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Ep 3043784 B9 (19) *EP003043784B9* (11) EP 3 043 784 B9 (12) CORRECTED EUROPEAN PATENT SPECIFICATION (15) Correction information: (51) Int Cl.: Corrected version no 1 (W1 B1) A61K 31/085 (2006.01) C07C 255/54 (2006.01) (2006.01) Corrections, see C07D 213/85 Claims EN 1, 8, 10 (86) International application number: (48) Corrigendum issued on: PCT/US2014/054375 20.11.2019 Bulletin 2019/47 (87) International publication number: (45) Date of publication and mention WO 2015/035223 (12.03.2015 Gazette 2015/10) of the grant of the patent: 15.05.2019 Bulletin 2019/20 (21) Application number: 14842085.4 (22) Date of filing: 05.09.2014 (54) ARYL ETHERS AND USES THEREOF ARYLETHER UND VERWENDUNGEN DAVON ARYLÉTHERS ET UTILISATIONS DE CEUX-CI (84) Designated Contracting States: • RIZZI, James P. AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Irving, TX 75063 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • SCHLACHTER, Stephen, T. PL PT RO RS SE SI SK SM TR Dallas, TX 75208 (US) • WALLACE, Eli, M. (30) Priority: 09.09.2013 US 201361875674 P Richardson, TX 75080 (US) 11.04.2014 US 201461978421 P • WANG, Bin Dallas, TX 75229 (US) (43) Date of publication of application: • WEHN, Paul 20.07.2016 Bulletin 2016/29 Dallas, TX 75205 (US) • XU, Rui (60) Divisional application: Dallas, TX 75205 (US) 18185557.8 / 3 417 851 • YANG, Hanbiao 18185565.1 / 3 417 852 Coppell, TX 75019 (US) 19192594.0 (74) Representative: Mewburn Ellis LLP (73) Proprietor: Peloton Therapeutics, Inc. City Tower Dallas, TX 75235-7323 (US) 40 Basinghall Street London EC2V 5DE (GB) (72) Inventors: • DIXON, Darryl David (56) References cited: Dallas, TX 75235 (US) WO-A1-93/24434 WO-A1-2007/071441 • GRINA, Jonas DE-C- 705 530 US-A- 4 214 103 Coppell, TX 75019 (US) US-A- 4 665 097 US-A1- 2005 085 541 • JOSEY, John A. US-A1- 2007 244 071 US-A1- 2008 312 313 Dallas, TX 75208 (US) US-A1- 2012 295 937 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 3 043 784 B9 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 3 043 784 B9 • YING-TING LIN ET AL: "Efficient In Silico Assay • DATABASE PUBCHEM [Online] 09 July 2005 of Inhibitors of Hepatitis C Virus RNA-Dependent ’ZINC00344684’, XP055323153 Retrieved from RNA Polymerase by Structure-Based Virtual NCBI pubchem Database accession no. CID Screening and In Vitro Evaluation", ASSAY AND 825455 DRUG DEVELOPMENT TECHNOLOGIES, vol. 9, no. 3, 1 June 2011 (2011-06-01), pages 290-298, XP55350132, US ISSN: 1540-658X, DOI: 10.1089/adt.2010.0341 • DATABASE PUBCHEM [Online] 05 December 2007 ’SCHEMBL5392074’, XP055323150 Retrieved from NCBI pubchem Database accession no. CID 21110550 2 EP 3 043 784 B9 Description [0001] This invention was in part funded by a grant from Cancer Prevention Research Institute of Texas (Grant number R1009). 5 [0002] The present application claims benefit of priority to U.S. Provisional Application Serial Nos. 61/875,674, filed September 9, 2013, and 61/978,421, filed April 11, 2014. [0003] Intratumoral hypoxia is a driving force in cancer progression and is closely linked to poor patient prognosis and resistance to chemotherapy and radiation treatment. Progress over the past several decades in mapping the molecular mechanisms that enable cellular adaptation to chronic oxygen deprivation has intensified interest in identifying drugs 10 that effectively block the hypoxic response pathway in tumors. Hypoxia-Inducible Factors (HIF-1α and HIF-2α) are transcription factors that play central roles in this pathway, and thus represent attractive targets for therapeutic interven- tion. The half-life of HIF-α proteins is tightly regulated by the oxidative status within the cell. Under normoxic conditions, specific proline residues on the HIF proteins are hydroxylated by the oxygen sensitive HIF-specific prolyl-hydroxylases (PHD). The tumor suppressor von Hippel-Lindau (VHL) protein binds to the specific hydroxylated proline residues and 15 recruits E3 ubiquition-ligase complex that targets HIF-α proteins for proteasomal degradation. Because PHDs require oxygen to function, under hypoxic conditions, HIF-α proteins accumulate and enter the nucleus to activate gene expres- sion. Genetic mutations of the VHL gene that result in loss of function lead to constitutively active HIF-α proteins regardless of oxygen levels. Upon activation, these transcription factors stimulate the expression of genes that coordinately regulate anaerobic metabolism, angiogenesis, cell proliferation, cell survival, extracellular matrix remodeling, pH homeostasis, 20 amino acid and nucleotide metabolism, and genomic instability. While many gene products involved in the hypoxic response have been explored individually as therapeutic targets for cancer, broad inhibition of the pathway through direct targeting of HIF-α proteins offers an exciting opportunity to attack tumors on multiple fronts (Keith, et al. Nature Rev. Cancer 12: 9-22, 2012). [0004] Both HIF-1α and HIF-2α form a dimeric complex with HIF-1β (or ARNT: aryl hydrocarbon receptor nuclear 25 translocator) and subsequently bind to hypoxia response elements (HRE) in target genes. Because the level of HIF-1β is unaffected by oxygen levels or VHL, transcriptional activity of the complex is largely driven by the availability of the HIF-α proteins. While HIF-1α and HIF-2α share significant sequence homology, they differ in tissue distribution, sensitivity to hypoxia, timing of activation and target gene specificity (Hu, et al. Mol. Cell Biol. 23: 9361-9374, 2003 and Keith, et al. Nature Rev. Cancer 12: 9-22, 2012). Whereas HIF-1α mRNA is ubiquitously expressed, the expression of HIF-2α 30 mRNA is found primarily in kidney fibroblasts, hepatocytes and intestinal lumen epithelial cells. Consistent with the tight regulation of the HIF-α proteins under normal physiology, neither is detected in normal tissue with the exception of HIF- 2α in macrophages (Talks, et al. Am. J. Pathol. 157: 411-421, 2000). However, HIF-2α protein has been detected in various human tumors of the bladder, breast, colon, liver, ovaries, pancreas, prostate and kidney as well as tumor- associated macrophages (Talks, et al. Am. J. Pathol. 157: 411-421, 2000). HIF-1α has been reported to give a transient, 35 acute transcriptional response to hypoxia while HIF-2α provides more prolonged transcriptional activity. Furthermore, HIF-2α has greater transcriptional activity than HIF-1α under moderately hypoxic conditions like those encountered in end capillaries (Holmquist-Mengelbier, et al. Cancer Cell 10: 413-423, 2006). Whereas some hypoxia-regulated genes are controlled by both HIF-1α and HIF-2α, some are only responsive to specific HIF-α proteins. For example, lactate dehydrogenase A (LDHA), phosphoglycerate kinase (PGK) and pyruvate dehydrogenase kinase 1 (PDK1) are uniquely 40 controlled by HIF-1α whereas Oct-4 and erythropoietin (EPO) by HIF-2α. Often the relative contributions of the HIF-α proteins to gene transcription are cell type-, and disease-specific. More importantly, the HIF-α proteins may play con- trasting roles in tumorigenesis. For example, the oncogene MYC is a transcription factor that controls cell cycle Gl/S transition. MYC is overexpressed in 40% of human cancer. It has been shown that HIF-2α activity increases MYC transcription activity whereas HIF-1α inhibits MYC activity. As a result, in MYC driven tumors, HIF-2α inhibition reduced 45 proliferation whereas HIF-1α inhibition increased growth (Gordan, et al. Cancer Cell 11: 335-347, 2007 and Koshiji et al. EMBO J. 23: 1949-1956, 2004). [0005] Therefore, the identification of effective small molecules to modulate the activity of HIF-2α is desirable. [0006] WO 2007/071441 discloses certain substituted arenesulfonamides which act as inhibitors of CC chemokine receptor 9 (CCR9). The expression of CCR9 is reported to correlate with the ability of peripheral T lymphocytes to home 50 to the small intestine. Certain disclosed arenesulfonamides are shown to inhibit CCR9 in an in vitro assay. Summary [0007] In a first aspect, the present disclosure provides a compound of Formula III 55 3 EP 3 043 784 B9 5 10 or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, 3 or 4; 15 R1 is phenyl or pyridyl, wherein said phenyl or pyridyl is substituted with at least one substituent selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and cyano; R4 is cyano, fluoroalkyl, sulfonamide, sulfinyl, sulfonyl or sulfoximinyl; R5 is hydrogen, halo or unsubstituted alkyl; R8 is hydrogen, hydroxy, unsubstituted alkylamino, unsubstituted alkoxy or amino; 20 R9 is hydrogen, unsubstituted alkyl, unsubstituted alkenyl or unsubstituted alkynyl; or R8 and R9 in combination form oxo or oxime; and each of Rio is independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxy, and unsubsti- tuted alkyl; or two Rio and the carbon atom(s) to which they are attached form a 3- to 8-membered unsubstituted cycloalkyl or unsubstituted heterocycloalkyl. 25 [0008] In a second aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the first aspect and a pharmaceutically acceptable carrier. The compound may exist in an amorphous form, a crystalline form, or as a salt, solvate or hydrate. [0009] In a third aspect, the present disclosure provides a compound of the first aspect for use as a medicament for 30 the treatment of von Hippel-Lindau (VHL) disease.
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