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Ep 3241833 A1 (19) TZZ¥ _¥¥_T (11) EP 3 241 833 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.11.2017 Bulletin 2017/45 C07D 495/04 (2006.01) C07D 401/04 (2006.01) C07D 401/14 (2006.01) A61K 31/506 (2006.01) (2006.01) (2006.01) (21) Application number: 17175212.4 A61P 9/00 A61P 3/08 A61P 35/00 (2006.01) A61P 25/28 (2006.01) (22) Date of filing: 18.10.2011 (84) Designated Contracting States: • DASSEUX, Jean-Louis Henri AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 31300 Toulouse (FR) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • GEOFFROY, Otto PL PT RO RS SE SI SK SM TR Gainesville, 32605 (US) • BARBARAS, Ronald (30) Priority: 18.10.2010 US 394136 P 31840 Seilh (FR) 18.02.2011 US 201161444212 P (74) Representative: Lavoix (62) Document number(s) of the earlier application(s) in Bayerstrasse 83 accordance with Art. 76 EPC: 80335 München (DE) 11835025.5 / 2 629 776 Remarks: (71) Applicant: Cerenis Therapeutics Holding SA This application was filed on 09.06.2017 as a 31670 Labege (FR) divisional application to the application mentioned under INID code 62. (72) Inventors: • ONICIU, Daniela Carmen 31200 TOULOUSE (FR) (54) COMPOUNDS, COMPOSITIONS AND METHODS USEFUL FOR CHOLESTEROL MOBILISATION (57) The invention relates to classes of pharmaceu- to methods for treating or preventing a disease or disor- tically-active heterocyclic compounds and pharmaceuti- der, which comprises administering a therapeutically or cally acceptable salts, and hydrates thereof, and com- prophylactically effective amount a compound described positionscomprising the same.The invention also relates herein. EP 3 241 833 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 241 833 A1 Description [0001] This application claims the benefit of U.S. Provisional Application No. 61/394,136, filed October 18, 2010, and U.S. Provisional Application No. 61/444,212, filed February 18, 2011, the disclosure of each of which are hereby incor- 5 porated by reference herein in its entirety. Field of the Invention [0002] The invention provides compounds, compositions, and methods of treatment or prevention of abnormal con- 10 ditions in a subject. Background of the Invention [0003] Cholesterol circulating in the human body is carried by plasma lipoproteins, which are particles of complex lipid 15 and protein composition that transport lipids in the blood. Two types of plasma lipoproteins that carry cholesterol are low density lipoproteins ("LDL") and high density lipoproteins ("HDL"). LDL particles are believed to be responsible for the delivery of cholesterol from the liver (where it is synthesized or obtained from dietary sources) to extrahepatic tissues in the body. HDL particles, on the other hand, are believed to aid in the transport of cholesterol from the extrahepatic tissues to the liver, where the cholesterol is catabolized and eliminated. Such transport of cholesterol from the extrahepatic 20 tissues to the liver is referred to as "reverse cholesterol transport." [0004] The reverse cholesterol transport ("RCT") pathway has three main steps: (i) cholesterol efflux,i.e., the initial removal of cholesterol from various pools of peripheral cells; (ii) cholesterol esterification by the action of lecithin:cho- lesterol acyltransferase ("LCAT"), thereby preventing a re-entry of effluxed cholesterol into cells; and (iii) uptake of the cholesteryl ester by HDL and delivery of the HDL-cholesteryl ester complex to liver cells. 25 [0005] The RCT pathway is mediated by HDL particles. A pathway in the liver involving F1-ATPase and the P2Y13 receptor (Martinez et al. 2003 Nature 421; 75-79) that regulates HDL-cholesterol removal was recently described. The presence of a nucleotidase activity of F1-ATPase subunit at the cell surface of hepatocytes, allowing the hydrolysis of ATP to ADP, which in turn stimulates the P2Y13 receptor activities resulting in the uptake of the HDL by the cells was recently described. (Jacquet et al. 2005 Cell Mol Life Sci 62; 2508-2515). More recently, Fabre et al (Fabre et al. 30 Hepatology 52; 1477-1483) confirmed the relationship between P2Y13r and the reverse cholesterol transport in mice. Summary of the Invention [0006] In one embodiment, the invention provides compounds of the following Formula (I) 35 40 and pharmaceutically acceptable salts thereof, wherein 45 1 2 3 each of R , R , and R is independently H, -OH, -NH2, -NH(alkyl), - N(alkyl)(alkyl), hydrocarbyl, -O-hydrocarbyl, aryl, -O-aryl, aralkyl, -O-aralykl, heteroaryl, -O-heteroaryl, heterocyclyl, -O-heterocyclyl, halo,3, -OCF -C(O)O(alkyl),-OC(O)(alkyl), -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)(alkyl), -NHC(O)(alkyl), N(alkyl)C(O)(alkyl), -OC(O)O(alkyl), -OC(O)NH2, -OC(O)NH(alkyl),-OC(O)N(alkyl)(alkyl), -CHNH, -CHN(alkyl), or -SO 2NH2; 50 4 R is -H, -OH, -COOH, -NH2, -NH(alkyl), -N(alkyl)(alkyl), -hydrocarbyl, -O-hydrocarbyl, -aryl, -O-aryl, -aralkyl, -O- aralkyl, -heteroaryl, -O-heteroaryl, -heterocyclyl, -O-heterocyclyl, -halo, -C(O)O(alkyl), -OC(O)(alkyl), -C(O)NH2, -C(O)NH(alkyl),-C(O)N(alkyl)(alkyl), -NHC(O)(alkyl), N(alkyl)C(O)(alkyl), -OC(O)O(alkyl),-OC(O)NH2, -OC(O)NH(alkyl), or -OC(O)N(alkyl)(alkyl); 1 2 Z is CH2, S, O, NH, N-hydrocarbyl, N-aryl, N-heteroaryl, or N-heterocyclyl; Z is CH or N; and 55 n is an integer from 1-6. [0007] In another embodiment, the invention provides compounds of the following Formula (II) 2 EP 3 241 833 A1 5 10 and pharmaceutically acceptable salts thereof, wherein 15 each R9 is independently -H, -hydrocarbyl, -aryl, -aralkyl, -heteroaryl, - heterocyclyl, -C(O)O(alkyl), -OC(O)(alkyl), -C(O)NH2, -C(O)NH(alkyl), - C(O)N(alkyl)(alkyl), -NHC(O)(alkyl), N(alkyl)C(O)(alkyl), or -SO2NH2; 10 each R is independently -H, -OH, -NH 2, -NH(alkyl), -N(alkyl)(alkyl), hydrocarbyl, -O-alkyl, -O-alkenyl, aryl, -O-aryl, aralkyl, -O--aralykl, heteroaryl, -O-heteroaryl, heterocyclyl, -O-heterocyclyl, halo,3 , -OCF-C(O)O(alkyl), -OC(O)(alkyl),-C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)(alkyl), NHC(O)(C2-C10-alkyl), N(alkyl)C(O)(alkyl), 20 -OC(O)O(alkyl), -OC(O)NH2, -OC(O)NH(alkyl), - OC(O)N(alkyl)(alkyl), -CHNH, -CHN(alkyl), or -SO2NH2; each of Q1, Q2, and Q3 is independently CR10 or N; X is CHR10, S, O, or NR9; and each m is independently an integer from 0-3. 25 [0008] In another embodiment, the invention provides compounds of the following Formula III: 30 35 40 and pharmaceutically acceptable salts thereof, wherein 1 2 3 each of R , R , and R is independently H,- OH, -NH 2, -NH(alkyl),-N(alkyl)(alkyl), hydrocarbyl, -O-hydrocarbyl, aryl, -O-aryl, aralkyl, -O-aralykl, heteroaryl, -O-heteroaryl, heterocyclyl, -O-heterocyclyl, 3, halo, -OCF -C(O)O(alkyl),-OC(O)(alkyl), -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)(alkyl), -NHC(O)(alkyl), N(alkyl)C(O)(alkyl), 45 -OC(O)O(alkyl), -OC(O)NH2, -OC(O)NH(alkyl),-OC(O)N(alkyl)(alkyl), -CHNH, -CHN(alkyl), or -SO 2NH2; 5 R is -H, -OH, -NH2, -NH(alkyl), -N(alkyl)(alkyl), hydrocarbyl, -O-hydrocarbyl, aryl, -O-aryl, aralkyl, -O-aralkyl, het- eroaryl, -O-heteroaryl, heterocyclyl, or -O-heterocyclyl; 1 Z is CH2, S, O, NH, N-hydrocarbyl, N-aryl, N-heteroaryl, or N-heterocyclyl; Z2 is CH or N; and 50 n is an integer from 1-6. [0009] In another embodiment, the invention provides compounds of the following Formula IV: 55 3 EP 3 241 833 A1 5 10 and pharmaceutically acceptable salts thereof, wherein 1 R is H, -OH, -NH 2, -NH(alkyl), -N(alkyl)(alkyl), hydrocarbyl, -O-hydrocarbyl, aryl, -O-aryl, aralkyl, -O-aralykl, heter- 15 oaryl, -O-heteroaryl, heterocyclyl, -O-heterocyclyl, halo, 3-OCF, -C(O)O(alkyl), -OC(O)(alkyl), -C(O)NH2, -C(O)NH(alkyl), - C(O)N(alkyl)(alkyl), -NHC(O)(alkyl), N(alkyl)C(O)(alkyl), -OC(O)O(alkyl), - 2OC(O)NH, -OC(O)NH(alkyl), -OC(O)N(alkyl)(alkyl), -CHNH, -CHN(alkyl), or - SO2NH2; 1 2 Z is CH2, S, O, NH, N-hydrocarbyl, N-aryl, N-heteroaryl, or N-heterocyclyl; and Z is CH or N. 20 [0010] In another embodiment, the invention provides compounds of the following Formula V: 25 30 and pharmaceutically acceptable salts thereof, wherein 35 1 2 3 each of R , R , and R is independently H, -OH, -NH 2, -NH(alkyl),-N(alkyl)(alkyl), hydrocarbyl, -O-hydrocarbyl, aryl, -O-aryl, aralkyl, -O-aralykl, heteroaryl, -O-heteroaryl, heterocyclyl, -O-heterocyclyl, 3, halo, OCF -C(O)O(alkyl),-OC(O)(alkyl), -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)(alkyl), -NHC(O)(alkyl), N(alkyl)C(O)(alkyl), -OC(O)O(alkyl), -OC(O)NH2, -OC(O)NH(alkyl),-OC(O)N(alkyl)(alkyl), -CHNH, -CHN(alkyl), or -SO 2NH2; 4 R is -H, -OH, -COOH, -NH2, -NH(alkyl), -N(alkyl)(alkyl), hydrocarbyl, -O-hydrocarbyl, aryl, -O-aryl, aralkyl, -O- 40 aralkyl, heteroaryl, -O-heteroaryl, heterocyclyl,-O-heterocyclyl, halo, -C(O)O(alkyl), -OC(O)(alkyl), -C(O)NH2, -C(O)NH(alkyl),-C(O)N(alkyl)(alkyl), -NHC(O)(alkyl), N(alkyl)C(O)(alkyl), -OC(O)O(alkyl),-OC(O)NH2, -OC(O)NH(alkyl), or -OC(O)N(alkyl)(alkyl),; 6 R is -H, -OH, -SH, -S-hydrocarbyl, -COOH, -NH 2, -NH(alkyl), -N(alkyl)(alkyl), hydrocarbyl, -O-hydrocarbyl, aryl, -O- aryl, aralkyl, -O-aralkyl, heteroaryl, -O-heteroaryl, heterocyclyl, -O-heterocyclyl, halo, -C(O)O(alkyl), -OC(O)(alkyl), 45 -C(O)NH2,-C(O)NH(alkyl), -C(O)N(alkyl)(alkyl), -NHC(O)(alkyl), N(alkyl)C(O)(alkyl),-OC(O)O(alkyl), -OC(O)NH2, -OC(O)NH(alkyl), or -OC(O)N(alkyl)(alkyl); R7 is H, hydrocarbyl, aryl, aralkyl, heteroaryl, or heterocyclyl; Z2 is CH or N; and n is an integer from 1-6.
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