Hypoxia inducible factor-2 (α) inhibitor and its use in disease treatment

Abstract

The present disclosure relates to certain hypoxia-inducible factor 2α (HIF-2α) inhibitors and their use in treating diseases mediated by HIF-2α, such as cancer. Also provided are uses of HIF-2α inhibitors in combination with poly (ADP-ribose) polymerase (PARP) inhibitors. In particular, the present disclosure relates to methods of treating cancer using a HIF-2α inhibitor in combination with a PARP inhibitor and pharmaceutical compositions comprising the inhibitors.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Non-Provisional Application No. 16 / 851,018, filed on April 16, 2020, and U.S. Provisional Application No. 63 / 093,734, filed on October 19, 2020, the contents of each of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure relates to certain hypoxia-inducible factor 2α (HIF-2α) inhibitors and their use in treating diseases mediated by HIF-2α, such as cancer. Also provided are uses of HIF-2α inhibitors in combination with poly (ADP-ribose) polymerase (PARP) inhibitors. In particular, the present disclosure relates to methods of treating cancer using a HIF-2α inhibitor in combination with a PARP inhibitor and pharmaceutical compositions comprising the inhibitors. Background Art

[0004] Hypoxia is a typical feature of solid tumors, and the adaptation of cancer cells to hypoxia contributes to the development of an aggressive phenotype and is associated with a poor prognosis in cancer patients. The cellular response to hypoxia is primarily controlled by a family of transcription factors called hypoxia-inducible factors (HIFs), including HIF-1α, HIF-2α, and HIF-3α (see Wang, GL, et al. (1995), Proc Natl Acad Sci U SA [Proceedings of the National Academy of Sciences of the United States of America], 92(12), 5510-5514; Tian, ​​H., et al. (1997), Genes Dev [Genes and Development], 11(1), 72-82; and Gu, YZ, et al. (1998), Gene Expr [Gene Expression], 7(3), 205-213). In well-oxygenated cells, HIFα subunits are hydroxylated by prolyl-4-hydroxylase and then polyubiquitinated by the Von Hippel Lindau (VHL) E3 ubiquitin ligase complex, followed by proteasome-mediated degradation (see Bishop, T., et al. (2014), Hypoxia [low oxygen] (Auckl), 2, 197-213). Under hypoxic conditions, hydroxylation of HIFα is inhibited, resulting in the stabilization and accumulation of HIFα in the nucleus, where they dimerize with HIF-1β and regulate the transcription of a large number of target genes (see Greer, SN, et al. (2012), EMBO J [Journal of the European Molecular Biology Association], 31 (11), 2448-2460). This allows the coordinated activation of genes essential for the adaptive response to hypoxia (including genes important for angiogenesis, metabolic reprogramming, survival, proliferation, and metastasis).

[0005] Angiogenic genes that are increased in response to hypoxia by the HIF transcription complex include VEGF, FLT-1, ANG1, ANG2, TIE2, PDGF, MMP2, 9, and FLK1 (see Favaro, E., et al. (2011), Genome Med, 3(8), 55; and Semenza, GL (2014), Annu Rev Pathol, 9, 47-71). The clinical benefits of both VEGFR inhibitors and anti-VEGF antibodies in multiple types of cancer, including colorectal cancer, glioblastoma, hepatocellular carcinoma, renal cell carcinoma, thyroid cancer, and neuroendocrine cancer, have validated the importance of tumor angiogenesis in driving tumor progression. Despite initial responses to anti-VEGF pathway therapy, many patients develop one or more resistance mechanisms and become refractory. Important resistance mechanisms to anti-angiogenic therapy include HIF-mediated upregulation of alternative pro-angiogenic factors and metabolic reprogramming (see Bergers, G., & Hanahan, D. (2008), Nat Rev Cancer, 8(8), 592-603; Welti, J., et al. (2013), J Clin Invest, 123(8), 3190-3200). Therefore, targeting HIF represents an alternative strategy to directly targeting VEGF or VEGFR.

[0006] HIF-1α and HIF-2α are the best characterized HIFα subunits, of which HIF-2α is considered to be a key oncogenic driver of clear cell renal cell carcinoma (ccRCC), and a high frequency of VHL functional deficiency (up to 90%) is caused by genetic inactivation of the VHL gene or hypermethylation of its promoter, which often constitutively expresses HIF-2α (see Network, CGAR (2013), Nature, 499(7456), 43-49; Sato, Y., et al. (2013), Nat Genet, 45(8), 860-867; Meléndez-Rodríguez, F., et al. (2018), Front Oncol, 8, 214; Rathmell, WK, & Chen, S. (2008), Expert Rev Anticancer Ther [Expert review of anticancer therapy], 8(1), 63-73). Preclinical and clinical data have demonstrated that pharmacological inhibitors of HIF-2α can effectively combat the growth of ccRCC (see Wallace, EM, et al. (2016), Cancer Res [Cancer Research], 76(18), 5491-5500; Courtney, KD, et al. (2018), J Clin Oncol [Journal of Clinical Oncology], 36(9), 867-874; and Choueiri, TK, et al. (2020), ASCO).

[0007] Poly(ADP-ribose) polymerase-1 (PARP1) is an enzyme highly expressed in the nucleus of mammalian cells and plays an important role in repairing damaged DNA and maintaining genome stability. The function of PARP is to detect and initiate cellular responses to metabolic, chemical or radiation-induced single-strand DNA breaks (SSBs) by synthesizing polymeric adenosine diphosphate ribose (poly(ADP-ribose) or PAR) chains, followed by signaling a complex enzymatic machinery (including DNA repair enzymes, DNA ligase III (LigIII), DNA polymerase β (polβ) and scaffolding proteins such as X-ray cross-complementing gene 1 (XRCC1)) to repair these SSBs (see Dulaney, C., et al. (2017), Semin Cell Dev Biol [Symposium on Cell and Developmental Biology], 63, 144-153; and Morales, J., et al. (2014), Crit Rev Eukaryot Gene Expr [Critical Reviews of Eukaryotic Gene Expression], 24(1), 15-28). When PARP activity is impaired (e.g., when inhibited by PARP inhibitors), SSBs will eventually progress to double-strand breaks (DSBs) that can be highly toxic to cells (see Dulaney, C., et al. (2017), Semin Cell Dev Biol [Cell and Developmental Biology Seminar], 63, 144-153). DSBs can be repaired by homologous recombination (HR) mechanisms (see Li, X., & Heyer, WD (2008), Cell Res [Cell Research], 18(1), 99-113). Tumors that lack the ability to repair DSBs, i.e., those with mutations in the BRCA1 / 2 genes (key components of the HR pathway), are particularly sensitive to PARP inhibitors (see Slade, D. (2020), Genes Dev [Genes and Development], 34(5-6), 360-394). This synthetic lethality has been validated preclinically and clinically by the approval of PARP inhibitors for BRCA1 / 2-deficient ovarian, fallopian tube or primary peritoneal cancer and breast cancer (see Yi et al., et al. (2019), Exp Hematol Oncol [Experimental Hematology and Oncology], 8, 29; and Slade, D. (2020), Genes Dev [Genes and Development], 34(5-6), 360-394). In addition, PARP inhibitors such as veliparib are currently being tested in clinical trials in various cancer settings, including renal cell carcinoma (RCC).

[0008] RCC is usually not associated with genetic alterations in the HR pathway (such as BRCA1 / 2 mutations), but instead exhibits a "BRCAness" phenotype (see Warsow et al., (2018), Sci Rep, 8(1), 7477). "BRCAness" is a term coined to describe tumors that are defective in DNA double-strand break repair by homologous recombination in the absence of BRCA1 or BRCA2 mutations (see Turner, N., et al., (2004), Nat Rev Cancer, 4(10), 814-819). Recently, VHL-deficient RCC has been shown to share some features with "BRCAness" tumors (see Scanlon, SE, et al., (2018), Oncotarget, 9(4), 4647-4660). Analysis of the Cancer Genome Atlas (TCGA) ccRCC database of DNA repair gene expression in VHL-deficient and VHL-WT renal tumor samples identified a correlation between VHL inactivation and reduced expression of homologous recombination pathway genes, including ANCD2, BRCA1, RAD51 (see Scanlon, SE, et al. (2018), Oncotarget, 9(4), 4647-4660). Therefore, VHL-deficient ccRCC may show a higher sensitivity to PARP inhibitors than normal tissues.

[0009] In addition, it has been found that hypoxia can lead to downregulation of BRCA1 expression, resulting in a reduction in homologous recombination activity that is important for mediating sensitivity to PARP inhibitors (see Bindra, RS, et al. (2005), Cancer Res, 65(24), 11597-11604). Since one of the key mechanisms of HIF-2α inhibition is the creation of hypoxic conditions in tumor tissues, administering HIF-2α inhibitors together with PARP inhibitors should lead to a reduction in important genes in the HR pathway, thereby providing greater therapeutic effects in inhibiting ccRCC tumor progression or inducing ccRCC tumor regression.

[0010] In addition to VHL deficiency, other ccRCC tumors show frequent mutations or deletions in many genes known to have functions in chromatin remodeling and DNA damage response. Regardless of the stage, PBRM1 (the second most commonly mutated gene in ccRCC) encodes BRG1-associated factor (BAF) 180, which is a defining subunit of the approximately 2MDa polybrominated BAF (PBAF) SWI / SNF complex that plays a role in regulating chromatin structure (see Hsieh et al., et al. (2017), Eur Urol [European Urology], 71 (3), 405-414; and Varela et al., et al. (2011), Nature [Natural], 469 (7331), 539-542). Other frequently altered genes in ccRCC, including SETD2 (histone methyltransferase), KDM5C (demethylase), and BAP1 (deubiquitinase), are also associated with chromatin remodeling and genomic stability (see Mehdi, A., & Riazalhosseini, Y. (2017), Int J Mol Sci [International Journal of Molecular Sciences], 18(8)). These defects can also be used for treatment with PARP inhibitors by inducing excessive genomic instability and catastrophic DNA damage. For example, it was recently discovered that ccRCC cells with PBRM1 defects are more sensitive to PARP inhibitor treatment (see Chabanon, RM, et al. (2020), AACR [American Association for Cancer Research]). Therefore, by targeting different key oncogenic pathways in ccRCC, the combination of HIF-2α inhibitors with PARP inhibitors can significantly improve clinical benefits.

[0011] HIF-2α overexpression has also been found in a variety of tumor types, including renal cell carcinoma (RCC) other than the clear cell subtype (such as papillary RCC tumor models), breast cancer, brain cancer, bladder cancer, cartilage cancer, cervical cancer, colorectal cancer, endometrial cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, skin cancer, soft tissue cancer and gastric cancer (see Wong, SC, et al. (2018), Mol Cancer Ther, 17(1), 140-149; Moreno Roig, E., et al. (2018), Front Oncol, 8, 224; and Luo, D., et al. (2019), Cancer Epidemiol Biomarkers Prev, 28(5), 857-866). It is widely accepted that in tumors, especially large and rapidly growing tumor tissues, oxygen demand exceeds oxygen supply. Therefore, a heterogeneous hypoxic microenvironment exists within tumor tissues, which is increasingly severe due to impeded oxygen diffusion, which is related to the distance of tumor cells from the existing vasculature. This phenomenon has been observed in almost all solid tumor types and drives the stabilization and accumulation of HIF-1α and / or HIF-2α, thereby promoting the development of new blood vessels to increase the supply of oxygen and nutrients for tumor growth. Since inhibition of HIF-2α exacerbates the hypoxic state, this condition may subsequently increase DNA damage and reduce DNA repair capacity, creating a vulnerability that can be induced by treating these cancers with HIF-2α inhibitors in combination with PARP inhibitors.

[0012] Although PARP inhibitors are promising in the clinic, many patients do not respond or develop resistance after an initial response. It is known that certain tumor cells have cancer stem cell (CSC)-like characteristics, mediating resistance to targeted therapies and traditional chemotherapy in many tumor types (see Phi, LTH, et al. (2018), Stem Cells Int [International Stem Cells], 2018, 5416923). It has been found that HIF-2α regulates cancer stem cell characteristics in a variety of tumor types, including glioblastoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and breast cancer (see Peng, G., & Liu, Y. (2015), Trends Pharmacol Sci [Pharmacology Science Trends], 36 (6), 374-383). Indeed, HIF-2α silencing in glioblastoma reduces self-renewal, in vitro tumor cell proliferation, and in vivo tumor initiation capacity (see Nusblat, LM, et al. (2020), Cancer Drug Resist, 3(2), 199-208). Therefore, HIF-2α activity may also play a role in mediating patient resistance to PARP inhibitors by upregulating cancer stem cell-like properties. The combination of HIF-2α inhibitors with PARP inhibitors may have synergistic effects and may represent a new paradigm for the treatment of cancer types for which PARP inhibitors are either approved or currently in clinical development.

[0013] Because of their role in regulating the physiological response to changes in oxygen levels, HIF-α proteins are causally implicated in a number of hypoxia-related pathological processes in addition to cancer. Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disease of the intestine. Normally, the intestine maintains dynamic, dramatic fluctuations in cellular oxygen tension, with hypoxia at the tips of the epithelial villi and better oxygenation at the base of the villi. Dysregulation of epithelial oxygen tension plays a role in intestinal inflammation and resolution in IBD (see Shah YM, Molecular and Cellular Pediatrics, 2016 Dec;3(1):1). Although HIF-1α and HIF-2α can bind to the same canonical hypoxia response element (HRE), multiple studies have demonstrated that HIF-1α and HIF-2α regulate different subsets of genes, leading to contrasting effects on IBD symptoms. HIF-1α in intestinal epithelial cells is widely considered to be a major protective factor against 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). However, HIF-2α activation contributes to IBD through multiple mechanisms, including direct regulation of multiple proinflammatory cytokines (such as tumor necrosis factor-α) to drive inflammation, and indirect disruption of intestinal barrier integrity by increasing turnover of tight junction proteins (occludin) (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). Therefore, in IBD, HIF-2α inhibitors hold promise for suppressing chronic activation of HIF-2α to restore proinflammatory responses and increase intestinal barrier integrity.

[0014] With the increasing prevalence of obesity and metabolic syndrome, NASH is becoming a common chronic liver disease with limited available treatment options. Recent studies have shown a positive correlation between intestinal HIF-2α signaling and body mass index and liver toxicity, and further animal model studies support the causal relationship of this correlation (see Xie C, et al. Nat Med [Nature Medicine]. 2017 November; 23 (11): 1298-1308.). Therefore, targeting intestinal HIF-2α represents a new therapeutic strategy for NASH.

[0015] PAH is a life-threatening disease with a very poor prognosis. Progressive pulmonary vascular remodeling, characterized by concentric pulmonary artery wall thickening and occlusive intimal lesions, is one of the main causes of increased pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP) in PAH patients (Aggarwal S, et al. Compr Physiol. 2013 Jul;3(3):1011-34). Recently, HIF-2α was found to contribute to the hypoxic pulmonary vascular remodeling process, reduce the plasticity of the vascular bed, and ultimately make PAH debilitating (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 new insights into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia and offer a much-needed therapeutic intervention strategy by targeting HIF-2α.

[0016] Iron is an essential nutrient required for oxygen transport and acts as a cofactor in many key enzymatic and redox reactions. HIF-2α regulates the expression of key genes that contribute to iron absorption, and when these genes are disrupted, iron loading disorders can result. For example, an excellent study of mice lacking HIF-2α in intestinal epithelial cells showed that HIF-2α knockout resulted in a significant decrease in the levels of Dmt1, Dcytb, and FPN mRNA in the duodenum, which are all important genes for iron transport and absorption. More importantly, HIF-1α did not compensate for these effects (see Mastrogiannaki M, et al. J Clin Invest [Journal of Clinical Research]. 2009; 119 (5): 1159-1166). Therefore, small molecules targeting HIF-2α have the potential to improve iron homeostasis in patients with iron disorders. Summary of the invention

[0017] In a first aspect, a method of treating cancer in a patient is provided, the method comprising administering to the patient a HIF-2α inhibitor having formula (I):

[0018]

[0019] in:

[0020] X 1 is CH or N;

[0021] R 1Hydroxyl, halogen, amino, -OP(O)(OH)2, -OCH2OP(O)(OH)2, -OCOR 10 、-OCOOR 11 ,

[0022] -OCONR 12 R 13 、-OCHR 14 OCOR 15 or-OCHR 14 OCOOR 15a , where R 10 , R 11 , and R 15 and R 15a are independently alkyl or alkyl substituted by amino, carboxyl or hydroxyl, R 12 and R 13 are independently hydrogen, alkyl, or alkyl substituted with amino, carboxyl or hydroxyl, or R 12 and R 13 Together with the nitrogen atom to which they are attached, they form an optionally substituted heterocyclic group, and each R 14 is hydrogen, alkyl, or haloalkyl;

[0023] R 2 is hydrogen, deuterium, alkyl, halo, haloalkyl, alkenyl, or alkynyl;

[0024] R 2a is hydrogen, halogen, or deuterium;

[0025] R 3 and R 4 is independently hydrogen, deuterium, alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl; or

[0026] R 3 and R 4 together with the carbon to which they are attached form oxo, 3- to 6-membered cycloalkylene, or 4- to 6-membered optionally substituted heterocyclylene;

[0027] R 5 is hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxy, or alkoxy;

[0028] R 6 is hydrogen, deuterium, alkyl, cycloalkyl, or halo; or

[0029] R 5 and R 6 together with the carbon to which they are attached form oxo, alkyldienyl, 3- to 6-membered cycloalkylene, or 4- to 6-membered optionally substituted heterocyclylene; provided that R 5 and R 6 and R3 and R 4 together with the carbon to which they are attached do not simultaneously form oxo, cycloalkylene, or optionally substituted 4- to 6-membered heterocyclylene;

[0030] R 7 is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, or haloalkoxy;

[0031] L is a bond, S, SO, SO2, O, CO, or NR 16 , where R 16 is hydrogen or alkyl;

[0032] R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, wherein aryl or heteroaryl, each by itself or as part of aralkyl or heteroaralkyl, or heterocyclyl, by itself or as part of heterocyclylalkyl, is replaced by R a , R b , R c , R g and R h Substitution, where R a , R b , and R c are independently selected from hydrogen, deuterium, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidene, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, and R g and R h independently selected from hydrogen, deuterium, and halo;

[0033] R 9 R is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, haloalkoxy, alkylsulfoxide, alkylsulfonyl, or heteroaryl, wherein the heteroaryl is optionally independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and cyano d , R e , and R f replace; or

[0034] When R 9 and R 2 When attached to the same carbon atom, they may combine to form oxo, alkyldienyl, 3- to 6-membered cycloalkylene, or 4- to 6-membered heterocyclylene; and

[0035] R 9a is hydrogen, halogen, or deuterium; or

[0036] a pharmaceutically acceptable salt thereof;

[0037] In combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof.

[0038] In a second aspect, a combination is provided, comprising a Hif-2α inhibitor of formula (I) or a pharmaceutically acceptable salt thereof, and a PARP inhibitor or a pharmaceutically acceptable salt thereof as described in the first aspect (and Examples 1 to 52 below). In an embodiment of the second aspect, the combination of the second aspect is for use in treating cancer in a patient.

[0039] In a third aspect, a combined use is provided, comprising a Hif-2α inhibitor of formula (I) or a pharmaceutically acceptable salt thereof as described in the first aspect (and Examples 1 to 52 below), and a PARP inhibitor or a pharmaceutically acceptable salt thereof for treating cancer in a patient.

[0040] In a fourth aspect, a pharmaceutical composition comprising a HIF-2α inhibitor of formula (I) or a pharmaceutically acceptable salt thereof as described in the first aspect (and Examples 1 to 52 below), and a PARP inhibitor (or an embodiment thereof disclosed below) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In an embodiment of the fourth aspect, the drug combination of the fourth aspect is used to treat cancer in a patient.

[0041] In the first sub-embodiment of the first, second, third and fourth aspects and their sub-embodiments, the HIF-2α inhibitor is 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (Compound 5).

[0042] Compounds having formula (I) including compound 5 and one or more polymorphs thereof are disclosed in PCT application number PCT / US20 / 28579 filed on April 16, 2020.

[0043] In the first, second, third and fourth aspects and any embodiment and the fourth sub-embodiment of the sub-embodiments contained therein, the cancer is selected from kidney cancer, brain cancer, cartilage cancer, renal cancer, salivary gland cancer, skin cancer, stomach cancer, glioblastoma, neuroblastoma, paraganglioma, pheochromocytoma, somatostatinoma, hemangioblastoma, gastrointestinal stromal tumor, pituitary tumor, leiomyoma, leiomyosarcoma, polycythemia vera, retinal cancer, lung cancer, pancreatic cancer, liver cancer, ovarian cancer, breast cancer, prostate cancer, colorectal cancer, head and neck cancer, cervical cancer , endometrial cancer, bladder cancer, gastric cancer, esophageal cancer, lymphoma, melanoma, mesothelioma, sarcoma, neuroendocrine tumors, uveal melanoma, urothelial carcinoma, fallopian tube cancer, primary peritoneal cancer, bile duct cancer, Ewing sarcoma, uterine leiomyosarcoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, T-cell prolymphocytic leukemia, multiple myeloma, acute myeloid leukemia, chronic myelogenous leukemia, germ cell cancer, osteosarcoma, biliary tract cancer, soft tissue sarcoma, rhabdomyosarcoma, mantle cell lymphoma, and endocrine gland neoplasms.

[0044] In a fifth aspect, provided are compounds of formula (IA):

[0045]

[0046] in:

[0047] R 2 is hydrogen or deuterium;

[0048] R 9 It is fluorine;

[0049] R 7 It is hydrogen;

[0050] R 8 Is R a , R b , R c , R g and R h Substituted phenyl, wherein R a , R b , and R c is independently selected from hydrogen, deuterium, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, and R g and R h independently selected from hydrogen, deuterium, and halo;

[0051] R 2a is hydrogen, deuterium, or fluorine; and

[0052] R 9a is fluorine; or

[0053] or pharmaceutically acceptable salts thereof.

[0054] Compounds of formula (IA) are a subset of compounds of formula (I).

[0055] In a sixth aspect, a method of treating a disease treatable by inhibiting HIF-2α in a patient (preferably a patient in need of such treatment) is provided, the method comprising administering to the patient (preferably a patient in need of such treatment) a therapeutically effective amount of a compound of formula (IA) (or any embodiment thereof as described herein) or a pharmaceutically acceptable salt thereof. The therapeutically effective amount of compound (IA) may be administered as a pharmaceutical composition comprising a compound of formula (IA) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0056] In one embodiment of the sixth aspect, the disease is cancer such as kidney cancer, glioblastoma (see PNAS 2017, 114, E6137-E6146), renal cell carcinoma (particularly clear cell renal cell carcinoma), small cell lung cancer, glioblastoma, ovarian cancer, liver cancer, neuroblastoma, pheochromocytoma and paraganglioma (see European Journal of Cancer 2017, 86, 1-4), somatostatinoma, hemangioblastoma, gastrointestinal stromal tumor (GIST), pituitary tumor, leiomyoma, leiomyosarcoma, polycythemia vera or retinoma. In another embodiment, non-cancer diseases that may benefit from Hif-2α inhibition include VHL (Hippel-Lindau) disease (see Oncotarget, 2015, 6, 23036-23037), lung diseases such as PAH (pulmonary arterial hypertension) (see Mol. Cell. Biol. 2016, 36, 1584-1594), reflux esophagitis (see Current Opinion in Pharmacology 2017, 37:93-99), hepatic steatosis (see Nature Medicine 2017, 23, 1298-1308), liver diseases such as NASH, inflammatory diseases such as inflammatory bowel disease (see Nature Reviews 2017, 36, 1584-1594), reflux esophagitis (see Current Opinion in Pharmacology 2017, 37:93-99), liver steatosis (see Nature Medicine 2017, 23, 1298-1308), liver diseases such as NASH, inflammatory diseases such as inflammatory bowel disease (see Nature Reviews 2017, 36, 1584-1594), reflux esophagitis (see Current Opinion in Pharmacology 2017, 37:93-99), liver steatosis (see Nature Medicine 2017, 36 ...584-1594), reflux esophagitis (see Current Opinion in Pharmacology 2017 Gastroenterology & Hepatology [Nature Reviews, Gastroenterology and Hepatology] 2017, 14, 596), autoimmune diseases such as graft-versus-host disease (see Blood [Blood], 2015, 126, 1865), or iron overload.

[0057] In a seventh aspect, the present disclosure relates to a pharmaceutical composition comprising a compound having Formula (IA) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0058] In an eighth aspect, a compound of formula (IA) (or any embodiment thereof as described herein) or a pharmaceutically acceptable salt thereof is provided for use as a medicament. In one embodiment, the compound of formula (IA) (and any embodiment thereof as described herein) or a pharmaceutically acceptable salt thereof can be used to treat one or more of the diseases disclosed in the sixth aspect or the embodiments of the sixth aspect above.

[0059] In a ninth aspect, there is provided a compound of formula (IA) or a pharmaceutically acceptable salt thereof (and any embodiments thereof disclosed herein) for use in the manufacture of a medicament for treating a disease in a patient, wherein the activity of HIF-2α contributes to the pathology and / or symptoms of the disease. In one embodiment, the disease is one or more of the diseases disclosed in the sixth aspect or embodiments of the sixth aspect.

[0060] In a tenth aspect, a method for inhibiting HIF-2α is provided, the method comprising contacting HIF-2α with a compound having formula (IA) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof; or contacting HIF-2α with a pharmaceutical composition comprising a compound having formula (IA) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1 Results are presented for a co-immunoprecipitation assay used to measure inhibition of HIF-2α and ARNT dimerization in primary pulmonary artery smooth muscle cells (PASMCs) and human pulmonary artery endothelial cells (HPAECs). DETAILED DESCRIPTION

[0062] definition:

[0063] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings:

[0064] "Alkyl" refers to a straight chain saturated monovalent hydrocarbon radical having one to six carbon atoms or a branched chain saturated monovalent hydrocarbon radical having three to six carbon atoms, for example, methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc. Those skilled in the art will recognize that the term "alkyl" may include "alkylene" groups.

[0065] Unless otherwise specified, "alkylene" refers to a straight-chain saturated divalent hydrocarbon group having one to six carbon atoms or a branched saturated divalent hydrocarbon group having three to six carbon atoms, for example, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0066] The "alkenyl group" refers to a straight-chain monovalent hydrocarbon group having two to six carbon atoms or a branched monovalent hydrocarbon group having three to six carbon atoms containing a double bond, for example, propenyl, butenyl, and the like.

[0067] "Alkaldienyl" is an alkenyl group as defined above attached via a terminal divalent carbon. For example, in the following compound:

[0068] The arrow indicates an alkyldienyl group.

[0069] "Haloalkyldienyl" is an alkyldienyl substituted with one or two halo groups, each as defined herein.

[0070] The "alkynyl group" refers to a straight-chain monovalent hydrocarbon group having two to six carbon atoms or a branched monovalent hydrocarbon group having three to six carbon atoms containing a triple bond, for example, propynyl, butynyl, and the like.

[0071] "Alkylthio" refers to a -SR radical wherein R is alkyl as defined above, for example, methylthio, ethylthio, and the like.

[0072] "Alkylsulfonyl" means a -SO2R radical (wherein R is alkyl as defined above) such as methylsulfonyl, ethylsulfonyl, and the like.

[0073] "Alkyl sulfoxide" refers to a -SOR group (wherein R is alkyl as defined above), for example, methyl sulfoxide, ethyl sulfoxide, and the like.

[0074] "Amino" refers to -NH2.

[0075] "Alkylamino" refers to a -NHR radical (wherein R is alkyl as defined above), for example, methylamino, ethylamino, propylamino, or 2-propylamino and the like.

[0076] "Aminoalkyl" refers to a linear monovalent hydrocarbon radical having one to six carbon atoms or a branched monovalent hydrocarbon radical having three to six carbon atoms substituted with -NR'R" (wherein R' and R" are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkylcarbonyl, each as defined herein), for example, aminomethyl, aminoethyl, methylaminomethyl, and the like.

[0077] "Alkoxy" refers to a -OR radical (wherein R is alkyl as defined above), for example, methoxy, ethoxy, propoxy or 2-propoxy, n-butoxy, isobutoxy, or tert-butoxy and the like.

[0078] "Alkoxyalkyl" refers to a straight chain monovalent hydrocarbon radical having one to six carbon atoms or a branched monovalent hydrocarbon radical having three to six carbon atoms substituted with at least one alkoxy radical as defined above (e.g., one or two alkoxy radicals), for example, 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0079] "Alkoxycarbonyl" refers to a -C(O)OR radical (wherein R is alkyl as defined above) such as methoxycarbonyl, ethoxycarbonyl, and the like.

[0080] "Alkylcarbonyl" means a -C(O)R radical wherein R is alkyl as defined herein, for example, methylcarbonyl, ethylcarbonyl, and the like.

[0081] "Aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, for example phenyl or naphthyl.

[0082] "Aralkyl" refers to a -(alkylene)-R radical wherein R is aryl as defined above, for example, benzyl, phenethyl, and the like.

[0083] "Bicyclic cycloalkyl" refers to a fused bicyclic saturated monovalent hydrocarbon radical having six to ten carbon atoms, optionally substituted by one or two substituents independently selected from alkyl, halo, alkoxy, hydroxyl, and cyano. Examples include, but are not limited to, decalin, octahydro-1H-indene, and the like.

[0084] "Cycloalkyl" refers to a monocyclic saturated monovalent hydrocarbon radical having three to ten carbon atoms, optionally substituted by one or two substituents independently selected from alkyl, alkyldienyl, halo, alkoxy, hydroxy, cyano, haloalkyldienyl, and cyanoalkyl. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocyclopropyl-1-yl, 1-cyanomethylcyclopropyl-1-yl, 3-fluorocyclohexyl, and the like. Cycloalkyl may include cycloalkylene as defined herein.

[0085] "Cycloalkylalkyl" refers to a -(alkylene)-R radical wherein R is cycloalkyl as defined above, for example, cyclopropylmethyl, cyclohexylmethyl, and the like.

[0086] Unless otherwise indicated, "cycloalkylene" means a divalent cycloalkyl group as defined above.

[0087] "Cycloalkenyl" refers to a monocyclic monovalent hydrocarbon group having three to ten carbon atoms, optionally substituted by one or two substituents independently selected from alkyl, halo, alkoxy, hydroxyl, cyano, and cyanoalkyl. Examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, etc.

[0088] "Oxocycloalkenyl" refers to a monocyclic monovalent hydrocarbon group having three to ten carbon atoms containing one or two double bonds and an oxo group, and is optionally substituted by one or two substituents independently selected from alkyl, halo, alkoxy, hydroxyl, cyano, and cyanoalkyl. Examples include, but are not limited to, 3-oxocyclohex-1-enyl, etc.

[0089] "Cyanoalkyl" refers to a straight chain monovalent hydrocarbon group having one to six carbon atoms or a branched monovalent hydrocarbon group having three to six carbon atoms substituted with a cyano group, for example, cyanomethyl, cyanoethyl, and the like.

[0090] "Carboxyl" refers to -COOH.

[0091] "Dialkylamino" refers to a -NRR' group wherein R and R' are alkyl as defined above, for example, dimethylamino, methylethylamino, and the like.

[0092] "Disubstituted amino" refers to a -NRR' group (wherein R and R' are independently alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkylcarbonyl, each as defined herein), for example, dimethylamino, ethylmethylamino, bishydroxyethylamino, bismethoxyethylamino, diethylaminoethylamino, and the like.

[0093] "Halo" refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0094] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halogen atoms, e.g., one to five halogen atoms such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When an alkyl group is substituted only with fluorine, it may be referred to as a fluoroalkyl group in this application.

[0095] "Haloalkoxy" refers to a -OR group (wherein R is a haloalkyl group as defined above), for example -OCF3,

[0096] -OCHF2, etc. When R is a haloalkyl group (wherein the alkyl group is substituted only with fluorine), it may be referred to as a fluoroalkoxy group in the present application.

[0097] "Hydroxyalkyl" refers to a linear monovalent hydrocarbon radical having one to six carbon atoms or a branched monovalent hydrocarbon radical having three to six carbon atoms substituted with one or two hydroxyl groups, provided that if two hydroxyl groups are present, they are not on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl.

[0098] Unless otherwise specified, "heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic radical having 4 to 8 ring atoms, one or two of which are selected from N, O or S(O). n (wherein n is an integer from 0 to 2) heteroatom, remaining annular atoms are C. In addition, one or two ring carbon atoms in the heterocyclic ring can be optionally replaced by-CO-group. More particularly, term heterocyclic includes but is not limited to pyrrolidine generation, piperidinyl generation, homopiperidinyl generation, 2-oxopyrrolidinyl, 2-oxopiperidyl, morpholino, piperazine generation, tetrahydro-pyranyl, thiomorpholino etc. When the heterocyclic ring is unsaturated, it can contain one or two ring double bonds, and condition is that the ring is not aromatic. When the heterocyclic group contains at least one nitrogen-atoms, it is also referred to as heterocyclic amino in this article and it is the subset of heterocyclic group.

[0099] "Heterocyclylalkyl" or "heterocycloalkyl" refers to a -(alkylene)-R radical where R is a heterocyclyl ring as defined above, for example, tetrahydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.

[0100] Unless otherwise indicated, "heterocyclylene" refers to a divalent heterocyclyl as defined above. When the heterocyclene contains 4, 5 or 6 ring atoms, it is also referred to herein as a 4- to 6-membered heterocyclylene.

[0101] Unless otherwise indicated, "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic group with 5 to 10 ring atoms, wherein one or more (in one embodiment, one, two or three) ring atoms are heteroatoms selected from N, O or S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc. As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive. When the heteroaryl ring contains 5 or 6 ring atoms, it may also be referred to as a 5-yuan or 6-yuan heteroaryl in this article.

[0102] "Heteroarylene" means a divalent heteroaryl group as defined above.

[0103] "Heteroaralkyl" refers to a -(alkylene)-R radical, wherein R is heteroaryl as defined above, such as pyridylmethyl, etc. When the heteroaryl ring in the heteroaralkyl contains 5 or 6 ring atoms, it is also referred to herein as a 5-membered or 6-membered heteroaralkyl radical.

[0104] The phrase “R 2 and R 9 Attached to a ring carbon atom that is located adjacent to the ring attached to R 1 The "meta position" of the ring carbon refers to R 2 and R 9 The location is as follows:

[0105]

[0106] The term "oxo," as used herein, alone or in combination, refers to =(O).

[0107] When needed, any definition in this article can be used in combination with any other definition to describe a composite structural group. As a rule, the subsequent element of any such definition is the element attached to the parent part. For example, the composite group alkoxyalkyl refers to an alkoxy group attached to the parent molecule through an alkyl group.

[0108] The disclosure also includes protected derivatives of compounds with formula (I). For example, when compounds with formula (I) contain groups (such as hydroxyl, carboxyl, thiol or any group containing one or more nitrogen atoms), these groups can be protected by suitable protecting groups. A comprehensive list of suitable protecting groups can be found in TW Greene, Protective Groups in Organic Synthesis [protective groups in organic synthesis], 5th edition, John Wiley & Sons, Inc [John Wiley & Sons Publishing Company]. (2014), the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of the compounds disclosed herein can be prepared by methods well known in the art.

[0109] The present disclosure also includes polymorphic forms of compounds of formula (I) or pharmaceutically acceptable salts thereof. Polymorphs are different crystalline forms of a compound that differ in the arrangement of the molecules of the compound in the crystal lattice. Therefore, a single compound can produce a variety of polymorphic forms. The polymorphs of a compound typically have different melting points, solubility, density and optical properties. The polymorphic forms of a compound can be distinguished by several techniques, such as X-ray diffraction, IR or Raman spectroscopy.

[0110] The term "prodrug" refers to a compound that becomes more active in vivo. Certain compounds of formula (I) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of compounds of formula (I) are structurally modified forms of compounds that are susceptible to chemical changes under physiological conditions to provide active compounds. Because prodrugs are easier to administer than compounds or parent drugs in some cases, they are often useful. For example, they can be bioavailable by oral administration, whereas parent drugs cannot. A variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of prodrugs. Examples of prodrugs (but not limited to) are compounds that are administered as esters (the "prodrugs"), but are then metabolically hydrolyzed to carboxylic acids, the active entities. Further examples include peptidyl derivatives of compounds of formula (I).

[0111] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include:

[0112] Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptanoic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or

[0113] Salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or salts formed by coordination with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.). It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference in its entirety.

[0114] Compounds with formula (I) may have asymmetric centers. Compounds with formula (I) containing asymmetrically substituted atoms can be separated in optically active forms or racemic forms. The individual stereoisomers of compounds can be prepared by synthesizing from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products and then separating (e.g., converting into a mixture of diastereomers and then separating or recrystallizing, chromatographic techniques, directly separating enantiomers on a chiral chromatographic column, or any other appropriate method known in the art). Unless specific stereochemical forms or isomeric forms are specifically indicated, all chiral forms, diastereomeric forms, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure.

[0115] Some compounds with formula (I) can exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers (as separate forms and mixtures thereof) are within the scope of this disclosure. In addition, as used herein, although only a few examples have been listed, the term alkyl includes all possible isomeric forms of the alkyl group. In addition, when these cyclic groups (e.g., aryl, heteroaryl, heterocyclic radical) are substituted, although only a few examples have been listed, they include all possible isomers. In addition, all hydrates of compounds with formula (I) are within the scope of this disclosure.

[0116] Compounds of formula (I) may also contain unnatural amounts of isotopes at one or more atoms constituting such compounds. Unnatural amounts of isotopes may be defined as amounts ranging from the amount found in nature to 100% of the atom in question. The only difference is the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into compounds of formula (I) (and any embodiments thereof disclosed herein, including specific compounds)) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P. 33 P. 35 S. 18 F. 36 Cl, 123 I and 125 1. Isotope-labeled compounds (e.g., 3 H and 14 C-labeled compounds) can be used in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are useful because of their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e. 2 H) can confer certain therapeutic advantages resulting from better metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in the compounds disclosed herein, including those in Table 1 below, one or more hydrogen atoms are replaced by 2 H or 3 H is replaced, or one or more carbon atoms are 13 C- or 14 C-enriched carbon substitution. Positron emitting isotopes (e.g.15 O. 13 N. 11 C and 15 F) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures similar to those disclosed in the Schemes or Examples herein.

[0117] Certain structures provided herein are drawn with one or more floating substituents. Unless otherwise provided or otherwise clear from the context, one or more substituents may be present on any atom of the ring to which they are attached, where chemically feasible and permitted by the rules of valence. For example, in the structure: In, R 7 Substituents may replace any hydrogen on the benzo portion of the tricyclic ring, including the hydrogen of CH (when X 1 is CH).

[0118] "Optionally substituted aryl" refers to aryl groups optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxy, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano.

[0119] "Optionally substituted heteroaryl" refers to a heteroaryl group as defined above optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkylthio, alkylsulfonyl, hydroxy, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano.

[0120] Unless otherwise indicated, "optionally substituted heterocyclyl" refers to a heterocyclyl as defined above optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkylthio, alkylsulfonyl, hydroxy, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl, haloalkoxy, and cyano.

[0121] "Optionally substituted heterocyclylene" is a divalent optionally substituted heterocyclyl as defined above.

[0122] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient useful in preparing a pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable carrier / excipient" as used in this specification and claims includes both one and more than one such excipient.

[0123] "Spiro cycloalkyl" refers to a saturated bicyclic ring with 6 to 10 ring carbon atoms, wherein these rings are connected only by an atom, and the connecting atom is also referred to as a spiral atom, most commonly a quaternary carbon ("spiro carbon"). The spiro cycloalkyl ring is optionally substituted with one or two substituents, and these substituents are independently selected from alkyl, halo, alkoxy, hydroxyl and cyano. Representative examples include but are not limited to spiral [3.3] heptane, spiral [3.4] octane, spiral [3.5] nonane, spiral [4.4] nonane (1:2:1:1) etc.

[0124] "Spiroheterocyclyl" refers to a saturated bicyclic ring having 6 to 10 ring atoms, one, two or three of which are selected from N, O or S(O). n (wherein n is an integer from 0 to 2) heteroatom, the remaining annular atoms are C, and these rings are connected only by an atom, and the connecting atom is also referred to as spiral atom, most commonly quaternary carbon ("spiro carbon"). Spiro heterocyclic ring is optionally substituted by one, two or three substituents, and these substituents are independently selected from alkyl, alkylthio, alkyl sulfonyl, hydroxyl, cycloalkyl, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl, haloalkoxy and cyano. Representative examples include but are not limited to 2,6-diazaspiro [3.3] heptane, 2,6-diazaspiro [3.4] octane, 2-azaspiro [3.4] octane, 2-azaspiro [3.5] nonane, 2,7-diazaspiro [4.4] nonane etc.

[0125] As used herein, the term "about" is intended to qualify the numerical value it modifies, indicating that this value is a variable within the error range. When no specific error range is listed (e.g., the standard deviation of the mean value given in a data graph or table), the term "about" should be understood to mean a range covering ±10%, preferably ±5%, including the listed values ​​and ranges.

[0126] In formula (I), R 9 In the definition of "heteroaryl", the phrase "heteroaryl, wherein the heteroaryl is optionally substituted with R independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and cyano d , R e , and R f"substituted" (and similar phrases used to define other groups in formula (I)) is intended to encompass unsubstituted heteroaryl and heteroaryl groups substituted with R d , R e , and R f Any one of the substituted heteroaryl groups.

[0127] As used herein, the term "disease" is intended to be generally synonymous and may be used interchangeably with the terms "disorder," "syndrome," and "condition" (in the case of medical conditions), all of which reflect an abnormal condition of one of the parts of the human or animal body or of the body that impairs its normal functioning, typically manifests itself by distinctive signs and symptoms, and causes the human or animal to have a reduced life span or quality of life.

[0128] The term "combination therapy" or "administered in combination with" refers to the administration of two or more therapeutic agents to treat the diseases or disorders described in the present disclosure. Such administration encompasses the co-administration of these therapeutic agents in a simultaneous manner, such as in a single capsule or tablet having a fixed ratio of active ingredients or in multiple separate capsules or tablets of each active ingredient. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide a beneficial effect of the drug combination in treating the conditions or disorders described herein.

[0129] The term "patient" is often synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock (e.g., cattle, goats, sheep, pigs, and rabbits), and pets (e.g., dogs, cats, rabbits, and horses). Preferably, the patient is a human.

[0130] The term "synergistic" or "synergistic" is used to mean that the result of the combination of a HIF-2α inhibitor or a pharmaceutically acceptable salt thereof and a PARP inhibitor or a pharmaceutically acceptable salt thereof is greater than the sum of each compound alone. This improvement in the disease, condition or disorder being treated is a "synergistic" effect.

[0131] A "synergistic amount" is an amount of a combination of a HIF-2α inhibitor, or a pharmaceutically acceptable salt thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt thereof, that produces a synergistic effect ("synergistic" as defined herein).

[0132] “Treating” or “treatment” illnesses include:

[0133] (1) preventing the disease, that is, causing clinical symptoms of the disease to not develop in a mammal that may be exposed to or susceptible to the disease but does not yet experience or display symptoms of the disease;

[0134] (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or

[0135] (3) Alleviate the disease, that is, cause the disease or its clinical symptoms to subside.

[0136] "Therapeutically effective amount" refers to the amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment 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 to be treated.

[0137] The terms "inhibit" and "reduce" or any variants of these terms in relation to HIF-2α include any measurable reduction or complete inhibition to achieve the desired result. For example, reduction can be a reduction in HIF-2α activity by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therein, compared to normal activity.

[0138] The following compound Table I discloses representative HIF-2α inhibitors having formula (I):

[0139] Table I

[0140]

[0141]

[0142]

[0143]

[0144]

[0145] Example:

[0146] In the following additional embodiments 1-52, the present disclosure includes:

[0147] 1. In Example 1, a method of treating cancer in a patient is provided, the method comprising administering to the patient a HIF-2α inhibitor having formula (I):

[0148]

[0149] in:

[0150] X 1 is CH or N;

[0151] R 1 Hydroxyl, halogen, amino, -OP(O)(OH)2, -OCH2OP(O)(OH)2, -OCOR10 、-OCOOR 11 ,

[0152] -OCONR 12 R 13 、-OCHR 14 OCOR 15 or-OCHR 14 OCOOR 15a , where R 10 , R 11 , and R 15 and R 15a are independently alkyl or alkyl substituted by amino, carboxyl or hydroxyl, R 12 and R 13 are independently hydrogen, alkyl, or alkyl substituted with amino, carboxyl or hydroxyl, or R 12 and R 13 Together with the nitrogen atom to which they are attached, they form an optionally substituted heterocyclic group, and each R 14 is hydrogen, alkyl, or haloalkyl;

[0153] R 2 is hydrogen, deuterium, alkyl, halo, haloalkyl, alkenyl, or alkynyl;

[0154] R 2a is hydrogen or deuterium;

[0155] R 3 and R 4 is independently hydrogen, deuterium, alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl; or

[0156] R 3 and R 4 together with the carbon to which they are attached form oxo, 3- to 6-membered cycloalkylene, or 4- to 6-membered optionally substituted heterocyclylene;

[0157] R 5 is hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxy, or alkoxy;

[0158] R 6 is hydrogen, deuterium, alkyl, cycloalkyl, or halo; or

[0159] R 5 and R 6 together with the carbon to which they are attached form oxo, alkyldienyl, 3- to 6-membered cycloalkylene, or 4- to 6-membered optionally substituted heterocyclylene; provided that R 5 and R 6 and R 3 and R 4together with the carbon to which they are attached do not simultaneously form oxo, cycloalkylene, or optionally substituted 4- to 6-membered heterocyclylene;

[0160] R 7 is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, or haloalkoxy;

[0161] L is a bond, S, SO, SO2, O, CO, or NR 16 , where R 16 is hydrogen or alkyl;

[0162] R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, wherein aryl or heteroaryl, each by itself or as part of aralkyl or heteroaralkyl, or heterocyclyl, by itself or as part of heterocyclylalkyl, is replaced by R a , R b , R c , R g and / or R h Substitution, where R a , R b , and R c are independently selected from hydrogen, deuterium, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidene, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, and R g and R h are independently selected from hydrogen, deuterium, and halo; and

[0163] R 9 R is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, haloalkoxy, alkylsulfoxide, alkylsulfonyl, or heteroaryl, wherein the heteroaryl is optionally independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and cyano d , R e , and R f replace; or

[0164] When R 9 and R 2 When attached to the same carbon atom, they may combine to form oxo, alkyldienyl, 3- to 6-membered cycloalkylene, or 4- to 6-membered heterocyclylene;

[0165] R 9a is hydrogen or deuterium;

[0166] Pharmaceutically acceptable salts thereof;

[0167] In combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof.

[0168] 2. In Example 2, a method of treating cancer in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of a HIF-2α inhibitor having formula (I):

[0169]

[0170] in:

[0171] X 1 is CH or N;

[0172] R 1 Hydroxyl, halogen, amino, -OP(O)(OH)2, -OCH2OP(O)(OH)2, -OCOR 10 、-OCOOR 11 ,

[0173] -OCONR 12 R 13 、-OCHR 14 OCOR 15 or-OCHR 14 OCOOR 15a , where R 10 , R 11 , and R 15 and R 15a are independently alkyl or alkyl substituted by amino, carboxyl or hydroxyl, R 12 and R 13 are independently hydrogen, alkyl, or alkyl substituted with amino, carboxyl or hydroxyl, or R 12 and R 13 Together with the nitrogen atom to which they are attached, they form an optionally substituted heterocyclic group, and each R 14 is hydrogen, alkyl, or haloalkyl;

[0174] R 2 is hydrogen, deuterium, alkyl, halo, haloalkyl, alkenyl, or alkynyl;

[0175] R 2a is hydrogen, halogen, or deuterium;

[0176] R 3 and R 4 is independently hydrogen, deuterium, alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl; or

[0177] R 3 and R 4together with the carbon to which they are attached form oxo, 3- to 6-membered cycloalkylene, or 4- to 6-membered optionally substituted heterocyclylene;

[0178] R 5 is hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxy, or alkoxy;

[0179] R 6 is hydrogen, deuterium, alkyl, cycloalkyl, or halo; or

[0180] R 5 and R 6 together with the carbon to which they are attached form oxo, alkyldienyl, 3- to 6-membered cycloalkylene, or 4- to 6-membered optionally substituted heterocyclylene; provided that R 5 and R 6 and R 3 and R 4 together with the carbon to which they are attached do not simultaneously form oxo, cycloalkylene, or optionally substituted 4- to 6-membered heterocyclylene;

[0181] R 7 is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, or haloalkoxy;

[0182] L is a bond, S, SO, SO2, O, CO, or NR 16 , where R 16 is hydrogen or alkyl;

[0183] R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, wherein aryl or heteroaryl, each by itself or as part of aralkyl or heteroaralkyl, or heterocyclyl, by itself or as part of heterocyclylalkyl, is replaced by R a , R b , R c , R g and R h Substitution, where R a , R b , and R c are independently selected from hydrogen, deuterium, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidene, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, and R g and R h are independently selected from hydrogen, deuterium, and halo; and

[0184] R 9R is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, haloalkoxy, alkylsulfoxide, alkylsulfonyl, or heteroaryl, wherein the heteroaryl is optionally independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and cyano d , R e , and R f replace; or

[0185] When R 9 and R 2 When attached to the same carbon atom, they may combine to form oxo, alkyldienyl, 3- to 6-membered cycloalkylene, or 4- to 6-membered heterocyclylene;

[0186] R 9a is hydrogen, halogen, or deuterium; or

[0187] Pharmaceutically acceptable salts thereof;

[0188] in combination with a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof.

[0189] 3. In embodiment 3, the method of embodiment 1 or 2 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 3 and R 4 are independently halo.

[0190] 4. In embodiment 4, the method of embodiment 1 or 2 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 3 is halogenated and R 4 It's hydrogen.

[0191] 5. In embodiment 5, the method of embodiment 1, 2 or 3 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 1 It's a hydroxyl group.

[0192] 6. In Embodiment 6, the method of any one of Embodiments 1 to 3 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 1 It's amino.

[0193] 7. In embodiment 7, the method of any one of embodiments 1 to 6 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 6 It is halogenated.

[0194] 8. In embodiment 8, the method of any one of embodiments 1 to 6 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 6 is an alkyl group, preferably R 6It's methyl.

[0195] 9. In embodiment 9, the method of any one of embodiments 1 to 6 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 6 It's hydrogen.

[0196] 10. In embodiment 10, the method of any one of embodiments 1 to 6 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 6 is cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0197] 11. In embodiment 11, the method of any one of embodiments 1 to 10 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 5 is halogenated, preferably fluorine.

[0198] 12. In embodiment 12, the method of any one of embodiments 1 to 10 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 5 is a haloalkyl group, preferably R 5 It is difluoromethyl or trifluoromethyl.

[0199] 13. In embodiment 13, the method of any one of embodiments 1 to 10 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 5 is an alkyl group, preferably R 5 It is methyl or ethyl.

[0200] 14. In embodiment 14, the method of any one of embodiments 1 to 10 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 5 is hydrogen or alkoxy.

[0201] 15. In embodiment 15, the method of any one of embodiments 1 to 6 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 5 and R 6 Together with the carbon to which they are attached they form a 3- to 6-membered cycloalkylene, preferably cyclopropylene, cyclobutylene or cyclopentylene optionally substituted by one or two fluorines.

[0202] 16. In embodiment 16, the method of any one of embodiments 1 to 15 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein X 1 Yes CR 7 .

[0203] 17. In embodiment 17, the method of embodiment 1 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has a structure of formula (IIa1) or (IIb1):

[0204]

[0205] 18. In embodiment 18, the method of embodiment 1 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has a structure of formula (IIa1′) or (IIb1′):

[0206]

[0207] 19. In embodiment 19, the method of embodiment 1 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has a structure of formula (IIa) or (IIb):

[0208]

[0209] 20. In embodiment 20, the method of embodiment 1 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has a structure of formula (IIa') or (IIb'):

[0210]

[0211] 21. In embodiment 21, the method of embodiment 1 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has a structure of formula (IVa):

[0212]

[0213] Where R 5 and R 6 Together with the carbon to which they are attached they form a 3- to 6-membered cycloalkylene, preferably cyclopropylene, cyclobutylene or cyclopentylene optionally substituted by one or two fluorines.

[0214] 22. In embodiment 22, the method of any one of embodiments 17 to 21 is wherein the compound of formula (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb'), and (IVa) or a pharmaceutically acceptable salt thereof is wherein R 3 It's fluorine.

[0215] 23. In embodiment 23, the method of any one of embodiments 17 to 21 is wherein the compound of formula (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb'), and (IVa) or a pharmaceutically acceptable salt thereof is wherein R 3 and R 4 It's fluorine.

[0216] 24. In embodiment 24, the method as described in any one of embodiments 1 to 23 is wherein the compound of formula (I), (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb'), and (IVa) or a pharmaceutically acceptable salt thereof is wherein L is O, S, SO, SO2, or NH.

[0217] 25. In embodiment 25, the method as described in embodiment 24 is wherein the compound having formula (I), (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb'), and (IVa), or a pharmaceutically acceptable salt thereof is wherein L is O.

[0218] 26. In embodiment 26, the method of any one of embodiments 1 to 25 is wherein the compound of formula (I), (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb'), and (IVa) is wherein R 8 R is cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, wherein aryl or heteroaryl, each by itself or as part of aralkyl or heteroaralkyl, or heterocyclyl, by itself or as part of heterocyclylalkyl, is independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidene, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl. a , R b , and R c replace.

[0219] 27. In Embodiment 27, the method as described in any one of Embodiments 1 to 25 and the sub-embodiments contained therein is wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb'), and (IVa) or a pharmaceutically acceptable salt thereof is wherein R8 Is R a , R b , R c , R g and R h Substituted phenyl, wherein R a , R b , and R c is independently selected from hydrogen, deuterium, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, and R g and R h are independently selected from hydrogen and halo.

[0220] 28. In Embodiment 28, the method of Embodiment 27 and the sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, is wherein the compound of Formula (I), (IIa1), (IIb1), (IIa1′), (IIb1′), (IIa), (IIb), (IIa′), (IIb′) and (IVa) is wherein R 8 is 3-chloro-5-fluorophenyl, 3,5-difluorophenyl, 3-fluoro-5-methoxyphenyl, 3-cyano-5-fluorophenyl, 3-chloro-5-cyanophenyl, 3-cyano-5-methylphenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-fluoro-5-methylphenyl, 3-cyanophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3-chloro-2-methylphenyl, 3,5-dichlorophenyl, 3,5-dimethylphenyl, 2-chloro-6-methylphenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 4-fluoro-3-methylphenyl, 3-cyano-4-fluorophenyl, 3-cyano-5-difluoromethylphenyl, or 3-cyano-5-fluoro-2,4,6-trideuteriophenyl. In the first sub-embodiment of Embodiment 28, R 10 It is 3-cyano-5-fluorophenyl or 3-cyano-5-fluoro-2,4,6-trideuteriophenyl.

[0221] 29. In embodiment 29, the method of any one of embodiments 1 to 25 and any sub-embodiments contained therein is wherein the compound of formula (I), (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb'), and (IVa) or a pharmaceutically acceptable salt thereof is wherein R 8 is cycloalkyl or cycloalkylalkyl, each optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, cyano, and hydroxy.

[0222] 30. In embodiment 30, the method of any one of embodiments 1 to 25 and any sub-embodiments contained therein is wherein the compound of formula (I), (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb'), and (IVa) or a pharmaceutically acceptable salt thereof is wherein R 8 R is independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl. a , R b , and R c Substituted heteroaryl.

[0223] 31. In embodiment 31, the method of any one of embodiments 1 to 25 is wherein the compound of formula (I), (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb') and (IVa) or a pharmaceutically acceptable salt thereof is wherein R 8 is pyridin-3-yl, pyridin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, pyrimidin-2-yl, thiophen-2-yl, furan-2-yl, thiazol-5-yl, oxazol-5-yl, imidazol-5-yl, furan-3-yl, thiophen-3-yl, thiazol-4-yl, pyridin-4-yl, oxazol-2-yl, imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, or thiazol-2-yl, and R a , R b , and R c Substitution, where R a and R b are independently selected from hydrogen, methyl, methoxy, hydroxy, chloro, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy, and R c is selected from the group consisting of hydrogen, methyl, cyano, chlorine, fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.

[0224] 32. In embodiment 32, the method of any one of embodiments 1 to 31, wherein the compound of formula (I), (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb') and (IVa) or a pharmaceutically acceptable salt thereof is wherein R 7 is hydrogen, methyl, ethyl, methoxy, fluorine, trifluoromethyl, or trifluoromethoxy, preferably R 7 It's hydrogen.

[0225] 33. In embodiment 33, the method of any one of embodiments 1 to 32 is wherein the compound of formula (I), (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb') and (IVa) or a pharmaceutically acceptable salt thereof is wherein R 2 is hydrogen, fluorine, methyl or ethyl.

[0226] 34. In embodiment 34, the method of any one of embodiments 1 to 33 is wherein the compound of formula (I), (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIB') and (IVa) or a pharmaceutically acceptable salt thereof is wherein R 9 is hydrogen, alkyl, halo, hydroxy, or alkoxy.

[0227] 35. In embodiment 35, the method of any one of embodiments 1 to 33 is wherein the compound of formula (I), (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb') and (IVa) or a pharmaceutically acceptable salt thereof is wherein R 9 is hydrogen, methyl, methoxy, or fluorine.

[0228] 36. In embodiment 36, the method as described in embodiments 1 to 35 is wherein the compound of formula (I), (IIa1), (IIb1), (IIa1'), (IIb1'), (IIa), (IIb), (IIa'), (IIb'), and (IVa) or a pharmaceutically acceptable salt thereof is wherein R 2 and R 9 Attached to a ring carbon atom that is located adjacent to the ring attached to R 1 The meta position of the ring carbon.

[0229] 37. In embodiment 37, the method of any one of embodiments 28 or 31 is wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof, and has a structure of formula (VIIIa1) or (VIIIb1):

[0230]

[0231] Preferred are those having the structure of formula (VIIIb).

[0232] 38. In embodiment 38, the method of embodiment 37 is wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is wherein R 2 is hydrogen or deuterium, R 9 is hydrogen, fluorine, or methyl, and R2a and R 9a are independently hydrogen, deuterium or fluorine.

[0233] 39. In embodiment 39, the method of embodiment 1 is wherein the compound of formula (I) is selected from:

[0234] 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;

[0235] 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;

[0236] 3-Fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;

[0237] 3-Fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;

[0238] 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;

[0239] 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;

[0240] 3-Fluoro-5-(((1R,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;

[0241] 1,3,3,4,4-Pentafluoro-7-((5-fluoropyridin-3-yl)oxy)-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol;

[0242] 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydrospiro[cyclopenta[cd]-indene-1,1'-cyclopropane]-7-yl)oxy)benzonitrile;

[0243] 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;

[0244] 3-Fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;

[0245] 3-Fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;

[0246] 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;

[0247] 3-((2a-amino-1,3,3,4,4-pentafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile;

[0248] 3-Fluoro-5-((1,1,2a,3,3,4,4-heptafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;

[0249] 3-((3,3-difluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile;

[0250] 3-((3,3-difluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile;

[0251] 3-((3,3-difluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile;

[0252] 3-Fluoro-5-((1,3,3-trifluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile;

[0253] 3-Fluoro-5-((1,2,2,3,3,4,4-heptafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]-inden-7-yl)oxy)benzonitrile;

[0254] 3-Fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile;

[0255] 3-Fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d3;

[0256] (R)-3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;

[0257] (S)-3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;

[0258] 3-Fluoro-5-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; and

[0259] 3-Fluoro-5-(((1R,2R,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; or

[0260] or pharmaceutically acceptable salts thereof.

[0261] 40. In embodiment 40, the method of embodiment 1 is wherein the compound of formula (I) is selected from:

[0262] 3-Fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopentyl-[cd]inden-7-yl)oxy)benzonitrile;

[0263] 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

[0264] or pharmaceutically acceptable salts thereof.

[0265] 41. In embodiment 41, the method of embodiment 1 is wherein the compound of formula (I) is 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile.

[0266] 42. In embodiment 42, the method of embodiment 1 is wherein the compound of formula (I) is 3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile.

[0267] 46. ​​In embodiment 46, the method of any one of embodiments 1 to 46 is wherein the PARP inhibitor is olaparib (4-[(3-[(4-cyclopropylcarbonyl)piperazin-1-yl]carbonyl)-4-fluorophenyl]methyl (2H)-phthalazin-1-one), rucaparib (8-fluoro-2-{4-[(methylamino)-methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepine [5,4,3-cd]indol-6-one), niraparib (2-[4-[(3S)-3-piperidinyl]phenyl]indazole-7-carboxamide), talazoparib ((8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one), or pamiparib ((2R)-14-fluoro-2-methyl-6,9,10,19-tetraazapentacyclo[14.2.1.0 2,6 .0 8,18 .0 12,17 ]Nineteen-1(18),8,12(17),13,15-pentaen-11-one; trihydrate).

[0268] 47. In embodiment 47, the method of any one of embodiments 1 to 46 is wherein the cancer is selected from renal cancer, glioblastoma, neuroblastoma, paraganglioma, pheochromocytoma, somatostatinoma, hemangioblastoma, gastrointestinal stromal tumor, pituitary tumor, leiomyoma, leiomyosarcoma, polycythemia vera, retinal cancer, lung cancer, pancreatic cancer, liver cancer, ovarian cancer, breast cancer, prostate cancer, colorectal cancer, head and neck cancer, cervical cancer, endometrial cancer, bladder cancer, gastric cancer, esophageal cancer, lymphoma, melanoma, mesothelioma, sarcoma and neuroendocrine tumor.

[0269] 48. In embodiment 48, the method of embodiment 47, wherein the cancer is clear cell renal carcinoma.

[0270] 49. In embodiment 49, the method of any one of embodiments 1 to 46 is wherein the cancer is selected from ovarian cancer, breast cancer, prostate cancer, kidney cancer, colorectal cancer, uveal melanoma, pancreatic cancer, urothelial carcinoma, endometrial cancer, lung cancer, lymphoma, head and neck cancer, fallopian tube cancer, primary peritoneal cancer, cervical cancer, melanoma, esophageal cancer, gastric cancer, mesothelioma, bile duct cancer, glioblastoma, Ewing's sarcoma, uterine leiomyosarcoma, chronic lymphocytic leukemia, T-cell prolymphocytic leukemia, multiple myeloma, acute myeloid leukemia, chronic myelogenous leukemia, germ cell cancer, bladder cancer, neuroendocrine tumors, osteosarcoma, biliary tract cancer, soft tissue sarcoma, rhabdomyosarcoma, mantle cell lymphoma, and endocrine gland neoplasms.

[0271] 50. In embodiment 50, the method of any one of embodiments 1 to 49 is wherein the compound of formula (I) and the PARP inhibitor are administered sequentially or simultaneously.

[0272] 51. In embodiment 51, the method of any one of embodiments 1 to 50 is wherein the combination is a synergistic combination.

[0273] 52. In embodiment 52, the method of any one of embodiments 1 to 51 further comprises administering one or more additional anti-cancer agents.

[0274] Embodiment A:

[0275] A1. In embodiment A1, a compound of formula (IA) or a pharmaceutically acceptable salt thereof as provided in the fifth aspect of the present invention is provided.

[0276] A2. In Embodiment A2, the compound having (IA) or a pharmaceutically acceptable salt thereof has a structure according to Formula (IA'):

[0277]

[0278] A3. In embodiment A3, the compound as described in embodiment A1 or A2 or a pharmaceutically acceptable salt thereof is wherein R a , R b , and R c are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano.

[0279] A4. In embodiment A4, the compound as described in embodiment A1 or A2 or a pharmaceutically acceptable salt thereof is wherein R a , R b, and R c are independently selected from hydrogen, deuterium, methyl, methoxy, hydroxy, chlorine, fluorine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy, and R g and R h is independently hydrogen or deuterium.

[0280] A5. In embodiment A5, the compound as described in embodiment A1 or A2 or a pharmaceutically acceptable salt thereof is wherein R 8 It is 3-chloro-5-fluorophenyl, 3,5-difluorophenyl, 3-fluoro-5-methoxyphenyl, 3-cyano-5-fluorophenyl, 3-chloro-5-cyanophenyl, 3-cyano-5-methylphenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-fluoro-5-methyl, 3-cyanophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3-chloro-2-methylphenyl, 3,5-dichlorophenyl, 3,5-dimethylphenyl, 2-chloro-6-methylphenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 4-fluoro-3-methylphenyl, 3-cyano-4-fluorophenyl, 3-cyano-5-difluoromethylphenyl, or 3-cyano-5-fluoro-2,4,6-trideuteriophenyl.

[0281] A6. In embodiment A6, the compound as described in embodiment A1 or A2 or a pharmaceutically acceptable salt thereof is wherein R 8 It is 3-cyano-5-fluorophenyl or 3-cyano-5-fluoro-2,4,6-trideuteriophenyl.

[0282] A7. In embodiment A7, the compound as described in embodiment A1 or A2 is selected from:

[0283] 3-Fluoro-5-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; and

[0284] 3-Fluoro-5-(((1R,2R,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; or

[0285] or pharmaceutically acceptable salts thereof.

[0286] General synthetic scheme

[0287] The compounds of the present disclosure can be prepared by the methods depicted in the reaction schemes shown below.

[0288] Starting materials and reagents used to prepare these compounds can be obtained from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or prepared by methods known to those skilled in the art following the procedures set forth in, for example, Fieser and Fieser's Reagents for Organic Synthesis, Vols. 1-17 (John Wiley & Sons, 1991); Rodd's Chemistry of Carbon Compounds, Vols. 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Vols. 1-40 (John Wiley & Sons, 1991); March's Advanced Chemistry, Vols. 1-41 (John Wiley & Sons, 1991); Organic Chemistry (John Wiley & Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some of the methods by which the disclosed compounds may be synthesized, and various modifications may be made to these schemes and will be enlightening to those of ordinary skill in the art upon reading this disclosure. If desired, these starting materials and intermediates, as well as the final products of the reactions, may be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0289] Unless indicated to the contrary, the reactions described herein occur at atmospheric pressure, at a temperature range from about -78°C to about 150°C, such as from about 0°C to about 125°C, and further such as at about room temperature (or ambient temperature), such as about 20°C.

[0290] Compounds of formula (I) can be prepared as illustrated and described in Scheme 1 below, wherein X 1 It is CH, R 1 is hydroxyl, R 3 , R 4 , R 5 , R 6 , R 7 , and R8 As defined in the Summary of the Invention (or any embodiment thereof), and R 9 With R 2 Combine to form an alkyldiene group.

[0291] Solution 1

[0292]

[0293] An aldehyde having the formula 1-a (wherein R 7 is as described in the Summary of the Invention or a precursor thereof) and a compound having Formula 1-b (wherein X 1 is a halide, and R 3 A zinc metal-mediated Reformastky reaction between (as defined, for example, independently hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl) provides a compound of formula 1-c. Compounds of formula 1-a and 1-b are commercially available or they can be prepared by methods well known in the art. For example, 2-bromo-4-fluorobenzaldehyde, ethyl 2-bromo-2,2-difluoroacetate, ethyl 2-bromo-2-methylpropionate, ethyl 2-bromopropionate, ethyl 2-bromoacetate are commercially available. The hydroxyl group in 1-c can be oxidized under oxidizing conditions (such as 2-iodobenzoic acid (IBX) or TPAP, NMO) to give a ketone of formula 1-d. By methods well known in the art, the ketone group in the compound of formula 1-d can be functionalized to provide a compound of formula 1-e, wherein R 5 and R 6 As described in the Summary of the Invention. For example, compounds of formula 1-e, wherein R 5 and R 6 is fluorine. Cyclization of 1-e can be achieved by treating it with an alkyl lithium reagent such as n-BuLi to give ketone 1-f. The carbonyl group in 1-f can be reduced with a reducing agent such as NaBH4 to provide alcohol 1-g.

[0294] Compounds of formula 1-g can be converted to compounds of formula 1-h by lithiation of 1-g followed by treatment of the lithium intermediate with CBr4. Oxidation of 1-h with an oxidant such as IBX provides ketones of formula 1-i. Addition of an allyl metal reagent such as allyl magnesium bromide to compounds of formula 1-i provides compounds of formula 1-j.

[0295] Alternatively, a compound of formula 1-j can be prepared from 1-f by adding an allyl metal reagent (such as allyl magnesium bromide) to a compound of formula 1-f as shown below:

[0296]

[0297] Lithiation of 1-g with a base (such as LDA) followed by treatment of the lithium intermediate with a brominating agent (such as CBr4 or 1,2-dibromotetrafluoroethane) provides compounds of formula 1-j. If desired, the enantioselective synthesis of compounds of formula 1-g can be achieved by adding 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane to compounds of formula 1-f in the presence of a ligand (such as 1-m) and a suitable base (such as tBuONa) in an organic solvent (such as MeOH, toluene) as shown below:

[0298]

[0299] Compounds of formula 1-j can be cyclized in the presence of a Pd catalyst and a suitable ligand (such as Pd(dppf)Cl2CH2Cl2 or Pd(PPh3)2Cl2) to provide compounds of formula 1-k. Compounds of formula R can be cyclized by methods well known in the art. 8 -LH compound (wherein L is N, O, or S, and R 8 As defined in the Summary of the Invention), treating compound 1-k to convert the fluorine group in the compound of formula 1-k into a compound of formula -LR 8 A group (where L and R 8 As described in the Summary of the Invention). having the formula R 8 -LH compounds are commercially available or they can be prepared by methods well known in the art. For example, 3-fluoro-5-hydroxybenzonitrile, 3,5-difluorophenol, 3-chloro-5-fluorophenol, 3-chloro-5-hydroxy-benzonitrile, 5-fluoropyridine-3-ol, 5-chloropyridine-3-ol, 5-hydroxynicotinonitrile, 3-fluoro-5-mercaptobenzonitrile, 3-amino-5-fluorobenzonitrile, 3,3-difluorocyclobutane-1-ol, 3-amino-5-fluorobenzonitrile, 3-fluoro-5-mercaptobenzonitrile, 3-chloro-5-mercaptobenzonitrile, 3-amino-5-chlorobenzonitrile are commercially available.

[0300] Compounds of formula (I) can be prepared as illustrated and described in Scheme 2 below, wherein R 1 is hydroxyl, R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 As defined in the Summary of the Invention (or any embodiment thereof), and R 9 With R 2 Combine to form oxo.

[0301]

[0302] Compounds of formula 1-k can be converted to compounds of formula 1-1 by treating them with oxidative cleavage agents such as NaIO4 and RuCl3 hydrate under conditions well known in the art. 8 -LH compound to treat compound 1-1, the fluorine group in the compound of formula 1-1 is converted into a compound of formula -LR 8 A group (where L and R 8 as described in the Summary of the Invention).

[0303] Compounds of formula (I) may be converted to other compounds of formula (I) by methods well known in the art. For example, compounds of formula (I) (wherein R 9 With R 2 Combination to form oxo) to synthesize a compound having formula (I) (wherein R 1 is hydroxyl, R 2 is hydrogen, and R 9 is hydroxyl or fluorine).

[0304] Method (i)

[0305]

[0306] The compound of formula (I) (wherein R 1 is hydroxyl, R 9 With R 2 Combining to form an oxo group), converting it into a compound having formula (I) (wherein R 1 is hydroxyl, R 9 is hydroxyl).

[0307] Method (ii)

[0308]

[0309] Compounds of formula (I) (wherein R 1 is hydroxyl, R 9 is a hydroxyl group), which is converted into a compound having formula (I) (wherein R 1 is hydroxyl, R 9 is fluorine).

[0310] utility

[0311] HIF-2α plays an important role in the development and progression of many human cancers. Many extensive studies have demonstrated the key role of increased HIF-2α activity in driving clear cell renal cell carcinoma (ccRCC) (see Shen and Kaelin for review, Seminars in Cancer Biology 23:18-25, 2013). Abnormal HIF-2α activity is mainly due to the loss of function of the tumor suppressor VHL. It is known that more than 80% of ccRCC have defective VHL through deletion, mutation or disturbed post-translational modification. Defective VHL leads to constitutively active HIF-α protein regardless of oxygen content. Various studies using gain-of-function and loss-of-function approaches in mouse models have demonstrated that HIF-2α is a key oncogenic substrate of VHL (see Kondo et al. Cancer Cell 1:237-246, 2002; Kondo et al. PLoS Biology 1:439-444, 2002; Maranchi et al. Cancer Cell 1:247-255, 2002; Zimmer et al. Mol. Cancer Res 2:89-95, 2004). For example, knockdown of HIF-2α in VHL-null tumors inhibits tumor formation, while reintroduction of VHL and overexpression of HIF-2α overcome the tumor suppressive effects of VHL. In addition, single nucleotide polymorphisms in HIF-2α are associated with resistance to PHD-mediated degradation and are associated with an increased risk of RCC. In addition to being a typical tumor initiation event in ccRCC, the VHL-HIF-2α axis is also involved in ccRCC tumor metastasis through its downstream CXCR4 and CYTIP (see Vanharanta et al. Nature Medicine 19:50-59, 2013; Peter Staller et al. Nature. 2003 Sep 18; 425(6955):307-11). In summary, these studies strongly support the potential therapeutic utility of HIF-2α-targeted agents for the treatment of ccRCC.

[0312] Defective VHL not only predisposes patients to renal cancer (lifetime risk of 70%), but also to hemangioblastoma, pheochromocytoma, endolymphatic sac tumors, and pancreatic neuroendocrine tumors. Tumors derived from defective VHL are usually driven by constitutively active downstream HIF-α proteins, most of which depend on HIF-2α activity (see Maher et al. Eur. J. Hum. Genet [European Journal of Human Genetics]. 19: 617-623, 2011). Both genetic and epigenetic mechanisms can lead to loss of VHL function. Epigenetic inactivation of VHL expression and the constitutive activation of HIF-α protein have been found in many cancers, including RCC, multiple myeloma, retinoblastoma, NSCLC, pancreatic endocrine tumors, squamous cell carcinoma, acute myeloid leukemia, myelodysplastic syndrome, and esophageal squamous cell carcinoma (see the review by Nguyen et al. Arch. Phann. Res [Drug Research Literature] 36: 252-263, 2013). HIF-2α is also associated with retinal cancer, adrenal cancer, and pancreatic cancer through both VHL loss of function and activating mutations of HIF-2α. Recently, gain-of-function HIF-2α mutations have been identified in polycythemia vera and paraganglioma with polycythemia vera (see Zhuang et al. NEJM [New England Journal of Medicine] 367:922-930, 2012; Percy et al. NEJM [New England Journal of Medicine] 358:162-168, 2008; and Percy et al. Am. J. Hematol [American Journal of Hematology]. 87:439-442, 2012). Notably, many known HIF-2α target gene products (e.g., VEGF, PDGF, and cyclin D1) have been shown to play a key role in cancers originating from the kidney, liver, colon, lung, and brain. Therefore, HIF-2α targeted therapies may be beneficial for the above cancers when driven by these signaling events downstream of abnormal HIF-2α pathway activation. In addition to loss-of-function VHL and activating mutations in HIF-2α, HIF-α protein is frequently upregulated in the intratumoral environment of rapidly growing tumors due to hypoxic conditions caused by poor vascularization in large tumors. In turn, the activated HIF-α pathway further promotes tumor cell survival and proliferation by transcriptionally upregulating various essential factors.

[0313] Numerous studies have demonstrated that HIF-2α overexpression is associated with poor prognosis in various cancers, including astrocytoma, breast cancer, cervical cancer, colorectal cancer, glioblastoma, glioma, head and neck cancer, liver cancer, non-small cell lung cancer, melanoma, neuroblastoma, ovarian cancer, and prostate cancer, supporting HIF-2α as a therapeutic target for the treatment of these cancers (see review by Keith et al. Nature Rev. Cancer 12:9-22, 2012). HIF-2α has been shown to promote the growth of APC mutant colorectal cancer by regulating 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), knocking down HIF-2α in preclinical models resulted in inhibition of in vitro cell proliferation and in vivo tumor growth by downregulating VEGF and cyclin D1 (see He et al. Cancer Sci [Cancer Science] 103: 528-534, 2012). In NSCLC, approximately 50% of patients exhibit overexpression of HIF-2α protein, which is closely associated with higher VEGF expression and, more importantly, decreased overall survival. Interestingly, although HIF-1α expression is also often increased, it is not associated with decreased overall survival in lung cancer patients (see Giatromanolaki et al. Br. J. Cancer [British Journal of Cancer] 85: 881-890, 2001). Extensive studies of mice engineered with both non-degradable HIF-2α and mutant KRAS tumors showed increased tumor burden and decreased survival compared to mice with mutant KRAS expression alone (see Kim, et al. J. Clin. Invest [Journal of Clinical Research]. 119: 2160-2170, 2009). These studies indicate that HIF-2α promotes tumor growth and progression of lung cancer and is also negatively correlated with clinical prognosis.

[0314] HIF-2α activity has also been shown 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). In preclinical animal models of neuroblastoma, HIF-2α knockdown reduced tumor growth, whereas increased levels of HIF-2α were associated with advanced disease, poor prognosis, and higher VEGF levels, which may lead to poor clinical outcomes. Similarly, higher HIF-2α expression was associated with poor survival in gliomas. Experimentally, inhibition of HIF-2α in glioma stem cells reduced cell proliferation and survival in vitro and tumorigenesis in vivo. Although HIF-1α is expressed in both neural progenitor cells and brain tumor stem cells, HIF-2α is only found in the latter. In addition, the survival of patients with gliomas was associated with HIF-2α, but not with HIF-1α levels.

[0315] Somatostatinoma is a rare neuroendocrine tumor that produces somatostatin, but it is often malignant. It has been found that HIF-2α mutations lead to the destruction of the prolyl hydroxylation domain (PHD) of HIF-2α, thereby eliminating the modification of PHD and subsequently reducing the degradation of HIF-2α mediated by VHL (see Yang, et al. Blood [blood]. 121: 2563-2566, 2013). Then, stable HIF-2α can be translocated to the nucleus, thereby driving the increased expression of hypoxia-related genes, leading to somatostatinoma. Therefore, HIF-2α inhibitors will provide an alternative method for treating somatostatinoma.

[0316] Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors that usually develop in the context of susceptibility gene mutations, including loss of function of VHL or PHD2 or activating mutations of HIF-2α, all of which lead to HIF-2α protein, followed by high expression of downstream genes to promote carcinogenic progression (see Dahia, Nat Rev Cancer [Cancer Nature Review]. 14: 108-19, 2014). In addition, germline heterozygous mutations of genes encoding succinate dehydrogenase (SDH) subunits and SDH complex assembly factor 2 protein (SDHAF2) have been described in patients with hereditary pheochromocytoma and paraganglioma (PPGL). These mutations can lead to the accumulation of succinate, which in turn leads to the inhibition of prolyl-hydroxylases, which is essential for mediating the ubiquitination / degradation of HIF proteins by the VHL complex. Pituitary adenomas are often found to coexist with PPGL. Therefore, inhibition of HIF-2α should be useful for treating both PPGL and pituitary tumors. Succinate dehydrogenase subunit mutations are also associated with gastrointestinal stromal tumors (GIST), thus 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).

[0317] Function loss mutations in fumarate hydratase (FH) predispose patients to an autosomal dominant syndrome of skin and uterine leiomyoma. It has been shown that activation of HIF proteins promotes FH-related tumor development by activating hypoxia pathways. (See O'Flaherty, et al. Hum Mol Genet [Human Molecular Genetics]. 19: 3844-3851, 2010 and Wei, et al. J Med Genet [Journal of Medical Genetics]. 43: 18-27, 2006). In addition, high expression of HIF-2α has been found in leiomyosarcoma (a rare neoplasm of smooth muscle origin) (see Mayer, et al. Cancer Res [Cancer Research]. 68: 4719, 2008). Therefore, inhibition of HIF-2α may be beneficial in treating both leiomyoma and leiomyosarcoma.

[0318] Retinal capillary hemangioblastoma may be an ocular manifestation of VHL disease, which is caused by the loss of the tumor suppressor VHL. Upregulation of HIF-2α after VHL loss has been detected in patients with retinal hemangioblastoma, and this upregulation has been shown to promote the aggressive course of retinal hemangioblastoma, leading to resistance to multiple anti-VEGF and radiation therapies (see Wang, et al. Graefes Arch. Clin. Exp. Ophthalmol. 252: 1319-1327, 2014).

[0319] In addition to its direct role in promoting the occurrence, progression and metastasis of tumor cells (e.g., ccRCC), HIF-2α also indirectly promotes tumorigenesis by enhancing the immunosuppressive effects of hypoxia in the tumor microenvironment. The expression of HIF-2α has been detected in myeloid cells (see Talks KL, et al. Am J Pathol [American Journal of Pathology]. 2000; 157 (2): 411-421). For example, HIF-2α has been shown to favor the polarization of macrophages to the immunosuppressive M2 phenotype and enhance the migration and invasion of tumor-associated macrophages (see Imtiyaz HZ et al. J Clin Invest [Clinical Research Journal]. 2010; 120 (8): 2699-2714). Therefore, increased levels of HIF-2α in tumor-associated macrophages (TAMs) are associated with advanced tumors and are associated with poor prognosis. Furthermore, HIF-2α can indirectly promote other immunosuppressive pathways (e.g., adenosine and arginase, etc.) by modulating the expression of key signaling regulators (e.g., adenosine A2B / A2A receptors and arginase, etc.). These data support HIF-2α as a potential therapeutic target for the treatment of a wider range of inflammatory disorders and cancer, either as a single agent or in combination with other therapeutic agents (e.g., immunotherapy).

[0320] In addition, HIF-2α compounds can be used as a single agent to treat one or more cartilage cancers, one or more skin cancers, salivary gland cancer, stomach cancer, gastric cancer, liver cancer, endometrial cancer, bladder cancer, mesothelioma, sarcoma, esophageal cancer, lymphoma, uveal melanoma, urothelial carcinoma, fallopian tube cancer, primary peritoneal cancer, bile duct cancer, Ewing's sarcoma, uterine leiomyosarcoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, T-cell prolymphocytic leukemia, chronic myeloid leukemia, germ cell cancer, osteosarcoma, biliary tract cancer, soft tissue sarcoma, rhabdomyosarcoma, mantle cell lymphoma, and endocrine gland neoplasms.

[0321] Additionally, HIF-2α inhibitors (eg, compounds 24a or 24b disclosed herein) can be used to treat non-oncology indications (eg, arterial hypertension (PAH), NASH, inflammatory bowel disease (IBD), or iron overload).

[0322] test

[0323] The HIF-2α inhibitory activity of the disclosed compounds can be tested using the in vitro assay described in the following Biological Example 1. The ability of the disclosed HIF-2α compounds to inhibit the heterodimerization of HIF-2α to HIF-1β (ARNT) can be tested using the in vitro assay described in the following Example 2. The ability of the disclosed HIF-2α compounds to prevent or treat PAH can be determined using the hypoxia-induced PAH in vivo model described in Examples 36 and 37 of PCT Application Publication No. WO 2016145032. The anti-proliferative effect of the combination of HIF-2α inhibitors and PARP inhibitors in ccRCC cancer can be evaluated using the in vitro assay described in the following Biological Example 3.

[0324] Pharmaceutical composition

[0325] Typically, the HIF-2α and PARP inhibitors disclosed herein will be administered in a therapeutically effective amount by any accepted mode of administration for agents of similar utility. As a single agent, the therapeutically effective amount of the HIF-2α inhibitor disclosed herein can range from about 5 mg to about 500 mg / day, preferably 10 mg to 200 mg / day, which can be administered in a single dose or multiple doses. For oral administration, the composition can be provided in the form of a tablet or capsule containing about 5.0 to about 500 mg, preferably about 5, 10, 20, 50, 75, 100, 150, 200, 250, 300, 400, or 500 mg of the HIF-2α inhibitor.

[0326] For combination therapy, the therapeutically effective amount of the HIF-2α inhibitor can range from about 0.01 to about 100 mg / kg patient body weight / day, which can be administered in a single dose or multiple doses. Suitable dosage levels of the HIF-2α inhibitor can be about 0.1 to about 50 mg / kg / day; about 0.5 to about 15 mg / kg / day. For oral administration, the composition can be provided in the form of a tablet containing about 20 to about 800 mg of the HIF-2α inhibitor active ingredient, particularly about 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 mg of the active ingredient. The therapeutically effective amount of the PARP inhibitor for use in combination therapy can range from about 0.001 to about 100 mg / kg patient body weight / day, which can be administered in a single dose or multiple doses. Suitable dosage levels for the PARP inhibitor may be about 0.001 to about 50 mg / kg / day; 0.003 to about 50 mg / kg / day; about 0.001 to about 20 mg / kg / day; or about 0.001 to about 15 mg / kg / day. For oral administration, the composition can be provided in the form of a tablet containing about 0.25 to about 800 mg of the PARP inhibitor active ingredient, particularly about 0.25, 0.5, 1, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 mg of the PARP inhibitor active ingredient. In one embodiment, the PARP inhibitor is pamiparib and can be administered at 20 mg BID, 40 mg BID, or 60 mg BID, or at about 0.5 to about 2 mg / kg / day. In another embodiment, the PARP inhibitor is rucaparib, which can be administered at 600 mg PO BID (if there are adverse reactions, reduce the dose), or at about 10 to about 20 mg / kg / day. In another embodiment, the PARP inhibitor is olaparib, and can be administered at 300 mg PO BID (if there are adverse reactions, reduce the dose), or at about 2.5 to about 10 mg / kg / day. In another embodiment, the PARP inhibitor is niraparib, and can be administered at 300 mg PO Q day (if there are adverse reactions, reduce the dose), or at about 1 to about 6 mg / kg / day. In another embodiment, the PARP inhibitor is talazopanib, and can be administered at 1 mg PO per day (if there are adverse reactions, reduce the dose), or at about 0.003 to about 0.14 mg / kg / day.

[0327] The actual amount of HIF-2α and / or PARP inhibitor (i.e., active ingredient) will depend on 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.

[0328] Typically, the HIF-2α and PARP inhibitors of the present disclosure will be administered as a pharmaceutical composition by any of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous). The preferred mode of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of disease. The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained release formulation, solution, suspension, elixir, aerosol or any other appropriate composition.

[0329] The choice of formulation depends on factors such as the mode of drug administration (eg, for oral administration, formulations in the form of tablets, pills or capsules are preferred, including enteric-coated or sustained-release tablets, pills or capsules) and the bioavailability of the drug substance.

[0330] Typically, the composition consists of a HIF-2α and / or PARP inhibitor of the present disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, facilitate administration, and do not adversely affect the therapeutic benefits of the HIF-2α and PARP inhibitors. Such excipients can be any solid, liquid, semisolid, or in the case of an aerosol composition, a gaseous excipient commonly available to those of ordinary skill in the art.

[0331] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skim milk powder, etc. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers (especially for injectable solutions) include water, saline, aqueous dextrose and glycerol.

[0332] The compound can be formulated for parenteral administration by injection (e.g., by push injection or continuous infusion). Injectable preparations can be provided in unit dosage form, for example, in ampoules with preservatives added or in multi-dose containers. The composition can take the form of a suspension, solution or emulsion, for example, in an oily or aqueous vehicle, and can contain a preparaton (such as a suspending agent, a stabilizer and / or a dispersant). The preparation can be present in a unit dose or multi-dose container (e.g., sealed ampoules and vials), and can be stored in powder form or stored under freeze drying (lyophilization) conditions, requiring only the immediate addition of a sterile liquid carrier (e.g., saline or sterile pyrogen-free water) before use. Temporary injection solutions and suspensions can be prepared by sterile powders, granules and tablets of the aforementioned types.

[0333] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil), or synthetic fatty acid esters (such as ethyl oleate or triglycerides), or liposomes. Aqueous injection suspensions may include substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain a suitable stabilizer or an agent that increases the solubility of the compound to allow the preparation of a highly concentrated solution.

[0334] In addition to the aforementioned formulations, the compound can also be formulated into a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compound can be formulated with a suitable polymeric or hydrophobic material (e.g., formulated into an emulsion in an acceptable oil) or with an ion exchange resin, or formulated into a poorly soluble derivative, such as a poorly soluble salt.

[0335] For buccal or sublingual administration, the composition may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0336] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0337] The level of the compound in the formulation can vary within the full range used by those skilled in the art. Typically, the formulation will contain about 0.01-99.99 wt.% HIF-2α and / or one or more PARP inhibitors, based on weight percentage (wt.%), with the remainder being one or more suitable pharmaceutical excipients. For example, HIF-2α and / or one or more PARP inhibitors are present at a level of about 1-80 wt.%.

[0338] The HIF-2α inhibitors disclosed herein can be administered alone or in combination with a PARP inhibitor together with one or more other anticancer drugs that can be used to treat cancers for which the compounds disclosed herein are effective. Such one or more other drugs can be administered simultaneously or sequentially with the HIF-2α inhibitor and / or one or more PARP inhibitors by a route and in an amount commonly used therefor. It is also contemplated that when used in combination with such one or more other active ingredients, the HIF-2α inhibitor and / or the PARP inhibitor and the other active ingredients can be used at a lower dose than when each is used alone.

[0339] Therefore, in addition to one or more HIF-2α inhibitors and / or one or more PARP inhibitors, the pharmaceutical compositions of the present disclosure also include those containing one or more other drugs. The weight ratio of the compounds of the present disclosure to such other active ingredients may vary and will depend on the effective dose of each ingredient. Generally, the respective effective doses will be used.

[0340] Examples of such other anticancer agents include, but are not limited to, gossypol, genaquinoxaline, polyphenol E, chlorofusion protein, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all trans-retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec TM ), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, Taxol TM (also known as "paclitaxel," which is a well-known anticancer drug that works by enhancing and stabilizing microtubule formation), and Taxol TM Analogues (such as Taxotere TM ).

[0341] Other anticancer agents include inhibitors of kinases associated with cell proliferative disorders. These kinases include, but are not limited to, Aurora-A, BTK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, MEK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, RAF, Rsk, and SGK.In particular, inhibitors of CDK4 / 6, including abemaciclib (Verzenio), palbociclib (Ibrance), and ribociclib (Kisqali), have the potential to synergize with HIF-2α inhibitors and reverse resistance to HIF-2α inhibition; mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; antibodies (e.g., rituximab); MET inhibitors (e.g., foretinib, carbozantinib, or crizotinib); VEGFR inhibitors (e.g., sunitinib, sorafenib, regorafinib, lenvatinib, vandetanib); ndetanib, cabozantinib, axitinib); EGFR inhibitors (such as afatinib, brivanib, carbozatinib, erlotinib, gefitinib, neratinib, lapatinib); PI3K inhibitors (such as XL147, XL765, BKM120 (buparlisib), GDC- 0941, BYL719, IPI145, BAY80-6946, BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771, TG100-115; MTOR inhibitors (such as rapamycin (sirolimus), temsirolimus, everolimus), XL388, XL765, AZD2013, PF 04691502, 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.); TGFβ receptor kinase inhibitors (such as LY2157299); BTK inhibitors (such as ibrutinib).

[0342] Other anticancer agents 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 (such as azacytidine, decitabine) and other epigenetic regulators; 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); β-catenin pathway inhibitors, notch pathway inhibitors, and hedgehog pathway inhibitors. Antibodies or other therapeutic proteins to VEGF include bevacizumab and aflibercept.

[0343] Other anticancer 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 LXRβ-selective agonists); aryl hydrocarbon receptor (AhR) inhibitors.

[0344] Other anticancer agents that can be used in combination with the compounds of the present disclosure include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; aclonine; adolesin; aldesleukin; hexamethylmelamine; ambromycin; ametrine acetate; aminoglutethimide; amsacrine anastrozole; anthramycin; asparaginase; tricholin; azacitidine; azatepa; azomycin; batimastat; benzotepa; bicalutamide; bisantrene hydrochloride; binefad dimesylate; bierexin; bleomycin sulfate; brequinar sodium; bropiridamine; busulfan; actinomycin; caprotestosterone; caracetamide; carbetim; carboplatin; carmustine; carrubicin hydrochloride; carzeresin; cedifingol; chlorambucil; siromycin; cladribine; cristal mesylate mesylate); cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dextromaplatin; dezaguanine; dezaguanine mesylate; diazocone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drolostanone propionate; dazomicin; edatrexamate; eflornithine hydrochloride; elsamitrucin; enloplatin; enprobamate; epipipridine; epirubicin hydrochloride; erbulazole; isorubicin hydrochloride; estramustine; estramustine sodium phosphate; estramustine Tanidazole; etoposide; etoposide phosphate; clofenac; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flucitabine; fosquatone; fostramoxine sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; imofosine; interleukin II (including recombinant interleukin II, or Ril2), interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; lirazo hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprofen; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menolipir; mercaptopurine; methotrexate; methotrexate sodium; chlorpheniramine; metodepa; mibutidamide; mitoxine; mitoclocycline; mitoxine; mitomasin; mitoxine; mitoxine Pe; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; noramycin; ormaplatin; oxysulam; pegaspargase; pelimycin; pentamidine; pelimycin sulfate; perfosfamide; piperobroman; piperosulfan; pyroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; methyl mitomycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyraclostrobin; riboadenylate; roglutimide; safinol; safinol hydrochloride; semustine; sintrazine;Sodium spalfosate; sparmyn; spirogermanium hydrochloride; spiromustine; spiroplatin; streptozocin; streptozotocin; sulfaquinoxaline; talithromycin; tecogalan sodium; tegafur; tiloxantrone hydrochloride; temoporfin; teniposide; tiroxilon; testolactone; thiabendazole; thioguanine; thiotepa; thiazofurine; tirapazamine; toremifene citrate; triptolan acetate; Triciribine phosphate; Trimetrexate; Trimetrexate glucuronide; Triptorelin; Tobradazole hydrochloride; Uramustine; Uredepa; Vapreotide; Verteporfin; Vinblastine sulfate; Vincristine sulfate; Vindesine; Vindesine sulfate; Vinpitidine sulfate; Vingolide sulfate; Vinpoline sulfate; Vinorelbine tartrate; Vinprodine sulfate; Vinpoptidine sulfate; Vorozole; Zoniplatin; Zoloft; Zorubicin hydrochloride. ;

[0345] Other anticancer agents that can be used in combination with the compounds of the present disclosure include: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adenosine; adolesin; aldesleukin; ALL-TK antagonists; hexamethylmelamine; aminomustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide ; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; antiandrogen, prostate cancer; antiestrogens; antineoplastons; antisense oligonucleotides; glycine aphidicolin; apoptosis gene modulator; apoptosis modulator; apurinic nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; amustine; axinastatin 1; amustine 2; amustine 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonist; benzochlorin; benzoylstaurosporine; beta-lactam derivatives; beta-alethine; aclarubicin B; betulinic acid; Bfg f inhibitor; bicalutamide; bisantrene; diazinonespermine; binefad; bistratene A; biszelesin; breflate; bropiridamine; budotitan; butyrosine sulfenyl imine; calcipotriol; carvstatin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage-derived inhibitor; cardzelesin; casein kinase inhibitor (ICOS); castanespermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cisporphyrin; cladribine; clomiphene analogs; clotrimazole; collismycin A; collismycin B; conagenin A4; conagenin analogs; conagenin; crambescidin )816; Clinato; Nostoc cyclotide 8; Nostoc cyclotide A derivative; Curacao A; Cyclopentanthraquinone; Cycloplatam; Cypemycin; Cytarabine octadecyl phosphate; Cytolytic factor; Hexylestradiol phosphate; Dacilizumab; Decitabine; Dehydroaspartate B; Deslorelin; Dexamethasone; Dexifosfamide; Dexrazoxane; Dexverapamil; Diazocone; Aspartate B; Didox; Diethylnorspermine;dihydro-5-azacytidine; 9-dioxazolidinone; biphenylspiromustine; docosinol; dolasetron; deoxyfluridine; droloxifene; dronabinol; duocamisin SA; ebselen; ecomustine; edilfosine; edrecolomab; eflornithine; elemene; ethidium bromide; epirubicin; eristeride; estramustine analogs; estrogen agonists; estrogen antagonists; etaninazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavin; fluasterone; fludarabine; fluorodaunorunicin hydrochloride hydrochloride); fofolmek; formestane; fostramcin; fostramustine; gadotisalen; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylenediethylamide; hyperforin; ibandronic acid; idarubicin; idoxifene; idemenone; imofosine; ilomastat; imidazoacridone; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitors; Interferon agonists; interferon; interleukin; iodobenzylguanidine; iodoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate triacetate; lanreotide; leinamycin; leigostim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; interferon-alpha; leuprolide + estrogen + progesterone; leuprolide; levamisole; lirozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; earthworm phospholipids; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lutetone; tessarin lutetium; lisofylline; lytic peptide ; Metansine; mannostatin A; Marimastat; Masoprofen; Masospin; Matrix lytic factor inhibitor; Matrix metalloproteinase inhibitor; Menoliol; Mebaron; Metirelin; Methioninase; Metoclopramide; MIF inhibitor; Mifepristone; Miltefosine; Miregrastim; Mismatched double-stranded RNA; Mitoguanazone; Dibromodulanol; Mitomycin analog; Mitoxantrone; Mitotoxin fibroblast growth factor-saponin; Mitoxantrone; Mofaroten; Moragrastim; Monoclonal antibody, human chorionic gonadotropin; Mopidarol; Multidrug resistance gene inhibitor;Multiple tumor suppressor 1-based therapy; mustard anticancer agent; Indian Ocean sponge (mycaperoxide) B; mycobacterial cell wall extract; myriaporone; N-acetyl pyridazine; N-substituted benzamides; nafarelin; naritipen; naloxone + pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin (ni samycin; nitric oxide modulators; nitric oxide antioxidants; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; oracin; oral cytokine inducers; oramaplatin; oxatrome; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoctonia zoxin; pamidronate; panaxytriol; panomifen; paracoccin; pazeptine; pegaspargase; perdecan; sodium polysulfide; pentostatin; pentozole; perflurane; perphosphamide; perillyl alcohol; benzodiazepine; phenylacetate; phosphatase inhibitors; saperin; pilocarpine hydrochloride; pirarubicin; pirexine; placetin A; placetin B; plasminogen activator inhibitors; platinum complex; platinum compound; platinum-triamine complex; porfimer sodium; methyl mitomycin; 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; hydroxyrubiacin; pyrazoline acridine; pyridoxalyl hemoglobin polyoxyethylene conjugates; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylated retiptine; etidronate rhenium Re 186; Gentomycin; Ribozyme; R.sub.11 retinoic acid amide; Roglulimide; Roxitocin; Romotide; Roquineme; Rubiginone B1; Ruboxyl; Safingol; Saintopin; SarCNU; Myophylline A; Sargramostim; Sdi1 mimetic; Semustine; Senescence-derived 1; Sense oligonucleotide; Signal transduction inhibitor; Signal transduction regulator; Single-chain antigen binding protein; Sizoran; Sobuzosine: Sodium borocarb; Sodium phenylacetate; Solvorol; Somatomedin binding protein; Sonamin; Fospartate; Spiromycin D; Spiromustine; Snapantin; Spongin 1; Squalamine; Stem cell inhibitor; Stem cell division inhibitor; Stipiamide; Matrix degrading inhibitor;sulfinosine; potent vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycan; tamustine; tamoxifen methyl iodide; tauromustine; tazarotene; tecogalan sodium; fluridine; tellurapyrylium; telomerase inhibitor; temoporfin; temozolomide; teniposide; tetrachlorodecoxide; tetrazomine; thaliblastine; thiocoratine; thrombopoietin; thrombopoietin mimetic; thymofasin; thymopoietin receptor agonist; thymosin; thyroid stimulating hormone; tin ethylprotoporphyrin ethyletiopurpurin); tirapazamine; bis-cyclopentyl titanium dichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; retinoic acid; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; torosterol; tyrosine kinase inhibitors; tyrosine phosphorylation inhibitors; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector systems, erythrocyte gene therapy; vilarezo; veratramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoteron; zeniplatin; zilascorb; and statins ester. ;

[0346] Still other anticancer agents that can be used in combination with the compounds of the present disclosure include alkylating agents, antimetabolites, natural products, or hormones, for example, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, etc.), or triazenes (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).

[0347] Examples of natural products that can be used in combination with the compounds of the present disclosure include, but are not limited to, vinca alkaloids (e.g., vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).

[0348] Examples of alkylating agents that can be used in combination with the compounds of the present disclosure include, but are not limited to, nitrogen mustards (e.g., dichloromethyldiethylamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethyleneimine and methylmelamine (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozotocin, etc.), or triazenes (oxadiazine, 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).

[0349] Examples of hormones and antagonists that can be used in combination with the compounds of the present disclosure include, but are not limited to, adrenocortical steroids (e.g., prednisone), progesterone (e.g., hydroxyprogesterone caproate, megestrol acetate, and 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 for treating or preventing cancer that can be used in the methods and compositions described herein include platinum coordination complexes (e.g., cisplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide).

[0350] Other anticancer agents that can be used in combination with the compounds of the present disclosure include: Anticancer agents that work by arresting cells in the G2-M phase due to stabilized microtubules include Erbuclozole (also known as R-55104), Aplysia 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtine (such as Atorhyrtine A and Atorhyrtine C), Spongistatin (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4 , spongotoxin 5, spongotoxin 6, spongotoxin 7, spongotoxin 8, and spongotoxin 9), cytomedin hydrochloride (also known as LU-103793 and NSC-D-669356), epothilones (such as epothilone A, epothilone B, epothilone C (also known as deoxyepothilone A or dEpoA), epothilone D (also known as KOS-862, dEpoB, and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone AN-oxide, 16-aza-epothilone B , 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as deoxyepothilone F and dEpoF), 26-fluoroepothilone), auristatin PE (also known as NSC-654663), solidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), L S-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 of Sciences), BSF-223651 (BASF,Also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Eli Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Nostoc 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. Cl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Park Hughes Institute), Fijianolide B. Laulimalide, SPA-2 (Park Hughes Institute), SPA-1 (Park Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine,Also known as MF-191), TMPN (Arizona State University), Vanadoceneacetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton / Mount Sinai), A-204197 (Abbott), T-607 (Tularik, also known as T-900607), RPR-115781 (Annette), Eleutherobin (as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A), and Z-Eleutherobin), Caribaeolin, Halichondrin B, D-64131 (Astar Pharmaceuticals), D-68144 (Astar Pharmaceuticals), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Annette), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Astar Pharmaceuticals), D-68836 (Astar Pharmaceuticals), Myoseverin B 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), Resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0351] One or more additional immune checkpoint inhibitors can be used in combination with the compounds disclosed herein. Exemplary immune checkpoint inhibitors include inhibitors (smack molecules or biological products) for immune checkpoint molecules (such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM, arginase, CD137 (also referred to 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 certain embodiments, immune checkpoint molecules are stimulatory checkpoint molecules, which are 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 TGFRβ inhibitors.

[0352] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, for example, 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, pembrolizumab or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.

[0353] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, for example, 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).

[0354] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, for example, 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, for example, 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, for example, 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, for example, 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 LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.

[0355] Additionally, the combination therapies disclosed herein may be administered with radiation.

[0356] Examples

[0357] The following preparations of compounds of formula (I) are given to enable those skilled in the art to more clearly understand and practice the present disclosure. They should not be considered to limit the scope of the present disclosure, but merely as an illustration and representation thereof.

[0358] Example 1

[0359] 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopentadienyl

[0360] Synthesis of [cd] (inden-7-yl) (oxy) benzonitrile

[0361]

[0362] Step 1: Ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate

[0363]

[0364] At room temperature, under nitrogen atmosphere, to zinc (6.97g, 106.56mmol, 1.03 equivalents), 1,2-dibromoethane (388.71mg, 2.069mmol, 0.02 equivalents) and chlorotrimethylsilane (1.12g, 10.31mmol, 0.10 equivalents) in THF (200mL) in a stirred mixture was added dropwise ethyl 2-bromo-2,2-difluoroacetate (21.0g, 103.45mmol, 1.0 equivalents) and 2-bromo-4-fluorobenzaldehyde (21.0g, 103.45mmol, 1.0 equivalents) in THF (100mL). At 75 ° C, under nitrogen atmosphere, the resulting mixture was stirred for 16h. The reaction was cooled and quenched with ice / water. The organic solvent was removed under vacuum, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give the title compound (18 g, 53.2%) as a yellow oil.

[0365] Step 2: Ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropanoate

[0366]

[0367] At room temperature, 2-iodoacylbenzoic acid (27.4 g, 97.83 mmol, 2.0 equiv) was added to a stirred solution of ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate (16 g, 48.9 mmol, 1.0 equiv) in CH3CN (200 mL), and the resulting mixture was stirred for 3 h at 80 ° C. The reaction solution was then cooled to room temperature, filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10: 1) to give the title compound (10.3 g, 64.8%) as a yellow oil.

[0368] Step 3: Ethyl 3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropionate

[0369]

[0370] At room temperature, DAST (30.25 g, 187.6 mmol, 10.0 equiv) was added dropwise to a stirred solution of ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropanoate (6.1 g, 18.8 mmol, 1.0 equiv) in CHCl (6 mL), and the resulting mixture was stirred for 16 h at 70 ° C under a nitrogen atmosphere. The reaction solution was allowed to cool to room temperature and quenched with ice / water. The mixture was extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10: 1) to give the title compound (2.4 g, 36.8%) as a yellow oil.

[0371] Step 4: 2,2,3,3,6-Pentafluoro-2,3-dihydro-1H-inden-1-one

[0372]

[0373] To a stirred solution of ethyl 3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropanoate (4.20 g, 12.10 mmol, 1.0 equiv) in THF (50 mL) was added n-BuLi (2.5 M, 7.26 mL, 18.15 mmol, 1.5 equiv) dropwise at -78 °C under a nitrogen atmosphere, and the resulting mixture was stirred for 2 h between -70 °C and -80 °C under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl(aq) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (20:1) to give the title compound (2.25 g, 83.7%).

[0374] Step 5: 2,2,3,3,6-Pentafluoro-2,3-dihydro-1H-inden-1-ol

[0375]

[0376] To a stirred solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (300 mg, 1.35 mmol, 1.0 equiv) and triethylamine (273.35 mg, 2.70 mmol, 2.0 equiv) in DCM (3 mL) was added formic acid (186.49 mg, 4.05 mmol, 3.0 equiv) dropwise at 0°C, followed by RuCl(p-cymene)[(S,S)-Ts-DPEN] (8.59 mg, 0.014 mmol, 0.01 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h and then washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (5:1) to give the title compound (300 mg, 99.1%).

[0377] Step 6: 7-Bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol

[0378]

[0379] To a stirred solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol (2500 mg, 11.154 mmol, 1.00 equiv) in tetrahydrofuran (60 mL) was added LDA (2.0 M, 16.73 mL, 33.463 mmol, 3.00 equiv) dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was warmed to -30 °C over 30 min and stirred at -30 °C for another 30 min. A solution of carbon tetrabromide (3699.05 mg, 11.154 mmol, 1.00 equiv) in THF was added dropwise at -78 °C. The resulting mixture was allowed to warm to -30 °C over 30 min and stirred at -30 °C for another 30 min. The reaction was quenched with saturated NH4Cl (aqueous solution) at -30 °C. The resulting mixture was extracted with EtOAc, and the organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10:1) to give the title compound (2600 mg, 76.9%) as a light yellow oil. MS (ES, m / z): [MH] - =300.9,302.9.

[0380] Step 7: 7-Bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one

[0381]

[0382] To a stirred mixture of 7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-indene-1-ol (2.63 g, 8.679 mmol, 1.00 equiv) in CH3CN (45 mL) was added IBX (4.86 g, 17.356 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred for 3 h at 80 ° C, then cooled and filtered. The filter cake was washed with EtOAc. The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10: 1) to give the title compound (1.8 g, 68.9%) as an off-white solid.

[0383] Step 8: 1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol

[0384]

[0385] At -78 ° C, under a nitrogen atmosphere, to a stirred solution of 7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (100 mg, 0.332 mmol, 1.00 equiv) in THF (3 mL) was added dropwise allylmagnesium bromide (1.0 M, 0.50 mL, 0.50 mmol, 1.50 equiv). At -78 ° C, under a nitrogen atmosphere, the resulting mixture was stirred for 1 h. The reaction was quenched with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc, and the organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5: 1) to obtain the title compound (90 mg, 79.0%) as a yellow oil. MS (ES, m / z): [MH] - =340.9,342.9.

[0386] Step 9: 3,3,4,4,7-Pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol

[0387]

[0388] To a stirred mixture of 1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol (1050 mg, 3.060 mmol, 1.00 equiv) in DMF (25 mL) was added AcONa (753.17 mg, 9.181 mmol, 3.00 equiv) and Pd(dppf)Cl2·CH2Cl2 (249.93 mg, 0.306 mmol, 0.10 equiv) at room temperature. The resulting mixture was stirred for 3 h at 100 ° C under a nitrogen atmosphere. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give the title compound (370 mg, 46.1%) as a light yellow oil.

[0389] Step 10: 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

[0390]

[0391] To a stirred mixture of 3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol (40 mg, 0.15 mmol, 1.00 equiv) and 3-fluoro-5-hydroxybenzonitrile (20.92 mg, 0.153 mmol, 1.00 equiv) in DMF (1 mL) was added CsCO (49.71 mg, 0.15 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at 100 °C for 24 h. The resulting mixture was filtered and the filtrate was purified by preparative HPLC to give (16.77 mg, 29.0%). MS (ES, m / z): [MH] - =378.1.

[0392] Example 2

[0393] 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]

[0394] Synthesis of (7-indenyl)oxy)benzonitrile

[0395]

[0396] Step 1: 3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one

[0397]

[0398] To a stirred mixture of 3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]indene-2a-ol (320 mg, 1.22 mmol, 1.00 equiv) in a mixed solvent (DCM / CH3CN / H2O=3mL / 3mL / 4.50mL) was added NaIO4 (1044.25 mg, 4.882 mmol, 4.00 equiv) and RuCl3·H2O (13.76 mg, 0.061 mmol, 0.05 equiv) at room temperature. The resulting mixture was stirred for 6 h at room temperature. The resulting mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give the title compound (250 mg, 77.5%) as a white solid. MS (ES, m / z): [MH] - =263.0.

[0399] Step 2: 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

[0400]

[0401] To a stirred mixture of 3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one (200 mg, 0.757 mmol, 1.00 equiv) and 3-fluoro-5-hydroxybenzonitrile (103.81 mg, 0.757 mmol, 1.0 equiv) in DMF (3 mL) was added Cs2CO3 (246.69 mg, 0.76 mmol, 1.0 equiv) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3: 1) to give the title compound (200 mg, 69.3%) as a white semi-solid. MS(ES,m / z):[MH] - =380.0.

[0402] Example 3

[0403] 3-Fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]indene

[0404] Synthesis of benzonitrile

[0405]

[0406] To a solution of 3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (40 mg, 0.105 mmol, 1.00 equiv) in MeOH (1 mL) was added NaBH4 (7.94 mg, 0.210 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched with aqueous HCl (2.0 M) to pH = 7 at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EtOAc (3:1) to give the title compound (40 mg, 99.5%) as a colorless oil. MS (ES, m / z): [MH] - =382.0.

[0407] Example 4

[0408] 3-Fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]indene-7-

[0409] Synthesis of (4-(2-(4-yl)oxy)benzonitrile

[0410]

[0411] To a stirred solution of 3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (20 mg, 0.05 mmol, 1.00 equiv) in DCM (0.5 mL) was added DAST (6.73 mg, 0.04 mmol, 0.80 equiv) dropwise at -50 °C. The resulting mixture was stirred for 30 min at -50 °C to -40 °C. The reaction mixture was quenched with NaHCO3(aq) and extracted with DCM. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (4.3 mg, 21.3%) as a white solid. MS (ES, m / z): [MH] - =384.1.

[0412] Example 5

[0413] 1,3,3,4,4-Pentafluoro-7-((5-fluoropyridin-3-yl)oxy)-1,2,3,4-tetrahydro-2aH-cyclopentadienyl

[0414] Synthesis of [cd]inden-2a-ol

[0415]

[0416] Step 1: 3,3,4,4-tetrafluoro-7-((5-fluoropyridin-3-yl)oxy)-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one

[0417]

[0418] At room temperature, under a nitrogen atmosphere, to a stirred mixture of 3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one (95 mg, 0.36 mmol, 1.00 equiv) and 5-fluoropyridine-3-ol (41 mg, 0.36 mmol, 1.00 equiv) in DMF (2.00 mL) was added CsCO (128.90 mg, 0.40 mmol, 1.10 equiv). After stirring at room temperature for 4 h, the reaction mixture was quenched with water at 0 ° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc=3 / 1) to give the title compound (85 mg, 66%) as a white solid. MS (ES, m / z): [M+1] + =358.1.

[0419] Step 2: 3,3,4,4-tetrafluoro-7-((5-fluoropyridin-3-yl)oxy)-1,2,3,4-tetrahydro-2aH-cyclopenta-[cd]indene-1,2a-diol

[0420]

[0421] To a stirred solution of 3,3,4,4-tetrafluoro-7-((5-fluoropyridin-3-yl)oxy)-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one (85 mg, 0.24 mmol, 1.00 equiv) in MeOH (1.50 mL) was added NaBH4 (18 mg, 0.48 mmol, 2.00 equiv) at room temperature. After stirring at room temperature for 1 h, the reaction mixture was quenched with saturated NH4Cl (aqueous solution) at 0 ° C. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (0-60%) to give the title compound (80 mg, 93.7%) as a light yellow solid. MS (ES, m / z): [M+1] + =360.1.

[0422] Step 3: 1,3,3,4,4-Pentafluoro-7-((5-fluoropyridin-3-yl)oxy)-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol

[0423]

[0424] At -50 ° C, under a nitrogen atmosphere, DAST (20 mg, 0.12 mmol, 1.50 equiv) was added to a stirred solution of 3,3,4,4-tetrafluoro-7-((5-fluoropyridin-3-yl)oxy)-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]indene-1,2a-diol (30 mg, 0.08 mmol, 1.00 equiv) in THF (1.00 mL). After stirring for 2 h at -50 ° C to -30 ° C, the reaction mixture was quenched with saturated NaHCO3 (aqueous solution) at 0 ° C. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (3 mg, 10%) as a white solid. MS (ES, m / z): [M+1] + =362.1.

[0425] Example 6

[0426] 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydrospiro[cyclopenta[cd]indene-1,1'-

[0427] Synthesis of [cyclopropane]-7-yl)oxy)benzonitrile

[0428]

[0429] To a stirred mixture of diethylzinc (0.53 mL, 0.53 mmol, 1.0 M in hexanes) in DCM (3 mL) was added TFA (60 mg, 0.526 mmol, 4.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at 0°C. CH2I2 (141 mg, 0.53 mmol, 4.0 equiv) was added dropwise to the above mixture at 0°C. The resulting mixture was stirred for another 10 min at 0°C, followed by the addition of 3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (50 mg, 0.132 mmol, 1.00 equiv). The reaction mixture was stirred for 10 min at 0°C, and then stirred for another 1 h at room temperature. The reaction mixture was quenched with water and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC to give the title compound (5.6 mg, 10.8%) as a white solid. MS (ES, m / z): [MH] - =392.1.

[0430] Example 7

[0431] 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopentadienyl

[0432] Synthesis of [cd] (inden-7-yl) (oxy) benzonitrile

[0433]

[0434] To a stirred mixture of 3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (30 mg, 0.08 mmol, 1.00 equiv) and phenyl sulfide (1.47 mg, 0.008 mmol, 0.10 equiv) in ethyl acetate (3 mL) and CH3OH (3 mL) was added 10% Pd / C (20 mg) at room temperature. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 48 h and then filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by preparative HPLC to give the title compound (9 mg, 30%) as a white solid. MS (ES, m / z): [MH] - =380.1.

[0435] Example 8

[0436] Synthesis of 3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

[0437]

[0438] To a stirred solution of 3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (20 mg, 0.05 mmol, 1.00 equiv) in THF (0.60 mL) was added bromo(methyl)magnesium (1.0 M, 0.16 mL, 0.16 mmol, 3.05 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C under nitrogen atmosphere for 1 h and then quenched with saturated NH4Cl(aq) (2 mL) at -78 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (10 mg, 48.0%) as a white solid. MS (ES, m / z): [MH] - =396.2.

[0439] Example 9

[0440] 3-Fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopentadienyl

[0441] Synthesis of [cd] (inden-7-yl) (oxy) benzonitrile

[0442]

[0443] To a stirred mixture of 3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (30 mg, 0.07 mmol, 1.00 equiv) in DCM (1.5 mL) was added DAST (12 mg, 0.07 mmol, 1.00 equiv) dropwise at -50 °C under nitrogen atmosphere. The resulting mixture was stirred at -50 °C to -40 °C under nitrogen atmosphere for 1.5 h and then quenched with saturated NaHCO3(aq) at 0 °C. The resulting mixture was extracted with DCM and the combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the crude product was purified by preparative HPLC to give the title compound (4.3 mg, 14.3%) as a white solid. MS(ES,m / z):[MH] - =398.1.

[0444] Example 10

[0445] 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]indene-7-

[0446] Synthesis of (4-(2-(4-(2-yl)oxy)benzonitrile

[0447]

[0448] Step 1: O-(7-(3-cyano-5-fluorophenoxy)-3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-yl)1H-imidazole-1-carbothioate

[0449]

[0450] To a stirred solution of 3-fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (100 mg, 0.26 mmol, 1.00 equiv) and DMAP (6 mg, 0.05 mmol, 0.20 equiv) in DCE (2.0 mL) was added di(1H-imidazole-1-yl)methanethione (56 mg, 0.31 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated and the residue was purified by preparative TLC (PE / EtOAc 2:1) to give the title compound (80 mg, 62%). MS (ES, m / z): [M+H] + =494.1.

[0451] Step 2: 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

[0452]

[0453] To a stirred solution of O-(7-(3-cyano-5-fluorophenoxy)-3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-yl)1H-imidazole-1-carbothioate (65 mg, 0.13 mmol, 1.00 equiv) and Bu3SnH (115 mg, 0.40 mmol, 3.00 equiv) in toluene (2.0 mL) was added AIBN (65 mg, 0.40 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 16 h, cooled and diluted with water, and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC (PE / EtOAc=2 / 1) and preparative HPLC to give the title compound (12 mg, 25%) as a white solid. MS (ES, m / z): [MH] - =366.2.

[0454] Example 11

[0455] Synthesis of 3-((2a-amino-1,3,3,4,4-pentafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile

[0456]

[0457] Step 1: N-(7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfenamide

[0458]

[0459] To a stirred mixture of 7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (1.00 g, 3.32 mmol, 1.00 equiv) and 2-methylpropane-2-sulfinamide (0.81 g, 6.64 mmol, 2.00 equiv) in THF (20.0 mL) was added Ti(OEt)4 (3.03 g, 13.29 mmol, 4.00 equiv) at room temperature. After stirring at 75 ° C for 4 h, the reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (0-60%) to give the title compound (900 mg, 67.0%) as a brown oil. MS (ES, m / z): [M+1] + =404.0.

[0460] Step 2: N-(1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfenamide

[0461]

[0462] At 0 ° C, to a stirred solution of N-(7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide (900 mg, 2.23 mmol, 1.00 equiv) in THF (15.0 mL) was added allylmagnesium bromide (2.0 M, 1.34 mL, 2.70 mmol, 1.20 equiv). After stirring at 0 ° C for 1.5 h, the reaction mixture was quenched with saturated NH4Cl (aqueous solution) at 0 ° C and then extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (0-50%) to give the title compound (750 mg, 75.5%) as a light yellow oil. MS (ES, m / z): [M+1] + =446.1.

[0463] Step 3: 2-Methyl-N-(3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]-inden-2a-yl)propane-2-sulfenamide

[0464]

[0465] To a stirred mixture of N-(1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (750 mg, 1.68 mmol, 1.00 equiv) and Pd(dppf)Cl2.CH2Cl2 (137 mg, 0.17 mmol, 0.10 equiv) in DMF (15.0 mL) was added NaOAc (414 mg, 5.05 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. After stirring at 100°C for 1.5 h, the reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (10%-40%) to give the title compound (450 mg, 73.3%) as a light yellow solid. MS (ES, m / z): [M+1] + =366.1.

[0466] Step 4: 3,3,4,4,7-Pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-amine

[0467]

[0468] At room temperature, to a stirred solution of 2-methyl-N-(3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopentadien [cd] indene-2a-yl) propane-2-sulfinamide (150 mg, 0.41 mmol, 1.00 equivalent) in 1,4-dioxane (1.0 mL) was added a solution of HCl in 1,4-dioxane (4.0 M, 1.00 mL, 4.0 mmol, 9.74 equivalent). After stirring at room temperature for 5 h, the reaction mixture was quenched with NaHCO3 (aqueous solution) at room temperature and extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (0-60%) to give the title compound (85 mg, 79.3%) as a light yellow oil. MS (ES, m / z): [M+1] + =262.1.

[0469] Step 5: 2a-Amino-3,3,4,4,7-pentafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one

[0470]

[0471] To a stirred mixture of 3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]indene-2a-amine (85 mg, 0.325 mmol, 1.00 equiv) and NaIO4 (278 mg, 1.30 mmol, 4.00 equiv) in CH3CN (0.50 mL) and DCM (0.50 mL) was added water (0.75 mL) and RuCl3.HO (7.34 mg, 0.03 mmol, 0.10 equiv) at room temperature. After stirring at room temperature for 1 h, the resulting mixture was diluted with DCM. The organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (PE / EtOAc=3 / 1) to give the title compound (45 mg, 52.5%) as a light yellow oil. MS (ES, m / z): [M-1] - =261.9.

[0472] Step 6: 3-((2a-amino-3,3,4,4-tetrafluoro-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile

[0473]

[0474] To a stirred mixture of 2a-amino-3,3,4,4,7-pentafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one (40 mg, 0.15 mmol, 1.00 equiv) and 3-fluoro-5-hydroxybenzonitrile (21 mg, 0.15 mmol, 1.00 equiv) in DMF (1.00 mL) was added Cs2CO3 (50 mg, 0.15 mmol, 1.00 equiv) at room temperature. After stirring at room temperature for 1.5 h, the reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc=3 / 1) to give the title compound (35 mg, 60.3%) as a white solid. MS (ES, m / z): [M+1] + =381.1.

[0475] Step 7: 3-((2a-amino-3,3,4,4-tetrafluoro-1-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile

[0476]

[0477] To a stirred solution of 3-((2a-amino-3,3,4,4-tetrafluoro-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile (35 mg, 0.09 mmol, 1.00 equiv) in MeOH (0.50 mL) was added NaBH4 (5 mg, 0.13 mmol, 1.4 equiv) at room temperature. After stirring at room temperature for 0.5 h, the reaction mixture was quenched with saturated NH4Cl(aq) at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EtOAc / PE (0-60%) to give the title compound (30 mg, 85.3%) as a light yellow oil. MS (ES, m / z): [M+1] + =383.1.

[0478] Step 8: 3-((2a-amino-1,3,3,4,4-pentafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile

[0479]

[0480] To a stirred solution of 3-((2a-amino-3,3,4,4-tetrafluoro-1-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-5-fluorobenzonitrile (25 mg, 0.07 mmol, 1.00 equiv) in DCM (1.0 mL) was added DAST (16 mg, 0.10 mmol, 1.5 equiv) at room temperature. After stirring for 2 h at room temperature, the reaction mixture was quenched with saturated NaHCO3(aq) at 0 °C and extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by preparative HPLC to give the title compound (6 mg, 24%) as a white solid. MS (ES, m / z): [M+1] + =385.1.

[0481] Example 12

[0482] Synthesis of 3-fluoro-5-((1,1,2a,3,3,4,4-heptafluoro-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

[0483]

[0484] To a stirred mixture of 3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (30 mg, 0.08 mmol, 1.00 equiv) in DCM (1.0 mL) was added 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (59 mg, 0.24 mmol, 3.00 equiv) and pyridine hydrofluoride (0.05 mL, 65%-70%) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 24 h, then diluted with water and extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by preparative HPLC to give the title compound (9.9 mg, 31.1%) as a white solid. MS (ES, m / z): [MH] - =404.1.

[0485] Example 13

[0486] 3-((3,3-difluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]indene-5-

[0487] Synthesis of 5-fluorobenzonitrile

[0488]

[0489] Step 1: 3-Fluoro-5-((7-iodo-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

[0490]

[0491] 3-Fluoro-5-((1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile (28 g, 104.77 mmol, 1.00 equiv), F-TEDA-BF4 (33 g, 93.15 mmol, 0.89 equiv) and CH3CN (840 mL) were added to a 2L round-bottom flask. A solution of I2 (24 g, 94.56 mmol, 0.90 equiv) in CH3CN (560 mL) was added dropwise to the stirred solution at 60 °C. The resulting mixture was stirred for 3 h at 60 °C. The mixture was cooled to room temperature and then concentrated under vacuum. Ethyl acetate (250 mL) was added to the residue, and the resulting mixture was stirred at 80 °C for 1 h. The mixture was cooled to room temperature, and the precipitated solid was collected by filtration and washed with Et2O to give the title compound (16.8 g, 40.8%) as an off-white solid. MS (ES, m / z): [M+H] + =394.0.

[0492] Step 2: 3-((2,2-difluoro-7-iodo-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

[0493]

[0494] To a stirred mixture of 3-fluoro-5-((7-iodo-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-benzonitrile (3.600 g, 9.15 mmol, 1.00 equiv) and butan-1-amine (6.7 g, 91.57 mmol, 10.00 equiv) in toluene (90 mL) was added TFA (209 mg, 1.83 mmol, 0.20 equiv) dropwise at room temperature. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 16 h and then concentrated under vacuum. The residue was dissolved in CH3CN (90 mL) and then Na2SO4 (5.2 g, 36.62 mmol, 4.00 equiv) and F-TEDA-BF4 (6.5 g, 18.31 mmol, 2.00 equiv) were added at room temperature. The resulting mixture was stirred at 80 °C for 2 h, diluted with water, and extracted with EtOAc. The combined organic layers were washed with water, brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give the title compound (1.60 g, 40.7%) as a yellow solid.

[0495] Step 3: 3-((1-allyl-2,2-difluoro-1-hydroxy-7-iodo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

[0496]

[0497] To a stirred mixture of 3-((2,2-difluoro-7-iodo-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (449 mg, 1.05 mmol, 1.00 equiv) and allyl bromide (253.15 mg, 2.093 mmol, 2.00 equiv) in THF (10 mL) at room temperature was added pyridine (165.52 mg, 2.09 mmol, 2.00 equiv) and (1S,2R)-2-amino-1,2-diphenylethanol (446.30 mg, 2.09 mmol, 2.00 equiv). Indium powder (240.26 mg, 2.09 mmol, 2.00 equiv) was then added to the solution, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 8 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated and purified by silica gel column chromatography eluting with PE / EtOAc (9:1) to give the title compound (430 mg, 87.2%) as a yellow oil. MS (ES, m / z): [MH] - =470.0.

[0498] Step 4: 3-((3,3-difluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile

[0499]

[0500] To a stirred solution of 3-((1-allyl-2,2-difluoro-1-hydroxy-7-iodo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (430 mg, 0.91 mmol, 1.00 equiv) and NaOAc (225 mg, 2.74 mmol, 3.00 equiv) in DMF (10 mL) was added Pd(dppf)Cl2.CH2Cl2 (75 mg, 0.09 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 3 h and then filtered. The filter cake was washed with EtOAc, and the filtrate was washed with H2O, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to give the title compound (223 mg, 71.2%) as a yellow oil.

[0501] Example 14

[0502] Synthesis of 3-((3,3-difluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile

[0503]

[0504] To a 25 mL 2-necked round bottom flask was added 3-((3,3-difluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile (210 mg, 0.61 mmol, 1.00 equiv), DCM (2.0 mL), MeCN (2.0 mL) and H2O (3.0 mL) at room temperature. RuCl3.H2O (7 mg, 0.03 mmol, 0.05 equiv) was then added to the solution. To the above mixture was added NaIO4 (523 mg, 2.45 mmol, 4.00 equiv) in portions over 2 min at room temperature and the resulting mixture was stirred at room temperature for 3 h. The resulting mixture was extracted with DCM and the combined organic layers were washed with Na2S2O3 (aq.), H2O and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to give the title compound (107 mg, 50.7%) as a yellow oil. MS (ES, m / z): [2M-H] - =689.1.

[0505] Example 15

[0506] Synthesis of 3-((3,3-difluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile

[0507]

[0508] 3-((3,3-difluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile (100 mg, 0.29 mmol, 1.00 equiv) and MeOH (2.00 mL) were added to an 8 mL sealed tube at room temperature. NaBH4 (22 mg, 0.58 mmol, 2.0 equiv) was added to the above mixture in batches at 0°C, and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water at 0°C and neutralized to pH=7 with aqueous HCl (1.0 M). The resulting mixture was extracted with DCM, and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by preparative TLC (PE / EtOAc=5 / 1) to give the title compound (78 mg, 77.6%) as a white solid.

[0509] Example 16

[0510] Synthesis of 3-fluoro-5-((1,3,3-trifluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

[0511]

[0512] To a stirred solution of 3-((3,3-difluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile (20 mg, 0.06 mmol, 1.00 equiv) in THF (0.50 mL) was added a solution of DAST (9.35 mg, 0.06 mmol, 1.00 equiv) in DCM (0.2 mL) dropwise at -50 °C under a nitrogen atmosphere. The resulting mixture was stirred at -50 °C under a nitrogen atmosphere for 1 h and then quenched with water at -40 °C. The mixture was neutralized to pH = 7 with saturated NaHCO3(aq) and then extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by preparative HPLC to give the title compound (5.7 mg, 28.3%) as a white solid. MS (ES, m / z): [2M-H] - =697.2.

[0513] Example 17

[0514] 3-Fluoro-5-((1,1,2,2,3,3,4-heptafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]

[0515] Synthesis of (5-(inden-5-yl)oxy)benzonitrile

[0516]

[0517] Step 1: Ethyl 2,2-difluoro-2-(2,2,3,3,6-pentafluoro-1-hydroxy-2,3-dihydro-1H-inden-1-yl) acetate

[0518]

[0519] At 60 ° C, under N2 atmosphere, a mixture of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-indene-1-one (10.0 g, 45.02 mmol, 1.00 equiv), In (7.7 g, 67.06 mmol, 1.5 equiv) and ethyl 2-bromo-2,2-difluoroacetate (13.7 g, 67.5 mmol, 1.50 equiv) in THF (150 mL) was stirred for 16 h. The reaction was quenched with HCl aqueous solution (2.0 M, 50 mL) at room temperature, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1) to obtain the title compound (8.0 g, 51.3%) as a light yellow oil. MS (ES, m / z): [M-1] - =345.0

[0520] Step 2: 1,1,2,2,3,3,5-Heptafluoro-2a-hydroxy-1,2,2a,3-tetrahydro-4H-cyclopenta[cd]inden-4-one

[0521]

[0522] At -78 ° C, under N2 atmosphere, to ethyl 2,2-difluoro-2-(2,2,3,3,6-pentafluoro-1-hydroxy-2,3-dihydro-1H-inden-1-yl) acetate (500 mg, 1.44 mmol, 1.00 equiv) in THF (10 mL) was added dropwise LDA (2.2 mL, 4.40 mmol, 2.0 M, 3.06 equiv). The resulting mixture was stirred at -78 ° C for 1 h, then quenched with saturated NH4Cl aqueous solution (10 mL) at -78 ° C. The resulting mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography, eluted with PE / EA (3 / 1) to obtain a crude product. The crude product was purified by preparative HPLC to obtain the title product (34 mg, 7.8%) as a light yellow oil. MS (ES, m / z): [M-1] - =298.9

[0523] Step 3: 3-Fluoro-5-((1,1,2,2,3,3-hexafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

[0524]

[0525] A mixture of 1,1,2,2,3,3,5-heptafluoro-2a-hydroxy-1,2,2a,3-tetrahydro-4H-cyclopenta-[cd]inden-4-one (100 mg, 0.33 mmol, 1.00 equiv), Cs2CO3 (217 mg, 0.67 mmol, 2.00 equiv) and 3-fluoro-5-hydroxybenzonitrile (50 mg, 0.36 mmol, 1.10 equiv) in DMF (2 mL) was stirred at -10 °C under N2 atmosphere for 1 h. The crude reaction mixture was used directly in the next step without further purification. MS (ES, m / z): [M-1] - =416.0.

[0526] Step 4: 3-Fluoro-5-((1,1,2,2,3,3-hexafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

[0527]

[0528] To a stirred solution of crude 3-fluoro-5-((1,1,2,2,3,3-hexafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (0.33mmol, 1.00 equiv) in MeOH (2mL) was added NaBH4 (25mg, 0.66mmol, 2.00 equiv) in batches at -10°C under N2 atmosphere. The resulting mixture was stirred at -10°C for 1h and then quenched with saturated NH4Cl aqueous solution. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 1) to give the title compound (90mg, 63.6%) as a light yellow oil for two steps. MS (ES, m / z): [M-1] - =418.0.

[0529] Step 5: 3-Fluoro-5-((1,1,2,2,3,3,4-heptafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

[0530]

[0531] To a stirred solution of 3-fluoro-5-((1,1,2,2,3,3-hexafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (50 mg, 0.12 mmol, 1.00 equiv) in DCM (1.0 mL) was added DAST (38 mg, 0.24 mmol, 2.00 equiv) dropwise at -20 °C under N2 atmosphere. The resulting mixture was stirred at room temperature for 2 h and quenched with saturated aqueous NaHCO3. The resulting mixture was extracted with DCM and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the crude product was purified by preparative HPLC to give the title compound (14 mg, 27.5%) as a light yellow solid. MS (ES, m / z): [M-1] - =420.0.

[0532] Example 18

[0533] Synthesis 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-1,2,2-d3)oxy)benzonitrile

[0534]

[0535] Step 1: (R)-1-allyl-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol

[0536]

[0537] To a stirred solution of t-BuONa (21.6 mg, 0.225 mmol, 0.10 equiv) in toluene (3.0 mL) was added a solution of (S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethylbutanamide (275.8 mg, 0.90 mmol, 0.40 equiv) in toluene (0.5 mL) followed by a solution of MeOH (90.2 mg, 2.8 mmol, 1.25 equiv) in toluene (0.5 mL) followed by a solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (0.50 g, 2.25 mmol, 1.00 equiv) in toluene (0.5 mL). After stirring at room temperature for 15 min, a solution of 4,4,5,5-tetramethyl-2-(prop-2-ene-1-yl)-1,3,2-dioxaborolane (416.1 mg, 2.48 mmol, 1.10 equiv) in toluene (0.5 mL) was slowly added. The resulting mixture was stirred at 60 ° C for 6.5 h, cooled and diluted with ethyl acetate. After separation, the organic layer was washed with water and brine and dried over Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography, eluting with DCM / PE (0-40%) to give the title compound (0.52 g, 87.4%) as a light yellow oil. MS (ES, m / z): [M-1] - =263.0.

[0538] Step 2: (1R)-7-Bromo-2,2,3,3,6-pentafluoro-1-(prop-2-en-1-yl)inden-1-ol

[0539]

[0540] At -40 ° C, under a nitrogen atmosphere, to a stirred solution of (R)-1-allyl-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-indene-1-ol (5.0 g, 18.93 mmol, 1.00 equiv) in tetrahydrofuran (60 mL) was added dropwise 2.0 M LDA (28.4 mL, 56.8 mmol, 3.0 equiv). After stirring at -40 ° C for 1 h, a solution of carbon tetrabromide (7.53 g, 22.71 mmol, 1.20 equiv) in THF was added dropwise at -40 ° C. The resulting mixture was stirred for another 10 min at -40 ° C and then quenched with 1.0 M HCl (aqueous solution) (100 mL) at -40 ° C. The resulting mixture was extracted with MTBE. The organic layer was washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography, eluting with EtOAc / PE (0-30%) to give a crude product as a light yellow oil. The crude product was further purified by a reverse phase C18 silica gel column (mobile phase, ACN in water, gradient: 50% to 95% in 12 min) to give the title compound (3.5 g, 53.9%) as a light yellow oil. MS (ES, m / z): [M-1] - =340.9.

[0541] Step 3: (R)-3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol

[0542]

[0543] To a stirred mixture of (R)-1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol (3.50 g, 10.20 mmol, 1.00 equiv) in DMF (5.0 mL) was added AcONa (2.51 g, 30.60 mmol, 3.00 equiv) and Pd(dppf)Cl2.CH2Cl2 (0.83 g, 1.02 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 ° C. under nitrogen atmosphere for 3 h, cooled and diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography eluted with EtOAc / PE (0-40%) to give the title compound (2.0 g, 74.8%) as a light yellow solid. MS (ES, m / z): [M-1] - =260.9.

[0544] Step 4: (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one

[0545]

[0546] To a stirred mixture of (R)-3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]indene-2a-ol (2.00 g, 7.63 mmol, 1.00 equiv) in a mixed solvent (DCM / MeCN / H2O=1 / 1 / 1.5, 70.0 mL) was added RuCl3·H2O (86.0 mg, 0.38 mmol, 0.05 equiv) at room temperature. To the resulting mixture was added NaIO4 (6.53 g, 30.53 mmol, 4.0 equiv) in portions at room temperature. After stirring at room temperature for 1 h, the reaction mixture was diluted with water and then extracted with DCM. The organic layer was washed with saturated Na2S2O3 (aq.), water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to give the crude title compound (1.85 g, 91.8%) as a light yellow solid, which was used in the next step without further purification. MS (ES, m / z): [M-1] - =262.9.

[0547] Step 5: (R)-3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

[0548]

[0549] To a stirred solution of (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one (1.85 g, 7.0 mmol, 1.00 equiv) and 3-fluoro-5-hydroxybenzonitrile (0.86 g, 6.30 mmol, 0.90 equiv) in DMF (20.0 mL) was added CsCO (2.28 g, 7.00 mmol, 1.00 equiv) at room temperature. After stirring at room temperature for 16 h, the reaction mixture was quenched with water at 0 ° C and then extracted with EtOAc. The organic layer was washed with water and brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated and purified by silica gel column chromatography, eluted with EtOAc / PE (0-40%) to give the title compound (1.95 g, 73.0%) as a white solid. MS (ES, m / z): [M-1]-=380.1. Step 6: (R)-3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-2,2-d2)oxy)benzonitrile

[0550]

[0551] To a stirred mixture of (R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (3.0 g, 7.87 mmol, 1.00 equiv) in THF (60 mL) was added a solution of NaOD (645 mg, 15.737 mmol, 2.00 equiv) in D2O (24 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 4 h, then diluted with D2O and extracted with MTBE. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give the title compound (2.3 g, 76.3%) as a white solid. MS (ES, m / z): [MH] - =382.1.

[0552] Step 7: 3-Fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile

[0553]

[0554] To a stirred mixture of (R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-2,2-d2)oxy)benzonitrile (1.5 g, 3.883 mmol, 1.00 equiv) in CD3OD (15 mL) was added NaBD4 (329 mg, 7.827 mmol, 2.00 equiv) at 5 °C. The resulting mixture was stirred at room temperature for 2 h and then quenched with D2O at room temperature. The resulting mixture was extracted with MTBE and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluted with PE / EA (3:1) to give the title compound (1.5 g, 99.2%) as a light yellow solid. MS(ES,m / z):[MH] - =385.1.

[0555] Step 8: 3-Fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1,2,2-d3)oxy)benzonitrile

[0556]

[0557] To a stirred mixture 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-1,2,2-d3)oxy)benzonitrile (1.5 g, 3.88 mmol, 1.00 equiv) in THF (21 mL) was added DBU (1.18 g, 7.77 mmol, 2.00 equiv) and pyridine-2-sulfonyl fluoride (814 mg, 5.05 mmol, 1.30 equiv) in THF (2 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (4:1). The resulting product was further purified by chiral preparative HPLC to give the optically pure title compound (740 mg, 49.1%) as a white solid. MS (ES, m / z): [MH] - =387.1.

[0558] Example 19

[0559] Synthesis 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-1-d)oxy)benzonitrile-2,4,6-d3

[0560]

[0561] Step 1: 3-Bromo-5-fluorobenzene-2,4,6-d3-ol

[0562]

[0563] At room temperature in D2O, 3-bromo-5-fluorophenol (5.00 g, 26.18 mmol, 1.00 equiv) and 60% D2SO4 (13.09 g, 78.53 mmol, 3.00 equiv) were added to a 40 mL sealed tube. The resulting mixture was stirred at 75 ° C for 18 h and then slowly poured into ice. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product. Under D2O, the product was added into 60% D2SO4, and the above procedure was repeated 4 more times to give the title compound (4.20 g, 82.7% yield) as a yellow oil. MS (ES, m / z): [MH] - =191.9.

[0564] Step 2: 3-Fluoro-5-hydroxybenzonitrile-2,4,6-d3

[0565]

[0566] At room temperature, under a nitrogen atmosphere, to a stirred solution of 3-bromo-5-fluorobenzene-2,4,6-d3-ol (100 mg, 0.515 mmol, 1.00 equiv) and Zn(CN)2 (121 mg, 1.03 mmol, 2.0 equiv) in DMF (2.0 mL) was added Pd(PPh3)4 (60 mg, 0.05 mmol, 0.10 equiv). The resulting mixture was stirred at 100 ° C under a nitrogen atmosphere for 3 h, and then quenched with water at room temperature. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1: 1) to give the title compound (37 mg, 51.2%) as a white solid. MS (ES, m / z): [MH] -=139.0. Step 3: (R)-3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile-2,4,6-d3

[0567]

[0568] To a stirred mixture of (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]indene-1-one (179 mg, 0.68 mmol, 1.00 equiv) and 3-fluoro-5-hydroxybenzonitrile-2,4,6-d3 (95 mg, 0.68 mmol, 1.00 equiv) in DMF (3.5 mL) was added CsCO (221 mg, 0.68 mmol, 1.00 equiv) at room temperature. After stirring at room temperature for 16 h, the reaction mixture was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with H2O, brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (0-40%) to give the title compound (170 mg, 65.3%) as a white solid. MS (ES, m / z): [MH] - =383.0.

[0569] Step 4: 3-Fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d3

[0570]

[0571] To a stirred mixture of (R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile-2,4,6-d3 (170 mg, 0.442 mmol, 1.00 equiv) in CD3OD (3.5 mL) was added NaBD4 (37 mg, 0.885 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature for 3 h, diluted with D2O (3.0 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluted with EtOAc / PE (0-40%) to give the title compound (120 mg, 70.0%) as a white solid. MS (ES, m / z): [2M-H] - =773.1.

[0572] Step 5: 3-Fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl-1-d)oxy)benzonitrile-2,4,6-d3

[0573]

[0574] To a stirred mixture 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-1-d)oxy)benzonitrile-2,4,6-d3 (125 mg, 0.32 mmol, 1.00 equiv) in THF (1.6 mL) was added DBU (98 mg, 0.65 mmol, 2.00 equiv) and pyridine-2-sulfonyl fluoride (68 mg, 0.42 mmol, 1.30 equiv) in THF (0.4 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The reaction solution was purified by silica gel column chromatography, eluting with PE / EtOAc (4:1), followed by preparative HPLC to give the title compound (10 mg, 8.0%) as a white solid. MS (ES, m / z): [MH] - =388.1.

[0575] Example 20

[0576] (R)-3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile [23a] and (S)-3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

[0577]

[0578] To a stirred mixture of (R)-3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]indene-2a-ol (400 mg, 1.53 mmol, 1.0 equiv., about 80% ee) and 3-fluoro-5-hydroxybenzonitrile (209 mg, 1.53 mmol, 1.0 equiv.) in DMF (10 mL) was added CsCO (497 mg, 1.53 mmol, 1.0 equiv.) at room temperature, and the resulting mixture was stirred at 100 ° C for 24 h. After the reaction mixture was cooled to room temperature, it was filtered. The filtrate was purified by preparative HPLC to give 131 mg of the product as a mixture of enantiomers. The enantiomers were separated by chiral preparative HPLC [column: CHIRALPAK OD-3, 50*4.6 mm, 3um OD30CC-QE001, flow rate: 1.0 mL / min; oven temperature: 25°C; mobile phase A: n-hexane; mobile phase B: ethanol; concentration of phase B: 10%) to give 23a (65 mg, 11.2%). MS (ES, m / z): [MH] - =378.0.tR: 1.34min and 23b (6mg, 1.0%); MS (ES, m / z): [MH] - =378.0.tR:1.77min.

[0579] Example 21

[0580] Synthesis of 3-fluoro-5-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile[24a] and 3-fluoro-5-(((1R,2R,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile[24b]

[0581]

[0582] Step 1: (R)-3-((4-(butylimino)-1,1,2,2-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile

[0583]

[0584] A solution of (R)-3-fluoro-5-((1,1,2,2-tetrafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (700 mg, 1.84 mmol, 1.0 equiv, ca. 80% ee), TFA (42 mg, 0.37 mmol, 0.2 equiv) and butylamine (1343 mg, 18.36 mmol, 10.0 equiv) in toluene (15 mL) was stirred at 100 °C under N2 atmosphere for 16 h. The resulting mixture was concentrated under vacuum to give the title compound (1.0 g, crude) as a light brown oil, which was used directly in the next step. MS (ES, m / z): [M+1] + =437.2.

[0585] Step 2: 3-Fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile and 3-Fluoro-5-(((2aS,3R)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

[0586]

[0587] A mixture of (R)-3-((4-(butylimino)-1,1,2,2-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)-5-fluorobenzonitrile (1.0 g crude, 1.84 mmol, 1.0 equiv), sodium sulfate (651 mg, 4.58 mmol, 2.5 equiv) and Selectfluor (1.05 g, 2.96 mmol, 1.6 equiv) in MeCN (15 mL) was stirred at 60 °C under N2 atmosphere for 4 h. The crude product was purified by preparative HPLC to give 150 mg of 3-fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile and 300 mg of 3-fluoro-5-(((2aS,3R)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile. MS (ES, m / z): [M-1] - =397.9.

[0588] Step 3: 3-Fluoro-5-(((2aS,3R,4S)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

[0589]

[0590] To a stirred solution of 3-fluoro-5-(((2aS,3S)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (100 mg, 0.25 mmol, 1.0 equiv) in MeOH (2 mL) was added NaBH4 (19 mg, 0.50 mmol, 2.0 equiv) in portions at 0 °C under N2 atmosphere. The resulting mixture was stirred at room temperature under N2 atmosphere for 1 h and then quenched with saturated NH4Cl solution (2 mL) at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine (2x2 mL), dried over anhydrous Na2SO4, and concentrated to give the title compound (90 mg, 90%). MS (ES, m / z): [2M-1] - =801.2

[0591] Step 4: 3-Fluoro-5-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile [24a]

[0592]

[0593] To a stirred solution of 3-fluoro-5-(((2aS,3R,4S)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (70 mg, 0.17 mmol, 1.0 equiv) in DCM (2 mL) was added DAST (42 mg, 0.26 mmol, 1.5 equiv) dropwise at -40 °C under N2 atmosphere, and the resulting mixture was stirred at -40 °C under N2 atmosphere for 2 h. The reaction was quenched with saturated NH4Cl solution (2 mL) at room temperature, and the resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC to give the title compound (10 mg, 14%) as a light yellow solid. MS (ES, m / z): [M-1] - =402.0

[0594] Step 5: 3-Fluoro-5-(((2aS,3S,4S)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile

[0595]

[0596] To a stirred solution of 3-fluoro-5-(((2aS,3R)-1,1,2,2,3-pentafluoro-2a-hydroxy-4-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (250 mg crude, 0.63 mmol, 1.0 equiv) in MeOH (3 mL) was added NaBH4 (47 mg, 1.25 mmol, 2.0 equiv) in portions at 0°C under N2 atmosphere. The resulting mixture was stirred at room temperature under N2 atmosphere for 1.0 h. The reaction was quenched with saturated NH4Cl solution (2 mL) at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC to give the title compound (90 mg). MS (ES, m / z): [M-1] - =400.0

[0597] Step 6: 3-Fluoro-5-(((1R,2R,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile [24b]

[0598]

[0599] To a stirred solution of 3-fluoro-5-(((2aS,3S,4S)-1,1,2,2,3-pentafluoro-2a,4-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-5-yl)oxy)benzonitrile (70 mg, 0.17 mmol, 1.00 equiv) in DCM (2 mL) was added DAST (42 mg, 0.26 mmol, 1.5 equiv) dropwise at -40 °C under N2 atmosphere. The resulting mixture was stirred for 2 h at -40 °C under N2 atmosphere. The reaction was quenched with saturated NH4Cl solution (2 mL) at room temperature. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC to give the title compound. MS (ES, m / z): [M-1] - =402.1

[0600] Biological Examples

[0601] Example 1

[0602] VEGF ELISA assay

[0603] The ability of the disclosed compounds to inhibit HIF-2α was measured by measuring VEGF expression in 786-O cells. Approximately 7500 786-O cells were inoculated into each well of a 96-well white transparent bottom plate (07-200-566, Fisher Scientific) containing 200ul growth medium. Four hours later, the compound was dispensed into the wells by a Tecan D300e digital dispenser, with a starting concentration of 10uM and a 1 / 2 logarithmic dilution to 1nM as a final concentration. The treatment of each concentration was performed in duplicate. After about 20 hours, the culture medium was removed and fresh culture medium was added, followed by the treatment of the compound as described above. After 24 hours, the cell culture medium was collected to determine the VEGF concentration using an ELISA kit (R&D systems, catalog number DVE00) according to the manufacturer's instructions.

[0604] EC was calculated using the dose-response-inhibition (four-parameter) equation by GraphPadPrism. 50Plates containing cells were then subjected to the CellTiter-Glo luminescent cell viability assay (Promega) to determine the effects of these compounds on cell numbers following the above treatments.

[0605]

[0606] Example 2

[0607] Co-immunoprecipitation assay for inhibition of HIF-2α dimerization

[0608] Cell culture and compound treatment

[0609] Primary pulmonary artery smooth muscle cells (PASMC, ATCC#PCS-100-023) were cultured in vascular cell basal medium (ATCC#PCS-100-030) supplemented with vascular smooth muscle cell growth kit (ATCC#PCS-100-042). Primary pulmonary artery endothelial cells (HPAEC, ATCC#PCS-100-022) were cultured in vascular cell basal medium (ATCC#PCS-100-030) supplemented with endothelial cell growth kit-BBE (ATCC#PCS-100-040). 0.5×10 6 Cells were seeded into 6-well cell culture plates (Corning #3736) containing 2 mL of culture medium and cultured overnight in a 37° C. cell culture incubator under atmospheric oxygen and 5% CO 2 . The next day, cells were cultured under normoxic conditions (atmospheric oxygen and 5% CO 2 ) or hypoxic conditions (1% O 2 and 5% CO 2 ) and treated with dimethyl sulfoxide (DMSO) or 0.001, 0.01, 0.1, and 1 μM of compound 24a for 24 h.

[0610] Co-immunoprecipitation analysis of HIF and ARNT

[0611] After treatment, cells are washed with ice-cold PBS (containing compounds as in the treatment step). PBS washing solution is completely removed, and 1 mL of ice-cold lysis buffer (#9803, Cell Signaling Tech) containing protease inhibitors and phosphatase inhibitors (#A32959, Thermo Scientific) is added to each well. Cells are then scraped off the wells and transferred to Eppendorf tubes. Samples are incubated on ice for 10 minutes, then centrifuged at 4°C for 15 minutes at 13,500rpm (Eppendorf#5417R). Supernatant (cell lysate) is transferred to a new tube, and protein concentration is measured by BCA protein assay. Lysate is then adjusted to the same concentration by adding lysis buffer. For co-immunoprecipitation, 40 μL of anti-human ARNT-protein A / G bead slurry (#sc-55526AC, Santa Cruz Biotech) was added to 1 mL of supernatant and then rotated at room temperature for 3 hr. The tube was rotated at 8,000 g for 5 minutes, and the supernatant was removed. The beads were then washed 3 times with cold lysis buffer (rotated at 8,000 g for 5 minutes between washes). After the last wash, the supernatant was removed as much as possible. 30 μL of loading buffer was added to the washed beads, which were then heated at 98°C for 5 minutes. The sample was briefly rotated to collect all the liquid at the bottom of the tube. The supernatant was subjected to immunoblotting analysis.

[0612] Cell lysates were also analyzed by immunoblotting (Western blot analysis). For each immunoblot, equal amounts of protein samples were loaded onto SDS-PAGE gels and, after electrophoresis, transferred to nitrocellulose membranes. The membranes were incubated in 25 mL of blocking buffer (tris-buffered saline (TBS) containing 0.1% Tween-20 and 5% skim milk) for 1 hour at room temperature. The blocked membranes were then incubated with primary antibodies (1:1000 dilution, HIF-2α (D9E3 rabbit mAb, #7098, Cell Signaling Technology), HIF1β / ARNT (D28F3 Rabbit mAb, #5537, Cell Signaling Technology) and β-tubulin (D2N5G rabbit mAb, #15115, Cell Signaling Technology)) were incubated overnight with gentle agitation in 10 mL of primary antibody dilution buffer (5% skim milk in 1X TBST). After incubation with the primary antibody, the membrane was washed three times for 5 minutes. 15 mL of 1× TBST was used for each wash. The washed membrane was then incubated with HRP-linked secondary antibody (1:2000 dilution) in 10 mL of secondary antibody dilution buffer (5% skim milk in 1X TBST) for 1 hour. After incubation with the secondary antibody, the membrane was washed three times for 5 minutes, using 15 mL of 1× TBST for each wash. The washed membrane was incubated with 2 mL of SuperSignalWestFemto Maximum Sensitivity Substrate (#PI34095, Thermo Scientific) for 1 minute at room temperature with gentle agitation. Excess chromogenic substrate was drained off and the membrane was imaged using the Bio-Rad ChemiDoc MP imaging system.

[0613] Disruption of HIF-2α and ARNT dimerization

[0614] like Figure 1 As shown, in both PASMC and HPAEC, HIF-2α expression was very low under normoxic culture conditions, while its expression was significantly enhanced under hypoxic culture conditions. Compound 24a disrupted HIF-2α / ARNT dimerization, and HIF-2α protein co-precipitated with ARNT was reduced in a dose-dependent manner in the lysates of cells treated with compound 24a. Under hypoxic conditions, 0.01 μM of compound 24a can effectively disrupt HIF-2α / ARNT dimerization in PASMC / HPAEC.

[0615] Example 3

[0616] Combination study of compound 5 with niraparib in the 786-OccRCC xenograft tumor model

[0617] 786-OccRCC cells (5x10 6 ) were subcutaneously inoculated into the right flank of each nude mouse (BALB / C) at 6-8 weeks of age for tumor development. When the xenograft tumor size reached approximately 100-150 mm 3At 14:00, the tumor-bearing mice were randomly divided into four groups (n=8) and started to be treated with vehicle (BID), compound 5 (1 mg / kg, BID), niraparib (45 mg / kg, QD) or compound 5 (1 mg / kg, BID) in combination with niraparib (45 mg / kg, QD). During the four-week study, the tumor size was measured in two dimensions with a caliper once every two weeks and the formula V=0.5×A×B was used. 2 The volume was calculated (A and B are the long and short diameters of the tumor, respectively). The body weight of these mice was measured biweekly. The effect of treatment on tumor growth was plotted and shown as the mean and standard error of the mean (SEM).

Claims

1. Use of a HIF-2α inhibitor of formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer in a patient in need thereof: in: R 2 is hydrogen, deuterium or C1-C6 alkyl; R 3 and R 4 are independently hydrogen, deuterium or halogen; R 7 is hydrogen or deuterium; L is O; R 8 is an aryl or heteroaryl group, wherein aryl refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, and heteroaryl refers to a monovalent monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, wherein one or more ring atoms are heteroatoms selected from N, O or S and the remaining ring atoms are carbon, and aryl and heteroaryl are each replaced by R a , R b and R c Substitution, where R a , R b , and R c are independently selected from hydrogen, halogen and cyano; and R 9 is hydrogen, C1-C6 alkyl, hydroxy or halogen; or When R 9 and R 2 When attached to the same carbon atom, they can combine to form oxo, C2-C6 alkyldienyl, or 3- to 6-membered cycloalkylene; The HIF-2α inhibitor of formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof is administered in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof.

2. The use as claimed in claim 1, wherein R 3 It's fluorine.

3. The use as claimed in claim 1, wherein R 3 and R 4 It's fluorine.

4. The method of claim 1, wherein L is O.

5. The method of claim 2, wherein L is O.

6. The use as claimed in claim 4, wherein R 8 R is independently selected from hydrogen, halogen and cyano a , R b and R c Substituted phenyl.

7. The use as claimed in claim 6, wherein R 8 It is 3-chloro-5-fluorophenyl, 3,5-difluorophenyl, 3-cyano-5-fluorophenyl, 3-chloro-5-cyanophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-cyanophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4-difluorophenyl or 3-cyano-4-fluorophenyl.

8. The use as claimed in claim 4, wherein R 8 R is independently selected from hydrogen, halogen and cyano a , R b , and R c Substituted heteroaryl.

9. The use according to any one of claims 1 to 8, wherein R 2 is hydrogen, and R 9 is hydrogen, C1-C6 alkyl, halogen or hydroxy, and R 2 and R 9 Attached to a ring carbon atom that is located adjacent to the ring attached to R 1 The meta position of the ring carbon.

10. The use according to claim 1, wherein the HIF-2α inhibitor having formula (IIa) or (IIb) is selected from: 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 3-Fluoro-5-((3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 3-Fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 3-Fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 3-Fluoro-5-(((1R,2aS)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 3-Fluoro-5-(((1R,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 1,3,3,4,4-Pentafluoro-7-((5-fluoropyridin-3-yl)oxy)-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol; 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydrospiro[cyclopenta[cd]-indene-1,1'-cyclopropane]-7-yl)oxy)benzonitrile; 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 3-Fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-1-methyl-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; 3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; (R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; and (S)-3-Fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-methylene-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; or or pharmaceutically acceptable salts thereof.

11. The use according to claim 1, wherein the HIF-2α inhibitor is selected from: 3-Fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile; or or pharmaceutically acceptable salts thereof.

12. The use according to claim 1, wherein the HIF-2α inhibitor is 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile.

13. The use according to claim 1, wherein the HIF-2α inhibitor is 3-fluoro-5-((1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile.

14. The use according to claim 1, wherein the PARP inhibitor is olaparib (4-[(3-[(4-cyclopropylcarbonyl)piperazin-1-yl]carbonyl)-4-fluorophenyl]methyl(2H)phthalazin-1-one), rucaparib (8-fluoro-2-{[(4-methylamino)-methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepine [5,4,3-cd]indol-6-one), niraparib (2-[4-[(3S)-3-piperidinyl]phenyl]indazole-7-carboxamide), talazoparib ((8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one), or pamiparib ((2R)-14-fluoro-2-methyl-6,9,10,19-tetraazapentacyclo[14.2.1.0 2,6 .0 8,18 .0 12,17 ]Nineteen-1(18),8,12(17),13,15-pentaen-11-one; trihydrate).

15. The use according to claim 9, wherein the PARP inhibitor is olaparib (4-[(3-[(4-cyclopropylcarbonyl)piperazin-1-yl]carbonyl)-4-fluorophenyl]methyl(2H)phthalazin-1-one), rucaparib (8-fluoro-2-{[(4-methylamino)-methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepine [5,4,3-cd]indol-6-one), niraparib (2-[4-[(3S)-3-piperidinyl]phenyl]indazole-7-carboxamide), talazoparib ((8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one), or pamiparib ((2R)-14-fluoro-2-methyl-6,9,10,19-tetraazapentacyclo[14.2.1.0 2,6 .0 8,18 .0 12,17 ]Nineteen-1(18),8,12(17),13,15-pentaen-11-one; trihydrate).

16. The use according to any one of claims 10 to 13, wherein the PARP inhibitor is olaparib (4-[(3-[(4-cyclopropylcarbonyl)piperazin-1-yl]carbonyl)-4-fluorophenyl]methyl(2H)phthalazin-1-one), rucaparib (8-fluoro-2-{[(4-methylamino)-methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepine [5,4,3-cd]indol-6-one), niraparib (2-[4-[(3S)-3-piperidinyl]phenyl]indazole-7-carboxamide), talazoparib ((8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one), or pamiparib ((2R)-14-fluoro-2-methyl-6,9,10,19-tetraazapentacyclo[14.2.1.0 2,6 .0 8,18 .0 12,17 ]Nineteen-1(18),8,12(17),13,15-pentaen-11-one; trihydrate).

17. The method of claim 15, wherein the cancer is selected from the group consisting of renal cancer, glioblastoma, neuroblastoma, paraganglioma, pheochromocytoma, somatostatinoma, hemangioblastoma, gastrointestinal stromal tumor, pituitary tumor, leiomyoma, leiomyosarcoma, polycythemia vera, retinal cancer, lung cancer, pancreatic cancer, liver cancer, ovarian cancer, breast cancer, prostate cancer, colorectal cancer, head and neck cancer, cervical cancer, endometrial cancer, bladder cancer, gastric cancer, esophageal cancer. , lymphoma, melanoma, mesothelioma, sarcoma, uveal melanoma, urothelial carcinoma, fallopian tube carcinoma, primary peritoneal carcinoma, bile duct carcinoma, Ewing sarcoma, uterine leiomyosarcoma, chronic lymphocytic leukemia, T-cell prolymphocytic leukemia, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, germ cell carcinoma, osteosarcoma, biliary tract cancer, soft tissue sarcoma, rhabdomyosarcoma, mantle cell lymphoma, endocrine gland neoplasms, and neuroendocrine tumors.

18. The method of claim 16, wherein the cancer is selected from the group consisting of renal cancer, glioblastoma, neuroblastoma, paraganglioma, pheochromocytoma, somatostatinoma, hemangioblastoma, gastrointestinal stromal tumor, pituitary tumor, leiomyoma, leiomyosarcoma, polycythemia vera, retinal cancer, lung cancer, pancreatic cancer, liver cancer, ovarian cancer, breast cancer, prostate cancer, colorectal cancer, head and neck cancer, cervical cancer, endometrial cancer, bladder cancer, gastric cancer, esophageal cancer , lymphoma, melanoma, mesothelioma, sarcoma, uveal melanoma, urothelial carcinoma, fallopian tube carcinoma, primary peritoneal carcinoma, bile duct carcinoma, Ewing sarcoma, uterine leiomyosarcoma, chronic lymphocytic leukemia, T-cell prolymphocytic leukemia, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, germ cell carcinoma, osteosarcoma, biliary tract cancer, soft tissue sarcoma, rhabdomyosarcoma, mantle cell lymphoma, endocrine gland neoplasms, and neuroendocrine tumors.

19. The use of claim 17 or 18, wherein the cancer is clear cell renal carcinoma.

20. The use according to claim 17 or 18, wherein the HIF-2α inhibitor having formula (IIa) or (IIb) and the PARP inhibitor are administered sequentially or simultaneously.

21. The use according to claim 19, wherein the HIF-2α inhibitor having formula (IIa) or (IIb) and the PARP inhibitor are administered sequentially or simultaneously.

22. The use according to claim 20, wherein the HIF-2α inhibitor of formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof is further administered in combination with one or more additional anticancer agents.

23. The use according to claim 21, wherein the HIF-2α inhibitor of formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof is further administered in combination with one or more additional anti-cancer agents.

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