inflammatory bowel disease (see Nature Reviews gastroenterology & Hepatology 2017, 14, 596), autoimmune diseases such as graft versus host disease (see Blood, 2015, 126, 1865), and iron overload.

[0020] In an eleventh aspect, there is provided a pharmaceutical composition comprising the crystalline Form A polymorph of Compound 1 as defined in the first aspect above, or any one of its embodiments disclosed herein; and a pharma- ceutically acceptable excipient.

[0021] In a twelfth aspect, there is provided a pharmaceutical composition prepared using the crystalline Form A polymorph of Compound 1 as defined in the first aspect above, or any one of its embodiments disclosed herein; and a pharma- ceutically acceptable excipient.

[0022] In a thirteenth aspect, there is provided a method of inhibiting HIF2α, the method comprising contacting HIF2α with the crystalline form A polymorph of compound 1 as defined in the first aspect above or any one of its embodiments disclosed herein; or contacting HIF2α with a pharmaceutical composition comprising the crystalline form A polymorph of compound 1 as defined in the first aspect above or any one of its embodiments disclosed herein; and a pharmacologically acceptable excipient.

[0023] In a fourteenth aspect, there is provided the crystalline Form A polymorph of Compound 1 as defined in the first aspect above or any one of its embodiments disclosed herein for use in the treatment of a disease mediated by HIF-2α. In an embodiment of the fourteenth aspect, the disease is as disclosed herein, including as disclosed in the first embodiment of the tenth aspect.

[0024] In any of the above aspects relating to the treatment of cancer, further embodiments are provided which comprise administering the crystalline form A polymorph of compound 1 as defined in the first aspect above or any one of its embodiments in combination with at least one additional anticancer agent, such as the EGFR inhibitors gefitinib, erlotinib, afatinib, icotinib, neratnib, rociletinib, cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab. In another embodiment, the crystalline form A polymorph of compound 1 as defined in the first aspect above or any one of its embodiments is administered in combination with a HER2 / neu inhibitor, including lapatinib, trastuzumab, and pertuzumab. In another embodiment, the crystalline form A polymorph of compound 1 as defined in the first aspect above or any one of its embodiments is administered in combination with a PI3k / mTOR inhibitor, including idelalisib, buparlisib, BYL719, and LY3023414. In another embodiment, the crystalline Form A polymorph of Compound 1 as defined in the first aspect above or any one of its embodiments is administered in combination with a VEGF inhibitor, such as bevacizumab, and / or a multi-tyrosine kinase inhibitor, such as sorafenib, sunitinib, pazopanib, and cabozantinib. In another embodiment, the crystalline Form A polymorph of Compound 1 as defined in the first aspect above or any one of its embodiments is administered in combination with an immunotherapeutic agent such as a PD-1 and PD-L1 inhibitor, a CTLA4 inhibitor, an IDO inhibitor, a TDO inhibitor, an A2A agonist, an A2B agonist, a STING agonist, a RIG-1 agonist, a Tyro / Axl / Mer inhibitor, a glutaminase inhibitor, an arginase inhibitor, a CD73 inhibitor, a CD39 inhibitor, a TGF-β inhibitor, an IL-2, an interferon, a PI3K-γ inhibitor, a CSF-1R inhibitor, a GITR agonist, an OX40 agonist, a TIM-3 antagonist, a LAG-3 antagonist, a CAR-T therapy, and a therapeutic vaccine. When a combination therapy is used, the agents can be administered simultaneously or sequentially. [Brief description of the drawings]

[0025] [Figure 1]1 shows a representative XRPD diffractogram of the crystalline Form B polymorph of the diethylamine (DEA) solvate of Compound 1, prepared according to the method described in Example 4. [Diagram 2] 1 shows a representative 1H NMR spectrum of the diethylamine solvate of compound 1, prepared according to the method described in Example 4. [Diagram 3] 1 shows a representative XRPD diffractogram of the crystalline Form A polymorph of Compound 1, prepared according to the method described in Example 3. [Figure 4] 1 shows comparative XRPD diffractograms of crystalline Form A polymorph of Compound 1, prepared according to the method described in Example 3, and Form B polymorph of the diethylamine solvate of Compound 1, prepared according to the method described in Example 4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Definition: Unless otherwise stated, the following terms used in the specification and claims are defined for purposes of this application and have the following meanings:

[0027] "Alkyl" means a linear or branched saturated monovalent hydrocarbon radical of one to six carbon atoms, i.e., C1-C6 alkyl, unless otherwise specified, e.g., C2-C 12 Alkyl means an alkyl radical as defined above (i.e., a straight-chain or branched saturated monovalent hydrocarbon radical) containing 2 to 12 carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.

[0028] "C1-C6 alkylene" means a linear or branched saturated divalent hydrocarbon radical of 1 to 6 carbon atoms. Examples include, but are not limited to, methylene, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)-, -CH2CH2CH2CH2- (and its isomers), -CH2CH2CH2CH2CH2- (and its isomers), and the like.

[0029] "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.

[0030] "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.

[0031] "C3-C7 cycloalkyl" means a monocyclic saturated monovalent hydrocarbon radical of three to seven carbon atoms optionally substituted with one or two alkyl groups. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0032] "C3-C7 Cycloalkyl-C 1~6 Alkyl" is C 1~6 alkylene is as defined above and R is C-C cycloalkyl as defined above 1~6 alkylene-R groups. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, cyclohexylmethyl, and the like.

[0033] A "cyclylamine" is an amine having one ring atom being nitrogen and additional ring atoms being N, O, and S(O). n (wherein n is an integer selected from 0-2), and the remaining ring atoms are C. The cyclylamine may be substituted with one or two alkyl groups as defined herein. Representative examples include, but are not limited to, pyrrolidine, piperidine, homopiperidine, morpholine, piperazine, thiomorpholine, and the like.

[0034] The term "solvate" refers to a form of a compound in which the compound is non-covalently associated with solvent molecules. This physical association may include hydrogen bonding. As used herein, an amine solvate of Compound 1 is an amine NHR solvate, each as defined herein. 1 R 2 or R 3 R 4 N-(CH2) n -NR 5 R 6 The term "amine solvate" refers to the form of Compound 1 associated with, including both stoichiometric and non-stoichiometric solvates. In certain cases, the amine solvate of Compound 1 is isolable, for example, when the amine molecule is incorporated into the crystal lattice of the crystalline solid of Compound 1. In certain cases, the amine solvate of Compound 1 exists in situ. The amine solvate of Compound 1 therefore includes both isolable and in situ solvates. The amine solvate of Compound 1 existing in situ is also referred to herein as an adduct.

[0035] The present disclosure includes polymorphs of Compound 1 and diethylamine solvate of Compound 1. A polymorph is a crystalline form of a compound that differs in the arrangement of the molecules of that compound in the crystal lattice. Thus, a single compound can produce various polymorphs. Polymorphs of a compound usually have different melting points, solubilities, densities and optical properties. Polymorphs of a compound can be distinguished by several techniques well known in the art, such as X-ray diffraction measurement, IR, or Raman spectroscopy.

[0036] "XRPD" means X-ray powder diffraction, an analytical technique that measures the diffraction of X-rays in the presence of solid components. Materials that are crystalline, that is, have a regular repeating arrangement of atoms, produce unique powder patterns.

[0037] As used herein, "substantially free" refers to the crystalline Form A polymorph of Compound 1 (i.e., 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile) having less than about 10% by weight of the 3-fluoro-5-(((1R,2aS)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile enantiomer (hereinafter "(1R,2aS) enantiomer") of Compound 1. In one embodiment, the crystalline Form A polymorph of Compound 1 has less than about 8% by weight of the (1R,2aS) enantiomer. In another embodiment, the crystalline form A polymorph of compound 1 has less than about 7% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline form A polymorph of compound 1 has less than about 6% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline form A polymorph of compound 1 has less than about 5% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline form A polymorph of compound 1 has less than about 4% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline form A polymorph of compound 1 has less than about 3% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline form A polymorph of compound 1 has less than about 2% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline form A polymorph of compound 1 has less than about 1% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline Form A polymorph of Compound 1 has less than about 0.8% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline Form A polymorph of Compound 1 has less than about 0.7% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline Form A polymorph of Compound 1 has less than about 0.6% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline Form A polymorph of Compound 1 has less than about 0.5% by weight of the (1R,2aS) enantiomer.In yet another embodiment, the crystalline Form A polymorph of Compound 1 has less than about 0.4% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline Form A polymorph of Compound 1 has less than about 0.3% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline Form A polymorph of Compound 1 has less than about 0.2% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline Form A polymorph of Compound 1 has less than about 0.1% by weight of the (1R,2aS) enantiomer. In yet another embodiment, the crystalline Form A polymorph of Compound 1 has less than about 0.05% by weight of the (1R,2aS) enantiomer.

[0038] As used herein, "substantially pure" refers to a solid form of Compound 1 that contains less than about 5% total impurities by weight or less than about 5% total impurities as measured by HPLC. The phrase "the crystalline Form A polymorph is substantially pure" means that the Form A polymorph of Compound 1 contains less than about 5% total impurities by weight or less than about 5% total impurities as measured by HPLC. In one embodiment, the crystalline Form A polymorph of Compound 1 contains less than about 4% total impurities by weight or less than about 4% total impurities as measured by HPLC. In another embodiment, the crystalline Form A polymorph of Compound 1 contains less than about 3% total impurities by weight or less than about 5% total impurities as measured by HPLC. In yet another embodiment, the crystalline Form A polymorph of Compound 1 contains less than about 2% total impurities by weight or less than about 2% total impurities as measured by HPLC. In yet another embodiment, the crystalline Form A polymorph of Compound 1 contains less than about 1% total impurities by weight or less than about 1% total impurities as measured by HPLC. In yet another embodiment, the crystalline form A polymorph of Compound 1 contains less than about 0.9% total impurities by weight or less than about 0.9% total impurities as measured by HPLC. In yet another embodiment, the crystalline form A polymorph of Compound 1 contains less than about 0.8% total impurities by weight or less than about 0.8% total impurities as measured by HPLC. In yet another embodiment, the crystalline form A polymorph of Compound 1 contains less than about 0.7% total impurities by weight or less than about 0.7% total impurities as measured by HPLC. In yet another embodiment, the crystalline form A polymorph of Compound 1 contains less than about 0.6% total impurities by weight or less than about 0.6% total impurities as measured by HPLC. In yet another embodiment, the crystalline form A polymorph of Compound 1 contains less than about 0.5% total impurities by weight or less than about 0.5% total impurities as measured by HPLC. In yet another embodiment, the crystalline form A polymorph of Compound 1 contains less than about 0.4% total impurities by weight or less than about 0.4% total impurities as measured by HPLC. In yet another embodiment, the crystalline Form A polymorph of Compound 1 contains less than about 0.3% by weight total impurities or less than about 0.3% total impurities as measured by HPLC.In yet another embodiment, the crystalline Form A polymorph of Compound 1 contains less than about 0.2% total impurities by weight or less than about 0.2% total impurities as measured by HPLC. In yet another embodiment, the crystalline Form A polymorph of Compound 1 contains less than about 0.1% total impurities by weight or less than about 0.1% total impurities as measured by HPLC. Impurities include, but are not limited to, synthetic by-products, residual starting materials, reagents, residual organic solvents, and the like.

[0039] As used herein, "substantially identical" refers to measured physical properties that are comparable in terms of comparable values ​​or data traces of peak location and amplitude or intensity, within the range of variation typically associated with sample positioning or handling or the identity of the equipment used to obtain the trace or physical property, or due to other variations or fluctuations commonly encountered within or between laboratory environments or analytical equipment.

[0040] As used herein, the terms "reacting," "treating," or "contacting," when describing certain processes, are used as known in the art and generally refer to bringing together chemical reagents in a manner that allows the chemical reagents to interact at a molecular level to accomplish a chemical or physical transformation. The "reacting," "treating," or "contacting" steps of the processes described herein can be carried out for times and under conditions appropriate to prepare a particular product.

[0041] As used herein, "antisolvent" refers to a solvent in which Compound 1 or a diethylamine solvate of Compound 1 is poorly soluble. In one embodiment, the antisolvent is a solvent in which Compound 1 is poorly soluble. In another embodiment, the antisolvent is a solvent in which Compound 1 has a solubility of less than about 50 mg / mL. In yet another embodiment, the antisolvent is a solvent in which Compound 1 has a solubility of less than about 25 mg / mL.

[0042] "Suitable organic solvent" or "first suitable organic solvent" refers to an organic solvent that does not enter into any appreciable reaction with any of the reactants, intermediates, and / or products under the reaction conditions of the processes disclosed herein and at the temperature at which the reaction is carried out. A given reaction disclosed herein can be carried out in one organic solvent or a mixture of two or more organic solvents. Examples of suitable organic solvents that can be used in the reactions described herein include polar (protic and / or aprotic) and non-polar organic solvents, such as halogenated alkanes, such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, diisopropyl ether, methyl t-butyl ether, alcohols, such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butyl alcohol, 1-, 2-, or 3-pentanol, neopentyl alcohol, esters, such as ethyl acetate, isopropyl acetate, ketones, such as acetone, aromatic hydrocarbons, such as benzene, toluene, and xylene, or alkanes, such as cyclohexane, pentane, hexane, heptane, etc. Additional organic solvents that can be used in the reactions described herein include polar organic solvents, including, but not limited to, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethyl acetate, alcohols, and the like. When polar organic solvents (e.g., alcohols, acetonitrile, DMF, N-methylpyrrolidinone, nitromethane) contain water, they are referred to herein as aqueous organic solvents. Depending on the nature of the reaction step, a solvent that is suitable for a particular reaction step can be readily selected by one of skill in the art.

[0043] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), infrared spectroscopy, spectrophotometry, or mass spectrometry; or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography. The compound obtained by the reaction 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, etc.), HPLC, or preparative thin layer chromatography; distillation; sublimation, trituration, or recrystallization. The purity of the compound is generally measured by physical methods, such as measuring the melting point (if solid), obtaining an NMR spectrum, or performing an HPLC separation.

[0044] "Alcohol" refers to an aliphatic hydrocarbon compound having one or more, such as one or two hydroxyl groups. Representative examples include, but are not limited to, methanol, ethanol, propanol, butanol, 1,2-propanediol, and the like.

[0045] 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 with 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, acid, acid addition salts formed with organic acids such as benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or Salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., either an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordination with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It is understood that pharma- ceutically acceptable salts are non-toxic. Additional information regarding suitable pharma- ceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

[0046] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes carriers or excipients that are acceptable for veterinary use as well as for human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one and more than one such excipient.

[0047] As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may occur but need not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, in step (d1) of the fourth aspect of this Summary, the phrase "optionally converting an amine solvate of Compound 1 from any one of steps (a1)-(c1) to Compound 1" means that the process described in the fourth aspect may or may not include a step in which an amine solvate of Compound 1 from any one of steps (a1)-(c1) is converted to Compound 1.

[0048] The term "about" as used herein is intended to specify the numerical value it modifies and indicates such value as variable within a margin of error. When no particular margin of error is stated, such as a standard deviation to the average value stated in a chart or table of data, the term "about" should be understood to mean a range that includes the stated value and range, and that would encompass ±10%, preferably ±5%.

[0049] The term "disease" as used herein is generally intended to be 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 one of its parts that impairs normal functioning, typically indicated by distinguishing signs and symptoms, and causing a decrease in the duration or quality of life of the human or animal.

[0050] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a disease or disorder described in this disclosure. Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, such as a single capsule having a fixed ratio of active ingredients or separate multiple capsules for each active ingredient. Furthermore, such administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen provides the beneficial effect of the drug combination in treating the condition or disorder described herein.

[0051] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, domestic animals such as cows, goats, sheep, pigs and rabbits, and companion animals such as dogs, cats, rabbits and horses. Preferably, the patient is a human.

[0052] "Treating" or "treatment" of a disease includes: (1) inhibiting the disease, i.e., preventing (i.e., stabilizing) or reducing the onset of the disease or its clinical symptoms; or (3) alleviating the disease, i.e., causing regression of the disease or its clinical symptoms; Includes: Includes:

[0053] "Therapeutically effective amount" means the amount of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, that, when administered to a patient for treating a disease, is sufficient to affect such treatment of 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 being treated.

[0054] Embodiments: In the following embodiments, the numerical ranges of an embodiment may refer to the numbering ranges of another embodiment. For example, in the following embodiment D, process embodiments D47-D54 refer to the numerical ranges of embodiments C2-C9, respectively, of composition embodiment C, and embodiments D60-69 refer to the numerical ranges of embodiments A2-A11, respectively, of composition embodiment C. This means that process embodiments D47-D54 produce product embodiments C2-C9, respectively, i.e. process embodiment D47 produces a product according to embodiment C2, process embodiment C48 produces a product according to embodiment C3, etc. Similarly, process embodiment D60 produces a product according to embodiment A2, and process embodiment D69 produces a product according to embodiment A11.

[0055] In further embodiments, the present disclosure includes:

[0056] Embodiment A: A1. In embodiment A1, there is provided a crystalline Form A polymorph of Compound 1 having an X-ray powder diffraction pattern as described in the first aspect of this Summary.

[0057] A2. In embodiment A2, the crystalline form A polymorph of embodiment A1 is such that the X-ray powder diffraction pattern of form A further comprises a peak at angular position 20.1, which may vary by ±0.2 degrees 2θ.

[0058] A3. In embodiment A3, the crystalline form A polymorph of embodiment A1 has an X-ray powder diffraction pattern of form A further comprising peaks at angular positions 12.9 and 20.1, which may vary by ±0.2 degrees 2θ.

[0059] A4. In embodiment A4, the crystalline form A polymorph of embodiment A1 has an X-ray powder diffraction pattern of form A further comprising peaks at angular positions 11.4, 12.9, and 20.1, which may vary by ±0.2 degrees 2θ.

[0060] A5. In embodiment A5, the crystalline form A polymorph of embodiment A1 has an X-ray powder diffraction pattern of form A further comprising peaks at angular positions 10.1, 11.4, 12.9, and 20.1, which may vary by ±0.2 degrees 2θ.

[0061] A6. In embodiment A6, there is provided a crystalline Form A polymorph of Compound 1 having an X-ray powder diffraction pattern comprising at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight peaks at angular positions selected from Table 1 below, where the angular positions may vary by ±0.2° 2θ.

[0062] [Table 1]

[0063] [Table 2]

[0064] In embodiment A7, the crystalline form A polymorph of embodiment A6 has at least two, at least three, at least four, at least five, or at least six peaks selected from 10.1, 11.4, 12.9, 13.7, 15.8, 18.6, 19.6, 20.1, 21.4, 21.7, 25.0, and 26.0, and the angular positions may vary by ±0.2° 2θ. In an embodiment of A6, at least two, at least three, at least four, at least five, or at least six peaks selected from 10.1, 11.4, 12.9, 13.7, 15.8, 18.0, 19.6, 20.1, 21.4, 21.7, 25.0, and 26.0, and the angular positions may vary by ±0.2° 2θ.

[0065] A8. In embodiment A8, there is provided a crystalline Form A polymorph of Compound 1 having an X-ray powder diffraction pattern substantially identical to that shown in FIG.

[0066] A9. In embodiment A9, the crystalline form A polymorph of any one of A1-A8 exhibits X-ray diffraction pattern peaks which may vary in angular position by ±0.1° 2θ.

[0067] A10. In embodiment A10, the crystalline Form A polymorph of any one of A1-A9 is substantially pure.

[0068] A11. In embodiment A10, the crystalline form A polymorph of any one of A1-A10 is substantially free of 3-fluoro-5-(((1R,2aS)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile enantiomer of compound 1.

[0069] Embodiment B: B1. In embodiment B1, there is provided an amine solvate of compound 1 as defined in the second aspect of the present summary.

[0070] B2. In embodiment B2, the amine solvate of embodiment B1 is an amine solvate wherein the amine is NHR1 R 2 It is.

[0071] B3. In embodiment B3, the amine solvate of embodiment B1 is such that the amine is R 3 R 4 -N-(CH2) n -NR 5 R 6 It is.

[0072] B4. In embodiment B4, the amine solvate of embodiment B1 or B2 is R 1 is hydrogen, and R 2 But, C2~C 12 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C 1~6 It is an alkyl.

[0073] B5. In embodiment B5, the amine solvate of embodiment B1, B2, or B4 is R 1 is hydrogen, and R 2 But, C2~C 12 It is an alkyl.

[0074] B6. In embodiment B6, the amine solvate of embodiment B1, B2, or B4 is R 1 is hydrogen, and R 2 is a C3-C7 cycloalkyl.

[0075] B6A. In embodiment B6A, the amine solvate of embodiment B1, B2, or B4 is R 1 is hydrogen, and R 2 C3-C7 cycloalkyl-C 1~6 It is an alkyl.

[0076] B7. In embodiment B7, the amine solvate of embodiment B1 or B2 is R 1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and R 2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C 1~6 It is an alkyl.

[0077] B8. In embodiment B8, the amine solvate of embodiment B1, B2, or B7 is R 1 is C1-C6 alkyl, and R 2 is a C1-C6 alkyl.

[0078] B9. In embodiment B9, the amine solvate of embodiment B1, B2, or B7 is R 1 is C1-C6 alkyl, and R 2 is a C3-C7 cycloalkyl.

[0079] B10. In embodiment B10, the amine solvate of embodiment B1, B2, or B7 is R 1 is C1-C6 alkyl, and R 2 C3-C7 cycloalkyl-C 1~6 It is an alkyl.

[0080] B10A. In embodiment B10A, the amine solvate of embodiment B1 or B2 is R 1 and R 2 are independently C3-C7 cycloalkyl-C 1~6 It is an alkyl.

[0081] B11. In embodiment B11, the amine solvate of embodiment B1 or B2 is R 1 and R 2 together with the nitrogen atom to which they are attached form a cyclylamine.

[0082] B12. In embodiment B12, the amine solvate of embodiment B1 or B3 is wherein 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.

[0083] B13. In embodiment B13, the amine solvate of embodiment B1 or B3 is wherein n is selected from 2 to 4. In a first embodiment of B13, n is 3 or 4. In a second embodiment of B13, n is 3.

[0084] B14. In embodiment B14, the amine solvate of embodiment B1 or B3 is wherein n is 2 or 3.

[0085] B15. In embodiment B15, the amine solvate of embodiment B1 or B3 is wherein n is 2.

[0086] B16. In embodiment B16, the amine solvate of any one of embodiments B1, B3, and B12-B15 and subembodiments therein comprises R 3 is hydrogen.

[0087] B17. In embodiment B17, the amine solvate of any one of embodiments B1, B3, and B12-B15 and subembodiments therein comprises R 3 is a C1-C6 alkyl.

[0088] B18. In embodiment B18, the amine solvate of any one of embodiments B1, B3, and B12-B15 and subembodiments therein comprises R 3 is a C3-C7 cycloalkyl.

[0089] B19. In embodiment B19, the amine solvate of any one of embodiments B1, B3, and B12-B18 and subembodiments therein comprises R 4 is hydrogen.

[0090] B20. In embodiment B20, the amine solvate of any one of embodiments B1, B3, and B12-B18 and subembodiments therein comprises R 4 is a C1-C6 alkyl.

[0091] B21. In embodiment B21, the amine solvate of any one of embodiments B1, B3, and B12-B18 and subembodiments therein comprises R 4 is a C3-C7 cycloalkyl.

[0092] B22. In embodiment B22, the amine solvate of any one of embodiments B1, B3, and B12 to B21 and subembodiments therein comprises R 5 is hydrogen.

[0093] B23. In embodiment B23, the amine solvate of any one of embodiments B1, B3, and B12 to B21 and subembodiments therein comprises R 5 is a C1-C6 alkyl.

[0094] B24. In embodiment B24, the amine solvate of any one of embodiments B1, B3, and B12 to B21 and subembodiments therein comprises R 5 is a C3-C7 cycloalkyl.

[0095] B25. In embodiment B25, the amine solvate of any one of embodiments B1, B3, and B12 to B24 and subembodiments therein comprises R 6 is hydrogen.

[0096] B26. In embodiment B26, the amine solvate of any one of embodiments B1, B3, and B12 to B24 and subembodiments therein comprises R 6 is a C1-C6 alkyl.

[0097] B27. In embodiment B27, the amine solvate of any one of embodiments B1, B3, and B12 to B24 and subembodiments therein comprises R 6 is a C3-C7 cycloalkyl.

[0098] B28. In embodiment B28, the amine solvate of any one of embodiments B1, B2, and B4 through B6A is any one of the above-mentioned embodiments, 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-ethylbutylamine, 2-methylpentylamine, 1,1-dimethylbutylamine, 1,3-dimethylbutylamine, 3,3-dimethylbutylamine, 2-methyl-3-pentylamine, 1,2-dimethylbutylamine, 1,3 ... , 3-methylpentylamine, 3-methyl-3-pentylamine, 3-methyl-2-pentylamine, 2-methylbutylamine, 1,2,2-trimethylpropylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, cyclobutylmethylamine, cyclopropyl-methylamine, 2-methylcyclopropylamine, 2-cyclopropylethylamine, 2-methylcyclopentylamine, 3-methylcyclopentylamine, cyclopentylmethylamine, 2-cyclobutylethylamine, 3-cyclopropyl-propylamine, 2-ethylcyclopropylamine, allylamine or propargylamine.

[0099] B29. In embodiment B29, the amine solvate of any one of embodiments B1, 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, neopentyl-amine, n-hexylamine, 2-hexylamine, 3-hexylamine, isohexylamine, 1-methylpentylamine, 2-ethylbutylamine, 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, 2-methylbutyl-1-amine, or 1,2,2-trimethyl-propylamine.

[0100] B30. In embodiment B30, the amine solvate of any one of embodiments B1, B2, B4, and B6 is wherein the amine is cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexyl-amine, 2-methylcyclopropylamine, 2-methylcyclopentylamine, 3-methyl-cyclopentylamine, or 2-ethylcyclopropylamine.

[0101] B31. In embodiment B31, the amine solvate of any one of embodiments B1, B2, and B7-B10 is any one of the above-mentioned embodiments, 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-tert-butyl-methylamine, N-methyl-cyclobutylamine, N-ethylcyclopropylamine, 1-cyclopropyl-N-methylmethanamine, N-ethyl-2-yn-1-amine, N- ethylallylamine, N-methylpentylamine, N-methyl-2-pentylamine, N-methyl-3-pentylamine, N,3-dimethylbutan-2-amine, N,2-dimethyl-butan-2-amine, N,3-dimethylbutan-2-amine, N-methylcyclopentylamine, N-ethyl-1-butylamine, N-ethyl-2-butylamine, N-ethyl-2-methyl-2-propylamine, N-ethyl-2-methylpropylamine, N-ethylcyclobutylamine, di-n-propylamine, di-isopropylamine, N-isopropylpropylamine, diallylamine, dipropargylamine, or allylpropargylamine. In one embodiment of B31, the amine is not diethylamine.

[0102] B32. In embodiment B32, the amine solvate of any one of embodiments B1, B2, B7, and B8 is wherein the amine is N-methylethylamine, diethylamine, N-methyl-n-propylamine, N-methyl-isopropylamine, N-ethyl-n-propylamine, N-ethyl-isopropylamine, N-methylbutylamine, N-methyl-2-butylamine, N-tert-butyl-methyl-amine, N-methylpentyl-1-amine, N-methyl-2-pentylamine, N-methyl-3-pentylamine, N,3-dimethylbutan-2-amine, N,2-dimethylbutan-2-amine, N,3-dimethylbutan-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. In one embodiment of B32, the amine is not diethylamine.

[0103] B33. In embodiment B33, the amine solvate of any one of embodiments B1, B2, B7, and B9 is wherein the amine is N-methylcyclobutylamine, N-ethylcyclopropylamine, N-methylcyclopentylamine, or N-ethylcyclobutylamine.

[0104] B34. In embodiment B34, the amine solvate of any one of embodiments B1, B2, and B11 is wherein the amine is azetidine, pyrrolidine, piperidine, piperazine, morpholine, azepane, or azocane.

[0105] B35. In embodiment B35, the amine solvate of any one of embodiments B1, B3, and B12 through B16, B19, B20, B22, B23, and B25 is any one of the amines selected from the group consisting of ethylenediamine, propane-1,3-diamine, butane-1,4-diamine, pentane-1,5-diamine, hexane-1,6-diamine, N 1 ,N 2 -Dimethylethane-1,2-diamine, or N 1 ,N 2-diethylethane-1,2-diamine.

[0106] B36. In embodiment B36, the amine solvate of embodiment B1 or B2 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.

[0107] B37. In embodiment B37, the amine solvate of embodiment B1 or B36 is wherein the amine is diethylamine.

[0108] B38. In embodiment B38, the amine solvate of embodiment B37 has a stoichiometric ratio of diethylamine to compound 1 in the diethylamine solvate of compound 1 of about 1:1.

[0109] B39. In embodiment B39, the amine solvate of any one of embodiments B1 through B38, wherein the amine solvate of Compound 1 is a solid.

[0110] B39A. In embodiment B39A, the amine solvate of embodiment B37, B38, or B39 is wherein the amine solvate of Compound 1 is a crystalline solid.

[0111] B40. In embodiment B40, the amine solvate of any one of embodiments B1 through B38 is an amine solvate of Compound 1 present in situ.

[0112] B41. In embodiment B41, the amine solvate of embodiment B40 is such that the amine solvate of Compound 1 is present in a mixture comprising one or more suitable organic solvents, Compound 1, and an amine.

[0113] B42. In embodiment B42, the amine solvate of embodiment B37 is wherein a diethylamine solvate of Compound 1 is present in a mixture comprising one or more suitable organic solvents, Compound 1, and diethylamine.

[0114] B43. In embodiment B43, the amine solvate of any one of embodiments B40-B42, wherein the one or more suitable organic solvents are polar organic solvents independently selected from ethers, alcohols, esters, halogenated alkanes, ketones, dimethylformamide, dimethylacetamide, acetonitrile, nitromethane, n-methylpyrrolidinone, toluene, and xylene.

[0115] B43a. In embodiment B43a, the amine solvate of any one of embodiments B40-B43, the one or more suitable organic solvents are polar organic solvents independently selected from ethers, esters, halogenated alkanes, ketones, dimethylformamide, dimethylacetamide, acetonitrile, nitromethane, n-methylpyrrolidinone, toluene, and xylene.

[0116] B44. In embodiment B44, 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 (IPA), n-butanol, 1,2-propanediol, methylene dichloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate (IPAc), butyl acetate, n-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAC), tetrahydrofuran (THF), 2-methylTHF (2-MeTHF), dimethoxyethane (DME), toluene, acetone, methyl ethyl ketone (MEK), nitromethane, acetonitrile (ACN), and 1,4-dioxane.

[0117] B44a. In embodiment B44a, the amine solvate of embodiment B44 is wherein the one or more suitable organic solvents are independently selected from n-pentanol, methanol (MeOH), n-propanol, isopropanol (IPA), n-butanol, 1,2-propanediol, methylene dichloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate (IPAc), butyl acetate, n-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAC), tetrahydrofuran (THF), 2-methylTHF (2-MeTHF), dimethoxyethane (DME), toluene, acetone, methyl ethyl ketone (MEK), nitromethane, acetonitrile (ACN), and 1,4-dioxane.

[0118] B44b. In embodiment B44b, the amine solvate of embodiment B43a is wherein the one or more suitable organic solvents are independently selected from methylene dichloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate (IPAc), butyl acetate, n-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAC), tetrahydrofuran (THF), 2-methylTHF (2-MeTHF), dimethoxyethane (DME), toluene, acetone, methyl ethyl ketone (MEK), nitromethane, acetonitrile (ACN), and 1,4-dioxane.

[0119] B45. In embodiment B45, the amine solvates of embodiments B43-B44b, the suitable organic solvent is methyl tert-butyl ether.

[0120] Embodiment C: C1. In embodiment C1, there is provided a crystalline Form B polymorph of the diethylamine solvate of Compound 1 having an X-ray powder diffraction pattern as described in the third aspect of this Summary.

[0121] C2. In embodiment C2, the crystalline form B of embodiment C1 is such that the X-ray powder diffraction pattern of form B further comprises a peak at angular position 8.4, which may vary by ±0.2 degrees 2θ.

[0122] C3. In embodiment C3, crystalline form B of embodiment C1 is such that the X-ray powder diffraction pattern of form B further comprises peaks at angular positions 8.4 and 23.5, which may vary by ±0.2 degrees 2θ.

[0123] C4. In embodiment C4, crystalline form B of embodiment C1 is such that the X-ray powder diffraction pattern of form B further comprises peaks at angular positions 8.4, 23.5, and 11.7, which may vary by ±0.2 degrees 2θ.

[0124] C5. In embodiment C5, crystalline form B of embodiment C1 is such that the X-ray powder diffraction pattern of form B further comprises peaks at angular positions 8.4, 23.5, 11.7, and 9.5, which may vary by ±0.2 degrees 2θ.

[0125] C6. In embodiment C6, there is provided a crystalline Form B polymorph of the diethylamine solvate of Compound 1 having an X-ray powder diffraction pattern comprising at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight peaks at angular positions selected from Table 2 below, where the angular positions may vary by ±0.2° 2θ.

[0126] [Table 3]

[0127] [Table 4]

[0128] [Table 5]

[0129] C7. In embodiment C7, crystalline form B of embodiment C6 has at least two, at least three, at least four, at least five, or six peaks selected from 8.4, 9.5, 11.7, 13.8, 21.3, and 23.5, and the angular positions may vary by ±0.2 degrees 2θ.

[0130] C8. In embodiment C8, there is provided the crystalline Form B polymorph of the diethylamine solvate of Compound 1, having an X-ray powder diffraction pattern substantially identical to that depicted in FIG.

[0131] C9. In embodiment C9, crystalline form B of any one of C1-C8 has peaks exhibiting a tolerance of ±0.1° 2θ.

[0132] Embodiment D: D1. In embodiment D1, there is provided a process for preparing an amine solvate of compound 1 as described in the fourth aspect of the summary.

[0133] D2. In embodiment D2, the process of embodiment D1, in step (a1), compound 1 is contacted with an amine by adding compound 1 to the amine or by adding the amine to a mixture of compound 1 in one or more suitable organic solvents.

[0134] D3. In embodiment D3, the process of embodiment D1 or D2, in step (a1), compound 1 is contacted with an amine by adding the amine to a mixture of compound 1 in one or more suitable organic solvents.

[0135] D4. In embodiment D4, the process of any one of embodiments D1-D3 further comprises the step of: 1 R 2 It is.

[0136] D5. In embodiment D5, the process of any one of embodiments D1-D3 further comprises the step of: 3 R 4 -N-(CH2) n -NR 5 R 6 It is.

[0137] D5A. In embodiment D5A, the process of any one of embodiments D1 to D4 further comprises R 1 is hydrogen, and R 2 But, C2~C 12 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C 1~6 It is an alkyl.

[0138] D6. In embodiment D6, the process of any one of embodiments D1 to D4 and D5A further comprises R 1 is hydrogen, and R 2 But, C2~C 12 It is an alkyl.

[0139] D7. In embodiment D7, the process of any one of embodiments D1 to D4 and D5A further comprises R 1 is hydrogen, and R 2 is a C3-C7 cycloalkyl.

[0140] D7A. In embodiment D7A, the process of any one of embodiments D1 to D4 and D5A further comprises R 1 is hydrogen, and R 2 C3-C7 cycloalkyl-C 1~6 It is an alkyl.

[0141] D7B. In embodiment D7B, the process of any one of embodiments D1 to D4 further comprises R 1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and R 2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C 1~6 It is an alkyl.

[0142] D8. In embodiment D8, the process of any one of embodiments D1-D4 and D7B further comprises R 1 is C1-C6 alkyl, and R 2 is a C1-C6 alkyl.

[0143] D9. In embodiment D9, the process of any one of embodiments D1-D4 and D7B further comprises: 1 is C1-C6 alkyl, and R 2 is a C3-C7 cycloalkyl.

[0144] D10. In embodiment D10, the process of any one of embodiments D1 to D4 and D7B further comprises R 1 is C1-C6 alkyl, and R 2 C3-C7 cycloalkyl-C 1~6 It is an alkyl.

[0145] D10A. In embodiment D10A, the process of any one of embodiments D1 to D4 is 1 and R 2 are independently C3-C7 cycloalkyl-C 1~6 It is an alkyl.

[0146] D11. In embodiment D11, the process of any one of embodiments D1 to D4 is 1 and R 2 together with the nitrogen atom to which they are attached form a cyclylamine.

[0147] In embodiment D12, the process of any one of embodiments D1 to D3 and D5, n is selected from 2 to 5. In a first embodiment of D12, n is 3 to 5. In a second embodiment of D12, n is 4 or 5.

[0148] D13. In embodiment D13, the process of any one of embodiments D1 to D3 and D5, n is selected from 2 to 4. In a first embodiment of D13, n is 3 or 4. In a second embodiment of D13, n is 3.

[0149] D14. In embodiment D14, the process of any one of embodiments D1 through D3, and D5, n is 2 or 3.

[0150] D15. In embodiment D15, the process of any one of embodiments D1-D3 and D5, n is 2.

[0151] D16. In embodiment D16, the process of any one of embodiments D1 to D3 and D12 to D15 and subembodiments therein may further comprise R 3 is hydrogen.

[0152] D17. In embodiment D17, the process of any one of embodiments D1 to D3 and D12 to D15 and subembodiments therein may further comprise R 3 is a C1-C6 alkyl.

[0153] D18. In embodiment D18, the process of any one of embodiments D1 to D3 and D12 to D15 and subembodiments therein may further comprise R 3 is a C3-C7 cycloalkyl.

[0154] D19. In embodiment D19, the process of any one of embodiments D1 to D3 and D12 to D18 and subembodiments therein may further comprise R 4 is hydrogen.

[0155] D20. In embodiment D20, the process of any one of embodiments D1 to D3 and D12 to D18 and subembodiments therein may further comprise R 4 is a C1-C6 alkyl.

[0156] D21. In embodiment D21, the process of any one of embodiments D1 to D3 and D12 to D18 and subembodiments therein may further comprise R 4 is a C3-C7 cycloalkyl.

[0157] D22. In embodiment D22, the process of any one of embodiments D1 to D3 and D12 to D21 and subembodiments therein may further comprise R 5 is hydrogen.

[0158] D23. In embodiment D23, the process of any one of embodiments D1 to D3 and D12 to D21 and subembodiments therein may further comprise R 5 is a C1-C6 alkyl.

[0159] D24. In embodiment D24, the process of any one of embodiments D1, D3, and D12 to D21 and subembodiments therein may further comprise R 5 is a C3-C7 cycloalkyl.

[0160] D25. In embodiment D25, the process of any one of embodiments D1 to D3 and D12 to D24 and subembodiments therein may further comprise R 6 is hydrogen.

[0161] D26. In embodiment D26, the process of any one of embodiments D1 to D3 and D12 to D24 and subembodiments therein may further comprise R 6 is a C1-C6 alkyl.

[0162] D27. In embodiment D27, the process of any one of embodiments D1 to D3 and D12 to D24 and subembodiments therein may further comprise R 6 is a C3-C7 cycloalkyl.

[0163] D28. In embodiment D28, the process of any one of embodiments D1-D4 and D5A-D7 is further characterized in that 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-ethylbutylamine, 2-methylpentylamine, 1,1-dimethylbutylamine, 1,3-dimethylbutylamine, 3,3-dimethylbutylamine, 2-methyl-3-pentylamine, 3 3-methylpentylamine, 3-methyl-3-pentylamine, 3-methyl-2-pentylamine, 2-methylbutylamine, 1,2,2-trimethylpropylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, cyclobutylmethylamine, cyclopropylmethylamine, 2-methylcyclopropylamine, 2-cyclopropylethylamine, 2-methyl-cyclopentylamine, 3-methylcyclopentylamine, cyclopentylmethylamine, 2-cyclobutylethylamine, 3-cyclopropylpropylamine, 2-ethylcyclopropylamine, allylamine or propargylamine.

[0164] D29. In embodiment D29, the process of any one of embodiments D1 through 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, 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, 2-methylbutyl-1-amine, or 1,2,2-trimethylpropylamine.

[0165] D30. In embodiment D30, the process of any one of embodiments D1 through D4, D5A, and D7 is wherein the amine is cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, 2-methylcyclopropylamine, 2-methylcyclopentylamine, 3-methylcyclopentyl-amine, or 2-ethylcyclopropylamine.

[0166] D31. In embodiment D31, the process of any one of embodiments D1-D4, and D7B-D9 is further characterized in that 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-tert-butyl-methylamine, N-methyl-cyclobutylamine, N-ethylcyclopropylamine, 1-cyclopropyl-N-methylmethanamine, N-ethyl-prop-2-yn-1- ... D31 is an allylamine, N-methylpentylamine, N-methyl-2-pentylamine, N-methyl-3-pentylamine, N,3-dimethylbutan-2-amine, N,2-dimethylbutan-2-amine, N,3-dimethylbutan-2-amine, N-methylcyclopentylamine, N-ethyl-1-butylamine, N-ethyl-2-butylamine, N-ethyl-2-methyl-2-propylamine, N-ethyl-2-methylpropyl-amine, N-ethylcyclobutylamine, di-n-propylamine, di-isopropylamine, N-isopropylpropylamine, diallylamine, dipropargylamine, or allylpropargylamine. In one embodiment of D31, the amine is not diethylamine.

[0167] D32. In embodiment D32, the process of any one of embodiments D1-D4, D7B, and D8 is wherein the amine is N-methylethylamine, diethylamine, N-methyl-n-propylamine, N-methyl-isopropylamine, N-ethyl-n-propylamine, N-ethyl-isopropylamine, N-methylbutylamine, N-methyl-2-butylamine, N-tert-butyl-methylamine, N-methylpentyl-1-amine, N-methyl-2-pentylamine, N-methyl-3-pentylamine, N,3-dimethylbutan-2-amine, N,2-dimethylbutan-2-amine, N,3-dimethylbutan-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. In one embodiment of B31, the amine is not diethylamine.

[0168] D33. In embodiment D33, the process of any one of embodiments D1 through D4, and D7B, and D9, wherein the amine is N-methylcyclobutylamine, N-ethylcyclopropylamine, N-methylcyclopentylamine, or N-ethylcyclobutylamine.

[0169] D34. In embodiment D34, the process of any one of embodiments D1 through D4, and D11 is wherein the amine is azetidine, pyrrolidine, piperidine, piperazine, morpholine, azepane, or azocane.

[0170] D35. In embodiment D35, the process of any one of embodiments D1 through D3, D5, and D12 through D16, D19, D20, D22, D23, and D25, wherein the amine is ethylenediamine, propane-1,3-diamine, butane-1,4-diamine, pentane-1,5-diamine, hexane-1,6-diamine, N 1 ,N 2 -Dimethyl-ethane-1,2-diamine, or N 1 ,N 2-diethylethane-1,2-diamine.

[0171] D36. In embodiment D36, the process of embodiments D1-D3 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.

[0172] D37. In embodiment D37, the process of embodiment D1-D3, or D36, the amine is diethylamine. In one embodiment, the process of embodiment D37 has a molar ratio of diethylamine to compound 1 in the mixture of at least about 1:0.5. In another embodiment, the process of embodiment D37 has a molar ratio of diethylamine to compound 1 in the mixture of from 1:1 to about 10:1. In yet another embodiment, the process of embodiment D37 has a molar ratio of diethylamine to compound 1 in the mixture of from 1:1 to about 9:1. In yet another embodiment, the process of embodiment D37 has a molar ratio of diethylamine to compound 1 in the mixture of from 1:1 to about 8:1. In yet another embodiment, the process of embodiment D37 has a molar ratio of diethylamine to compound 1 in the mixture of from 3:1 to about 6:1. In yet another embodiment, the process of embodiment D37 has a molar ratio of diethylamine to compound 1 in the mixture of about 5:1. In yet another embodiment, the process of embodiment D37 is wherein the molar ratio of diethylamine to compound 1 in the mixture is from 4:1 to about 6:1.

[0173] D38. In embodiment D38, the process of any one of embodiments D1 through D37, one or more anti-solvents are added to the mixture of step (a1) to obtain a solid amine solvate of compound 1.

[0174] D39. In embodiment D39, the process of any one of embodiments D1-D37, one or more anti-solvents and solid crystalline seeds of Compound 1 and / or solid crystalline seeds of an amine solvate of Compound 1 are added to the mixture of step (a1) to obtain a solid amine solvate of Compound 1.

[0175] D39A. In embodiment D39A, the process of any one of embodiments D1 through D39, the mixture of step (a1) is a solution.

[0176] D40. In embodiment D40, the process of embodiment D38, D39, or D39A, the one or more anti-solvents in step (b1) are independently selected from an alkane and water. In a subembodiment of embodiment D40, the one or more anti-solvents are independently selected from the group consisting of water, n-heptane, n-hexane, isooctane, pentane, cyclohexane, and cyclopentane.

[0177] D41. In embodiment D41, the process of embodiment D38, D39, D39A, or D40, wherein the anti-solvent in step (b1) is n-heptane.

[0178] D42. In embodiment D42, the process of any one of embodiments D2-D41, the one or more suitable organic solvents in step (a1) are polar organic solvents independently selected from the group consisting of alcohols, ethers, toluene, ketones, esters, halogenated alkanes, nitromethane, N-methylpyrrolidinone, acetonitrile, dimethylformamide, and dimethylacetamide.

[0179] D42a. In embodiment D42a, the process of any one of embodiments D2 through D41, wherein the one or more suitable organic solvents in step (a1) are polar organic solvents independently selected from the group consisting of ethers, toluene, ketones, esters, halogenated alkanes, nitromethane, N-methylpyrrolidinone, acetonitrile, dimethylformamide, and dimethylacetamide.

[0180] D43. In embodiment D43, the process of any one of embodiments D2-D42, the one or more suitable organic solvents in step (a1) are independently selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, 1,2-propanediol, methylene dichloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate (IPAc), butyl acetate, n-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran (THF), 2-methylTHF (2-MeTHF), dimethoxyethane (DME), toluene, acetone, methyl ethyl ketone (MEK), nitromethane, acetonitrile (ACN), and 1,4-dioxane.

[0181] D43a. In embodiment D43a, the process of any one of embodiments D2-D42 further comprises the step (a1) of selecting one or more suitable organic solvents from the group consisting of methanol, n-propanol, isopropanol, n-butanol, 1,2-propanediol, methylene dichloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate (IPAc), butyl acetate, n-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran (THF), 2-methylTHF (2-MeTHF), dimethoxyethane (DME), toluene, acetone, methyl ethyl ketone (MEK), nitromethane, acetonitrile (ACN), and 1,4-dioxane.

[0182] D43b. In embodiment D43b, the amine solvate of embodiment D43a is further characterized in that the one or more suitable organic solvents are independently selected from methylene dichloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate (IPAc), butyl acetate, n-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAC), tetrahydrofuran (THF), 2-methylTHF (2-MeTHF), dimethoxyethane (DME), toluene, acetone, methyl ethyl ketone (MEK), nitromethane, acetonitrile (ACN), and 1,4-dioxane.

[0183] D44. In embodiment D44, the process of embodiments D42-D43b wherein the suitable organic solvent in step (a1) is MTBE.

[0184] D45. In embodiment D45, the process of any one of embodiments D37-D44 wherein the diethylamine solvate of Compound 1 is a crystalline solid.

[0185] D46. In embodiment D46, the process of embodiment D45 is wherein the diethylamine solvate of Compound 1 is the crystalline Form B polymorph having an X-ray powder diffraction pattern as described in this Summary.

[0186] D47-D54. In embodiments D47-D54, the process of embodiment D46 is such that crystalline form B has an X-ray powder diffraction pattern as described above in any one of embodiments C2-C9, respectively.

[0187] D55. In embodiment D55, the process of any one of embodiments D1-D54, wherein an amine solvate of Compound 1 is converted to Compound 1.

[0188] D56. In embodiment D56, the process of any one of embodiments D1-D55, wherein an amine solvate of compound 1 is converted to compound 1 by heating the amine solvate to remove the amine from the amine solvate.

[0189] D57. In embodiment D57, the process of any one of embodiments D1-D55, an amine solvate of compound 1 is converted to compound 1 by partitioning the amine solvate between one or more suitable organic solvents and an acidic aqueous solution.

[0190] D58. In embodiment D58, the process of embodiment D57 is such that one or more suitable organic solvents containing compound 1 are isolated and concentrated to provide a solid form of compound 1.

[0191] D59. In embodiment D59, the process of embodiment D56 or D58 produces a crystalline Form A polymorph Compound 1 having an X-ray powder diffraction pattern as described herein.

[0192] D60-D69. In embodiments D60-D69, the process of embodiment D59 produces the crystalline Form A polymorph of Compound 1 having an X-ray powder diffraction pattern as described above in embodiments A2-A11, respectively.

[0193] D70. In embodiment D70, the process of any one of embodiments D1-D69 further comprises: (a) treating 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile with a deoxyfluorinating agent in a suitable organic solvent and optionally in the presence of triethylamine trihydrofluoride ((EtN·3HF) with or without a base; (b) purifying the mixture from step (a) to obtain compound 1; The method includes preparing compound 1 in step (a1), comprising:

[0194] D71. In embodiment D71, the process of embodiment D70 is wherein the deoxyfluorinating agent is pyridine-2-sulfonyl fluoride, PBSF, bis(2-methoxylethylamino)sulfur trifluoride (BAST), or (diethylamino)sulfur trifluoride (DAST).

[0195] D72. In embodiment D72, the process of embodiment D70 or D71 is wherein the organic base is (tert-butylimino)tris-(pyrrolidino)phosphorane (BTPP), 2-tert-butyl-1,1,3,3-tetramethyl-guanidine (BTMG), 1,8-diazabicyclo-[5.4.0]undec-7-ene, or 7-methyl-1,5,7-triaza-bicyclo-[4.4.0]dec-1-ene (DBU).

[0196] D73A. In embodiment D73A, the process of embodiment D70, D71 or D72 is wherein the deoxyfluorinating agent is PBSF or BAST.

[0197] D73. In embodiment D73, the process of embodiment D70, D71, or D72 is wherein the deoxyfluorinating agent is PBSF, the organic base is BTMG or BTPP, and Et3N·3HF is present.

[0198] D74. In embodiment D74, the process of any one of embodiments D70-D73, the one or more suitable organic solvents are selected from ethers, esters, ketones, haloalkanes, acetates, toluene, and xylene.

[0199] D75. In embodiment D75, the process of any one of embodiments D70-D74, the one or more suitable organic solvents are selected from dichloromethane, MTBE, IPAc, tetrahydrofuran, 2-methyl-tetrahydrofuran, ethyl acetate, and toluene.

[0200] D76. In embodiment D76, the process of any one of embodiments D70-D75 wherein the suitable organic solvent is 2-methyltetrahydrofuran.

[0201] D77. In embodiment D77, the process of any one of embodiments D73-D76, the reaction is carried out at about -20°C to about room temperature.

[0202] D78. In embodiment D78, the process of any one of embodiments D73-D77, the reaction is carried out at about -20°C.

[0203] D79. In embodiment D79, the process of any one of embodiments D73-D78, the molar ratio of BTPP or BTMG:Et3N·3HF is from about 6:1 to about 1:1.

[0204] D80. In embodiment D80, the process of any one of embodiments D73-D79, the molar ratio of BTPP or BTMG:Et3N·3HF is from about 6:1 to about 3:1.

[0205] D81. In embodiment D81, the process of any one of embodiments D73-D79, wherein the molar ratio of BTMG:Et3N·3HF is about 5:1.

[0206] D82. In embodiment D82, the process of any one of embodiments D73-D81, the molar ratio of PBSF:Et3N·3HF is from about 8:1 to about 1.7:1.

[0207] D83. In embodiment D83, the process of any one of embodiments D73-D82, wherein the molar ratio of PBSF:Et3N·3HF is about 8:1, about 5:1, about 3:1, or about 1.7:1.

[0208] D84. In embodiment D84, the process of any one of embodiments D73-D83, wherein the molar ratio of PBSF:Et3N·3HF is about 3:1.

[0209] D85. In embodiment D85, the process of embodiment D70, 71, or D72 is wherein the deoxyfluorinating agent is pyridine-2-sulfonyl fluoride and the base is 1,8-diazabicyclo-[5.4.0]undec-7-ene or 7-methyl-1,5,7-triaza-bicyclo-[4.4.0]dec-1-ene.

[0210] D86. In embodiment D86, the process of embodiment D70, D71, or D85 is wherein the suitable organic solvent is tetrahydrofuran.

[0211] Embodiment E: E1. In embodiment E1, there is provided a process for preparing the crystalline Form B polymorph of the diethylamine solvate of Compound 1 having an X-ray powder diffraction pattern as described in the third aspect of this Summary or any one of embodiments C2-C9.

[0212] E2. In embodiment E2, the process of embodiment E1, compound 1 is contacted with diethylamine in step (a2) by adding compound 1 to diethylamine or by adding diethylamine to a mixture of compound 1 in one or more suitable organic solvents.

[0213] E3. In embodiment E3, the process of embodiment E1 further comprises adding diethylamine to the mixture of compound 1 in one or more suitable organic solvents in step (a2). In one embodiment, the process of embodiment E3 further comprises a molar ratio of diethylamine to compound 1 in the mixture of at least about 1:0.5. In another embodiment, the process of embodiment E3 further comprises a molar ratio of diethylamine to compound 1 in the mixture of from 1:1 to about 10:1. In yet another embodiment, the process of embodiment E3 further comprises a molar ratio of diethylamine to compound 1 in the mixture of from 1:1 to about 9:1. In yet another embodiment, the process of embodiment E3 further comprises a molar ratio of diethylamine to compound 1 in the mixture of from 1:1 to about 8:1. In yet another embodiment, the process of embodiment E3 further comprises a molar ratio of diethylamine to compound 1 in the mixture of from 3:1 to about 6:1. In yet another embodiment, the process of embodiment E3 further comprises a molar ratio of diethylamine to compound 1 in the mixture of about 5:1. In yet another embodiment, the process of embodiment E3 has a molar ratio of diethylamine to compound 1 in the mixture of from 4:1 to about 6:1. In yet another embodiment, the process of embodiment E3 has a molar ratio of diethylamine to compound 1 in the mixture of about 1 or greater.

[0214] E4. In embodiment E4, the process of any one of embodiments E1-E3, wherein one or more anti-solvents are added to the mixture in step (a2) to obtain the crystalline Form B polymorph of the diethylamine solvate of Compound 1.

[0215] E5. In embodiment E5, the process of any one of embodiments E1-E3, wherein one or more anti-solvents and solid crystalline seeds of Compound 1 and / or solid crystalline seeds of a diethylamine solvate of Compound 1 are added to the mixture of step (a2) to obtain the crystalline Form B polymorph of the diethylamine solvate of Compound 1.

[0216] E5A. In embodiment E5A, the process of any one of embodiments E1-E5, wherein the mixture in step (a2) is a solution.

[0217] In embodiment E6, the process of any one of embodiments E1 through E5A, the one or more anti-solvents in step (b2) are independently selected from an alkane and water. In a subembodiment of embodiment E6, the one or more anti-solvents are independently selected from the group consisting of water, n-heptane, n-hexane, isooctane, pentane, cyclohexane, and cyclopentane.

[0218] E7. In embodiment E7, the process of any one of embodiments E1-E6, wherein the anti-solvent in step (b2) is n-heptane.

[0219] E8. In embodiment E8, the process of any one of embodiments E1-E7, the one or more suitable organic solvents in step (a2) are polar organic solvents independently selected from the group consisting of alcohols, ethers, toluene, ketones, esters, halogenated alkanes, nitromethane, N-methylpyrrolidinone, acetonitrile, dimethylacetamide, and dimethylformamide.

[0220] E8a. In embodiment E8a, the process of any one of embodiments E1-E7, wherein the one or more suitable organic solvents in step (a2) are polar organic solvents independently selected from the group consisting of ethers, toluene, ketones, esters, halogenated alkanes, nitromethane, N-methylpyrrolidinone, acetonitrile, dimethylacetamide, and dimethylformamide.

[0221] E9. In embodiment E9, the process of any one of embodiments E1-E7 is characterized in that the one or more suitable organic solvents in step (a2) are independently selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, 1,2-propanediol, methylene dichloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate (IPAc), butyl acetate, n-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran (THF), 2-methylTHF (2-MeTHF), dimethoxyethane (DME), toluene, acetone, methyl ethyl ketone (MEK), nitromethane, acetonitrile (ACN), and 1,4-dioxane.

[0222] E9a. In embodiment E9a, the process of any one of embodiments E1-E7, the one or more suitable organic solvents in step (a2) are independently selected from the group consisting of methanol, n-propanol, isopropanol, n-butanol, 1,2-propanediol, methylene dichloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate (IPAc), butyl acetate, n-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran (THF), 2-methylTHF (2-MeTHF), dimethoxyethane (DME), toluene, acetone, methyl ethyl ketone (MEK), nitromethane, acetonitrile (ACN), and 1,4-dioxane.

[0223] E9b. In embodiment E9b, the process of any one of embodiments E1-E7, the one or more suitable organic solvents in step (a2) are independently selected from the group consisting of methylene dichloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate (IPAc), butyl acetate, n-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran (THF), 2-methylTHF (2-MeTHF), dimethoxyethane (DME), toluene, acetone, methyl ethyl ketone (MEK), nitromethane, acetonitrile (ACN), and 1,4-dioxane.

[0224] E10. In embodiment D10, the process of embodiment E9, E9a, or E9b, wherein the suitable organic solvent is MTBE.

[0225] E11. In embodiment E11, the process of any one of embodiments E1-E10, optionally, the diethylamine solvate of compound 1 is converted to compound 1 by heating the diethylamine solvate of compound 1 to remove diethylamine from the diethylamine solvate of compound 1.

[0226] In embodiment E12, the process of any one of embodiments E1-E10, the diethylamine solvate of compound 1 is optionally converted to compound 1 by partitioning the diethylamine solvate of compound 1 between one or more suitable organic solvents and an aqueous acidic solution. In one embodiment, the acid is hydrochloric acid.

[0227] E13. In embodiment E13, the process of embodiment E12, wherein one or more organic solvents containing compound 1 are isolated and concentrated to provide a solid form of compound 1.

[0228] E14-E24. In embodiments E14-E24, the process of any one of embodiments E11-E13 is produced, wherein Compound 1 is a crystalline Form A polymorph of Compound 1 having an X-ray powder diffraction pattern as defined in any one of embodiments A1-A11, respectively.

[0229] Embodiment F: F1. In embodiment F1, there is provided a process for preparing the crystalline Form A polymorph of Compound 1 from a diethylamine solvate of Compound 1 as described in the sixth aspect of this Summary or a composition of any one of embodiments I1-I7A below.

[0230] F2-F10. In embodiments F2-F10, the process of embodiment F1 is such that the diethylamine solvate of compound 1 of the third aspect of this Summary is the crystalline Form B polymorph having the X-ray powder diffraction patterns as described above in embodiments C1-C9, respectively.

[0231] F11. In embodiment F11, the process of any one of embodiments F1-F10, wherein diethylamine is removed from the diethylamine solvate of Compound 1 by heating the diethylamine solvate of Compound 1 or the composition of any one of embodiments I1-I7A below.

[0232] F12. In embodiment F12, the process of any one of embodiments F1-F11, diethylamine is removed from the diethylamine solvate of Compound 1 by partitioning the diethylamine solvate of Compound 1 or the composition of any one of embodiments I1-I7A below between one or more suitable organic solvents and an acidic aqueous solution. In one embodiment, the acid is hydrochloric acid and the solvent is MTBE.

[0233] F13-F24. In embodiment F13, the process of embodiment F12 is further characterized in that one or more suitable organic solvents, including MTBE, are isolated and concentrated to provide a crystalline Form A polymorph of Compound 1 having an X-ray powder diffraction pattern as described in any one of embodiments A1-A11 above, respectively.

[0234] F25. In embodiment F25, the process of any one of embodiments F1-F24, the crystalline Form A polymorph of Compound 1 is recrystallized from one or more suitable organic solvents.

[0235] F26. In embodiment F26, the process of embodiment F25 is wherein the crystalline Form A polymorph of Compound 1 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.

[0236] F27. In embodiment F27, the process of embodiment 26 is characterized in that the one or more suitable organic solvents are selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, 1,2-propanediol, methylene dichloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate (IPAc), butyl acetate, n-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran (THF), 2-methylTHF (2-MeTHF), dimethoxyethane (DME), toluene, acetone, methyl ethyl ketone (MEK), nitromethane, acetonitrile (ACN), and 1,4-dioxane. In one embodiment, the suitable organic solvent is isopropyl acetate.

[0237] F28. In embodiment F28, the process of embodiment F26 or F27 is characterized in that one or more anti-solvents and / or solid crystalline seeds of Compound 1 are added.

[0238] F29. In embodiment F29, the process of embodiment F28, the one or more anti-solvents are independently selected from an alkane and water.

[0239] F30. In embodiment F30, the process of embodiment F29 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.

[0240] F31. In embodiment F31, the process of embodiment F30 is wherein the anti-solvent is n-heptane.

[0241] Embodiment G: G1. In embodiment G1, there is provided a process for making the crystalline Form A polymorph of Compound 1 having an X-ray powder diffraction pattern as described in the seventh aspect of the Summary.

[0242] G2. In embodiment G2, the process of embodiment G1 further comprises adding one or more suitable anti-solvents to a solution of compound 1 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.

[0243] G3. In embodiment G3, the process of embodiment G2 is further characterized in that the one or more suitable organic solvents are selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, 1,2-propanediol, methylene dichloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate (IPAc), butyl acetate, n-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran (THF), 2-methylTHF (2-MeTHF), dimethoxyethane (DME), toluene, acetone, methyl ethyl ketone (MEK), nitromethane, acetonitrile (ACN), and 1,4-dioxane. In some embodiments, the suitable organic solvent is isopropyl acetate.

[0244] G4. In embodiment G4, the process of embodiment G2 or G3 includes the addition of one or more anti-solvents.

[0245] G5. In embodiment G5, the process of embodiment G4, the one or more anti-solvents are independently selected from an alkane and water.

[0246] G6. In embodiment G6, the process of embodiment G5 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.

[0247] G7. In embodiment G7, the process of embodiment G6, wherein the anti-solvent is n-heptane.

[0248] G8. In embodiment G8, the process of any one of embodiments G1-G7, wherein the process is carried out at about 0°C to about 70°C.

[0249] Embodiment H: H1. In embodiment H1, there is provided a process for making compound 1 as described in the eighth aspect of the present Summary.

[0250] H2. In embodiment H2, the process of embodiment H1 is wherein the organic base in step (a5) is (tert-butylimino)tris-(pyrrolidino)phosphorane (BTPP) or 2-tert-butyl-1,1,3,3-tetramethyl-guanidine (BTMG).

[0251] H3. In embodiment H3, the process of embodiment H1 or H2 wherein the organic base in step (a5) is BTMG.

[0252] H4. In embodiment H4, the process of any one of embodiments H1-H3, the one or more suitable organic solvents in step (a5) are selected from ethers, esters, haloalkanes, ketones, acetates, toluene, and xylene.

[0253] H5. In embodiment H5, the process of any one of embodiments H1 through H4, the one or more suitable organic solvents in step (a5) is selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, ethyl acetate, IPAc, MTBE, methylene chloride, or toluene.

[0254] H6. In embodiment H6, the process of any one of embodiments H1 through H5, wherein the suitable organic solvent in step (a5) is 2-methyltetrahydrofuran.

[0255] H7. In embodiment H7, the process of any one of embodiments H1-H6, wherein the reaction of step (a5) is carried out at about -20°C to about room temperature.

[0256] H8. In embodiment H8, the process of any one of embodiments H1 through H7, the reaction of step (a5) is carried out at about -20°C.

[0257] H9. In embodiment H9, the process of any one of embodiments H1 through H8, wherein the molar ratio of BTPP or BTMG:Et3N·3HF in step (a5) is from about 6:1 to about 1:1.

[0258] H10. In embodiment H10, the process of any one of embodiments H1 through H9, the molar ratio of BTPP or BTMG:Et3N·3HF in step (a5) is from about 6:1 to about 3:1.

[0259] H11. In embodiment H11, the process of any one of embodiments H1 through H9, wherein the molar ratio of BTMG:Et3N·3HF in step (a5) is about 5:1.

[0260] H12. In embodiment H12, the process of any one of embodiments H1 through H11, wherein the molar ratio of PBSF:Et3N·3HF in step (a5) is from about 8:1 to about 1.7:1.

[0261] H13. In embodiment H13, the process of any one of embodiments H1 through H12, wherein the molar ratio of PBSF:Et3N·3HF in step (a5) is about 8:1, about 5:1, about 3:1, or about 1.7:1.

[0262] H14. In embodiment H14, the process of any one of embodiments H1 through H13, wherein the molar ratio of PBSF:Et3N·3HF in step (a5) is about 3:1.

[0263] H15-H68. In embodiments H15-68, the process of any one of embodiments H1-H14, wherein compound 1 is converted in step (c5) to an amine solvate of compound 1 by the process described above in embodiments D1-D54, respectively.

[0264] H70-H72. In embodiments H70-72, the process of any one of embodiments H15-H68, an amine solvate of compound 1 is converted to compound 1 by the process described above in embodiments D56-D58, respectively.

[0265] H73-H83. In embodiments H73-83, the process of any one of embodiments H70 or H72 is wherein Compound 1 is the crystalline Form A polymorph as described above in embodiments A1-A11, respectively.

[0266] Embodiment I: I1. In embodiment I1, there is provided a solid composition as described in the ninth aspect of the present summary. The weight percentage is calculated as follows: (weight percentage of diethylamine solvate of compound 1) / {(weight percentage of compound 1) and [weight percentage of diethylamine solvate of compound 1]}. In a subembodiment of embodiment I1, the weight percentage is measured by HPLC.

[0267] I2. In embodiment I2, the solid composition of embodiment I1 has a percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition of about 1 to 4 (or less), 1 to 3 (or less), 1 to 2 (or less), 1 to 1 (or less), or 1 to 0.25 (or less). In a subembodiment, the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is the crystalline form B polymorph of any one of embodiments C1-C9.

[0268] I2A. In embodiment I2A, the solid composition of embodiment I1 has a percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition of about 1:4, 1:3, 1:2; 1:1, or from 1:0.25 to about 1:0.001. In a subembodiment, the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is the crystalline form B polymorph of any one of embodiments C1-C9.

[0269] I3. In embodiment I3, the solid composition of embodiment I1 has a percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition of about 1 to 0.1 (or less). In a subembodiment, the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is the crystalline form B polymorph of any one of embodiments C1-C9.

[0270] I3A. In embodiment I3A, the solid composition of embodiment I1 has a percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition of about 1:0.1 to about 1:0.001. In a subembodiment, the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is the crystalline form B polymorph of any one of embodiments C1-C9.

[0271] I4. In embodiment I4, the solid composition of embodiment I1 has a percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition of about 1 to 0.05 (or less). In a subembodiment, the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is the crystalline form B polymorph of any one of embodiments C1-C9.

[0272] I4A. In embodiment I4A, the solid composition of embodiment I1 has a percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition of about 1:0.05 to about 1:0.001. In a subembodiment, the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is the crystalline form B polymorph of any one of embodiments C1-C9.

[0273] I5. In embodiment I5, the solid composition of embodiment I1 has a percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition of about 1 to 0.03 (or less). In a subembodiment, the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is the crystalline form B polymorph of any one of embodiments C1-C9.

[0274] I5A. In embodiment I5A, the solid composition of embodiment I1 has a percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition of about 1:0.03 to about 1:0.001. In a subembodiment, the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is the crystalline form B polymorph of any one of embodiments C1-C9.

[0275] I6. In embodiment I6, the solid composition of embodiment I1 has a percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition of about 1 to 0.02 (or less). In a subembodiment, the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is the crystalline form B polymorph of any one of embodiments C1-C9.

[0276] I6A. In embodiment I6A, the solid composition of embodiment I1 has a percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition of about 1:0.02 to about 1:0.001. In a subembodiment, the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is the crystalline form B polymorph of any one of embodiments C1-C9.

[0277] I7. In embodiment I7, the solid composition of embodiment I1 has a percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition of about 1 to 0.01 (or less). In a subembodiment, the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is the crystalline form B polymorph of any one of embodiments C1-C9.

[0278] I7A. In embodiment I7A, the solid composition of embodiment I1 has a percent weight ratio of diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition of about 1:0.01 to about 1:0.001. In a subembodiment, the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is the crystalline form B polymorph of any one of embodiments C1-C9.

[0279] In the above embodiments, references to embodiments include subembodiments thereof, for example reference to embodiment D31 includes combinations with the embodiments contained therein.

[0280] utility Compound I is useful for the treatment of HIF-2α mediated diseases, including, but not limited to, various types of cancer, liver diseases such as non-alcoholic steatohepatitis (NASH), inflammatory diseases such as inflammatory bowel disease (IBD), lung diseases such as pulmonary arterial hypertension (PAH), and iron loading disorders.

[0281] HIF-2α plays a key role in the development and progression of many human cancers. Many extensive studies have demonstrated the critical role of increased HIF-2α activity in driving clear cell renal cell carcinoma (ccRCC) (see review by Shen and Kaelin, Seminars in Cancer Biology 23:18-25, 2013). Aberrant HIF-2α activity is mainly due to loss of function of the tumor suppressor VHL. More than 80% of ccRCCs are known to have defective VHL, either by deletion, mutation or impaired post-translational modification. Defective VHL leads to constitutively active HIF-α protein, regardless of oxygen levels. Various studies utilizing gain-of-function and loss-of-function approaches in mouse models have demonstrated that HIF-2α is an important 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). For example, knockdown of HIF-2α in VHL-null tumors inhibited tumor formation, while reintroduction of VHL and overexpression of HIF-2α overcame the tumor suppressive role of VHL. Furthermore, single nucleotide polymorphisms in HIF-2α have been associated with resistance to PHD-mediated degradation and associated with an increased risk of developing RCC. In addition to functioning as a typical tumor-initiating event in ccRCC, the VHL-HIF-2α axis has also been implicated in ccRCC tumor metastasis via 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):307-11). Collectively, these studies strongly support the potential therapeutic utility of HIF-2α targeting agents for the treatment of ccRCC.

[0282] Defective VHL predisposes patients to kidney cancer (70% lifetime risk), as well as hemangioblastoma, pheochromocytoma, endolymphatic sac tumors, and pancreatic neuroendocrine tumors. Tumors derived from defective VHL are often driven by constitutively active downstream HIF-α proteins, the majority of which are dependent on HIF-2α activity (see Maher, et al. Eur. J. Hum. Genet. 19:617-623, 2011). Both genetic and epigenetic mechanisms can lead to loss of function of VHL. Epigenetic inactivation of VHL expression, and therefore constitutive activation of HIF-α protein, has been found in many cancers, including RCC, multiple myeloma, retinoblastoma, NSCLC, pancreatic endocrine tumors, squamous cell carcinoma, acute myeloid leukemia, myelodysplastic syndromes, and esophageal squamous cell carcinoma (see review in Nguyen, et al. Arch. Phann. Res 36:252-263, 2013). HIF-2α has also been linked to cancers of the retina, adrenal gland, and pancreas through both loss of function of VHL and activating mutations in HIF-2α. Recently, HIF-2α gain-of-function mutations have been identified in erythrocytosis and paraganglioma with erythrocytosis (see Zhuang, et al. NEJM 367:922-930, 2012; Percy, et al. NEJM 358:162-168, 2008; and Percy, et al. Am. J. Hematol. 87:439-442, 2012). In particular, many of the known HIF-2α target gene products (e.g., VEGF, PDGF and cyclin Dl) have been demonstrated to play important roles in cancers originating from kidney, liver, colon, lung and brain. Therefore, HIF-2α target therapy may be beneficial for the above cancers when triggered by these signaling events downstream of aberrant HIF-2α pathway activation. In addition to loss-of-function of VHL and activating mutations of HIF-2α, HIF-α protein is also frequently upregulated in the intratumoral environment of rapidly growing tumors due to hypoxic conditions resulting from poor vascularization of large tumors. The activated HIF-α pathway then transcriptionally upregulates various essential factors, thereby further promoting tumor cell survival and proliferation.

[0283] Numerous studies have shown a correlation between overexpression of HIF-2α and poor prognosis in various cancers, including astrocytoma, breast, cervical, colorectal, glioblastoma, glioma, head and neck, liver, non-small cell lung, melanoma, neuroblastoma, ovarian and prostate cancers, thereby supporting the pursuit of HIF-2α as a therapeutic target in treating these cancers (see review by Keith, et al. Nature Rev. Cancer 12:9-22, 2012). HIF-2α has been shown to enhance the growth of APC-mutated colorectal cancer through the regulation of genes involved in proliferation, iron utilization and inflammation (see Xue, et al. Cancer Res 72:2285-2293, 2012; and Xue and Shah, Carcinogenesis 32:163-169, 2013). In hepatocellular carcinoma (HCC), knockdown of HIF-2α in preclinical models inhibited cell proliferation in vitro and tumor growth in vivo through downregulation of VEGF and cyclin D 1 (see He, et al. Cancer Sci. 103:528-534, 2012). In NSCLC, approximately 50% of patients show overexpression of HIF-2α protein, which strongly correlates with higher VEGF expression and, more importantly, with shorter overall survival. Interestingly, HIF-1α does not correlate with reduced overall survival in lung cancer patients, even though its expression is also often increased (see Giatromanolaki, et al. Br. J. Cancer 85:881-890, 2001). Extensive studies in engineered mice bearing both non-degradable HIF-2α and mutant KRAS tumors have shown increased tumor burden and decreased survival when compared to mice expressing mutant KRAS alone (see Kim, et al. J. Clin. Invest. 119:2160-2170, 2009). These studies indicate that HIF-2α promotes tumor growth and progression in lung cancer and is negatively correlated with clinical prognosis.

[0284] HIF-2αs 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-2α 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-2α knockdown reduces tumor growth in preclinical animal models of neuroblastoma, and conversely, increased levels of HIF-2α correlate with advanced disease, poor prognosis, and higher VEGF levels, which may contribute to poor clinical outcome. Similarly, higher expression of HIF-2α has been associated with poor survival in gliomas. Experimentally, inhibition of HIF-2α in glioma stem cells reduced cell proliferation and survival in vitro and tumor development in vivo. HIF-1α is expressed in both neural progenitor cells and brain tumor stem cells, whereas HIF-2α is found exclusively in the latter. Furthermore, survival of glioma patients correlates with HIF-2α, but not with HIF-1α levels.

[0285] One of the downstream HIF-2α effectors is cyclin D, which is an essential partner in the activation of CDK4 and CDK6. Thus, administration of HIF-2α inhibitors with CDK4 / 6 inhibitors, including abemaciclib (Verzenio®), palbociclib (Ibrance®), and ribociclib (Kisqali®), should downregulate cyclin D and enhance the antiproliferative effect of CDK4 / 6 inhibitors. A recent study (Nicholson et al Sci Signal. 2019 Oct 1;12(601)) suggests that the antiproliferative effect of CDK4 / 6 inhibition is synergistic with HIF-2α inhibition in HIF-2α-dependent VHL- / - ccRCC cells.

[0286] Radiotherapy, alone or in combination with other therapies, is frequently used in approximately 50% of cancer patients. However, a hypoxic microenvironment within a tumor has long been associated with resistance to radiotherapy. Bhatt and coworkers found that reduced levels of HIF-2α increased the sensitivity of renal cell carcinoma cell lines to ionizing radiation (see Bhatt, et al. BJU Int. 102:358-363, 2008). Furthermore, mechanistic studies by Bertout et al. demonstrated that HIF-2α inhibition enhances the efficacy of radiation through increased p53-dependent apoptosis (see Bertout, et al. PNAS 106:14391-14396, 2009). Thus, HIF-2α targeted therapy may improve response to radiotherapy in various cancers.

[0287] Somatostatinoma is a rare but often malignant neuroendocrine tumor that produces somatostatin. HIF-2α mutations have been found to cause the destruction of the prolyl hydroxylation domain (PHD) of HIF-2α, thus abolishing the modification by PHD and subsequently reducing HIF-2α degradation mediated by VHL (see Yang, et al. Blood. 121:2563-2566, 2013). The stabilized HIF-2α can then translocate to the nucleus and increase the expression of hypoxia-related genes, contributing to somatostatinoma. Thus, HIF-2α inhibitors provide an alternative approach in the treatment of somatostatinoma.

[0288] Polycythemia, also known as erythrocytosis, is a blood disorder characterized by an elevated hematocrit (the volume percentage of red blood cells in the blood). Gain-of-function mutations in HIF-2α 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). In addition, mutations in the PHD of HIF-2α, which is involved in the signaling of HIF-2α ubiquitination and degradation by VHL, have also been found to cause erythrocytosis. Therefore, HIF-2α inhibitors can suppress HIF-2α downstream genes such as EPO by inhibiting HIF-2αn, which is stabilized by either gain-of-function HIF-2α mutations or loss-of-function mutations in PHD and VHL, which should reduce the hematocrit of erythrocytosis.

[0289] Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors that often arise against a background of predisposing genetic mutations, including loss of function of VHL or PHD2 or activating mutations of HIF-2α, all of which result in high expression of HIF-2α protein and subsequently downstream genes that promote oncogenic progression (see Dahia, Nat Rev Cancer. 14:108-19, 2014). In addition, germline heterozygous mutations in genes encoding succinate dehydrogenase (SDH) subunits and SDH complex assembly factor 2 protein (SDHAF2) have been reported in patients with hereditary pheochromocytoma and paraganglioma (PPGL). These mutations can result in the accumulation of succinate, which leads to the inhibition of prolyl hydroxylases that are essential for mediating ubiquitination / degradation of HIF proteins by the VHL complex. Pituitary adenomas are frequently found to coexist with PPGL. Therefore, inhibition of HIF-2α should be useful for the treatment of both PPGL and pituitary tumors. Mutations in succinate dehydrogenase subunits are also associated with gastrointestinal stromal tumors (GIST), supporting the exploration of HIF-2α inhibitors for the treatment of GIST (see Janeway, et al. Proc. Natl Acad. Sci. USA 108:314-318, 2011).

[0290] Loss-of-function mutations in fumarate hydratase (FH) predispose patients to the autosomal dominant syndrome of cutaneous and uterine leiomyomatosis. Activation of HIF protein has been suggested to contribute to the development of FH-associated tumors by activating the hypoxic pathway. (See O'Flaherty, et al. Hum Mol Genet. 19:3844-3851, 2010 and Wei, et al. J Med Genet. 43:18-27, 2006). In addition, high expression of HIF-2α is found in leiomyosarcoma, a rare neoplasm of smooth muscle origin (See Mayer, et al. Cancer Res. 68:4719, 2008). Thus, inhibition of HIF-2α may be beneficial for the treatment of both leiomyoma and leiomyosarcoma.

[0291] Retinal capillary hemangioblastoma may be an ocular manifestation of VHL disease caused by loss of the tumor suppressor VHL. Upregulation of HIF-2α upon VHL loss has been detected in patients with retinal hemangioblastoma and has been shown to contribute to the aggressive course of retinal hemangioblastoma and result in resistance to multiple anti-VEGF and radiation therapies (see Wang, et al. Graefes Arch. Clin. Exp. Ophthalmol. 252:1319-1327, 2014). Furthermore, uncontrolled vascular growth is a central pathological component of many human visual disorders, including diabetic retinopathy, age-related macular degeneration, glaucoma, and retinopathy of prematurity. Neuronal death and vision loss observed in these diseases are often caused by abnormal leaky blood vessels, a consequence of pathological angiogenesis (see Krock, et al. Genes Cancer. 2:1117-1133, 2011). Considering the causal role of HIF in angiogenesis, inhibitors of HIF-2α may have potential utility in treating various blinding diseases.Indeed, systemic reduction of HIF-2α expression by hypoxic Hif-2α alleles caused a marked reduction in retinal angiogenesis accompanied by defective EPO expression (see Morita, et al. EMBO J.22:1134-46,2003).

[0292] In addition to its direct role in promoting the development, progression, and metastasis of tumor cells (e.g., ccRCC), HIF-2α indirectly contributes to tumorigenesis by enhancing the immunosuppressive effects of hypoxia within the tumor microenvironment. HIF-2α expression has been detected in cells of the myeloid lineage (see Talks KL,et dal.Am J Pathol.2000;157(2):411-421). For example, HIF-2α has been shown to promote the polarization of macrophages into an immunosuppressive M2 phenotype and is essential for the migration and infiltration of tumor-associated macrophages (see Imtiyaz HZ et al.J Clin Invest.2010;120(8):2699-2714). Thus, elevated levels of HIF-2α in tumor-associated macrophages (TAMs) are associated with high-grade human tumors and correlate with poor prognosis. In addition, HIF-2α can indirectly promote additional immunosuppressive pathways (e.g., adenosine and arginase) by regulating the expression of key signaling regulators such as adenosine A2B / A2A receptor and arginase. These data support that HIF-2α is a potential therapeutic target for treating a broader range of inflammatory diseases and cancers, either as a single agent or in combination with other therapeutic agents, such as immunotherapeutic agents.

[0293] Due to the important role of HIF-2α proteins in regulating the physiological response to fluctuations in oxygen levels, they have been implicated in many hypoxia-related pathological processes in addition to cancer. One such disease is PAH, a debilitating and life-threatening disease with a very poor prognosis. Recent studies have shown that HIF-2α 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 USA. 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). These studies provide a new understanding of the role of pulmonary endothelial HIF-2α in regulating pulmonary vascular responses to hypoxia and provide much-needed new therapeutic strategies by targeting HIF-2α. Another example of a pathological process associated with hypoxia is IBD, a chronic recurrent inflammatory disease of the intestine. Intestinal inflammation and subsequent IBD have been found to occur when dysregulated epithelial oxygen tension occurs and intensifies across the intestinal epithelial villi (see Shah YM, Molecular and Cellular Pediatrics, 2016 Dec; 3(1): 1). Activation of HIF-2α contributes to IBD, while HIF-1α in intestinal epithelial cells is considered a major protective factor in IBD (see Karhausen J, et al. J Clin Invest. 2004; 114(8): 1098-1106; Furuta GT, et al. J Exp Med. 2001; 193(9): 1027-1034). Mechanistically, HIF-2α activation not only leads to the upregulation of inflammatory cytokines, directly promoting IBD, but also leads to the loss of intestinal barrier integrity, indirectly contributing to the development of IBD.(See Xue X, et al. Gastroenterology. 2013;145(4):831-841; Glover LE, et al. Proc Natl Acad Sci USA. 2013;110(49):19820-19825.) Thus, HIF-2α inhibitors are expected to reverse the proinflammatory state and enhance the integrity of the intestinal barrier, thereby alleviating the symptoms of IBD.

[0294] HIF-2α inhibitors also represent a novel therapeutic approach for NASH, which has limited available treatment options. Recent studies have shown that gut-specific disruption of HIF-2α leads to a significant reduction in fatty liver and obesity induced by a high-fat diet. Mechanistically, intestinal HIF-2α positively regulates the gene encoding neuraminidase 3, thus regulating ceramide metabolism, which contributes to the development of NASH (see Xie C, et al. Nat Med. 2017 Nov;23(11):1298-1308). Therefore, HIF-2α inhibitors should have preventive and therapeutic effects on metabolic disorders such as NASH.

[0295] Several relationships have been identified between HIF-2α levels and iron homeostasis (see Peyssonnaux C et al, Cell Cycle. 2008;7(1):28-32). Several studies have demonstrated a key role for HIF-2α in iron-loading disorders. HIF-2α, but not HIF-1α, has emerged as a key "local" regulator of intestinal iron status through the regulation of various genes important for iron transport and absorption (see Mastrogiannaki M, et al. J Clin Invest. 2009;119(5):1159-1166). Small molecule inhibitors targeting HIF-2α are therefore expected to improve iron homeostasis in patients with iron disorders.

[0296] Thus, the present disclosure provides methods for treating or reducing the severity of a disease, condition, or disorder in which activation or overactivation of HIF-2α is implicated in the pathology. In another aspect, the present disclosure provides a method of treating renal cell carcinoma in a subject with Compound I.

[0297] HIF-2α inhibitors also have therapeutic potential for a wide range of non-cancer indications, including but not limited to NASH, IBD, PAH and iron overload.

[0298] Pharmaceutical Compositions In general, the Form A polymorph of Compound 1 is administered in a therapeutically effective amount by any of the accepted methods of administration for agents providing similar utilities. The therapeutically effective amount of the Form A polymorph of Compound 1 may range from about 200 mg / day to about 1000 mg / day, which may be administered in a single or multiple doses. For oral administration, the composition may be provided in the form of a tablet containing about 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of active ingredient. The actual amount of the Form A polymorph of Compound 1 depends on many factors, such as the severity of the disease being treated, the age and relative health of the patient, the potency of the compound utilized, the route and form of administration, and other factors.

[0299] Generally, the Form A polymorph of Compound I is administered as a pharmaceutical composition by any of the following routes: oral, systemic (e.g., transdermal, intranasal or suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred method of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of affliction. The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained release formulation, solution, suspension, elixir, aerosol or other suitable composition.

[0300] The choice of formulation depends on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, with pills or capsules containing enteric coatings or delayed release tablets being preferred) and the bioavailability of the drug substance.

[0301] The compositions are generally comprised of Form A polymorph of Compound I in combination with at least one pharma- ceutically acceptable excipient. Acceptable excipients are non-toxic, aid in administration, and do not adversely affect the therapeutic benefits of Form A polymorph of Compound I. Such excipients can be any solid, liquid, semi-solid, or, in the case of aerosol compositions, gaseous excipient generally available to one of skill in the art.

[0302] 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, etc. Liquid and semi-solid excipients may be independently selected from glycerol, propylene glycol, water, ethanol, and various oils including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, preferably particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.

[0303] The Form A polymorph of Compound I may be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. Injectable formulations may be provided in unit dosage form, for example, in ampoules or multi-dose containers, with the addition of a preservative. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents, such as suspending, stabilizing and / or dispersing agents. The formulations may be provided in unit dosage or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder form or freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, for example, saline or sterile pyrogen-free water immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0304] Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the Form A polymorph of Compound I, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain 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 that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the Form A polymorph of Compound I, allowing for the preparation of highly concentrated solutions.

[0305] In addition to the above formulations, the Form A polymorph of Compound I can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the Form A polymorph of Compound I can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, e.g., a sparingly soluble salt.

[0306] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may include the Form A polymorph of Compound 1 with a flavor base, such as sucrose and acacia or tragacanth.

[0307] Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 20th ed., 2000).

[0308] The level of the Form A polymorph of Compound 1 in the formulation can vary within the full range used by those of skill in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, about 0.01-99.99 wt% of the Form A polymorph of Compound 1 based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt%.

[0309] Combinations and Combination Therapies The Form A polymorph of Compound 1 may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the Form A polymorph of Compound 1 or other drugs may be useful. Such other drugs may be administered simultaneously or sequentially with the Form A polymorph of Compound 1 by a route and in an amount commonly used therefor. When the Form A polymorph of Compound 1 is used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the Form A polymorph of Compound 1 is preferred. However, combination therapy may also include therapy in which the Form A polymorph of Compound 1 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, the Form A polymorph of Compound 1 and the other active ingredients may be used in lower doses than when each is used alone.

[0310] Thus, pharmaceutical compositions of the present disclosure include those that contain, in addition to the Form A polymorph of Compound 1, one or more other drugs.

[0311] The above combinations include not only combinations of the Form A polymorph of Compound 1 with one other drug, but also combinations with two or more other active drugs. Similarly, the Form A polymorph of Compound 1 may be used in combination with other drugs used to prevent, treat, control, ameliorate, or reduce the risk of a disease or condition for which the Form A polymorph of Compound 1 is useful. Such other drugs may be administered simultaneously or sequentially with the Form A polymorph of Compound 1 by a route and in an amount commonly used therefor. When the Form A polymorph of Compound 1 is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the Form A polymorph of Compound 1 may be used. Thus, the pharmaceutical compositions of the present disclosure also include those that contain, in addition to the Form A polymorph of Compound 1, one or more other active ingredients. The weight ratio of the Form A polymorph of Compound 1 to a second active ingredient may vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used.

[0312] If a subject in need has or is at risk of having cancer, the subject can be treated with the Form A polymorph of Compound I in any combination with one or more other anti-cancer agents. In some embodiments, the one or more anti-cancer agents are pro-apoptotic agents. Examples of anti-cancer agents include: gossyphol, genasense, polyphenol E, chlorofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec™), geldanamycin, 17-N-allylamino These include, but are not limited to, -17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY11-7082, PKC412 or PD184352, Taxol™, also known as "paclitaxel", which is a well-known anti-cancer drug that acts by enhancing and stabilizing microtubule formation, and any of its analogs such as Taxol™, Taxotere™. Compounds that share the basic taxane backbone as a common structural feature have also been shown to have the ability to arrest cells in the G2-M phase with stabilized microtubules, and may be useful in combination with the compounds described herein to treat cancer.

[0313] Suitable anti-cancer agents also include inhibitors of kinases associated with cell proliferation disorders, including, but not limited to, Aurora-A, BTK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinase, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, MEK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, RAF, Rsk, and SGK.In particular, inhibitors of CDK4 / 6, including abemaciclib (Verzenio), palbociclib (Ibrance), and ribociclib (Kisqali), which have shown synergy with HIF-2α inhibitors and the potential to reverse resistance to HIF-2α inhibition; inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, S P600125, BAY43-9006, wortmannin or LY294002; Syk inhibitors; antibodies (e.g., Rituxan); MET inhibitors such as foretinib, carbozantinib or crizotinib; VEGFR inhibitors such as sunitinib, sorafenib, regorafenib, lenvatinib, vandetanib, carbozantinib, axitinib; afatinib, brivanib, carbozatinib, erlotinib, gefitinib, neratinib, lapatinib, EGFR inhibitors such as nibs; XL147, XL765, BKM120 (buparlisib), GDC-0941, BYL719, IPI145, BAY80-6946. PI3K inhibitors such as BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771, TG100-115; rapamycin (sirolimus), temsirolimus, everolimus, XL388, XL765, AZD2013, PF04691502, MTOR inhibitors such as PKI-587, BEZ235, GDC0349; MEK inhibitors 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 inhibitors such as LY2157299; and BTK inhibitors such as ibrutinib.

[0314] Other anti-cancer drugs include proteasome inhibitors such as carfilzomib, MLN9708, delanzomib or bortezomib; BET inhibitors such as INCB054329, OTX015, CPI-0610; LSD1 inhibitors such as GSK2979552, INCB059872; HDAC inhibitors such as panobinostat, vorinostat; DNA methyltransferase inhibitors and other epigenetic modulators such as azacytidine, decitabine; SHP-2 inhibitors such as TNO155; Bcl2 inhibitor ABT-199 and other Bcl-2 family protein inhibitors; HIF-2α inhibitors such as PT2977 and PT2385; beta-catenin pathway inhibitors, notch pathway inhibitors and hedgehog pathway inhibitors. Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept.

[0315] Other anti-cancer agents / drugs that can be used in combination with the compounds of the present invention include, but are not limited to, Liver X Receptor (LXR) modulators, including LXR agonists and LXR beta selective agonists; aryl hydrocarbon receptor (AhR) inhibitors.

[0316] Other anticancer drugs that can be used in combination with the Form A polymorph of Compound I include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adzelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisamidine; Nafide dimesylate;Bizelesin;Bleomycin sulfate;Brequinar sodium;Bropirimine;Busulfan;Cactinomycin;Calsterone;Caracemide;Carbetimer;Carboplatin;Carmustine;Carubicin hydrochloride;Carzelesin;Cedefingol;Chlorambucil;Cladribine;Cladribine;Crisnatol mesylate;Cyclophosphamide;Cytarabine;Dacarbazine;Daunorubicin hydrochloride;Decitabine;Dexorumaplatin;Desaguanine;Desaguanine mesylate;Diaziquone;Doxorubicin;Doxorubicin hydrochloride;Doloro Xifene;Droloxifene citrate;Drotestosterone propionate;Duazomycin;Edatrexate;Eflornithine hydrochloride;Elsamitrucin;Enloplatin;Enpromate;Epipropizine;Epirubicin hydrochloride;Elburozole;Esorubicin hydrochloride;Estramustine;Estramustine-Estramustine phosphate sodium;Etanidazole;Etoposide;Etoposide phosphate;Etoprine;Fadrozole hydrochloride;Fazarabine;Fenretinide;Floxuridine;Fludarabine phosphate;Fluorouracil;Flurocitabine; Foskidon;Fostriesin sodium;Gemcitabine;Gemcitabine hydrochloride;Urea hydroxide;Idarubicin hydrochloride;Ifosfamide;Irmofosine;Interleukin II (including recombinant interleukin or Ril2);Interferon alpha-2a;Interferon alpha-2b;Interferon alpha-n1;Interferon alpha-n3;Interferon beta-1a;Interferon gamma-1b;Iproplatin;Irinotecan hydrochloride;Lanreotide acetate;Letrozole;Leuprolide acetate;Liarozole hydrochloride;Lometrexol sodium;Lomustine;Rosoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocalcin; Mitochromine; Mitodiline; Mitomarcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogalamycin; O Lumaplatin;Oxisuran;Pegaspargase;Periomycin;Pentamustine;Peplomycin sulfate;Perfosfamide;Pipobroman;Piposulfan;Piroxantrone hydrochloride;Plicamycin;Promestane;Porfimer sodium;Porfiromycin;Prednimustine;Procarbazine hydrochloride;Puromycin;Puromycin hydrochloride;Pyrazofurin;Riboprin;Rogletimide;Safingol;Safingol hydrochloride;Semustine; Simtrezen;Sparfosate sodium;Sparsomycin;Spirogermanium hydrochloride;Spiromustine;Spiroplatin;Streptonigrin;Streptozocin;Sulofenur;Tallysomycin;Tecogalan sodium;Tegafur;Teroxantrone hydrochloride;Temoporfin;Teniposide;Teroxylon;Testolactone;Thiamiprine;Thioguanine;Thiotepa;Tiazofurin;Tirapazamine;Toremifene citrate;Trestron acetate;Triciribine These include: vinphosfate; trimetrexate; trimetrexate glucuronide; triptorelin; tuburozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrocidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride;

[0317] Other anticancer drugs that can be used in combination with the Form A polymorph of Compound I include: 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adzelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein 1; antiandrogens, prostate cancer; antiestrogens; antitumor drugs; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modifiers; apoptosis regulators; apurinic acid ara-CDP-DL-PTBA; Arginine deaminase;Aslaculin;Atamestane;Atrimustine;Axinastatin 1;Axinastatin 2;Axinastatin 3;Azasetron;Azatoxin;Azatyrosine;Baccatin III derivatives;Balanol;Batimastat;BCR / ABL antagonists;Benzochlorins;Benzoylstaurosporine;β-lactam derivatives;β-arretin;Betaclamycin B;Betulinic acid;Bfgf inhibitors;Bicalutamide;Bisantrene;Bisaziridinylspermine;Bisnafide;Bistraten A;Bizelesin;Brefurate;Bropirimine;Budotitanium;Buthionine sulfoximine;Calcipotriol;Calfostin C;Camptothecin derivatives;Canarypox IL-2;Capecitabine;Carboxamido-amino-triazoles;Carboxamidotriazoles;CaRest M3;CARN 700;cartilage-derived inhibitor;carzelesin;casein kinase inhibitor (ICOS);castanospermine;cecropin B;cetrorelix;chlorln;chloroquinoxaline sulfonamide;cicaprost;cis-porphyrin;cladribine;clomiphene analogues;clotrimazole;collismycin A;collismycin B;combretastatin A4;combretastatin analogues;conagenin;crambescidin 816;crisnatol;cryptophycin 8;cryptophycin A derivatives;curacin A;cyclopentathraquinone;cycloplatam;sipemycin;Cytarabine ocphosphate;Cytolytic factors;Cytostatin;Dacliximab;Decitabine;Dehydrodidemnin B;Deslorelin;Dexamethasone;Dexyphosphamide;Dexrazoxane;Dexverapamil;Diaziquone;Didemnin B;Didox;Diethylnorspermine;Dihydro-5-azacytidine;9-dioxamycin;Diphenylspiromustine;Docosanol;Dolasetron;Doxifluridine;Droloxifene;Dronabinol;Duocarmycin SA;Ebselen;Ecomustine;Edelfosine;Edroxymethane Colomab;Eflomitin;Elemene;Emiteflu;Epirubicin;Epristeride;Estramustine analogs;Estrogen agonists;Estrogen antagonists;Etanidazole;Etoposide phosphate;Exemestane;Fadrozole;Fazarabine;Fenretinide;Filgrastim;Finasteride;Flavopiridol;Flezelastine;Fluasterone;Fludarabine;Fluorodaunornithine hydrochloride;Forfenimex;Formestane;Fostriecin;Fotemustine;Gadolinium texaphyrin;Gallium nitrate;Galocitabin ;Ganirelix;Gelatinase inhibitors;Gemcitabine;Glutathione inhibitors;Hepsulfame;Heregulin;Hexamethylene bisacetamide;Hypericin;Ibandronate;Idarubicin;Idoxifene;Idramantone;Ilmofosine;Ilomastat;Imidazoacridone;Imiquimod;Immunostimulating peptides;Insulin-like growth factor-1 receptor inhibitors;Interferon agonists;Interferon;Interleukin;Iobenguane;Iododoxorubicin;Ipomeanol, Ilopract;Irsogladine;Isobengazole;Isohomo Halichondrin B;Itasetron;Jasplakinolide;Kahalalide F;Lamellarin-N triacetate;Lanreotide;Leinamycin;Lenograstim;Lentinan sulfate;Leptolstatin;Letrozole;Leukemia inhibitory factor;Leukocyte alpha interferon;Leuprolide + estrogen + progesterone;Leuprorelin;Levamisole;Liarozole;Linear polyamine analogues;Lipophilic disaccharide peptides;Lysoclinamide 7;Lobplatin;Lombricin;Lometrexol;Lonidamine;Losoxantrone;Loxoribine;Raltotecan;Lutetium texaphyrin;Lysofylline;Cytolytic peptides;Maytansine;Mannostatin A;Marimastat;Masoprocol;Maspin;Matrilysine inhibitors;Matrix metalloproteinase inhibitors;Menogaril;Melbarone;Meterelin;Methioninase;Metoclopramide;MIF inhibitors;Mifepristone;Miltefosine;Milimostim;Mismatched double-stranded RNA;Mitoguazone;Mitolactol;Mitomycin analogues;Mitonafide;Mitotoxin fibroblast growth factor-saporin;Mitoxantrone;Mofalotene;Mo Rugramostim;monoclonal antibodies, human chorionic gonadotropin;mopidamol;multidrug resistance gene inhibitors;multiple tumor suppressor 1-based therapeutics;mustard anticancer drugs;mycaperoxide B;mycobacterial cell wall extracts;myriaporone;N-acetyldinaline;N-substituted benzamides;nafarelin;nagressip;naloxone + pentazocine;napavine;naphterpine;nartograstim;nedaplatin;nemorubicin;neridronic acid;neutral endopeptidase;nilutamide;nisamycin;nitric oxide modulators;nitroxide antioxidants;ni Nitraullyn;O6-benzylguanine;Octreotide;Oxenone;Oligonucleotides;Onapristone;Ondansetron;Ondansetron;Oracin;Oral cytokine inducer;Ormaplatin;Osateron;Oxaliplatin;Oxaunomycin;Palauamine;Palmitoylrhizoxin;Pamidronic acid;Panaxytriol;Panomyphen;Parabactin;Pazeliptin;Pegaspargase;Perdecin;Pentosan polysulfate sodium;Pentostatin;Pentrozole;Perflubron;Perphospha mide;perillyl alcohol;phenazinomycin;phenylacetic acid;phosphatase inhibitors;picibanil;pilocarpine hydrochloride;pirarubicin;piritrexim;prasetin A;prasetin B;plasminogen activator inhibitors;platinum complexes;platinum compounds;platinum-triamine complexes;porfimer sodium;porfiromycin;prednisone;propyl bis-acridone;prostaglandin J2;proteasome inhibitors;protein A-based immunomodulators;protein kinase C inhibitors;microalgae;protein tyrosine phosphatase inhibitors;Purine nucleoside phosphorylase inhibitors; Purpurin; Pyrazoloacridine; Pyridoxylated hemoglobin polyoxyethylene conjugates; Raf antagonists; Raltitrexed; Ramosetron; Ras farnesyl protein transferase inhibitors; Ras inhibitors; Ras-GAP inhibitors; Demethylated reteriptin; Rhenium etidronate Re186; Rhizoxin; Ribozyme; R; 11Retinamide;Rohitukin;Romurtide;Rokinimex;Rubiginone B1;Ruboxil;Safingol;Saintopin;SarCNU;Sarcophytol A;Sargramostim;Sdi1 mimetic;Semustine;Senescence derived 1;Sense oligonucleotide;Signal transduction inhibitors;Signal transduction modulators;Single-chain antigen binding protein;Schizofuran;Sobuzoxane;Sodium borocaptate;Sodium phenylacetate;Sorberol;Somatomedin binding protein;Sonermin ;Sparfosic acid;Spicamycin D;Spiromustine;Splenopentin;Spongistatin 1;Squalamine;Stem cell inhibitors;Stem cell division inhibitors;Stipiamide;Stromelysin inhibitors;Sulfinosine;Superactive vasoactive intestinal peptide antagonists;Sladista;Suramin;Swainsonine;Synthetic glycosaminoglycans;Talimustine;Tamoxifen methiodide;Tauromustine;Tazarotene;Tecogalan sodium;Tegafur;Terlapyrylium;Telomerase inhibitors;Temopo Lupin;Temozolomide;Teniposide;Tetrachlorodecaoxide;Tetrazomine;Taliblastine;Thiocoraline;Thrombopoietin;Thrombopoietin mimetics;Thymalfasin;Thymopoietin receptor agonists;Thymotrin;Thyroid-stimulating hormone;Tin ethyl etiopurpurin;Tirapazamine;Titanocene dichloride;Topsentin;Toremifene;Pluripotent stem cell factor;Translation inhibitors;Tretinoin;Triacetyluridine;Triciribine;Trimetrexate;Triptorelin;Tropicetro These include: turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector systems, red blood cell gene therapy agents; veraresol; veramine; verudin; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

[0318] Still other anticancer agents that can be used in combination with the Form A polymorph of Compound I include alkylating agents, antimetabolites, natural products or hormones such as nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, etc.) or triazenes (e.g., decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0319] Examples of useful natural products to combine with the 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).

[0320] Examples of alkylating agents that can be used in combination with the Form A polymorph of Compound I include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.) or triazenes (e.g., decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0321] Examples of hormones and antagonists useful in combination with the 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), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), gonadotropin-releasing hormone analogs (e.g., leuprolide). Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenal cortical suppressants (e.g., mitotane, aminoglutethimide).

[0322] Other anticancer drugs that can be used in combination with the Form A polymorph of Compound I include elbrozole (also known as R-55104), dolastatin 10 (also known as DLS-10 and NSC-376128), mibobulin 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), Altorhyrtin (including Altorhyrtin A and Altorhyrtin C), spongista, and the like. spongistatin (spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, spongistatin 9, etc.), cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), epothilones (epothilone A, epothilone B, epothilone C (also known as desoxyepothilone A or dEpoA), epothilone D (also known as KOS-862, dEpoB and desoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as desoxyepothilone F and dEpoF), 26-fluoroepothilone), auristatin PE (also known as NSC-654663), sobridotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), L S-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy ofSciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl and RPR-258062A), bitilebamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (also known as Tularik, T-67, TL-138067, TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine) Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona StateUniversity), vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, inanosin (also known as NSC-698666), 3-1AABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), eleutherobin (desmethyleleutherobin, desacetyleleutherobin, isoeleutherobin A, Z-eleutherobin, etc.), caribeoside, caribeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Anticancer drugs that act by arresting cells in the G2-M phase with stabilized microtubules include: Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resbelostatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0323] One or more additional immune checkpoint inhibitors can be used in combination with the Form A polymorph of Compound I for the treatment of HIF-2α-related diseases, disorders, or conditions. Exemplary immune checkpoint inhibitors include inhibitors (sumac molecules or biologics) against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, SHP-2, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137, and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

[0324] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.

[0325] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).

[0326] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of OX40, such as an anti-OX40 antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562 or INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600, or LAG 525. In some embodiments, the OX40L fusion protein is MEDI6383.

[0327] The Form A polymorph of Compound I can also be used to increase or enhance immune responses, including increasing immune responses to antigens; improve immunization, including increasing vaccine efficacy; and increase inflammation. In some embodiments, the compounds of the present invention can be used to enhance immune responses to vaccines, including, but not limited to, Listeria vaccines, oncolytic virus vaccines, and cancer vaccines such as GVAX® (a tumor cell vaccine transfected with the granulocyte-macrophage colony-stimulating factor (GM-CF) gene). Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. Other immunomodulatory agents include those that block immune cell migration, such as antagonists against chemokine receptors, including CCR2 and CCR4; Sting agonists, and Toll receptor agonists.

[0328] Other anti-cancer drugs include those that enhance the immune system, such as adjuvants or adoptive T cell transfer. Compound I Form A polymorph may be effective in combination with CAR (chimeric antigen receptor) T cell treatment as a booster of T cell activation. EXAMPLES

[0329] The following preparations of Compound 1 are provided to enable those skilled in the art to more clearly understand and practice the present disclosure, and should not be construed as limiting the scope of the disclosure, but merely as illustrative and representative thereof.

[0330] Example 1 Synthesis of the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile [ka] To a stirred solution of 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (100.00 g, 260.91 mmol, 1.00 equiv.) and DBU (79.44 g, 521.81 mmol, 2.00 equiv.) in THF (2.2 L) was added a solution of pyridine-2-sulfonyl fluoride (50.46 g, 313.12 mmol, 1.20 equiv.) in THF (400 mL) slowly at 20-25 °C over 2 h under nitrogen atmosphere. The resulting mixture was stirred at 20-25 °C for an additional 16 h and then quenched with 0.78 N aqueous NaOH (1.0 L). After stirring at 20-30°C for 30 min, the layers were separated. The aqueous layer was extracted with MTBE. The combined organic layers were washed with 10% brine and then concentrated to about 350 mL solution. This solution was diluted with MTBE and washed with 0.5N aqueous HCl and then water. The organic layer was concentrated to about 200 mL (HPLC purity of 94.1A% and chiral purity was 97.2% ee), diluted with EtOAc, then loaded onto a silica gel pad and rinsed the pad with EtOAc / n-heptane=1 / 5 until no product was eluted. The desired fractions were concentrated and solvent exchanged with MTBE to give a MTBE solution (about 350 mL).

[0331] Diethylamine (600 mL) was added, the resulting solution was heated to 35-45 °C, and n-heptane (400 mL) was added slowly over 2 h at this temperature. The resulting slurry was stirred at 35-45 °C for 1 h, then solid crystalline seeds (0.5 g) of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile form A polymorph were added. After further stirring at 35-45 °C for 1 h, the slurry was cooled slowly to -5-5 °C, then heptane (2.0 L) was added slowly over 5 h. After further stirring at -5-5 °C for 6 h, the mixture was filtered and the solid cake was washed with cold DEA / n-heptane (1:4) to give the title compound.

[0332] Example 2 Synthesis of crystalline form A of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile [ka] 3-Fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile: The DEA solvate was dried in vacuum at 65-70°C for 20 hours to give 53.2 g of the title compound. The HPLC purity of the title compound was 99.8A% and the chiral purity was 100.0%ee. 1 H NMR(400MHz,CDCl3)δ=7.71-7.67(m,1H),7.29-7.26(m,2H),7.25-7.09(m,2H),6.60-5.80(ddd,1H),2.87(s,1H),2.91-2.57(m,2H).

[0333] To a stirred, colorless, clear solution of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (50.0 g) in IPA (150 mL) was slowly added n-heptane (100 mL) over 1 h at 20-30 °C, followed by seed crystals of the title compound (0.25 g of Form A polymorph of Compound 1) and the resulting slurry was stirred at 20-30 °C for 3 h. n-heptane (150 mL) was slowly added over 4 h at 20-30 °C, followed by additional n-heptane (950 mL) over 8 h. After further stirring at 20-30 °C for 3 h, the slurry was slowly cooled to -10-0 °C over 4 h and then stirred at this temperature for 6 h. The mixture was filtered and the solid cake was rinsed with cold n-heptane. The solid was dried in vacuum at 45-55°C for 12 hours to give the title compound (46.73 g, 93.5% yield). The HPLC purity was 99.9A% and the chiral purity was 100.0%ee.

[0334] Alternative method for preparing compound 1 from its DEA solvate: To a stirred mixture of compound 1 DEA solvate (10.0 g) in EtOAc (150 mL) is added 0.5 M aqueous HCl (150 mL) at 20-30 °C. The resulting mixture is stirred at this temperature for 30 min. The organic layer is separated and then washed with water. The organic layer is concentrated and the residue is recrystallized from IPA / n-heptane to give the title compound 1.

[0335] Example 3 Alternative synthesis, purification, and polymorphic characterization of compound 1 [ka] A 3000 mL three-neck round-bottom flask was charged with 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrahydrofuran-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (350 g, 0.762 mol, 1.0 equiv.) in THF (3.5 L) at room temperature and DBU (232.1 g, 1.53 mol, 2.0 equiv.). To this solution was added dropwise a solution of pyridine-2-sulfonyl fluoride (159.7 g, 0.991 mmol, 1.3 equiv.) in THF (700 mL) at 10-15 °C. The resulting mixture was stirred at room temperature for 12 h and then diluted with water and EtOAc. The suspension was filtered through silica gel and the phases were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1 to 7 / 1) to give the crude product (400 g) as an off-white solid. The crude product was separated by SFC (column: DAICEL CHIRALPAK AS (250mm*50mm, 10um) to obtain 250g of crude product. Heptane (1.0L) was added to the crude product and the mixture was stirred at 40℃ for 2 hours. The mixture was filtered to obtain the pure title product (230g). The HPLC purity of the title compound was 98.7% and the chiral purity was 99.1%ee. SFC conditions: Column: Chiralpak AD-3 50×4.6mm ID, 3μm Mobile phase: Phase A, CO2; Phase B, EtOH (0.05%DEA) Gradient elution: 5% to 40% B in A; Flow rate: 3mL / min Column temperature: 35℃; Back pressure: 100 bar; t R :0.904 minutes.

[0336] Characterization of polymorphs: Compound 1 (15.5 mg) from Example 3 was added to 0.4 mL of a mixture of n-pentanol / heptane (9:1) at 50° C. The mixture was stirred for 3 days, after which the solid was collected by filtration to obtain the crystalline Form A polymorph. XRPD patterns were acquired on an X-ray diffractometer (Bruker D8 Advance) at ambient temperature (23-25° C.) using an incident beam of Cu Kα (1.5418 Å) from a generator operated at 40 kV and 40 mA. The system was equipped with a LynxEye detector. The sample of compound 5 was scanned from 3 to 40° 2θ with a step size of 0.02° 2θ. The data was analyzed using DIFFRAC plus Evaluation Package Release 2010. The XRPD spectrum of the crystalline Form A polymorph is shown in FIG. 3. The peak list of the XRPD spectrum, with the diffraction angles (2θ) reported in degrees, is shown in Table 1 below.

[0337] [Table 6]

[0338] [Table 7]

[0339] [Table 8]

[0340] Crystallization of Compound 1 under the following conditions also afforded the Form A polymorph.

[0341] Method A Compound 1 (15 mg / ml) was dissolved in MeOH, IPA, MTBE, EtOAc, IPAc or toluene and the solution was evaporated at room temperature to give Compound 1 as a crystalline solid, which was shown to be the Form A polymorph by XRPD analysis.

[0342] Method B Compound 1 (approximately 10 mg) was added to 0.5 mL of antisolvent at 50° C., and then solvent was added to dissolve the solid, as shown in Table 3 below. The mixture was filtered, and the solution was slowly cooled to room temperature and stirred at room temperature for 1 day. The crystals were filtered and XRPD analysis was performed.

[0343] [Table 9]

[0344] Method C Compound 1 was dissolved in a solvent as shown in Table 4 below, and an anti-solvent was added with stirring at room temperature, 50° C., or an ice bath. The crystalline solid was filtered and characterized by XRPD.

[0345] [Table 10]

[0346] Method D Compound 1 (about 10 mg) was dissolved in the solvent, and then the resulting solution was added to 0.5 mL of anti-solvent. The mixture was kept stirring at room temperature for 1 day, and the crystalline solid was analyzed by XRPD. The results are shown in Table 5 below.

[0347] [Table 11]

[0348] Example 4 Preparation of DEA solvate of compound 1 and compound 1 Synthesis and polymorphic characterization of the DEA solvate of compound 1 To a stirred solution of crude 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (25.1 g) in MTBE (75 mL) was added DEA (150 mL) at 35-45° C., followed by slow addition of n-heptane (100 mL) and solid crystalline seed crystals of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile form A polymorph. The resulting slurry was stirred at 35-45° C. for 1 h, cooled slowly to −5-5° C., and then stirred at this temperature for 6 h. n-Heptane (500 mL) was added slowly over 4 h at −5 to 5° C. After stirring for 4 h at −5 to 5° C., the slurry was filtered and washed with a cold solution of DEA / heptane=1V / 4V, and XPRD and NMR were performed on the DEA solvate of compound 1.

[0349] The XRPD pattern of the DEA solvate of compound 1 was acquired on an X-ray diffractometer (Bruker D8 advance) at ambient temperature (approximately 23-25 ​​°C) using an incident beam of Cu Kα (1.5406 Å) from a generator operated at 40 kV and 40 mA. The system was equipped with a LynxEye detector. A sample of the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile was scanned from 3 to 40 °2θ with a step size of 0.02 °2θ. The data was analyzed using DIFFRAC plus Evaluation Package Release 2010. The XRPD spectrum of the crystalline form B polymorph is shown in Figure 1. The peak list of the XRPD spectrum, with diffraction angles reported in degrees (2 theta), is given in Table 2 below.

[0350] [Table 12]

[0351] [Table 13]

[0352] Synthesis of compound 1: A solution of crude 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (26.3 g) in DCM (50 mL) was concentrated to dryness. The residue was charged with DCM (38 mL) and the resulting solution was heated to 35-40 °C followed by the addition of DEA (114 mL). After stirring at 35-40 °C for 10 min, n-heptane (190 mL) was added slowly. The resulting mixture was stirred at 35-40° C. for 30 min and solid crystalline seeds of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile form A polymorph were added. The slurry was stirred at 35-40° C. for 3 h and then n-heptane (266 mL) was added slowly over 8 h. The slurry was slowly cooled to 0° C. and then stirred at this temperature for 5.5 h. The slurry was filtered and washed with a cold solution of DEA / heptane=1V / 4V. The solid was dried under vacuum at 65° C. to give the title compound (14.7 g). XRPD measurements were performed under the conditions described in Example 4.

[0353] Example 5 Alternative deoxyfluorination reaction conditions for the synthesis of compound 1 [ka] Method A: To a stirred solution of 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (100.0 g, 260.91 mmol, 1.00 equiv) in MTBE (2.5 L) was added bis(2-methoxyethyl)aminosulfur trifluoride (BAST, 83.7 g, 378.32 mmol, 1.45 equiv) slowly over 2 h at −80 to −70 °C under a nitrogen atmosphere. After stirring at −80 to −70 °C for an additional 2.5 h, the reaction mixture was quenched with methanol (3344 mg, 104.37 mmol, 0.40 equiv) at −80 to −70 °C. The resulting mixture was warmed to 0-10° C. and then quenched with 10% aqueous K2CO3 (1 L). The organic layer was separated, washed with water (1 L) and then concentrated.

[0354] The residue was purified on a silica gel pad (100 g silica gel) eluted with MTBE / n-heptane=1 / 2 to give a crude product. The crude product was crystallized from MTBE / DEA / n-heptane=2V / 6V / 24V to give a diethylamine solvate of compound 1. The diethylamine solvate of compound 1 was dried under vacuum at 70° C. to give compound 1 as crystalline form A polymorph (75.8 g, 75.4% yield). The purity of compound 1 was 99.9% and the ee was 99.9%.

[0355] Method B: To a stirred solution of 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (100.0 g, 0.26 mol, 1.00 equiv) in 2-MeTHF (2.5 L) under nitrogen at -20 °C was added EtN 3HF (21.0 g, 0.13 mol, 0.50 equiv) followed by 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG, 111.0 g, 0.65 mol, 2.50 equiv). To the resulting stirred mixture was added slowly a solution of perfluorobutanesulfonyl fluoride (PBSF, 118.0 g, 0.39 mol, 1.50 equiv) in 2-MeTHF (500 mL) over 1 h at −20° C. After stirring for 2 h, the mixture was quenched with deionized water (1 L).

[0356] The separated organic layer was washed with aqueous HCl, water, aqueous NaOH, then 10% brine. The separated organic layer was concentrated, dissolved in 2-MeTHF (750 mL), and concentrated again. The residue was dissolved in MeOH (1.5 L) and decolorized with activated charcoal (30 g) at 50° C. for 4 h. The resulting mixture was filtered to obtain a yellow filtrate. The filtrate was concentrated, the residue was dissolved in 2-MeTHF (1.5 L), and then concentrated again. The residue was mixed with MTBE (2 L) at 40° C., stirred for 30 min, cooled to 20° C., and then filtered to remove the solids. The filtrate was concentrated, and the residue was crystallized from MTBE / DEA / n-heptane=3V / 6V / 24V to obtain the diethylamine solvate of compound 1 (85 g) as a beige solid.

[0357] The diethylamine solvate of compound 1 (42.5 g) was mixed with MTBE (850 mL), and the resulting mixture was washed with 0.1 M aqueous HCl, followed by 10% brine. The organic layer was separated and concentrated. The residue was dissolved in IPA (640 mL), then decolorized with activated charcoal (8.5 g) at 40° C. for 4 h. The mixture was filtered, and the filtrate was concentrated. The residue was recrystallized from IPA / n-heptane=3V / 24V, then dried in vacuum to obtain compound 1 as a white solid in the crystalline form A polymorph (30.5 g, 61.0% yield). The purity of compound 1 was 100.0%.

[0358] Alternative reaction conditions that were explored for Method B above and the results obtained therefrom are disclosed in Tables 3-6 below. In the tables below, 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile is referred to as SM and the compound is referred to as product.

[0359] [Table 14]

[0360] [Table 15]

[0361] [Table 16]

[0362] [Table 17]

[0363] Formulation examples The following are representative formulations containing the compounds of the present disclosure.

[0364] Tablet formulation The following ingredients are mixed and pressed into single scored tablets:

[0365] [Table 18]

[0366] Capsule formulation The following ingredients are mixed and loaded into a hard shell gelatin capsule:

[0367] [Table 19]

[0368] Injectable preparations A compound of the disclosure (e.g., a compound of Formula I) in an appropriate amount of DI water containing 2% HPMC, 1% Tween 80 to at least 20 mg / mL.

[0369] Inhalation composition To prepare 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, suitable for inhalation administration.

[0370] Topical gel compositions To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropylcellulose, 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 a container, such as a tube, suitable for topical administration.

[0371] Ophthalmic solution composition To prepare pharmaceutical eye drop composition, 100mg of compound disclosed herein is mixed with 0.9g of NaCl in 100mL of purified water, and filtered using a 0.2 micron filter.The resulting isotonic solution is then incorporated into an ophthalmic delivery unit, such as an eye dropper, suitable for ophthalmic administration.

[0372] Nasal spray solution To prepare a medicinal nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of 0.05 M phosphate buffer (pH 4.4). The solution is placed into a nasal applicator designed to deliver 100 ul of spray for each administration.

Claims

1. 1. An amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, wherein the amine is (i) NHR １ R ２ (In the formula, (1) R １ is hydrogen, and R ２ is C ２ ~C １２ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ７ cycloalkyl, or C ３ ~C ７ Cycloalkyl-C １～６ (2) R is alkyl; １ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ７ cycloalkyl, or C ３ ~C ７ Cycloalkyl-C １～６ alkyl, and R ２ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ７ cycloalkyl, or C ３ ~C ７ Cycloalkyl-C １～６ alkyl; or (3) R １ and R ２ together with the nitrogen atom to which they are attached form a cyclylamine; or (ii) R ３ R ４ N-(CH ２ ) ｎ -NR ５ R ６ (wherein n is an integer selected from 1 to 6, and R ３ , R ４ , R ５ , and R ６ are independently H, C １ ~C ６ Alkyl, or C ３ ~C ７ cycloalkyl) is an amine solvate.

2. The amine is NHR １ R ２ and the amine is other than diethylamine.

3. The amine is NHR 1 R 2 , where R １ is C １ ~C ６ alkyl, and R ２ is C １ ~C ６ 3. The amine solvate of claim 2, wherein the amine solvate is alkyl.

4. 4. The amine solvate of claim 3, wherein the amine is diethylamine.

5. 5. The amine solvate of claim 4, wherein the stoichiometric ratio of diethylamine to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile in the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is about 1:1 or 1:

1.

6. 6. The amine solvate of any one of claims 1 to 5, wherein the amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]-inden-7-yl)oxy)benzonitrile is a solid.

7. A crystalline form of the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, designated as the Form B polymorph, having an X-ray powder diffraction pattern comprising peaks at angular positions 13.8 and 21.3, said angular positions may vary by ±0.2 degrees 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα).

8. 8. The crystalline form B of claim 7, wherein the X-ray powder diffraction pattern of said form B further comprises a peak at an angular position of 8.4, said angular position may vary by ±0.2 degrees 2θ.

9. 9. The crystalline form B of claim 8, wherein the X-ray powder diffraction pattern of said form B further comprises a peak at an angular position of 23.5, said angular position may vary by ±0.2 degrees 2θ.

10. 9. The crystalline form B of claim 8, wherein the X-ray powder diffraction pattern of form B further comprises peaks at angular positions 23.5 and 11.7, the angular positions of which may vary by ±0.2 degrees 2θ.

11. 9. The crystalline form B of claim 8, wherein the X-ray powder diffraction pattern of form B further comprises peaks at angular positions 23.5, 11.7, and 9.5, wherein the angular positions may vary by ±0.2° 2θ.

12. 1. A process for preparing an amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile)-benzonitrile, wherein the amine is (i) NHR １ R ２ (In the formula, (1) R １ is hydrogen, and R ２ is C ２ ~C １２ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ７ cycloalkyl, or C ３ ~C ７ Cycloalkyl-C １～６ (2) R is alkyl; １ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ７ cycloalkyl, or C ３ ~C ７ Cycloalkyl-C １～６ alkyl, and R ２ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ７ cycloalkyl, or C ３ ~C ７ Cycloalkyl-C １～６ alkyl; or (3) R １ and R ２ together with the nitrogen atom to which they are attached form a cyclylamine; or (ii) R ３ R ４ N-(CH ２ ) ｎ -NR ５ R ６ (wherein n is an integer selected from 1 to 6, and R ３ , R ４ , R ５ , and R ６ are independently H, C １ ~C ６ Alkyl, or C ３ ~C ７ cycloalkyl) and (a1) 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the presence or absence of one or more suitable organic solvents, １ R ２ or R ３ R ４ -N-(CH ２ ) ｎ -R ５ R ６ and contacting the (b1) optionally, (i) one or more anti-solvents and / or (ii) solid crystalline seeds of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, or 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; adding solid crystalline seeds of an amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, or a combination thereof, to the mixture of step (a1) to precipitate said amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; (c1) isolating the precipitate of step (b1) to obtain a solid amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; (d1) optionally converting the amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile from any one of steps (a1)-(c1) to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; The process includes:

13. 13. The process of claim 12, wherein the amine is added in step (a1) to a mixture of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in one or more suitable organic solvents.

14. The amine is NHR １ R ２ and the amine is other than diethylamine.

15. 14. The process of claim 13, wherein the amine is diethylamine.

16. 16. The process of claim 15, wherein the molar ratio of amine to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile is 1:1 or greater.

17. 17. The process of claim 16, wherein one or more anti-solvents are added to the 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile mixture of step (a1) to precipitate a solid amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile.

18. One or more anti-solvents and solid crystalline seeds of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile and / or 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile 17. The process of claim 16, wherein crystalline seeds of the amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile are added to the solution of step (a1) to precipitate a solid amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile. (1) the one or more anti-solvents are added to the mixture of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in step (a1) to precipitate a solid amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; or (2) The one or more anti-solvents and solid crystalline seed crystals of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile and / or 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro crystalline seeds of said amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile are added to the solution of step (a1) to precipitate a solid amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; and 17. The process of claim 16, wherein the one or more anti-solvents are independently selected from alkanes and water.

20. 20. The process of claim 19, wherein the anti-solvent is n-heptane.

21. 20. The process of claim 19, wherein the one or more suitable organic solvents in step (a1) are independently selected from the group consisting of alcohols, ethers, toluene, ketones, esters, halogenated alkanes, nitromethane, N-methylpyrrolidinone, acetonitrile, dimethylformamide, and dimethylacetamide.

22. 20. The process of claim 19, wherein the one or more suitable organic solvents in step (a1) are independently selected from the group consisting of methanol, n-propanol, isopropanol, n-butanol, 1,2-propanediol, methylene dichloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, methyl acetate (MeOAc), ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate (IPAc), butyl acetate, n-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran (THF), 2-methyl THF (2-MeTHF), dimethoxyethane (DME), toluene, acetone, methyl ethyl ketone (MEK), nitromethane, acetonitrile (ACN), and 1,4-dioxane.

23. 23. The process of claim 22, wherein the suitable organic solvent in step (a1) is MTBE.

24. 24. The process of any one of claims 15 to 23, wherein the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is a crystalline solid.

25. The diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is (1) angular positions 13.8 and 21.3, said angular positions being variable by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); or (2) angular positions 13.8, 21.3, and 8.4, said angular positions being variable by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); or (3) angular positions 13.8, 21.3, 8.4, and 23.5, which may vary by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); or (4) angular positions 13.8, 21.3, 8.4, 23.5, and 11.7, said angular positions being variable by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); or (5) angular positions 13.8, 21.3, 8.4, 23.5, 11.7, and 9.5, said angular positions being variable by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); 25. The process of claim 24, wherein the crystalline form B polymorph has an X-ray powder diffraction pattern comprising a peak at

26. 25. The process of claim 24, wherein the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is converted to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile.

27. 24. The process of any one of claims 12 to 23, further comprising preparing the 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile of step (a1): (a) 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in a suitable organic solvent and, optionally, triethylamine trihydrofluoride (Et ３ N.3HF), with or without a base, and a deoxyfluorinating agent; (b) purifying the mixture from step (a) to obtain 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; The process includes:

28. 28. The process of claim 27, wherein the deoxyfluorinating agent is pyridine-2-sulfonyl fluoride, perfluoro-1-butanesulfonyl fluoride, bis(2-methoxylethylamino)sulfur trifluoride, or (diethylamino)sulfur trifluoride.

29. 29. The process of claim 28, wherein the organic base is (tert-butylimino)tris-(pyrrolidino)phosphorane or 2-tert-butyl-1,1,3,3-tetramethyl-guanidine or 1,8-diazabicyclo-[5.4.0]undec-7-ene, or 7-methyl-1,5,7-triaza-bicyclo-[4.4.0]dec-1-ene.

30. 30. The process of claim 29, wherein the suitable organic solvent is selected from ethers, esters, ketones, haloalkanes, acetates, toluene, and xylene.

31. 1. A process for preparing a crystalline form of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, designated as the Form A polymorph, having an X-ray powder diffraction pattern comprising peaks at angular positions 15.8 and 18.6, said angular positions may vary by ±0.2° 2θ, as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5418 Å (Cu Kα), from a diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, (a3) removing the diethylamine from the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; (b3) optionally recrystallizing the crystalline Form A polymorph of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile obtained from step (a3); The process includes:

32. The diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is (1) angular positions 13.8 and 21.3, said angular positions being variable by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); or (2) angular positions 13.8, 21.3, and 8.4, said angular positions being variable by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); or (3) angular positions 13.8, 21.3, 8.4, and 23.5, which may vary by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); or (4) angular positions 13.8, 21.3, 8.4, 23.5, and 11.7, said angular positions being variable by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); or (5) angular positions 13.8, 21.3, 8.4, 23.5, 11.7, and 9.5, said angular positions being variable by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); 32. The process of claim 31 , wherein the crystalline form B polymorph has an X-ray powder diffraction pattern comprising a peak at

33. 32. The process of claim 31 , wherein the diethylamine is removed from the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile by heating the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile.

34. 32. The process of claim 31 , wherein the diethylamine is removed from the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile by partitioning the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile between one or more suitable organic solvents and an acidic aqueous solution, and isolating and concentrating the one or more suitable organic solvents.

35. 35. The process of claim 34, wherein the acid is hydrochloric acid.

36. 35. The process of claim 34, wherein the suitable organic solvent is MTBE.

37. 37. The process of any one of claims 31 to 36, wherein the X-ray powder diffraction pattern of Form A further comprises a peak at angular position 20.1, which angular position may vary by ±0.2 degrees 2θ.

38. 37. The process of any one of claims 31 to 36, wherein the X-ray powder diffraction pattern of Form A further comprises peaks at angular positions 12.9 and 20.1, which angular positions may vary by ±0.2 degrees 2θ.

39. 37. The process of any one of claims 31 to 36, wherein the X-ray powder diffraction pattern of Form A further comprises peaks at angular positions 11.4, 12.9, and 20.1, which angular positions may vary by ±0.2 degrees 2θ.

40. 37. The process of any one of claims 31 to 36, wherein the X-ray powder diffraction pattern of Form A further comprises peaks at angular positions 10.1, 11.4, 12.9, and 20.1, which angular positions may vary by ±0.2 degrees 2θ.

41. 38. The process of claim 37, wherein the crystalline Form A polymorph of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is recrystallized from one or more suitable organic solvents.

42. 42. The process of claim 41, wherein the crystalline Form A polymorph of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile 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.

43. 43. The process of claim 42, wherein the suitable organic solvent is isopropyl acetate.

44. 44. The process of claim 43, wherein one or more anti-solvents and / or solid crystalline seeds of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile are added.

45. 45. The process of claim 44, wherein the one or more anti-solvents are independently selected from alkanes and water.

46. 46. ​​The process of claim 45, 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.

47. A solid composition comprising a diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile and 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, wherein 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is present in the composition.

1. A solid composition wherein the percent weight ratio of diethylamine solvate of 5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is from about 1:9 to about 1:0.

001.

48. 48. The solid composition of claim 47, wherein the percent weight ratio of the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition is from about 1:0.25 to about 1:0.

001.

49. 48. The solid composition of claim 47, wherein the percent weight ratio of the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile to 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile in the composition is from about 1:0.05 to about 1:0.

001.

50. The diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile is (1) angular positions 13.8 and 21.3, said angular positions being variable by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); or (2) angular positions 13.8, 21.3, and 8.4, said angular positions being variable by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); or (3) angular positions 13.8, 21.3, 8.4, and 23.5, which may vary by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); or (4) angular positions 13.8, 21.3, 8.4, 23.5, and 11.7, said angular positions being variable by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); or (5) angular positions 13.8, 21.3, 8.4, 23.5, 11.7, and 9.5, said angular positions being variable by ±0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using an X-ray wavelength of 1.5406 Å (Cu Kα); 50. The solid composition of any one of claims 47 to 49, which is the crystalline form B polymorph having an X-ray powder diffraction pattern comprising a peak at

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