(19) *EP003468966B1* (11) EP 3 468 966 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 405/14 (2006.01) C07D 403/04 (2006.01) (2006.01) (2006.01) 05.08.2020 Bulletin 2020/32 C07D 403/14 C07D 471/10 C07D 487/10 (2006.01) C07D 491/10 (2006.01) (2006.01) (2006.01) (21) Application number: 17739383.2 A61K 31/407 A61P 35/00 A61P 3/10 (2006.01) (22) Date of filing: 08.06.2017 (86) International application number: PCT/US2017/036506 (87) International publication number: WO 2017/214367 (14.12.2017 Gazette 2017/50) (54) INHIBITORS OF THE MENIN-MLL INTERACTION INHIBITOREN DER MENIN-MLL-INTERAKTION INHIBITEURS DE L’INTERACTION MÉNINE-MLL (84) Designated Contracting States: • MORALES-RAMOS, Angel AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Blue Bell, Pennsylvania 19422 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • SINGH, Suresh, B. PL PT RO RS SE SI SK SM TR Kendall Park, New Jersey 08824 (US) • VENKATRAMAN, Shankar (30) Priority: 10.06.2016 US 201662348496 P Lansdale, Pennsylvania 19446 (US) • YUAN, Jing (43) Date of publication of application: Lansdale, Pennsylvania 19446 (US) 17.04.2019 Bulletin 2019/16 • ZHENG, Yajun California 94404 (US) (73) Proprietor: Vitae Pharmaceuticals, LLC • ZHUANG, Linghang Madison, NJ 07940 (US) Chalfont, Pennsylvania 18914 (US) • PARENT, Stephan, D. (72) Inventors: West Lafayette, Indiana 47906 (US) • CACATIAN, Salvacion • HOUSTON, Travis, L. Conshohocken, Pennsylvania 19428 (US) Lafayette, Indiana 47905 (US) • CLAREMON, David, A. Maple Glen, Pennsylvania 19002 (US) (74) Representative: Cooley (UK) LLP • DILLARD, Lawrence, Wayne Dashwood Yardley, Pennsylvania 19067 (US) 69 Old Broad Street • DONG, Chengguo London EC2M 1QS (GB) Staten Island, New York 10305 (US) • FAN, Yi (56) References cited: Doylestown, Pennsylvania 18901 (US) WO-A1-2014/164543 WO-A1-2015/191701 • JIA, Lanqi Horsham, Pennsylvania 19044 (US) • A. SHI ET AL: "Structural insights into inhibition • LOTESTA, Stephen, D. of the bivalent menin-MLL interaction by small Burlington, New Jersey 08016 (US) molecules in leukemia", BLOOD, vol. 120, no. 23, • MARCUS, Andrew 29 November 2012 (2012-11-29), pages Media, Pennsylvania 19063 (US) 4461-4469, XP055245187, US ISSN: 0006-4971, DOI: 10.1182/blood-2012-05-429274 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 3 468 966 B1 Printed by Jouve, 75001 PARIS (FR) EP 3 468 966 B1 Description TECHNICAL FIELD 5 [0001] The present invention is directed to inhibitors of the interaction of menin with MLL and MLL fusion proteins, pharmaceutical compositions containing the same, and their use in the treatment of cancer and other diseases mediated by the menin-MLL interaction. BACKGROUND 10 [0002] The mixed-lineage leukemia (MLL) protein is a histone methyltransferase that is mutated in clinically and biologically distinctive subsets of acute leukemia. Rearranged mixed lineage leukemia (MLL-r) involves recurrent trans- locations of the 11q23 chromosome locus which lead to an aggressive form of acute leukemia with limited therapeutic options. These translocations target the MLL gene creating an oncogenic fusion protein comprising the amino-terminus 15 of MLL fused in frame with more than 60 different fusion protein partners. Menin, a ubiquitously expressed, nuclear protein encoded by the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene, has a high affinity binding interaction with MLL fusion proteins and is an essential co-factor of oncogenic MLL-r fusion proteins (Yokoyama et al., 2005, Cell, 123:207-18; Cierpicki & Grembecka, 2014, Future Med. Chem., 6:447-462). Disruption of this interaction leads to selective growth inhibition and apoptosis of MLL-r leukemia cells both in vitro (Grembecka et al., 2012, Nat. 20 Chem. Biol., 8:277-284) and in vivo (Yokoyama et al., 2005, op. cit.; Borkin et al., 2015, Cancer Cell, 27:589-602). [0003] The menin-MLL complex plays a role in castration-resistant/advanced prostate cancer, and a menin-MLL in- hibitor has been shown to reduce tumor growth in vivo (Malik et al., 2015, Nat. Med., 21:344-352). Additionally, a menin- MLL inhibitor has been shown to enhance human β cell proliferation (Chamberlain et al., 2014, J. Clin. Invest., 124:4093-4101), supporting a role for inhibitors of the menin-MLL interaction in the treatment of diabetes (Yang et al., 25 2010, Proc Natl Acad Sci U S A., 107:20358-20363). The interaction between menin and MLL or MLL fusion proteins is an attractive target for therapeutic intervention, and there is a need for novel agents that inhibit the menin-MLL interaction for the treatment of various diseases and conditions, including leukemia, other cancers and diabetes. SUMMARY 30 [0004] The present invention provides inhibitors of the menin-MLL interaction, such as a compound of Formula I: 35 40 45 50 or a pharmaceutically acceptable salt thereof, wherein constituent variables are defined herein. [0005] The present invention further provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. [0006] The present invention further provides pharmaceutically acceptable salt forms of the compounds of Formula I. [0007] The present invention further provides crystalline forms of the compounds of Formaul I. 55 [0008] The present invention further provides a method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with a compound of Formula I, or a pharmaceutically acceptable salt thereof. [0009] The present invention further provides a method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. 2 EP 3 468 966 B1 [0010] The present invention further provides a method of treating insulin resistance, pre-diabetes, diabetes, risk of diabetes, or hyperglycemia in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. 5 BRIEF DESCRIPTION OF THE DRAWINGS [0011] Figure 1 shows an XRPD pattern characteristic of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)- 10 2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide. Figure 2 shows an XRPD pattern characteristic of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)- 2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide sesquifumaric acid salt. Figure 3 shows an XRPD pattern characteristic of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)- 2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide bis-methanesulfonic acid salt. 15 Figure 4 shows an XRPD pattern characteristic of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)- 2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide bis-hydrochloric acid salt. Figure 5 shows an XRPD pattern characteristic of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonami- do)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide. Figure 6 shows an XRPD pattern characteristic of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonami- 20 do)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide bis-methanesulfonic acid salt. Figure 7 shows an XRPD pattern characteristic of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonami- do)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumaric acid salt. Figure 8 shows an XRPD pattern characteristic of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonami- do)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide bis-hydrochloric acid salt. 25 Figure 9 shows XRPD pattern characteristics of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cy- clohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumaric acid salt, crystalline Form A, Form B, Form C+Form A, Form D, Form, E, and Form F. Figure 10 shows an XRPD pattern characteristic of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonami- do)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumaric acid salt, crystal- 30 line Form A. Figure 11 shows a DSC thermogram characteristic of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfona- mido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumaric acid salt, crys- talline Form A. Figure 12 shows a TGA thermogram characteristic of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfona- 35 mido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumaric acid salt, crys- talline Form A. Figure 13 shows a DVS pattern characteristic of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cy- clohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumaric acid salt, crystalline Form A. 40 Figure 14 shows variable tempterature (VT)-XRPD patterns characteristic of 5-fluoro-N,N-diisopropyl- 2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)ben- zamide sesquifumaric acid salt, crystalline Form A.