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WO2025108420A1 - 一种降低rbp4的血清浓度的化合物及用途 - Google Patents

一种降低rbp4的血清浓度的化合物及用途 Download PDF

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Publication number
WO2025108420A1
WO2025108420A1 PCT/CN2024/133816 CN2024133816W WO2025108420A1 WO 2025108420 A1 WO2025108420 A1 WO 2025108420A1 CN 2024133816 W CN2024133816 W CN 2024133816W WO 2025108420 A1 WO2025108420 A1 WO 2025108420A1
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alkyl
acceptable salt
pharmaceutically acceptable
stereoisomer
deuterated derivative
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French (fr)
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WO2025108420A9 (zh
Inventor
邓小兵
苏亚宁
田文嘉
肖栋槐
付雨晴
于晓彧
赵燕
李勃
陈辉玲
王艳红
曹硕
崔巍祎
周宜遂
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Beijing Double Crane Runchuang Technology Co Ltd
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Beijing Double Crane Runchuang Technology Co Ltd
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Publication of WO2025108420A1 publication Critical patent/WO2025108420A1/zh
Publication of WO2025108420A9 publication Critical patent/WO2025108420A9/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present application belongs to the field of medicinal chemistry and relates to a compound for reducing the serum concentration of RBP4, and the use of the compound.
  • Retinol binding protein 4 (RBP4) is the only plasma transporter that transports vitamin A from the liver to peripheral tissues. Since retinol is involved in a variety of biological functions, including cell growth, immune function, fetal development and vision, research on RBP4 has attracted increasing interest in recent years (see Clin. Immunol. Immunopathol., 80 (1996), pp. S52-S62; Faseb. J., 10 (1996), pp. 961-968; Endocr. Rev., 10 (1989), pp. 308-316; Cell Metabol., 5 (2007), pp. 164-166; Harvey Lect., 90 (1994), pp. 105-117; Annu. Rev. Pharmacol. Toxicol., 46 (2006), pp. 451-480).
  • CVD cardiovascular disease
  • NASH non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • T2DM insulin resistance in type 2 diabetes mellitus
  • RBP4 is also believed to be related to the occurrence of cancer, age-related macular degeneration (AMD) and Stargardt disease (STGD) (see Oncotarget, 8 (2017), pp. 92254-92264; Medicine, 99 (2020), article e21254; J. Ovarian Res., 11 (2016), p. 29; Cancers, 12 (2020), p. 623; Endocr. Relat. Canc., 22 (2015), pp. L1-L4; BioMed Res. Int., 2014 (2014), p. 179040; Health Technol. Assess., 22 (2018), pp. 1-168).
  • studies have been conducted to reduce the expression level of RBP4 by directly antagonizing or inhibiting the level of RBP4.
  • RBP4 is mainly synthesized in the liver, with about 20% synthesized in adipose tissue (see J. Lipid Res., 30 (1989), pp. 171-180), it has been considered as a biomarker for insulin resistance and metabolism.
  • RBP4 is known as an adipokine involved in energy metabolism, insulin signal transduction, and insulin resistance (see Proc. Natl. Acad. Sci. United States Am., 108 (2011), pp. 4340-4345; Am. J. Physiol. Endocrinol. Metab., 297 (2009), pp. E1420-E1429; Diabetes, 64 (2015), pp. 1603-1614; Diabetology, 59 (2016), pp. 354-362).
  • RBP4 is also involved in fatty acid transport (see Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 1863 (2016), pp. 458-466).
  • many studies have reported elevated levels of RBP4 in patients with diabetes and insulin resistance (see J. Clin. Endocrinol., 92 (2007), pp. 1971-1974; Diabetes Care, 29 (2006), pp. 2457-2461; Diabetes Care, 30 (2007), pp. 1173-1178).
  • the present application provides a compound for reducing the serum concentration of RBP4. Specifically, it is as follows:
  • the present application provides a compound of formula (I), a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof,
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently -H, -halogen, -CF 3 or -C 1-4 alkyl; wherein at least two of R 1 , R 2 , R 3 , R 4 or R 5 are not H;
  • ⁇ , ⁇ , ⁇ , and ⁇ are each independently absent or present, and when present each is a bond;
  • X is C or N
  • Z 2 is O, S, N or NR 7 ,
  • R 7 is -H, -C 1-4 alkyl or -(oxetane)yl
  • Q is a substituted or unsubstituted heterobicyclic ring; preferably, Q is a substituted or unsubstituted 5-, 6- or 7-membered ring structure.
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently -H, -F, -Cl, -Br or -CF 3 .
  • R1 is -CF3 , R2 is -F, R3 is -F, R4 is -H and R5 is -H, or
  • R1 is -CF3 , R2 is -F, R3 is -H, R4 is -H and R5 is -H, or
  • R1 is -CF3 , R2 is -F, R3 is -H, R4 is -F and R5 is -H, or
  • R1 is -CF3 , R2 is -H, R3 is -F, R4 is -F and R5 is -H, or
  • R1 is -CF3 , R2 is -H, R3 is -H, R4 is -H and R5 is -F, or
  • R1 is -CF3 , R2 is -H, R3 is -F, R4 is -H and R5 is -H, or
  • R1 is -CF3 , R2 is -H, R3 is -H, R4 is -Cl and R5 is -H, or
  • R1 is -CF3 , R2 is -Cl, R3 is -H, R4 is -H and R5 is -H, or
  • R1 is -H
  • R2 is -CF3
  • R3 is -H
  • R4 is -CF3
  • R5 is -H
  • R1 is -Cl
  • R2 is -H
  • R3 is -H
  • R4 is -F
  • R5 is -H
  • R1 is -Cl
  • R2 is -F
  • R3 is -H
  • R4 is -H
  • R5 is -H.
  • R1 is -CF3 , R2 is -F, R3 is -F, R4 is -H and R5 is -H, or
  • R1 is -CF3
  • R2 is -F
  • R3 is -H
  • R4 is -H
  • R5 is -H.
  • n is an integer from 0 to 2;
  • R 7 is -H, -C 1-4 alkyl or -(oxetane)yl
  • ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ are each independently absent or present, and when present are each a bond;
  • Z 2 is O, S, N or NR 7 ,
  • X is C or N
  • Y 1 , Y 2 , Y 3 and each occurrence of Y 4 are each independently CR 8 , CH 2 or NR 9 ;
  • R 8 is -H, halogen, -OCH 3 , -CN or -CF 3 ;
  • R 9 is -H, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-6 cycloalkyl, -(C 1-4 alkylene)-(C 3-6 cycloalkyl), -(C 3-6 heterocyclyl), -(C 1-4 alkylene)-(C 3-6 heterocyclyl ), -(C 1-6 alkylene)-O(C 1-3 alkyl), -(C 1-6 alkylene)-CF 3 , -C(O)-(C 1-6 alkyl), -C(O) 2 -(C 1-6 alkyl), -C(O)-NH 2 , -C(O)-NH(C 1-3 alkyl), -C(O)-N(C 1-3 alkyl) 2 , -C(O)NH-(C 1-6 alkyl), -C(O)-(C 1-6 haloalkyl), -C(O)-(C
  • the second aspect of the present application provides a compound of formula (I), its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer or its acceptable salt of its deuterated derivative,
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently -H, -halogen, -CF 3 or -C 1-4 alkyl; wherein at least two of R 1 , R 2 , R 3 , R 4 or R 5 are not H;
  • A is selected from
  • R 7 is selected from -H, -C 1-4 alkyl or -(oxetane) group
  • n 0, 1 or 2;
  • R 9 is selected from hydrogen, -C 1-6 alkyl, -C( ⁇ O)(C 1-6 alkyl), -S( ⁇ O)(C 1-6 alkyl), -S( ⁇ O) 2 (C 1-6 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, 5-10 membered heteroaryl; said R 9 is optionally substituted by 1, 2, 3, 4, 5 or 6 members selected from halogen, -C 1-6 alkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -CN, -NH 2 , -COOH, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OH, -O(C 1-6 alkyl), -O(C 1-6 deuterated alkyl), -SH, -S(C 1-6 alkyl
  • Z 2 is selected from -O-
  • Z 3 is selected from -C(CH 3 ) 2 -
  • Z 1 and Z 4 are selected from -CH 2 -
  • Z 2 and Z 3 are each independently selected from -C(O)-, -N(CH 3 )- or -NH-
  • Z 1 and Z 4 are selected from -CH 2 -;
  • R 10 is selected from hydrogen or -CH 3 ;
  • Z 5 , Z 6 , Z 7 and Z 8 are each independently selected from CR 12 or N, and R 12 are each independently selected from hydrogen, F, Cl, -CN or -OCH 3 ;
  • R 11 is selected from hydrogen, -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 ;
  • W 1 , W 2 , W 3 and W 4 are each independently selected from -CH 2 -, -O-, -NH-, -N(CH 3 )- or
  • U1 is selected from O or S, and U2 is selected from N;
  • U 5 is selected from N, U 6 is selected from O or S; or, U 5 is selected from CH, U 6 is selected from NH;
  • U 3 is selected from N or CH
  • R 16 is selected from Cl
  • p is selected from 0 or 1;
  • U 4 is selected from N or CH
  • R 13 is selected from -CH 3 , -OCH 3 , F, Cl or -CF 3 ;
  • q is selected from 0 or 1;
  • W 6 , W 7 , W 8 and W 9 are each independently selected from N or CR 15 ;
  • R 14 is selected from hydrogen or -CH 3 ;
  • R 15 is independently selected from hydrogen, F, Cl, -CH 3 , -OCH 3 ,
  • the third aspect of the present application provides a compound, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof,
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently -H, -halogen, -CF 3 or -C 1-4 alkyl; wherein at least two of R 1 , R 2 , R 3 , R 4 or R 5 are not H;
  • A is selected from
  • R 7 is -H, -C 1-4 alkyl or -(oxetane)yl
  • n 0, 1 or 2, preferably 0 or 1; Y 1 , Y 2 and Y 4 are each -CH 2 -, and Y 3 is -NR 9 -; or
  • Y 1 , Y 3 and Y 4 are each -CH 2 -, and Y 2 is -NR 9 -;
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N, and
  • Each R 8 is independently -H, halogen, -O-(C 1-3 alkyl), -CN or -C 1-3 haloalkyl.
  • the compound described in the second aspect or the third aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative,
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently -H, -F, -Cl, -Br or -CF 3 ; the definitions of other groups are as defined in the second aspect or the third aspect of the present application.
  • the compound described in the second aspect or the third aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative,
  • R1 is -CF3 , R2 is -F, R3 is -F, R4 is -H and R5 is -H, or
  • R1 is -CF3 , R2 is -F, R3 is -H, R4 is -H and R5 is -H, or
  • R1 is -CF3 , R2 is -F, R3 is -H, R4 is -F and R5 is -H, or
  • R1 is -CF3 , R2 is -H, R3 is -F, R4 is -F and R5 is -H, or
  • R1 is -CF3 , R2 is -H, R3 is -H, R4 is -H and R5 is -F, or
  • R1 is -CF3 , R2 is -H, R3 is -F, R4 is -H and R5 is -H, or
  • R1 is -CF3 , R2 is -H, R3 is -H, R4 is -Cl and R5 is -H, or
  • R1 is -CF3 , R2 is -Cl, R3 is -H, R4 is -H and R5 is -H, or
  • R1 is -H
  • R2 is -CF3
  • R3 is -H
  • R4 is -CF3
  • R5 is -H
  • R1 is -Cl
  • R2 is -H
  • R3 is -H
  • R4 is -F
  • R5 is -H
  • R1 is -Cl
  • R2 is -F
  • R3 is -H
  • R4 is -H
  • R5 is -H
  • R 1 is -CF 3 , R 2 is -H, R 3 is -H, R 4 is -F and R 5 is -H; the definitions of other groups are as defined in the second aspect or the third aspect of the present application.
  • the compound described in the second aspect or the third aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative,
  • R1 is -CF3 , R2 is -F, R3 is -F, R4 is -H and R5 is -H, or
  • R 1 is -CF 3 , R 2 is -F, R 3 is -H, R 4 is -H and R 5 is -H; the definitions of other groups are as defined in the second aspect or the third aspect of the present application.
  • the compound described in the second aspect or the third aspect of the present application is any of the following formulas:
  • the compound described in the second aspect or the third aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative,
  • A is selected from n is 0 or 1, and
  • Y 1 and Y 3 are each -CH 2 -, and Y 2 is -NR 9 -;
  • R 9 is selected from hydrogen, -C 1-6 alkyl, -C( ⁇ O)(C 1-6 alkyl), -S( ⁇ O)(C 1-6 alkyl), -S( ⁇ O) 2 (C 1-6 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, 5-10 membered heteroaryl; said R 9 is optionally substituted by 1, 2, 3, 4, 5 or 6 members selected from -C 1-3 alkyl, -C 1-3 alkenyl, -C 1-3 alkynyl, -C 1-3 haloalkyl, -C 1-3 alkoxy, -CN, -NH 2 , -COOH,
  • R7 is -H, -C1-4 alkyl or -(oxetane)yl.
  • the compound described in the second aspect or the third aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative,
  • n 0;
  • R 7 is -H, -C 1-4 alkyl or -(oxetane)yl
  • Y 1 and Y 3 are each -CH 2 -, and Y 2 is -NR 9 -;
  • the compound described in the second aspect or the third aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative,
  • n 1;
  • R 7 is -H, -C 1-4 alkyl or -(oxetane)yl
  • Y 1 , Y 2 and Y 4 are each -CH 2 -, and Y 3 is -NR 9 -;
  • R 9 is -H, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-6 cycloalkyl, -(C 1-4 alkylene)-(C 3-6 cycloalkyl), -(C 3-6 heterocyclyl), -(C 1-4 alkylene)-(C 3-6 heterocyclyl), -(C 1-6 alkylene)-O(C 1-3 alkyl), -(C 1-6 alkylene)-CF 3 , -C(O)-(C 1-6 alkyl), -C(O) 2 -(C 1-6 alkyl), -C(O)-NH 2 , -C(O)-NH(C 1-3 alkyl) , -C(O)-N(C 1-3 alkyl) 2 , -C(O)NH-(C 1-6 alkyl), -C(O)-(C 1-6 haloalkyl), -C(O)-C
  • the compound described in the second aspect or the third aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative,
  • n 1;
  • R 7 is -H, -C 1-4 alkyl or -(oxetane)yl
  • Y 1 , Y 3 and Y 4 are each -CH 2 -, and Y 2 is -NR 9 -;
  • R 9 is -H, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-6 cycloalkyl, -(C 1-4 alkylene)-(C 3-6 cycloalkyl), -(C 3-6 heterocyclyl), -(C 1-4 alkylene)-(C 3-6 heterocyclyl), -(C 1-6 alkylene)-O(C 1-3 alkyl), -(C 1-6 alkylene)-CF 3 , -C(O)-(C 1-6 alkyl), -C(O) 2 -(C 1-6 alkyl), -C(O)-NH 2 , -CH 2 C(O)-NH 2 , -C(O)-C(O)-NH 2 , -C(O)-CH(C 1-6 alkylene)-C(O)-NH 2 , -CH 2 C(O)-NH(C 1-3 alkyl), -CH 2 C(
  • the fourth aspect of the present application provides a compound, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof, wherein:
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently -H, -halogen, -CF 3 or -C 1-4 alkyl; wherein at least two of R 1 , R 2 , R 3 , R 4 or R 5 are not H;
  • A is selected from
  • R7 and R9 are as defined in the second aspect or the third aspect of the present application.
  • the compound described in the fourth aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative acceptable salt,
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently -H, -F, -Cl, -Br or -CF 3 ; the definitions of other groups are as defined in the second aspect or the third aspect of the present application.
  • the compound described in the fourth aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative acceptable salt,
  • R1 is -CF3 , R2 is -F, R3 is -F, R4 is -H and R5 is -H, or
  • R1 is -CF3 , R2 is -F, R3 is -H, R4 is -H and R5 is -H, or
  • R1 is -CF3 , R2 is -F, R3 is -H, R4 is -F and R5 is -H, or
  • R1 is -CF3 , R2 is -H, R3 is -F, R4 is -F and R5 is -H, or
  • R1 is -CF3 , R2 is -H, R3 is -H, R4 is -H and R5 is -F, or
  • R1 is -CF3 , R2 is -H, R3 is -F, R4 is -H and R5 is -H, or
  • R1 is -CF3 , R2 is -H, R3 is -H, R4 is -Cl and R5 is -H, or
  • R1 is -CF3 , R2 is -Cl, R3 is -H, R4 is -H and R5 is -H, or
  • R1 is -H
  • R2 is -CF3
  • R3 is -H
  • R4 is -CF3
  • R5 is -H
  • R1 is -Cl
  • R2 is -H
  • R3 is -H
  • R4 is -F
  • R5 is -H
  • R 1 is -Cl, R 2 is -F, R 3 is -H, R 4 is -H and R 5 is -H; the definitions of other groups are as defined in the second aspect or the third aspect of the present application.
  • the compound described in the second aspect, the third aspect or the fourth aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative,
  • R 9 is -H, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -SO 2 -CH 3 , -C(O)-CH 3 , -C(O)-CH 2 CH 3 , -C(O)-CH 2 CH 2 CH 3 , -C(O)-CH(CH 3 ) 2 , -C(O)-CH 2 CH(CH 3 ) 2 , C(O)-C(CH 3 ) 3 , -C(O)-OCH 3 ,-C(O)-NHCH 3
  • R9 is -H , -CN , -CH3, -CH2CH3 , -CH2CH2CH3 , -CH(CH3) 2 , -CH2CH ( CH3 ) 2 , -C( CH3 ) 3 , -CH2CH ( CH3 ) 2 , -CH2C ( CH3 ) 3 , -CH2CF3 , -CH2CH2CF3 , -CH2OCH3 , -CH2CH2OCH3 , or -CH2CH2CH3 .
  • R 9 is -SO 2 -CH 3 , -C(O)-CH 3 , -C(O)-CH 2 CH 3 , -C(O)-CH 2 CH 2 CH 3 , -C(O)-CH(CH 3 ) 2 , -C(O)-CH 2 CH(CH 3 ) 2 , C(O)-C(CH 3 ) 3 , -C(O)-OCH 3 , -C(O)-NHCH 3 ,
  • R9 is -C(O) -CH3 , -C(O) -CH2CH3 , -C( O ) -CH2CH2CH3 , -C(O)-CH( CH3 ) 2 , -C(O)-CH2CH ( CH3 ) 2 , -C(O)-C(CH3)3 , -C ( O) -CH2OCH3 , -C(O) -CH2OCH2CH3 , -C(O) -CH2OCH ( CH3 ) 2 , -C(O) -CH2CF3 , -C (O) -CH2Cl , -C(O)-CH 2 F, -C(O)-CH
  • the compound described in the second aspect, the third aspect or the fourth aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative,
  • R 7 is -H, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 or
  • the compound described in the second aspect or the third aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative,
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N,
  • R 8 at each occurrence is independently -H, halogen, -OCH 3 , -CN or -CF 3 .
  • the compound described in the second aspect or the third aspect of the present application its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its deuterated derivative,
  • the fifth aspect of the present application provides a compound, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof, wherein the compound is any of the following formulas:
  • the sixth aspect of the present application provides a compound, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof, wherein the compound is any of the following formulas:
  • the seventh aspect of the present application provides a compound, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof, wherein the compound is any of the following formulas:
  • the present application provides a compound, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof, wherein the compound is any of the following formulas:
  • the ninth aspect of the present application provides a compound of the present application, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer or its acceptable salt of its deuterated derivative, wherein the compound is any of the following formulas:
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described in any of the foregoing schemes, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof; and at least one pharmaceutically acceptable excipient.
  • the present application provides a compound as described in any of the foregoing schemes, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or an acceptable salt of a deuterated derivative thereof; or the use of the pharmaceutical composition described in the present application in the preparation of a medicament for treating a disease with excessive accumulation of lipofuscin in the retina associated with the serum concentration of RBP4; wherein the disease with excessive accumulation of lipofuscin in the retina is retinoic acid-mediated macular degeneration, including but not limited to age-related macular degeneration, dry (atrophic) age-related macular degeneration, Stargardt disease, Best disease, adult vitelliform maculopathy or macular dystrophy similar to Stargardt disease, and the retinoic acid is A2E, isoA2E, A2-DHP-PE or atRALdi-PE.
  • the present application provides a method for treating a subject with a disease in which lipofuscin accumulates excessively in the retina and is associated with the serum concentration of RBP4, the method comprising administering to the subject a therapeutically effective amount of a compound as described in any of the foregoing schemes, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof; or a pharmaceutical composition as described in the present application; wherein the disease in which lipofuscin accumulates excessively in the retina is retinoic acid-mediated macular degeneration, including but not limited to age-related macular degeneration, dry (atrophic) age-related macular degeneration, Stargardt disease, Best disease, adult vitelliform maculopathy, or a macular dystrophy similar to Stargardt disease, and the retinoic acid is A2E, isoA2E, A2-DHP-PE,
  • the present application provides a compound as described in any of the foregoing schemes, its stereoisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers or acceptable salts of their deuterated derivatives; or the use of the pharmaceutical composition described in the present application in treating diseases with excessive accumulation of lipofuscin in the retina associated with the serum concentration of RBP4; wherein the disease with excessive accumulation of lipofuscin in the retina is retinoic acid-mediated macular degeneration, including but not limited to age-related macular degeneration, dry (atrophic) age-related macular degeneration, Stargardt disease, Best disease, adult vitelliform maculopathy or macular dystrophy similar to Stargardt disease, and the retinoic acid is A2E, isoA2E, A2-DHP-PE or atRALdi-PE.
  • halogen is used interchangeably herein to refer to fluorine, chlorine, bromine or iodine.
  • Preferred halogen groups include -F, -Cl and -Br.
  • alkyl used in this application includes saturated monovalent hydrocarbon groups having straight or branched chains.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.
  • C 1-6 in C 1-6 alkyl is defined as a group having a straight or branched arrangement of 1, 2, 3, 4, 5 or 6 carbon atoms.
  • haloalkyl refers to the above-mentioned alkyl substituted by one or more (1, 2, 3, 4, 5 or 6) halogens (-F, -Cl or -Br).
  • the haloalkyl is interchangeably -C 1-6 haloalkyl or halo-C 1-6 alkyl, wherein the C 1-6 in -C 1-6 haloalkyl or halo- C 1-6 alkyl means that the total number of carbon atoms of the alkyl is 1 to 6.
  • -C 1-6 haloalkyl is -C 1-3 haloalkyl.
  • -C 1-3 haloalkyl is substituted by 1, 2, 3, 4, 5 or 6 -F (methyl, ethyl, propyl or isopropyl); preferably, -C 1-3 haloalkyl is -CF 3 .
  • alkylene refers to a difunctional group obtained by removing an additional hydrogen atom from an alkyl group as defined above.
  • methylene i.e., -CH2-
  • ethylene i.e., -CH2- CH2- or -CH( CH3 )-
  • propylene i.e., -CH2 - CH2 - CH2- , -CH( -CH2 - CH3 )- or -CH2 -CH( CH3 )-).
  • alkenyl refers to a straight or branched hydrocarbon group containing one or more double bonds, typically 2 to 20 carbon atoms in length.
  • -C2-6 alkenyl contains 2 to 6 carbon atoms.
  • alkenyl includes, but is not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, etc.
  • alkynyl refers to a straight or branched hydrocarbon group containing one or more triple bonds, typically 2 to 20 carbon atoms in length.
  • -C2-6alkynyl contains 2 to 6 carbon atoms.
  • representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • alkoxy is an oxygen ether formed from the aforementioned alkyl group, including, but not limited to , -OCH3 , -OCH2CH3 , -OCH2CH2CH3 , -OCH( CH3 ) 2 , -CH2OCH3 , -CH2CH2OCH3 .
  • haloalkoxy refers to the above alkoxy group substituted by one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl or -Br).
  • the haloalkoxy group is interchangeably -C 1-6 haloalkoxy or halo-C 1-6 alkoxy, wherein the C 1-6 in -C 1-6 haloalkoxy or halo -C 1-6 alkoxy indicates that the total carbon atoms of the alkoxy group are 1 to 6.
  • the -C 1-6 haloalkoxy group is -C 1-3 haloalkoxy.
  • the -C 1-6 haloalkoxy group is substituted by 1, 2, 3, 4, 5 or 6 -F (methoxy, ethoxy, propoxy or isopropoxy); the preferred -C 1-3 haloalkoxy group is -OCF 3 .
  • aryl or “aromatic ring” as used herein refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing only carbon ring atoms.
  • Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups.
  • heterocyclyl or “heterocycle” as used herein refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more ring heteroatoms, including monocyclic heterocycles, bicyclic heterocycles, bridged heterocycles, fused heterocycles, and spirocyclic heterocycles.
  • Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
  • the heterocycle is a three- to ten-membered ring that is fully saturated or has one or more degrees of unsaturation.
  • the current definition of heterocycle includes multiple degrees of substitution (preferably one, two, or three degrees of substitution).
  • heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxazepanyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl.
  • heteroaryl as used herein means an aromatic ring system containing carbon and at least one heteroatom.
  • the heteroaryl or heteroaromatic ring can be monocyclic or polycyclic, substituted or unsubstituted.
  • Monocyclic heteroaryl can have 1 to 4 heteroatoms in its ring, while polycyclic heteroaryl can contain 1 to 10 heteroatoms.
  • Polycyclic heteroaryl rings can contain fused rings, spiro rings or bridged rings, for example, bicyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings can contain 8 to 12 atoms.
  • Monocyclic heteroaryl rings can contain 5 to 8 atoms (carbon atoms and heteroatoms).
  • heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl, or isoquinolinyl.
  • Carbocyclyl refers to a substituted or unsubstituted monocyclic, bicyclic, bridged, fused, spirocyclic non-aromatic ring system containing only carbon atoms.
  • the ring is three to ten members and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included in this definition.
  • Carbocyclyl includes, but is not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl.
  • Exemplary "cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • one or more means one or more. In some embodiments, “one or more” means 1, 2, 3, 4, 5, or 6. In some embodiments, “one or more” means 1, 2, 3, or 4. In some embodiments, “one or more” means 1, 2, or 3. In some embodiments, “one or more” means 1 or 2. In some embodiments, “one or more” means 1. In some embodiments, “one or more” means 2. In some embodiments, “one or more” means 3. In some embodiments, “one or more” means 4. In some embodiments, "one or more" means 5. In some embodiments, “one or more" means 6.
  • each substituent when a ring is substituted with one or more substituents, it means that each substituent can be substituted on each ring atom of the ring independently, including but not limited to ring carbon atoms or ring nitrogen atoms.
  • each substituent when the ring is polycyclic, such as condensed ring, bridged ring or spiro ring, each substituent can be substituted on each ring atom of the polycyclic ring independently.
  • oxo refers to an oxygen atom and the carbon atom to which it is attached together forming an Group.
  • composition is intended to cover a product comprising a specific amount of a specific ingredient, as well as any product produced directly or indirectly by a combination of specific amounts of specific ingredients. Therefore, pharmaceutical compositions containing the present application compound as an active ingredient and methods for preparing the present application compound are also part of the present application. Moreover, some crystalline forms of the compound may exist in the form of polymorphs and are therefore included in the present application. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included in the scope of the present application.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
  • pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • compounds of the present application are basic, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Since the compounds in the present application are intended for pharmaceutical use, they are preferably provided in a substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% by weight).
  • the present application includes within its scope prodrugs of the compounds of the present application.
  • prodrugs are functional derivatives of compounds that are easily converted into the desired compound in vivo. Therefore, in the therapeutic methods of the present application, the term “administration” shall include the treatment of various conditions with a specifically disclosed compound or with a compound that may not be specifically disclosed but is converted into a specific compound in vivo after administration to a subject.
  • Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in “Prodrug Design” ("Design of Prodrugs", ed. 25 H. Bundgaard, Elsevier, 1985).
  • any substituent or variable at a particular position in a molecule is intended to be independent of the definitions of substituents or variables at other positions in the molecule. It should be understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the present application to provide chemically stable compounds and can be readily synthesized by techniques known in the art and the methods illustrated in this application.
  • the compounds described herein may contain one or more asymmetric centers and may therefore produce diastereomers and optical isomers.
  • the present application includes all such possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the present application includes all stereoisomers of the compounds and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers and isolated specific stereoisomers are also included. In the process of synthetic steps for preparing these compounds, or in the process of using racemization or epimerization methods known to those skilled in the art, the products of these steps may be mixtures of stereoisomers.
  • stereoisomer used in this application refers to isomers caused by the same order of connection of atoms or atomic groups in a molecule but different spatial arrangements, including configurational isomers and conformational isomers, wherein configurational isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers. This application includes all possible stereoisomers of the compound.
  • Certain compounds provided herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation around a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule.
  • the compounds provided herein include all atropisomers, including pure individual atropisomers, each enriched atropisomer, or each non-specific mixture. If the barrier to rotation around a single bond is high enough and the interconversion between conformations is slow enough, separation of atropisomers may be allowed.
  • isotopes are atoms with the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of hydrogen can be represented by 1 H (hydrogen), 2 H (deuterium) and 3 H (tritium). They are also usually represented by D (deuterium) and T (tritium).
  • CD 3 represents a methyl group, wherein all hydrogen atoms are deuterium.
  • Isotopes of carbon include 13 C and 14 C.
  • the isotope-labeled compounds of the present application can be prepared generally by conventional techniques known to those skilled in the art or by methods similar to those described in the present application.
  • deuterated derivative refers to a compound having the same chemical structure as a reference compound, but in which one or more hydrogen atoms are replaced by a deuterium atom ("D"). It will be recognized that some variation in natural isotopic abundance will occur in the synthetic compounds, depending on the source of the chemical materials used in the synthesis. The concentration of the naturally abundant stable hydrogen isotope, compared to the degree of stable isotopic substitution of the deuterated derivatives described in this application, although such variation is small and insignificant.
  • the deuterated derivatives disclosed herein have an isotopic enrichment factor of at least 3500 (containing 52.5% deuterium in each specified deuterium), at least 4500 (containing 67.5% deuterium), at least 5000 (containing 75% deuterium), at least 5500 (containing 82.5% deuterium), at least 6000 (containing 90% deuterium), at least 6333.3 (containing 95% deuterium), at least 6466.7 (containing 97% deuterium), or at least 6600 (containing 99% deuterium) for each deuterium atom.
  • the present application includes any possible tautomerism and pharmaceutically acceptable salts thereof and mixtures thereof, unless otherwise specifically stated.
  • the pharmaceutical composition of the present application comprises the compound of the present application (or its pharmaceutically acceptable salt) as an active ingredient, a pharmaceutically acceptable carrier and optional other therapeutic ingredients or adjuvants.
  • a pharmaceutically acceptable carrier for the delivery of the pharmaceutical composition.
  • the composition includes compositions suitable for oral, rectal, local and parenteral (including subcutaneous, intramuscular and intravenous) administration.
  • the pharmaceutical composition can be conveniently present in unit dosage form and prepared by any method well known in the pharmaceutical field.
  • the compound of the present application or its prodrug or its metabolite or pharmaceutically acceptable salt can be combined with a drug carrier as an active ingredient and a drug carrier to form a close mixture.
  • the carrier can be in a variety of forms, such as oral or parenteral (including intravenous) routes of administration. Therefore, the pharmaceutical composition of the present application can exist as discrete units suitable for oral administration, such as capsules, cachets or tablets, each containing a predetermined amount of active ingredients.
  • the composition can exist as a powder form, a granular form, a solution form, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or an oil-in-water emulsion.
  • the compound represented by Formula I or its pharmaceutically acceptable salt can also be administered by controlled release and/or a delivery device.
  • the composition can be prepared by any pharmaceutical method. Generally, such methods include the step of combining the active ingredient with a carrier constituting one or more necessary ingredients. Generally, the composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both. The product can then be conveniently formed into the desired style.
  • the pharmaceutical composition of the present application may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt.
  • the compound of formula I or a pharmaceutically acceptable salt thereof may also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier used can be, for example, solid, liquid or gas.
  • solid carriers include lactose, gypsum, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid.
  • liquid carriers are syrup, peanut oil, olive oil and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oil, alcohol, flavoring agents, preservatives, colorants, etc.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc.
  • oral solid preparations such as powders, capsules and tablets. Tablets and capsules are preferred oral dosage units due to ease of administration, which use solid pharmaceutical carriers.
  • tablets can be coated by standard aqueous or non-aqueous techniques.
  • Tablets containing the composition of the present application can be prepared by compression or molding, optionally containing one or more auxiliary ingredients or adjuvants.
  • Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as a powder or granules in a suitable machine, and optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant.
  • Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.
  • Each tablet preferably contains about 0.05 mg to about 5 g of active ingredient, and each cachet or capsule preferably contains about 0.05 mg to about 5 g of active ingredient.
  • a formulation for oral administration to humans may contain about 0.5 mg to about 5 g of active agent mixed with an appropriate and convenient amount of carrier material, which may account for about 0.05 to about 95% of the total composition.
  • Dosage unit forms typically contain from about 0.01 mg to about 2 g of active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1500 mg or 2000 mg.
  • the pharmaceutical composition of the present application suitable for parenteral administration can be prepared as a solution or suspension of the active compound in water.
  • Suitable surfactants such as hydroxypropylcellulose, can be included.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycol and mixtures thereof in oil.
  • preservatives can be included to prevent the harmful growth of microorganisms.
  • compositions of the present application suitable for injection purposes include sterile aqueous solutions or dispersions.
  • the composition can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for injection.
  • the pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, it is best to preserve it to prevent the contamination of microorganisms such as bacteria and fungi.
  • the carrier can be, for example, a solvent or dispersion medium containing water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), a vegetable oil, and a suitable mixture thereof.
  • the pharmaceutical composition of the present application can be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, dusting powder, etc.
  • the composition can be in a form suitable for transdermal devices.
  • these preparations can be prepared by conventional processing methods.
  • a cream or ointment is prepared by mixing a hydrophilic material and water with about 0.05wt% to about 10wt% of the compound to produce a cream or ointment with a desired consistency.
  • the pharmaceutical composition of the present application can be a form suitable for rectal administration, wherein the carrier is a solid.
  • the mixture forms a unit dose suppository.
  • Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be easily formed by first mixing the composition with a softened or melted carrier, then cooling and molding in a mold.
  • the above-mentioned pharmaceutical preparations may suitably include one or more additional carrier components, such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc.
  • additional carrier components such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc.
  • other adjuvants may be included to make the preparation isotonic with the blood of the intended recipient.
  • Compositions containing compounds or pharmaceutically acceptable salts thereof may also be prepared in the form of powders or liquid concentrates.
  • dosage levels of about 0.001 mg/kg to about 150 mg/kg of body weight per day are useful for treating the above-mentioned conditions, or about 0.05 mg to about 7 g per patient per day.
  • about 0.001 to 50 mg of the compound per kg of body weight per patient per day, or about 0.05 mg to about 3.5 g of the compound per kg of body weight per patient per day may be effective in treating age-related macular degeneration, dry (atrophic) age-related macular degeneration, Stargardt disease, Best disease, adult vitelliform maculopathy, or macular dystrophy similar to Stargardt disease, etc.
  • the specific dosage level for any particular patient will depend on a variety of factors including age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination, and the severity of the particular disease being treated.
  • FIG1 is a hydrogen NMR spectrum of compound 1 synthesized in Example 1 of the present application.
  • FIG2 is a graph showing the comparison of the RBP4 reduction rates of the present compound 17 and the control compound (at a dose of 1 mg/kg) at different time points;
  • FIG3 is a graph showing the comparison of the RBP4 reduction rates of the present compound 17 and the control compound (dosage of 5 mg/kg) at different time points.
  • the compounds of the present application can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein.
  • the examples outlining specific synthetic routes are intended to provide guidance to synthetic chemists in the art, who will readily understand that solvents, concentrations, reagents, protecting groups, the order of synthetic steps, times, temperatures, etc. can be modified as needed within the skill and judgment of those skilled in the art.
  • FIG1 is a hydrogen nuclear magnetic spectrum of compound 1 synthesized in Example 1 of the present application.
  • N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (4.638 g, 15 mmol) was dissolved in anhydrous 1,4-dioxane (40 mL), and 3-fluoro-2-trifluoromethyl-bromobenzene (3.645 g, 15 mmol), Pd(PPh 3 ) 4 (1.733 g, 1.5 mmol), and 12 mL of K 2 CO 3 (2M aqueous solution, 24 mmol) were added.
  • the resulting mixture was heated to 80° C. and stirred overnight under a nitrogen atmosphere.
  • the resulting mixture was quenched with water and extracted with EtOAc.
  • the organic solution was dried over anhydrous Na 2 SO 4 and concentrated.
  • mice 7- to 8-week-old ICR male mice were adaptively raised for 3 to 7 days and randomly divided into groups (4 mice per group), and fasted for 12 hours before the experiment.
  • orbital venous blood samples were collected and plasma was separated before administration (0 hour value was taken as the initial content).
  • the test compound solvent: 5% DMSO + 10% cyclodextrin
  • the oral solvent 5% DMSO + 10% cyclodextrin
  • the Mouse RBP4 (Retinol Binding Protein 4, Plasma) ELISA kit (immunoway, KE1574) was used to detect the RBP4 content in the plasma sample, and the reduction rate was calculated, and the maximum reduction rate within 5 to 24 hours was selected.
  • the reduction rate of RBP4 content in mouse plasma at different sampling time points (RBP4 initial content - RBP4 content at sampling point) / RBP4 initial content.
  • the maximum reduction rate of each compound on RBP4 content in mouse plasma is shown in Table 2 below, and the results are shown in Table 2.
  • the present application also compares the RBP4 reduction rates of compound 17 and the control compound at different time points.
  • the comparison results at a dose of 1 mg/kg are shown in FIG2
  • the comparison results at a dose of 5 mg/kg are shown in FIG3 .
  • Solution of the compound to be tested Each compound was diluted to 10 different concentrations in a 3-fold gradient using 100 ⁇ M as the starting concentration.
  • the reaction composition includes the following components: 2 ⁇ L hFc-RBP4 (MCE, HY-P72031) (62.5nM, diluted in working solution), 1 ⁇ L Retinol (Sigma, A2056-25MG) (retinol, 5 ⁇ , diluted in working solution), 2 ⁇ L his-TTR (SinoBioloqical, 12091-H08H) (10nM, diluted in working solution) and 5 ⁇ L Anti-His-Tb (Cisbio, 61HISTLB) & Anti-IgG-XL665 (Cisbio, 61HFCXLB) working solution (the antibody is diluted with working solution to a 2 ⁇ mixed solution).
  • Incubation reaction process 100 nL of the test compound solution was transferred to a 384-well reaction plate (two replicate wells were set for each concentration), and each component of the reaction composition was added in sequence, followed by incubation at 25° C. for 60 minutes.
  • the HTRF signal 665/620 ratio was read using a BMG microplate reader.
  • Test method Three ICR mice (male) were used for each compound, for a total of five groups. Mice were treated with a single 10 mg/kg or 5 mg/kg (oral). For each mouse, blood samples were collected at 0.25, 0.5, 1, 2, 4 and 8 hours after administration. The whole blood sample was placed in a test tube containing EDTA-K2, inverted several times, and then centrifuged at 6000 rpm, 4 ° C for 15 minutes to obtain plasma. The concentration of the compound in the plasma sample was determined using the LC-MS/MS method. The results are shown in Table 4.
  • Preparation of compound working solution Prepare 10 mM DMSO stock solution of the test substance and control compound verapamil (ie, Varapamil), and dilute it to 200 ⁇ M working solution with acetonitrile before the test. The final concentration of the test substance and verapamil is 1 ⁇ M.
  • Preparation of phosphate buffer Weigh 7.098 g of disodium hydrogen phosphate, add 500 mL of pure water and ultrasonically dissolve to obtain a disodium hydrogen phosphate solution. Weigh 3.400 g of potassium dihydrogen phosphate, add 250 mL of pure water and ultrasonically dissolve to obtain a potassium dihydrogen phosphate solution. Mix the disodium hydrogen phosphate solution and the potassium dihydrogen phosphate solution and adjust the pH to 7.4 ⁇ 0.2.
  • Preparation of 10mM NADPH Weigh an appropriate amount of NADPH (reduced coenzyme II) and prepare a fresh 10mM working solution with phosphate buffered saline for a final concentration of 1mM.
  • Preparation of incubation system Prepare the suspension according to Table 5 and add it to the incubation plate, and pre-incubate in a 37°C water bath for 10 min.
  • the results show that most of the compounds in the present application have good metabolic stability, especially in human liver microsomes.
  • the clearance rate of some compounds in the present application in human liver microsomes is less than 10 ⁇ L/min/mg, which has good drug properties.

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Abstract

本申请涉及一种降低RBP4的血清浓度的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，以及制备该化合物的方法、其组合物及用途。

Description

一种降低RBP4的血清浓度的化合物及用途
本申请要求于2023年11月24日提交的国际申请号为PCT/CN2023/133891、发明名称为“一种降低RBP4的血清浓度的化合物及用途”的在先申请，2023年11月29日提交的国际申请号为PCT/CN2023/134874、发明名称为“一种降低RBP4的血清浓度的化合物及用途”的在先申请，2023年12月22日提交的国际申请号为PCT/CN2023/141113、发明名称为“一种降低RBP4的血清浓度的化合物及用途”的在先申请，2023年12月29日提交的国际申请号为PCT/CN2023/143407、发明名称为“一种降低RBP4的血清浓度的化合物及用途”的在先申请，2024年01月03日提交的国际局申请号为PCT/CN2024/070370、发明名称为“一种降低RBP4的血清浓度的化合物及用途”的在先申请，2024年03月08日提交的国际申请号为PCT/CN2024/080774、发明名称为“一种降低RBP4的血清浓度的化合物及用途”的在先申请，2024年06月13日提交的国际申请号为PCT/CN2024/098922、发明名称为“一种降低RBP4的血清浓度的化合物及用途”的在先申请，2024年10月15日提交的国际申请号为PCT/CN2024/124934、发明名称为“一种降低RBP4的血清浓度的化合物及用途”的在先申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请属于药物化学领域，涉及一种降低RBP4的血清浓度的化合物，以及所述化合物的用途。
背景技术
视黄醇结合蛋白4(RBP4)是唯一将维生素A从肝脏运送到外周组织的血浆转运蛋白。由于视黄醇涉及多种生物功能，包括细胞生长、免疫功能、胎儿发育和视力，因此近年来对RBP4的研究引起了越来越多的兴趣(参见Clin.Immunol.Immunopathol.,80(1996),pp.S52-S62；Faseb.J.,10(1996),第961-968页；Endocr.Rev.,10(1989),第308-316页；Cell Metabol.,5(2007),第164-166页；Harvey Lect.,90(1994),第105-117页；Annu.Rev.Pharmacol.Toxicol.,46(2006),第451-480页)。
多项研究阐明了RBP4在心血管疾病(CVD)、肥胖、非酒精性脂肪肝(NAFLD)、非酒精性脂肪性肝炎(NASH)和2型糖尿病(T2DM)胰岛素抵抗的发病机制中的作用(参见N.Engl.J.Med.,354(2006),第2552-2563页；Adv.Nutr.,6(2015),第748-762页；Nature,436(2005),第356-362页；Circulation,127(2013),第1938-1947页；脂质健康Dis.,16(2017),第180页)。
RBP4还被认为与癌症以及年龄相关性黄斑变性(AMD)和Stargardt病(STGD)的发生有关(参见Oncotarget,8(2017),第92254-92264页；Medicine,99(2020),文章e21254；J.Ovarian Res.,11(2018),第29页；Cancers，12(2020),第623页；Endocr.Relat.Canc.,22(2015),第L1-L4页；BioMed Res.Int.,2014(2014),p.179040；Health Technol.Assess.,22(2018),pp.1-168)。在治疗上述疾病时，通过直接拮抗或抑制RBP4的水平来降低RBP4的水平表达进行了研究。
尽管RBP4主要在肝脏中合成，有约20％在脂肪组织中合成(参见J.Lipid Res.,30(1989),pp.171-180)，但它已被视为胰岛素抵抗和代谢的生物标志物。RBP4被称为参与能量代谢、胰岛素信号转导和胰岛素抵抗的脂肪因子(参见Proc.Natl.Acad.Sci.United States Am.,108(2011),pp.4340-4345；Am.J.生理学内分泌代谢，297(2009)，第E1420-E1429页；糖尿病，64(2015)，第1603-1614页；糖尿病学，59(2016)，第354-362页)。除了具有选择性视黄醇转运蛋白的作用外，最近的一项研究表明，RBP4还参与脂肪酸转运(参见Biochim.Biophys.Acta Mol.Cell Biol.Lipids,1863(2018),pp.458-466)。此外，许多研究报告糖尿病和胰岛素抵抗患者的RBP4水平升高(参见J.Clin.Endocrinol.,92(2007),pp.1971-1974；Diabetes Care,29(2006),pp.2457-2461；糖尿病护理，30(2007)，第1173-1178页)。
研究还在探索RBP4在萎缩性(干性)AMD和STGD中的作用。AMD和STGD是缓慢进展的神经退行性疾病，可导致失明。视网膜色素上皮(RPE)中脂褐质的过度积累被认为是这些疾病的病因。脂褐质水平升高会抑制RPE的正常功能，从而促进其变性。RPE代谢支持的缺乏随后导致光感受器死亡(参见Exp.Eye Res.,80(2005),第595-606页；Faseb.J.,18(2004)，第562-564页)。因此，为了延长RPE效果和光感受器寿命，应降低脂褐质的浓度。脂褐质毒性主要由其双视黄醇成分之一的A2E介导。
因此，RBP4水平的降低将影响特定基因的表达和随后的生物学功能。最近的一篇论文讨论了RBP4的生物学功能及其在人类疾病中的病理相关性(参见Front.Physiol.,12(2021),p.659977)。还需要开发具有优异的RBP4降低作用的化合物。
发明内容
一方面，本申请提供了一种降低RBP4的血清浓度的化合物。具体如下：
本申请第一方面提供了一种式(I)的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，
其中，
R1、R2、R3、R4和R5各自独立地为-H、-卤素、-CF3或-C1-4烷基；其中，R1、R2、R3、R4或R5中的至少两个不为H；
A为
α、β、χ和δ各自独立地不存在或存在，并且当存在时每个都是键；
X是C或N；
Z1是N；
Z2是O、S、N或NR7，
R7是-H、-C1-4烷基或-(氧杂环丁烷)基；
Q是取代或未取代的杂双环；优选地，Q是取代或未取代的5、6或7元环结构。
在一些实施方式中，R1、R2、R3、R4和R5各自独立地为-H、-F、-Cl、-Br或-CF3。
在本申请的一些实施方式中，本申请第一方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
R1为-CF3、R2为-F、R3为-F、R4为-H且R5为-H，或
R1为-CF3、R2为-F、R3为-H、R4为-H且R5为-H，或
R1为-CF3、R2为-F、R3为-H、R4为-F且R5为-H，或
R1为-CF3、R2为-H、R3为-F、R4为-F且R5为-H，或
R1为-CF3、R2为-H、R3为-H、R4为-H且R5为-F，或
R1为-CF3、R2为-H、R3为-F、R4为-H且R5为-H，或
R1为-CF3、R2为-H、R3为-H、R4为-Cl且R5为-H，或
R1为-CF3、R2为-Cl、R3为-H、R4为-H且R5为-H，或
R1为-H、R2为-CF3、R3为-H、R4为-CF3且R5为-H，或
R1为-Cl、R2为-H、R3为-H、R4为-F且R5为-H，或
R1为-Cl、R2为-F、R3为-H、R4为-H且R5为-H。
在本申请的一些实施方式中，本申请第一方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
R1为-CF3、R2为-F、R3为-F、R4为-H且R5为-H，或
R1为-CF3、R2为-F、R3为-H、R4为-H且R5为-H。
在本申请的一些实施方式中，本申请第一方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，

在本申请的一些实施方式中，本申请第一方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
A为
其中当α存在时，那么Z1和Z2为N，X为N，β存在，且χ和δ不存在；以及
当α不存在时，那么Z1为N，Z2为NR7，X为C，β和δ存在，且χ不存在。
在本申请的一些实施方式中，本申请第一方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
A为
n为0-2的整数；
R7是-H、-C1-4烷基或-(氧杂环丁烷)基；
α、β、χ、δ、ε、和κ各自独立地不存在或存在，并且当存在时各自是键；
Z1是N；
Z2是O、S、N或NR7，
X是C或N；和
Y1、Y2、Y3和每次出现的Y4各自独立地为CR8、CH2或NR9；
其中，
R8是-H、卤素、-OCH3、-CN或-CF3；以及
R9是-H、-CN、-C1-6烷基、-C1-6卤代烷基、-C3-6环烷基、-(C1-4亚烷基)-(C3-6环烷基)、-(C3-6杂环基)、-(C1-4亚烷基)-(C3-6杂环基)、-(C1-6亚烷基)-O(C1-3烷基)、-(C1-6亚烷基)-CF3、-C(O)-(C1-6烷基)、-C(O)2-(C1-6烷基)、-C(O)-NH2、-C(O)-NH(C1-3烷基)、-C(O)-N(C1-3烷基)2、-C(O)NH-(C1-6烷基)、-C(O)-(C1-6卤代烷基)、-C(O)-(C1-6烷氧基)、-C(O)-(C1-6亚烷基)-(OC1-6烷基)、-C(O)-(C6芳基)、-C(O)-(C6杂芳基)、-C(O)-(C6杂环基)、-(C1-6亚烷基)-CO2H、-(C1 -6亚烷基)-CO2(C1-6烷基)或-SO2-(C1-6烷基)。
本申请第二方面提供了一种式(I)的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，
其中，
R1、R2、R3、R4和R5各自独立地为-H、-卤素、-CF3或-C1-4烷基；其中，R1、R2、R3、R4或R5中的至少两个不为H；
A选自
其中，R7选-H、-C1-4烷基或-(氧杂环丁烷)基；
当A选自时：
其中，n为0、1或2；
Y1、Y2和Y4各自为-CH2-，且Y3为-NR9-；或Y1、Y3和Y4各自为-CH2-，且Y2为-NR9-；或Y1、Y2和Y4各自为-CH2-，且Y3为-O-或-S(＝O)2-；或Y1、Y3和Y4各自为-CH2-，且Y2为-O-或-S(＝O)2-；
R9选自氢、-C1-6烷基、-C(＝O)(C1-6烷基)、-S(＝O)(C1-6烷基)、-S(＝O)2(C1-6烷基)、3-7元碳环基、3-7元杂环基、苯基、5-10元杂芳基；所述R9任选地被1、2、3、4、5或6个选自卤素、-C1-6烷基、-C1-6烯基、-C1-6炔基、-C1-6卤代烷基、-C1-6烷氧基、-CN、-NH2、-COOH、-NH(C1-6烷基)、-N(C1-6烷基)2、-OH、-O(C1-6烷基)、-O(C1-6氘代烷基)、-SH、-S(C1-6烷基)、＝O、-C(＝O)(C1-6烷基)、-C(＝O)(C1-6烷氧基)、-S(＝O)(C1-6烷基)、-S(＝O)2(C1-6烷基)、-C(＝O)NH2、-C(＝O)-C(＝O)NH2、-C(＝O)NH(C1-6烷基)、-C(＝O)N(C1-6烷基)2、-NHC(＝O)(C1-6烷基)、-C(＝O)O(C1-6烷基)、-OC(＝O)(C1-6烷基)、-S(＝O)NH2、-S(＝O)NH(C1-6烷基)、-S(＝O)N(C1-6烷基)2、-NHS(＝O)(C1-6烷基)、-S(＝O)2NH2、-S(＝O)2NH(C1-6烷基)、-S(＝O)2N(C1-6烷基)2、-NHS(＝O)2(C1-6烷基)、-C(＝O)-苯基、-C(＝O)-5-10元杂芳基、-C(＝O)-3-7元杂环基、3-7元碳环基、3-7元杂环基、苯基或5-10元杂芳基的取代基取代；所述杂环基或杂芳基在每次出现时独立地包括一个或多个选自N、O或S的杂原子；
当A选自
其中，Y1、Y2、Y3和Y4各自独立地位CR8或N，且每个R8独立地为-H、卤素、-C1-6烷基、-C(＝O)NH2、-C(＝O)NH(C1-6烷基)、-C(＝O)N(C1-6烷基)2、-COOH、-NHC(＝O)N(C1-6烷基)2、-S(＝O)2NH(C1-6烷基)、-O-(C1-6烷基)、-CN或-C1-6卤代烷基；
当A选自
其中，Z2选自-O-，Z3选自-C(CH3)2-，Z1和Z 4选自-CH2-；或者，Z2和Z3各自独立地选自-C(O)-、-N(CH3)-或-NH-，Z1和Z4选自-CH2-；
R10选自氢或-CH3；
当A选自
其中，Z5、Z6、Z7和Z8各自独立地选自CR12或N，R12各自独立地选自氢、F、Cl、-CN或-OCH3；
R11选自氢、-CH3、-CH2CH3、或-CH(CH3)2；
当A选自
其中，W1、W2、W3和W4各自独立地选自-CH2-、-O-、-NH-、-N(CH3)-或
当A选自
其中，U1选自O或S，U2选自N；
当A选自
其中，U5选自N，U6选自O或S；或者，U5选自CH，U6选自NH；
当A选自
其中，U3选自N或CH；
R16选自Cl；
p选自0或1；
当A选自
其中，U4选自N或CH；
R13选自-CH3、-OCH3、F、Cl或-CF3；
q选自0或1；
当A选自
其中，W6、W7、W8和W9各自独立地选自N或CR15；
R14选自氢或-CH3；
R15各自独立地选自氢、F、Cl、-CH3、-OCH3、
本申请第三方面提供了一种化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，
其中，R1、R2、R3、R4和R5各自独立地为-H、-卤素、-CF3或-C1-4烷基；其中，R1、R2、R3、R4或R5中的至少两个不为H；
A选自
其中，R7是-H、-C1-4烷基或-(氧杂环丁烷)基；
当A选自时：
n为0、1或2，优选0或1；Y1、Y2和Y4各自为-CH2-，且Y3为-NR9-；或
Y1、Y3和Y4各自为-CH2-，且Y2为-NR9-；
R9选自氢、-C1-6烷基、-C(＝O)(C1-6烷基)、-S(＝O)(C1-6烷基)、-S(＝O)2(C1-6烷基)、3-7元碳环基、3-7元杂环基、苯基、5-10元杂芳基；所述R9任选地被1、2、3、4、5或6个选自-C1-6烷基、-C1-6烯基、-C1-6炔基、-C1-6卤代烷基、-C1-6烷氧基、-CN、-NH2、-COOH、-NH(C1-6烷基)、-N(C1-6烷基)2、-OH、-O(C1-6烷基)、-SH、-S(C1-6烷基)、-C(＝O)(C1-6烷基)、-S(＝O)(C1-6烷基)、-S(＝O)2(C1-6烷基)、-C(＝O)NH2、-C(＝O)NH(C1-6烷基)、-C(＝O)N(C1-6烷基)2、-NHC(＝O)(C1-6烷基)、-C(＝O)O(C1-6烷基)、-OC(＝O)(C1-6烷基)、-S(＝O)NH2、-S(＝O)NH(C1-6烷基)、-S(＝O)N(C1-6烷基)2、-NHS(＝O)(C1-6烷基)、-S(＝O)2NH2、-S(＝O)2NH(C1-6烷基)、-S(＝O)2N(C1-6烷基)2、-NHS(＝O)2(C1-6烷基)、3-7元碳环基、3-7元杂环基、苯基或5-10元杂芳基的取代基取代；所述杂环基或杂芳基在每次出现时独立地包括一个或多个选自N、O或S的杂原子；
当A选自
其中，
Y1、Y2、Y3和Y4各自独立地为CR8或N，且
每个R8独立地为-H、卤素、-O-(C1-3烷基)、-CN或-C1-3卤代烷基。
在一些实施方式中，本申请第二方面或第三方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
R1、R2、R3、R4和R5各自独立地为-H、-F、-Cl、-Br或-CF3；其他基团的定义如本申请第二方面或第三方面所定义。
在一些实施方式中，本申请第二方面或第三方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
R1为-CF3、R2为-F、R3为-F、R4为-H且R5为-H，或
R1为-CF3、R2为-F、R3为-H、R4为-H且R5为-H，或
R1为-CF3、R2为-F、R3为-H、R4为-F且R5为-H，或
R1为-CF3、R2为-H、R3为-F、R4为-F且R5为-H，或
R1为-CF3、R2为-H、R3为-H、R4为-H且R5为-F，或
R1为-CF3、R2为-H、R3为-F、R4为-H且R5为-H，或
R1为-CF3、R2为-H、R3为-H、R4为-Cl且R5为-H，或
R1为-CF3、R2为-Cl、R3为-H、R4为-H且R5为-H，或
R1为-H、R2为-CF3、R3为-H、R4为-CF3且R5为-H，或
R1为-Cl、R2为-H、R3为-H、R4为-F且R5为-H，或
R1为-Cl、R2为-F、R3为-H、R4为-H且R5为-H，或
R1为-CF3、R2为-H、R3为-H、R4为-F且R5为-H；其他基团的定义如本申请第二方面或第三方面所定义。
在一些实施方式中，本申请第二方面或第三方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
R1为-CF3、R2为-F、R3为-F、R4为-H且R5为-H，或
R1为-CF3、R2为-F、R3为-H、R4为-H且R5为-H；其他基团的定义如本申请第二方面或第三方面所定义。
在一些实施方式中，本申请第二方面或第三方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，所述化合物为如下任一式：
其他基团的定义如本申请第二方面或第三方面所定义。
在一些实施方式中，本申请第二方面或第三方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
A选自n为0或1，并且
当n为0时，Y1和Y3各自为-CH2-，以及Y2是-NR9-；
当n为1时，Y1、Y2和Y4各自为-CH2-，以及Y3是-NR9-；或Y1、Y3和Y4各自为-CH2-，以及Y2是-NR9-；R9选自氢、-C1-6烷基、-C(＝O)(C1-6烷基)、-S(＝O)(C1-6烷基)、-S(＝O)2(C1-6烷基)、3-7元碳环基、3-7元杂环基、苯基、5-10元杂芳基；所述R9任选地被1、2、3、4、5或6个选自-C1-3烷基、-C1-3烯基、-C1-3炔基、-C1-3卤代烷基、-C1-3烷氧基、-CN、-NH2、-COOH、-NH(C1-3烷基)、-N(C1-3烷基)2、-OH、-O(C1-3烷基)、-SH、-S(C1-3烷基)、-C(＝O)(C1-3烷基)、-S(＝O)(C1-3烷基)、-S(＝O)2(C1-3烷基)、-C(＝O)NH2、-C(＝O)NH(C1-3烷基)、-C(＝O)N(C1-3烷基)2、-NHC(＝O)(C1-3烷基)、-C(＝O)O(C1-3烷基)、-C(＝O)-(C1-3亚烷基)-(OC1-3烷基)、-OC(＝O)(C1-3烷基)、-S(＝O)NH2、-S(＝O)NH(C1-3烷基)、-S(＝O)N(C1-3烷基)2、-NHS(＝O)(C1-3烷基)、-S(＝O)2NH2、-S(＝O)2NH(C1-3烷基)、-S(＝O)2N(C1-3烷基)2、-NHS(＝O)2(C1-3烷基)、3-7元碳环基、3-7元杂环基、苯基或5-10元杂芳基的取代基取代；所述杂环基或杂芳基在每次出现时独立地包括一个或多个选自N、O或S的杂原子；所述R9优选是-H、-CN、-C1-6烷基、-C1-6卤代烷基、-C3-6环烷基、-(C1 -4亚烷基)-(C3-6环烷基)、-C3-6杂环基、-(C1-4亚烷基)-(C3-6杂环基)、-(C1-6亚烷基)-O(C1-3烷基)、-(C1-6亚烷基)-CF3、-C(O)-(C1-6烷基)、-C(O)2-(C1-6烷基)、-C(O)-NH2、-CH2C(O)-NH2、-C(O)-C(O)-NH2、-C(O)-CH(C1-6亚烷基)-C(O)-NH2、-CH2C(O)-NH(C1-3烷基)、-CH2C(O)-N(C1-3烷基)2、-C(O)-NH(C1-3烷基)、-C(O)-N(C1-3烷基)2、-C(O)NH-(C1 -6烷基)、-C(O)-(C1-6卤代烷基)、-C(O)-(C1-6烷氧基)、-C(O)-(C1-6亚烷基)-(OC1-6烷基)、-C(O)-(C6芳基)、-C(O)-(C6杂芳基)、-C(O)-(C6杂环基)、-(C1-6亚烷基)-CO2H、-(C1-6亚烷基)-CO2(C1-6烷基)、--SO2-(C1-6烷基)、氧杂环丁烷基或
R7是-H、-C1-4烷基或-(氧杂环丁烷)基。
在一些实施方式中，本申请第二方面或第三方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
A为
其中，
n为0；
R7是-H、-C1-4烷基或-(氧杂环丁烷)基；
Y1和Y3各自为-CH2-，以及Y2是-NR9-；
所述R9是-H、-CN、-C1-6烷基、-C1-6卤代烷基、-C3-6环烷基、-(C1-4亚烷基)-(C3-6环烷基)、-(C1-4亚烷基)-(C3-6杂环基)、-(C1-6亚烷基)-O(C1-3烷基)、-(C1-6亚烷基)-CF3、-C(O)-(C1-6烷基)、-C(O)2-(C1-6烷基)、-C(O)-NH2、-C(O)-NH(C1-3烷基)、-C(O)-N(C1-3烷基)2、-C(O)NH-(C1-6烷基)、-C(O)-(C1-6卤代烷基)、-C(O)-(C1-6烷氧基)、-C(＝O)-(C1-6亚烷基)-(OC1-3烷基)、-C(O)-(C6芳基)、-C(O)-(C6杂芳基)、-C(O)-(C6杂环基)、-(C1-6亚烷基)-CO2H、-(C1-6亚烷基)-CO2(C1-6烷基)或-SO2-(C1-6烷基)。
在一些实施方式中，本申请第二方面或第三方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
A为
其中，
n为1；
R7是-H、-C1-4烷基或-(氧杂环丁烷)基；
Y1、Y2和Y4各自为-CH2-，以及Y3是-NR9-；
所述R9是-H、-CN、-C1-6烷基、-C1-6卤代烷基、-C3-6环烷基、-(C1-4亚烷基)-(C3-6环烷基)、-(C3-6杂环基)、-(C1 -4亚烷基)-(C3-6杂环基)、-(C1-6亚烷基)-O(C1-3烷基)、-(C1-6亚烷基)-CF3、-C(O)-(C1-6烷基)、-C(O)2-(C1-6烷基)、-C(O)-NH2、-C(O)-NH(C1-3烷基)、-C(O)-N(C1-3烷基)2、-C(O)NH-(C1-6烷基)、-C(O)-(C1-6卤代烷基)、-C(O)-(C1-6烷氧基)、-C(＝O)-(C1-6亚烷基)-(OC1-3烷基)、-C(O)-(C6芳基)、-C(O)-(C6杂芳基)、-C(O)-(C6杂环基)、-(C1-6亚烷基)-CO2H、-(C1 -6亚烷基)-CO2(C1-6烷基)或-SO2-(C1-6烷基)。
在一些实施方式中，本申请第二方面或第三方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
A为
其中，
n为1；
R7是-H、-C1-4烷基或-(氧杂环丁烷)基；
Y1、Y3和Y4各自为-CH2-，以及Y2是-NR9-；
所述R9是-H、-CN、-C1-6烷基、-C1-6卤代烷基、-C3-6环烷基、-(C1-4亚烷基)-(C3-6环烷基)、-(C3-6杂环基)、-(C1 -4亚烷基)-(C3-6杂环基)、-(C1-6亚烷基)-O(C1-3烷基)、-(C1-6亚烷基)-CF3、-C(O)-(C1-6烷基)、-C(O)2-(C1-6烷基)、-C(O)-NH2、-CH2C(O)-NH2、-C(O)-C(O)-NH2、-C(O)-CH(C1-6亚烷基)-C(O)-NH2、-CH2C(O)-NH(C1-3烷基)、-CH2C(O)-N(C1-3烷基)2、-C(O)-NH(C1-3烷基)、-C(O)-N(C1-3烷基)2、-C(O)NH-(C1-6烷基)、-C(O)-(C1-6卤代烷基)、-C(O)-(C1-6烷氧基)、-C(＝O)-(C1-6亚烷基)-(OC1-3烷基)、-C(O)-(C6芳基)、-C(O)-(C6杂芳基)、-C(O)-(C6杂环基)、-(C1-6亚烷基)-CO2H、-(C1-6亚烷基)-CO2(C1-6烷基)，-SO2-(C1-6烷基)或
本申请第四方面提供了一种化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，
R1、R2、R3、R4和R5各自独立地为-H、-卤素、-CF3或-C1-4烷基；其中，R1、R2、R3、R4或R5中的至少两个不为H；
A选自
R7和R9的定义如本申请第二方面或第三方面所定义。
在一些实施方式中，本申请第四方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
R1、R2、R3、R4和R5各自独立地为-H、-F、-Cl、-Br或-CF3；其他基团的定义如本申请第二方面或第三方面所定义。
在一些实施方式中，本申请第四方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
R1为-CF3、R2为-F、R3为-F、R4为-H且R5为-H，或
R1为-CF3、R2为-F、R3为-H、R4为-H且R5为-H，或
R1为-CF3、R2为-F、R3为-H、R4为-F且R5为-H，或
R1为-CF3、R2为-H、R3为-F、R4为-F且R5为-H，或
R1为-CF3、R2为-H、R3为-H、R4为-H且R5为-F，或
R1为-CF3、R2为-H、R3为-F、R4为-H且R5为-H，或
R1为-CF3、R2为-H、R3为-H、R4为-Cl且R5为-H，或
R1为-CF3、R2为-Cl、R3为-H、R4为-H且R5为-H，或
R1为-H、R2为-CF3、R3为-H、R4为-CF3且R5为-H，或
R1为-Cl、R2为-H、R3为-H、R4为-F且R5为-H，或
R1为-Cl、R2为-F、R3为-H、R4为-H且R5为-H；其他基团的定义如本申请第二方面或第三方面所定义。
在一些实施方式中，本申请第二方面、第三方面或第四方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
R9为-H、-CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2、-C(CH3)3、-CH2CH(CH3)2、-CH2C(CH3)3、-CH2CF3、-CH2CH2CF3、-CH2OCH3、-CH2CH2OCH3、-SO2-CH3、-C(O)-CH3、-C(O)-CH2CH3、-C(O)-CH2CH2CH3、-C(O)-CH(CH3)2、-C(O)-CH2CH(CH3)2、C(O)-C(CH3)3、-C(O)-OCH3,-C(O)-NHCH3、 -C(O)-CH2OCH3、-C(O)-CH2OCH2CH3、-C(O)-CH2OCH(CH3)2、-C(O)-CH2CH2OCH3、-C(O)-CH2CH2OCH2CH3、-C(O)-CH2CH2OCH(CH3)2、-C(O)-CH2CF3、-C(O)-CH2Cl、-C(O)-CH2F、-C(O)-CH2CH2OCH3、-C(O)-CH2CH2CF3、-C(O)-CH2CH2Cl、-C(O)-CH2CH2F、
在一些实施方式中，本申请第二方面、第三方面或第四方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，R9为-H、-CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2、-C(CH3)3、-CH2CH(CH3)2、-CH2C(CH3)3、-CH2CF3、-CH2CH2CF3、-CH2OCH3、-CH2CH2OCH3、
在一些实施方式中，本申请第二方面、第三方面或第四方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，R9为-SO2-CH3、-C(O)-CH3、-C(O)-CH2CH3、-C(O)-CH2CH2CH3、-C(O)-CH(CH3)2、-C(O)-CH2CH(CH3)2、C(O)-C(CH3)3、-C(O)-OCH3,-C(O)-NHCH3、
在一些实施方式中，本申请第二方面、第三方面或第四方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，R9为-C(O)-CH3、-C(O)-CH2CH3、-C(O)-CH2CH2CH3、-C(O)-CH(CH3)2、-C(O)-CH2CH(CH3)2、-C(O)-C(CH3)3、-C(O)-CH2OCH3、-C(O)-CH2OCH2CH3、-C(O)-CH2OCH(CH3)2、-C(O)-CH2CF3、-C(O)-CH2Cl、-C(O)-CH2F、-C(O)-CH2CH2OCH3、-C(O)-CH2CH2OCH2CH3、-C(O)-CH2CH2OCH(CH3)2、-C(O)-CH2CH2CF3、-C(O)-CH2CH2Cl、-C(O)-CH2CH2F、
在一些实施方式中，本申请第二方面、第三方面或第四方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
R7为-H、-CH3、-CH2CH3、-CH(CH3)2或
在一些实施方式中，本申请第二方面或第三方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
A为
其中，
Y1、Y2、Y3和Y4各自独立地为CR8或N，
R8在每次出现时独立地为-H、卤素、-OCH3、-CN或-CF3。
在一些实施方式中，本申请第二方面或第三方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，
A为
在一些实施方式中，本申请第二方面或第三方面所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐中，A为





本申请第五方面提供了一种化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，所述化合物为如下任一式：


本申请第六方面提供了一种化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，所述化合物为如下任一式：

本申请第七方面提供了一种化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，所述化合物为如下任一式：
本申请第八方面提供了一种化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，所述化合物为如下任一式：
本申请第九方面提供了一种本申请化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，所述化合物为如下任一式：
另一方面，本申请提供一种药物组合物，包括前文任一方案所述的化合物，其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐；和至少一种药学上可接受的赋形剂。
另一方面，本申请提供一种前文任一方案所述的化合物，其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐；或根据本申请所述的药物组合物在制备治疗与RBP4的血清浓度相关的视网膜中过量累积脂褐质的疾病的药物中的用途；其中，所述视网膜中过量累积脂褐质的疾病为双视黄酸介导的黄斑变性，包括但不限于与年龄相关性黄斑变性、干性(萎缩性)年龄相关性黄斑变性、斯特格氏病(Stargardt disease)、Best病、成人卵黄样黄斑病变或类似斯特格氏病的黄斑营养不良，所述双视黄酸是A2E、isoA2E、A2-DHP-PE或atRALdi-PE。
再一方面，本申请提供一种治疗与RBP4的血清浓度相关的视网膜中过量累积脂褐质的疾病的受试者的方法，所述方法包括给予该受试者治疗有效量的前文任一方案所述的化合物，其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐；或本申请所述的药物组合物；其中，所述视网膜中过量累积脂褐质的疾病为双视黄酸介导的黄斑变性，包括但不限于与年龄相关性黄斑变性、干性(萎缩性)年龄相关性黄斑变性、斯特格氏病(Stargardt disease)、Best病、成人卵黄样黄斑病变或类似斯特格氏病的黄斑营养不良，所述双视黄酸是A2E、isoA2E、A2-DHP-PE或atRALdi-PE。
又一方面，本申请提供一种前文任一方案所述的化合物，其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐；或本申请所述的药物组合物在治疗与RBP4的血清浓度相关的视网膜中过量累积脂褐质的疾病中的用途；其中，所述视网膜中过量累积脂褐质的疾病为双视黄酸介导的黄斑变性，包括但不限于与年龄相关性黄斑变性、干性(萎缩性)年龄相关性黄斑变性、斯特格氏病(Stargardt disease)、Best病、成人卵黄样黄斑病变或类似斯特格氏病的黄斑营养不良，所述双视黄酸是A2E、isoA2E、A2-DHP-PE或atRALdi-PE。
定义
除非另有说明，本申请中可互换使用的术语“卤素”是指氟、氯、溴或碘。优选的卤素基团包括-F、-Cl和-Br。
除非另有说明，本申请所用的术语“烷基”包括具有直链或支链的饱和一价烃基。例如，烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正已基、2-已基和2-甲基戊基。类似地，C1-6烷基中的C1-6被定义为标识具有1、2、3、4、5或6个碳原子的直链或支链排列的基团。
除非另有说明，本申请所用的术语“卤代烷基”是指上述被一个或多个(为1、2、3、4、5或6个)卤素(-F、-Cl或-Br)取代的烷基。在一些实施例中，卤代烷基为可互换的-C1-6卤代烷基或卤代C1-6烷基，其中，-C1-6卤代烷基或卤代C1-6烷基中的C1-6表示该烷基的总碳原子数为1到6个。在一些实施例中，-C1-6卤代烷基是-C1-3卤代烷基。在一些实施例中，-C1-3卤代烷基是被1、2、3、4、5或6个-F取代的(甲基、乙基、丙基或异丙基)；优选地，-C1-3卤代烷基是-CF3。
术语“亚烷基”是指通过从上述定义的烷基除去额外的氢原子而获得的双官能团。例如，亚甲基(即-CH2-)、亚乙基(即-CH2-CH2-或-CH(CH3)-)和亚丙基(即-CH2-CH2-CH2-、-CH(-CH2-CH3)-或-CH2-CH(CH3)-)。
术语“烯基”是指含有一个或多个双键的直链或支链烃基，通常长度为2至20个碳原子。例如，“-C2-6烯基”包含2至6个碳原子。例如，烯基包括但不限于乙烯基、丙烯基、丁烯基、2-甲基-2-丁烯-1-基、庚烯基、辛烯基等。
术语“炔基”是指含有一个或多个三键的直链或支链烃基，通常长度为2至20个碳原子。例如，“-C2-6炔基”包含2至6个碳原子。例如，代表性的炔基包括但不限于乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。
术语“烷氧基”是由前述烷基形成的氧醚，包括但不限于-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH(CH3)2、-CH2OCH3、-CH2CH2OCH3。
除非另有说明，本申请所用的术语“卤代烷氧基”是指被一个或多个(为1、2、3、4、5、或6个)卤素(-F,-Cl或-Br)取代的上述烷氧基。在某些实施例中，卤代烷氧基是可互换的-C1-6卤烷氧基或卤代C1-6烷氧基，其中，-C1-6卤代烷氧基或卤代C1-6烷氧基中的C1-6表明该烷氧基的总碳原子为1到6。在某些实施例中，-C1-6卤代烷氧基是-C1-3卤代烷氧基。在某些实施例中，-C1-6卤代烷氧基是被1、2、3、4、5或6个-F取代的(甲氧基、乙氧基、丙氧基或异丙氧基)；优选的-C1-3卤代烷氧基为-OCF3。
除非另有说明，本申请所用的术语“芳基”或“芳环”是指仅含有碳环原子的未取代或取代的单环或多环芳环系统。优选的芳基是单环或双环的6-10元芳环系统。苯基和萘基是优选的芳基。
除非另有说明，本申请所用的术语“杂环基”或“杂环”是指及含有一个或多个环杂原子的未取代和取代的单环或多环非芳环系统，其包括单环的杂环(基)、双环的杂环(基)、桥环的杂环(基)、稠环的杂环(基)及螺环的杂环(基)。优选的杂原子包括N、O和S，包括N-氧化物、硫氧化物和二氧化物。优选地，该杂环(基)是完全饱和的或具有一个或多个不饱和度的三至十元环。当前杂环(基)的定义包括多个取代度(优选一个、两个或三个取代度)。这种杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、氧杂氮杂环庚烷基、氮杂环庚烷基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢噁唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜和噁二唑基。
除非另有说明，本申请所用的术语“杂芳基”表示含有碳和至少一个杂原子的芳环系统。杂芳基或杂芳环可以是单环的或多环的，取代的或未取代的。单环杂芳基在其环中可具有1至4个杂原子，而多环杂芳基可包含1至10个杂原子。多环杂芳基环可含有稠环、螺环或桥环连接，例如，双环杂芳基是多环杂芳基。双环杂芳基环可含有8至12元原子。单环杂芳基环可含有5至8元原子(碳原子和杂原子)。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异噁唑基、噁唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异噁唑基、苯并噁唑基、苯并吡唑基、苯并噻唑基、苯并噻二唑基、苯并三唑基、腺嘌呤基、喹啉基或异喹啉基。
术语“碳环基”是指仅含有碳原子的取代或未取代的单环、双环、桥环、稠环、螺环非芳族环系统。优选地，该环是三至十元的，并且或者是完全饱和的或者是具有一个或多个不饱和度。多个取代度，优选为一、二或三，包括在本定义内。碳环基包括但不限于环烷基、环烯基和环炔基。示例性的“环烷基”基团包括但不限于环丙基、环丁基、环戊基、环己基等。
术语“一个或多个”是指一个或多个。在一些实施例中，“一个或多个”是指1、2、3、4、5或6个。在一些实施例中，“一个或多个”是指1、2、3或4个。在一些实施例中，“一个或多个”是指是指1、2或3。在一些实施例中，“一个或多个”是指1或2个。在一些实施例中，“一个或多个”是指1。在一些实施例中，“一个或多个”是指2。在一些实施例中，“一个或多个”是指3。在一些实施例中，“一个或多个”是指4。在一些实施例中，“一个或多个”是指5。在一些实施例中，“一个或多个”是指到6。
在本申请中，当一个环被一个或多个取代基取代时，这意味着每个取代基可以分别独立地取代在环的每个环原子上，包括但不限于环碳原子或环氮原子。此外，当环为多环时，如稠环、桥环或螺环，每个取代基可以分别独立地取代在多环的每个环原子上。
术语“氧代”是指氧和与其连接的碳原子共同形成基团。
在本申请中，术语“组合物”旨在涵盖一个包含特定量的特定成分的产品，以及直接或间接由特定量的特定成分的组合产生的任何产品。因此，含有本申请化合物作为活性成分的药物组合物以及制备本申请化合物的方法也是本申请的一部分。而且，化合物的一些结晶形式可能以多晶型物的形式存在，因此包括在本申请中。此外，一些化合物可能与水(即水合物)或常见的有机溶剂形成溶剂化物，并且此类溶剂化物也包括在本申请的范围内。
术语“药学上可接受的盐”是指由药学上可接受的无毒碱或酸制备的盐。当本申请化合物为酸性时，其相应的盐可以方便地由药学上可接受的无毒碱制备，包括无机碱和有机碱。当本申请化合物为碱性时，其相应的盐可以方便地由药学上可接受的无毒酸，包括无机酸和有机酸制备。由于本申请中的化合物旨在用于制药用途，因此它们优选以基本上纯的形式提供，例如至少60％纯，更合适地至少75％纯，尤其是至少98％纯(％以重量计)。
本申请在其范围内包括本申请化合物的前药。通常，此类前药是化合物的功能性衍生物，其易于在体内转化为所需化合物。因此，在本申请的治疗方法中，术语“给药”应包括用具体公开的化合物或用可能未具体公开的化合物但在向受试者给药后在体内转化为特定化合物的化合物治疗各种病症。用于选择和制备合适的前药衍生物的常规方法描述于例如“前药设计”(“Design of Prodrugs”,ed.25H.Bundgaard,Elsevier,1985)。
分子中特定位置的任何取代基或变量的定义旨在独立于该分子中其他位置的取代基或变量的定义。应当理解，本领域普通技术人员可以选择本申请化合物上的取代基和取代模式，以提供化学稳定的化合物，并且可以通过本领域已知的技术以及本申请阐明的方法容易地合成。
本申请所述化合物可含有一个或多个不对称中心，因此可产生非对映异构体和光学异构体。本申请包括所有这些可能的非对映异构体及其外消旋混合物、它们基本上纯的拆分的对映异构体、所有可能的几何异构体、及其药学上可接受的盐。
本申请包括化合物的所有立体异构体及其药学上可接受的盐。此外，还包括立体异构体的混合物以及分离的特定立体异构体。在用于制备这些化合物合成步骤的过程中，或在使用本领域技术人员已知的外消旋化或差向异构化方法的过程中，这些步骤的产物可以是立体异构体的混合物。
本申请所用术语“立体异构体”是指分子中原子或原子团互相连接次序相同，但空间排列不同而引起的异构体，其包括构型异构体和构象异构体，其中的构型异构体又包括几何异构体和旋光异构体，旋光异构体主要包括对映异构体和非对映异构体。本申请包括该化合物的所有可能的立体异构体。
本申请提供的某些化合物可以作为阻转异构体存在，其为构象立体异构体，当由于与分子的其他部分的空间相互作用而阻止或大大减缓围绕分子中单键的旋转时出现。本申请提供的化合物包括所有的阻转异构体，包括纯的单独的阻转异构体，各自富集的阻转异构体或各自非特异性的混合物。如果围绕单键的旋转势垒足够高，并且构象之间的相互转化足够慢，则可以允许阻转异构体的分离。
本申请旨在包括本申请化合物中存在的所有原子同位素。同位素是具有相同原子序数但质量数不同的原子。作为一般实例而非限制，氢的同位素包括氘和氚。氢的同位素可表示为1H(氢)、2H(氘)和3H(氚)。它们通常也表示为D(氘)和T(氚)。在本中请中，CD3表示甲基，其中所有氢原子都是氘。碳的同位素包括13C和14C。使用适当的同位素标记的试剂代替非标记试剂，本申请的同位素标记的化合物通常可以通过本领域技术人员已知的常规技术或通过与本申请所述类似的方法制备。
除非另有说明，否则本申请所用的术语“氘代衍生物”是指具有与参考化合物相同的化学结构，但一个或多个氢原子被氘原子(“D”)取代的化合物。将认识到，根据合成中使用的化学材料的来源，合成化合物中会出现一些天然同位素丰度的变化。天然丰富的稳定氢同位素的浓度，与本申请所述的氘代衍生物的稳定同位素取代程度相比，尽管这种变化很小且无关紧要。因此，除非另有说明，当提及本申请公开的化合物的“氘代衍生物”时，至少一个氢在远高于其天然同位素丰度(通常为约0.015％)时被氘置换。在一些实施例中，本申请公开的氘代衍生物对于每个氘原子具有至少3500的同位素富集因子(在每个指定的氘中含有52.5％的氘)，至少4500(含有67.5％氘)，至少5000(含有75％氘)，至少5500(含有82.5％氘)，至少6000(含有90％氘)，至少6333.3(含有95％氘，至少6466.7(含有97％氘)，或至少6600(含有99％氘)。
当本申请化合物存在互变异构体时，本申请包括任何可能的互变异构体及其药学上可接受的盐及其混合物，另有特别说明的除外。
本申请的药物组合物包含作为活性成分的本申请化合物(或其药学上可接受的盐)、药学上可接受的载体和任选的其他治疗成分或佐剂。尽管在任何给定情况下最合适的途径将取决于特定宿主，以及为病症(为治疗该病症而正在施用该活性成分)的性质和严重程度，但该组合物包括适用于口服、直肠、局部和非肠胃(包括皮下、肌内和静脉内)给药的组合物。药物组合物可以方便地以单位剂型存在，并通过药学领域众所周知的任何方法制备。
在实践中，根据常规药物配制技术，本申请的化合物或其前药或其代谢物或药学上可接受的盐可以作为活性成分与药物载体与药物载体组合成紧密混合物。根据给药途径所需的制剂形式，例如，载体可以采用多种形式，例如口服或肠胃外(包括静脉内)给药途径。因此，本申请的药物组合物可以作为适于口服给药的离散单元存在，例如胶囊、扁囊剂或片剂，每个都含有预定量的活性成分。此外，组合物可以作为粉末形式、颗粒形式、溶液形式、水性液体中的悬浮液、非水液体、水包油乳液或油包水乳液形式存在。除了上述常见剂型外，式I代表的化合物或其药学上可接受的盐也可以通过控释方式和/或递送装置给药。该组合物可以通过任何药学方法制备。通常，此类方法包括将活性成分与构成一种或多种必要成分的载体结合的步骤。通常，组合物通过将活性成分与液体载体或细碎的固体载体或两者均匀且紧密地混合来制备。然后可以方便地将产品成形为所需的样式。
因此，本申请的药物组合物可包括药学上可接受的载体和化合物或药学上可接受的盐。式I化合物或其药学上可接受的盐也可以与一种或多种其他治疗活性化合物组合包含在药物组合物中。
所用的药物载体可以例如是固体、液体或气体。固体载体的实例包括乳糖、石膏粉、庶糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁和硬脂酸。液体载体的实例是糖浆、花生油、橄榄油和水。气态载体的实例包括二氧化碳和氮气。在制备用于口服剂型的组合物中，可以使用任何方便的药物介质。例如水、乙二醇、油、醇、调味剂、防腐剂、着色剂等可被用于形成例如悬浮液、酣剂和溶液的口服液体制剂；而淀粉、糖、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等载体可被用于形成如粉末、胶囊和片剂的口服固体制剂。由于易于给药，片剂和胶囊是优选的口服剂量单元，其使用固体药物载体。可选地，片剂可以通过标准水性或非水性技术包衣。
含有本申请组合物的片剂可以通过压制或模塑来制备，其可选地含有一种或多种辅助成分或佐剂。压制的片剂可以通过在合适的机器中压制如粉末或颗粒自由流动形式的活性成分，并可选地与粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂混合来制备。模塑的片剂可通过在合适的机器中模制用惰性液体稀释剂润湿的粉末状化合物的混合物来制备。每个片剂优选含有约0.05mg至约5g活性成分，每个扁囊剂或胶囊优选含有约0.05mg至约5g的活性成分。例如，用于人口服给药的制剂可含有与适当和方便量的载体物质混合的约0.5mg至约5g活性剂，载体物质可占总组合物的约0.05至约95％。单位剂型通常包含约0.0lmg至约2g的活性成分，通常为0.01mg、0.02mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、25mg、50mg、l00mg、200mg、300mg、400mg、500mg、600mg、800mg、l000mg、1500mg或2000mg。
适用于肠胃外给药的本申请药物组合物可以制备为活性化合物在水中的溶液或悬浮液。可以包括合适的表面活性剂，例如羟丙基纤维素。分散体也可以在甘油、液体聚乙二醇及其在油中的混合物中制备。此外，可以包括防腐剂以防止微生物的有害生长。
适用于注射用途的本申请药物组合物包括无菌水溶液或分散液。此外，组合物可以是用于临时制备这种无菌可注射溶液或分散体的无菌粉末的形式。在所有情况下，最终的可注射形式必须是无菌的并且必须是有效流动的以便于注射。药物组合物在制造和储存条件下必须是稳定的；因此，最好应加以保存以防止如细菌和真菌的微生物的污染作用。载体可以是例如含有水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)、植物油及其合适的混合物的溶剂或分散介质。
本申请的药物组合物可以是适于局部使用的形式，例如气溶胶、乳膏、软膏、洗剂、撒粉等。此外，组合物可以是适用千透皮装置的形式。利用本申请式(I)所示的化合物或其药学上可接受的盐，这些制剂可以通过常规加工方法来制备。例如，通过将亲水性材料和水与约0.05wt％至约10wt％的化合物混合以产生具有所需稠度的乳膏或软膏来制备乳膏或软膏。
本申请的药物组合物可以是适于直肠给药的形式，其中载体是固体。优选混合物形成单位剂量栓剂。合适的载体包括可可脂和本领域常用的其他材料。栓剂可以通过首先将组合物与软化或熔化的载体混合，然后在模具中冷却和成型来方便地形成。
除了上述载体成分之外，上述药物制剂可以适当地包括一种或多种另外的载体成分，例如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂、防腐剂(包括抗氧化剂)等等。此外，可以包括其他佐剂以使制剂与预期接受者的血液等渗。含有化合物或其药学上可接受的盐的组合物也可以制备成粉末或液体浓缩物形式。
通常，每天约0.001mg/kg至约150mg/kg体重的剂量水平可用于治疗上述病症，或者每位患者每天约0.05mg至约7g。例如，让每名患者每天以每公斤体重服用约0.001至50毫克的化合物，或者让每名患者每天以每公斤体重服用约0.05毫克至约3.5克的化合物可以有效治疗与年龄相关性黄斑变性、干性(萎缩性)年龄相关性黄斑变性、斯特格氏病(Stargardtdisease)、Best病、成人卵黄样黄斑病变或类似斯特格氏病的黄斑营养不良等。然而，应当理解的是，任何特定患者的具体剂量水平将取决千包括年龄、体重、一般健康状况、性别、饮食、给药时间、给药途径、排泄率、药物组合以及接受治疗的特定疾病的严重程度等多种因素。
除非上下文另有说明，当一个值表示为“大约X”或“X左右”时，所述X的规定值将被理解为精确到±10％，最好是±5％，±2％。
从以下对本申请的书面描述中，这些和其他方面将变得显而易见。
附图说明
此处所说明的附图用来提供对本申请的进一步理解，构成本申请的一部分，本申请的示意性实施例及其说明用于解释本申请，并不构成对本申请的不当限定。
图1为本申请实施例1合成的化合物1的核磁氢谱图；
图2为本申请化合物17和对照化合物(剂量为1mg/kg)在不同时间点的RBP4降低率对比结果图；
图3为本申请化合物17和对照化合物(剂量为5mg/kg)在不同时间点的RBP4降低率对比结果图。
具体实施方式
可以使用本申请所述的合成方法和反应方案由市售试剂合成本申请的化合物。概述特定合成路线的示例旨在为本领域的合成化学家提供指导，他们将很容易理解溶剂、浓度、试剂、保护基团、合成步骤的顺序、时间、温度等可以根据需要在本领域技术人员的技术和判断范围内进行修改。
提供以下实施例以更好地说明本申请。除非另有明确说明，否则所有份数和百分比均以重量计，所有温度均为摄氏度。示例中使用了下表中的缩写：
实施例1
将3,4-二氟-2-三氟甲基-溴二苯(835mg，3.2mmol)、Pd(PPh3)4(370mg，0.32mmol)和K2CO3水溶液(2.6mL，2M，5.2mmol)加入到N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(989mg，3.2mmol)的1,4-二氧六环(干燥溶剂，40mL)中。在氮气氛围下，将所得反应混合物在80℃搅拌过夜，加入水淬灭，并用EtOAc萃取。将所得有机相用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩得到残余物。将所述残余物用硅胶柱层析(用V石油醚/V乙酸乙酯＝20/1洗脱)纯化，得到黄色液体化合物1-1(834.8mg，71.5％产率)。LCMS:m/z＝364.0[M+H]+。
将化合物1-1(832mg，2.29mmol)的HCl/1,4-二氧六环(32mmol，4M，8mL)溶液在室温下搅拌2小时后，减压浓缩后得到化合物1-2的盐酸盐粗产品，其可无需纯化直接用于下一步反应。LCMS:m/z＝264.4[M+H]+。
在室温条件下，将EDCI(527mg，2.748mmol)、HOBt(371mg，2.748mmol)和DIEA(1.2mL，6.87mmol)加入到6H-吡唑[3,4-C]1,4,5,7-四氢吡啶-3,6-羧酸6-(1,1-二甲基乙基)酯(612mg，2.29mmol)和化合物1-2的盐酸盐(2.29mmol)的DMF(干燥溶剂，20mL)的溶液中。将所得反应混合物在室温下搅拌过夜，加入水淬灭，并用EtOAc萃取。将所得有机相用饱和食盐水洗涤，用无水硫酸钠干燥后浓缩得到残余物。将所述残余物用硅胶柱层析(用VDCM/VMeOH＝30/1洗脱)纯化，得到浅黄色液体化合物1-3(793mg，67.5％产率)。LCMS:m/z＝513.3[M+H]+。
将化合物1-3(789mg,1.54mmol)的HCl/1,4-二氧六环(21.56mmol，4M，5.4mL)溶液在室温下搅拌2小时后，减压浓缩后得到化合物1-4的盐酸盐粗产品，其可无需纯化直接用于下一步反应。LCMS:m/z＝413.4[M+H]+。
在0℃条件下，将用DCM(干燥，1mL)稀释的醋酸酐(30μL，0.315mmol)缓慢加入到化合物1-4的盐酸盐(0.35mmol)、Et3N(0.15mL，1.05mmol)的DCM(5mL)溶液中。所得反应混合物在0℃搅拌30分钟，加水淬灭后用EtOAc萃取。将所得有机相用饱和食盐水洗涤，用无水硫酸钠干燥后浓缩得到残余物。将所述残余物用硅胶柱层析(用VDCM/VMeOH＝20/1洗脱)纯化，得到粗产品。将所得粗产品用Prep-HPLC(C18柱，用CH3CN/H2O洗脱)得到白色固体化合物1(32.1mg，20.2％产率)。LCMS:m/z＝455.3[M+H]+。图1为本申请实施例1合成的化合物1的核磁氢谱图。
1H NMR(400MHz,DMSO-d6)δ13.0-12.85(m,1H),7.78(q,J＝8.8Hz,1H),7.30-7.17(m,1H),5.73-5.58(m,1H),4.69-4.51(m,3H),4.21-4.03(m,2H),3.86-3.74(m,1H),3.72-3.59(m,2H),2.73-2.56(m,2H),2.41-2.29(m,2H),2.14-2.05(m,3H)。
实施例2
将N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(4.638g，15mmol)溶解在无水1,4-二氧六环(40mL)中，加入3-氟-2-三氟甲基-溴苯(3.645g，15mmol)、Pd(PPh3)4(1.733g，1.5mmol)、12mL K2CO3(2M的水溶液，24mmol)。将所得混合物加热至80℃，并在氮气气氛下搅拌过夜。用水淬灭所得混合物，并用EtOAc萃取。将有机溶液用无水Na2SO4干燥并浓缩。通过硅胶柱色谱法(PE/EtOAc＝20/1，体积比)纯化粗产物，得到无色液体的纯产物化合物3-1(4.5684g，88％产率)。LCMS:m/z＝346.02[M+H]+.
将化合物3-1(2.072g，6mmol)加入反应烧瓶中，然后将21mL HCl(84mmol，4M的1,4-二氧六环溶液)缓慢加入反应烧瓶。将所得混合物在室温下搅拌2小时。反应完成后，减压浓缩除去溶剂，得到白色固体粗产物化合物3-2，粗产物直接用于下一步。LCMS:m/z＝246.30[M+H]+.
称取6H-吡唑并[3,4-c]吡啶-3,6-二羧酸(1.604g，6mmol)和化合物3-2(6mmol)，加入无水DMF(50mL)溶解，随后加入EDCI(1.382g，7.2mmol)、HOBt(973mg，7.2mmol)和DIEA(3.1mL，18mmol)。将所得混合物在室温下搅拌过夜。然后用水淬灭所得混合物，并用EtOAc萃取。将有机溶液用无水Na2SO4干燥并浓缩。通过硅胶柱色谱法(DCM/MeOH＝30/1，体积比)纯化粗产物，得到淡黄色固体的化合物3-3(2.7094g，91％产率)。LCMS:m/z＝495.5[M+H]+.
将化合物3-3(2.67g，5.4mmol)加入反应烧瓶中，然后将19mL HCl(75.6mmol，4M的1,4-二氧六环)缓慢加入反应烧瓶。将所得混合物在室温下搅拌2小时。反应完成后，减压浓缩除去溶剂，得到淡黄色固体的粗产物化合物3-4，粗产物直接用于下一步。LCMS:m/z＝395.3[M+H]+.
称取化合物3-4(3.1mmol)，加入无水MeCN(15mL)溶解，加入Et3N(1.29mL，9.3mmol)和1-溴-2-甲氧基乙烷(0.29mL，3.1mmol)。混合物80℃搅拌过夜。然后用水淬灭所得混合物，并用EtOAc萃取。将有机溶液用无水Na2SO4干燥并浓缩。通过硅胶柱色谱法(DCM/MeOH＝20/1，体积比)纯化粗产物，得到白色固体的纯产物化合物3(760.2mg，54％产率)。
实施例3
向化合物3-4(137mg，0.34mmol)的DCM(5mL)溶液中加入3-氧杂环丁酮(30μL，0.51mmol)和HOAc(0.12mL，2.04mmol)。将所得混合物在室温下搅拌过夜。然后，将三乙酰氧基硼氢化钠(144mg，0.68mmol)加入反应体系中，将所得混合物在室温下搅拌24小时。然后用饱和碳酸氢钠淬灭所得混合物，并用DCM萃取。将有机溶液用无水Na2SO4干燥并浓缩。通过硅胶柱色谱法(DCM/MeOH＝20/1，体积比)纯化粗产物，得到白色固体化合物4(16mg，10.5％产率)。
实施例4
称取化合物3-4(310mg，0.721mmol)加入无水DCM(2mL)溶解，于冰浴下向体系中依次加入甲氧基乙酰氯(86mg，0.793mmol)和Et3N(0.12mL，0.865mmol)。保持该温度反应4小时，加水淬灭反应体系，并用EtOAc萃取。将有机溶液用无水Na2SO4干燥并浓缩。通过硅胶柱色谱法(DCM/MeOH＝20/1，体积比)纯化粗产物，得到白色固体纯产物(260mg，77％产率)。
实施例5
称取{4-[3,4-二氟-2-(三氟甲基)苯基]-1,2,3,6-四氢吡啶-1-基}(4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)甲酮盐酸盐(化合物1-4，135mg，0.3mmol)加入无水MeCN(5mL)溶解，向体系中加入Et3N(0.13mL，0.9mmol)和2-溴乙酰胺(62mg，0.45mmol)。将所得混合物在80℃下搅拌2小时。然后用水淬灭所得混合物，并用EtOAc萃取。将有机溶液用无水Na2SO4干燥并浓缩。通过硅胶柱色谱法(DCM/MeOH＝10/1，体积比)纯化粗产物，得到白色固体纯产物化合物10(110.7mg，78.5％)。
实施例6
在室温条件下，将EDCI(68g，354.16mmol)、HOBt(47.8g，354.16mmol)和DIEA(94g，729.15mmol)依次加入到化合物1-2(54.8g，208.33mmol)和1,4,6,7-四氢吡喃[4,3-C]吡唑-3-羧酸(35g，208.33mmol)的DMF(600mL)溶液中，反应体系在室温下搅拌12h，LCMS检测反应完成。将反应体系于冰浴下加入到4L水中，大量固体析出，搅拌45分钟过滤，收集固体。将所得固体加入到3L甲醇溶液中打浆，过滤，收集固体，油泵抽干4小时，得白色固体产物(56g，65％产率)。
实施例7
在室温条件下，将化合物1-4(150mg，0.36mmol)和(3R)-3-[(甲基磺酰基)氧基]-2-吡咯烷酮(59.8mg，0.36mmol)溶于3mL乙腈溶液中，随后滴加入DIEA(129.3mg，1.08mmol)。反应体系升温至80℃，搅拌反应过夜。将所得反应混合物冷却至室温，加入水淬灭，并用EtOAc萃取。将所得有机相用饱和食盐水洗涤，用无水硫酸钠干燥后浓缩得到残余物。将所述残余物用硅胶柱层析(用VDCM/VMeOH＝20/1洗脱)纯化，得到浅黄色液体化合物18(53mg，29.4％产率)。
使用上述步骤或采用相应中间体或反应物的类似步骤合成以下表1的化合物。
表1合成的化合物




对照化合物
参照CN111393434B的实施例19合成以下化合物，作为对照：
1-(3-(4-(3,4-二氟-2-(三氟甲基)苯基)哌啶-1-羰基)-4,5-二氢-1H-吡唑并[3,4-c]吡啶-6(7H)-基)乙酮。
一、血浆中RBP4含量检测试验
试验方法：适应性饲养7至8周龄ICR雄性小鼠3至7天，并随机分组(每组4只)，试验前禁食12小时。试验当天给药前(0小时值作为初始含量)收集眼眶静脉血样并分离血浆。而后，口服给予1mg/kg或5mg/kg剂量的试验化合物(溶剂∶5％ DMSO+10％环糊精)，同时口服溶媒(5％ DMSO+10％环糊精)作为对照组。给予化合物之后分别在5小时、8小时、10小时、12小时和24小时的时间点收集眼眶静脉血样，并分离血浆。使用Mouse RBP4(Retinol Binding Protein 4,Plasma)ELISA试剂盒(immunoway，KE1574)检测血浆样品内RBP4含量，并计算出降低率，选出5至24小时内的最大降低率。小鼠血浆中不同采样时间点的RBP4含量的降低率＝(RBP4初始含量-RBP4采样点含量)/RBP4初始含量。各化合物对小鼠血浆内RBP4含量的最大降低率如下表2所示，结果如表2所示。
表2不同化合的血浆RBP4降低水平
本申请还比较了化合物17和对照化合物在不同时间点的RBP4降低率，剂量为1mg/kg时的对比结果如图2，剂量为5mg/kg时的对比结果如图3。
结果显示，在单次1mg/kg或5mg/kg口服剂量后，与对照组相比，本申请化合物可以显著降低血浆RBP4含量。
二、拮抗活性试验
试验方法：
待测化合物溶液：每个化合物均以100μM作为起始浓度，以3倍为梯度逐级稀释至10个不同的浓度。
工作液：含有10mMTris-HCl pH7.5、1mM DTT、0.05％NP-40、6％甘油的缓冲液。
反应组合物包括以下各组分：2μL hFc-RBP4(MCE,HY-P72031)(62.5nM,工作液稀释)、1μL Retinol(Sigma,A2056-25MG)(视黄醇，5μΜ,工作液稀释)、2μL his-TTR(SinoBioloqical,12091-H08H)(10nM,工作液稀释)与5μL Anti-His-Tb(Cisbio,61HISTLB)&Anti-IgG-XL665(Cisbio,61HFCXLB)工作液(抗体用工作液稀释为2×混合液)。
孵育反应过程：将100nL待测化合物溶液转移至384孔反应板(每个浓度设置两个复孔)，依次加入反应组合物中的各组分，随后在25℃下孵育60分钟。使用BMG酶标仪读取HTRF信号665/620比率。
数据处理：化合物的抑制百分比(％inh)＝100×(高对照平均值-受试孔数值)/(高对照平均值-低对照平均值)。通过XLfit 5.5.0从非线性回归方程拟合化合物的IC50和HillSlope。结果如表3所示。
表3不同化合的RBP4-TTR相互作用拮抗活性
结果显示，与对照化合物相比，本申请化合物能显著拮抗RBP4-TTR相互作用。
三、药代动力学试验
试验方法：每种化合物用三只ICR小鼠(雄性)，共五组。小鼠用单次10mg/kg或者5mg/kg(口服)治疗。对于每只小鼠，在给药后0.25、0.5、1、2、4和8小时的时间点采集血样。将全血样品放入含有EDTA-K2的试管中，上下颠倒数次，然后在6000rpm，4℃下离心15分钟获得血浆。使用LC-MS/MS方法测定血浆样品中化合物的浓度。结果如表4所示。
表4不同化合物的药代动力学结果
四、肝微粒体稳定性
试验方法：
化合物工作液制备：配制受试物和对照化合物维拉帕米(即Varapamil)10mM的DMSO储备液，试验前用乙腈稀释到200μM的工作液，受试物和维拉帕米的终浓度为1μM。
磷酸缓冲盐制备：称取7.098g磷酸氢二钠，加入500mL纯水超声溶解，得到磷酸氢二钠溶液。称取3.400g磷酸二氢钾，加入250mL纯水超声溶解，得到磷酸二氢钾溶液。将磷酸氢二钠溶液和磷酸二氢钾溶液混合后调节pH为7.4±0.2。
10mM NADPH配制：称取适量NADPH(还原型辅酶Ⅱ)，用磷酸缓冲盐新鲜配制浓度为10mM的工作液，终浓度为1mM。
孵育体系的配制：根据表5配制混悬液至孵育板中，37℃水浴锅中预孵育10min。
表5孵育体系的配置表
向358μL孵育体系中加入2μL阳性对照或待测化合物工作溶液，涡旋混合均匀，所有样品均进行双平行制备。向体系中加入40μL 10mM NADPH，低速涡旋混合均匀，开始反应计时，分别于0.5min、5min、10min、15min、30min、60min取50μL上述混悬液，加入400μL乙腈(含100ng/mL地塞米松)终止液，涡旋混合均匀。于4700rpm、4℃下离心15分钟沉淀蛋白。转移100μL上清液到进样板，加入100μL纯水混匀，用于UPLC-MS/MS分析，结果如表6所示。
表6肝微粒体稳定性结果
结果显示本申请大部分化合物的代谢稳定性良好，特别是在人肝微粒体中的代谢比较稳定。此外，本申请部分化合物在人肝微粒体中的清除率小于10μL/min/mg，具备很好的成药特性。
应当理解，如果本申请引用了任何现有技术出版物；这样的引用并不意味着承认该出版物是任何国家本领域公知常识的一部分。
本申请通过引文使用的所有公开文本、专利、专利申请以及公开的专利申请通过引用整体并入本申请。
尽管为了清楚理解的目的，已经通过说明和实施例的方式对前述发明进行了相当详细的描述，但是对于本领域技术人员来说，实施某些细微的改变和修改是显而易见的。因此，描述和实施例不应被解释为限制本申请的范围。

Claims (21)

  1. 式(I)的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，
    其中，
    R1、R2、R3、R4和R5各自独立地为-H、-卤素、-CF3或-C1-4烷基；其中，R1、R2、R3、R4或R5中的至少两个不为H；
    A选自
    其中，R7选-H、-C1-4烷基或-(氧杂环丁烷)基；
    当A选自时：
    其中，n为0、1或2；
    Y1、Y2和Y4各自为-CH2-，且Y3为-NR9-；或Y1、Y3和Y4各自为-CH2-，且Y2为-NR9-；或Y1、Y2和Y4各自为-CH2-，且Y3为-O-或-S(＝O)2-；或Y1、Y3和Y4各自为-CH2-，且Y2为-O-或-S(＝O)2-；
    R9选自氢、-C1-6烷基、-C(＝O)(C1-6烷基)、-S(＝O)(C1-6烷基)、-S(＝O)2(C1-6烷基)、3-7元碳环基、3-7元杂环基、苯基、5-10元杂芳基；所述R9任选地被1、2、3、4、5或6个选自卤素、-C1-6烷基、-C1-6烯基、-C1-6炔基、-C1-6卤代烷基、-C1-6烷氧基、-CN、-NH2、-COOH、-NH(C1-6烷基)、-N(C1-6烷基)2、-OH、-O(C1-6烷基)、-O(C1-6氘代烷基)、-SH、-S(C1-6烷基)、＝O、-C(＝O)(C1-6烷基)、-C(＝O)(C1-6烷氧基)、-S(＝O)(C1-6烷基)、-S(＝O)2(C1-6烷基)、-C(＝O)NH2、-C(＝O)-C(＝O)NH2、-C(＝O)NH(C1-6烷基)、-C(＝O)N(C1-6烷基)2、-NHC(＝O)(C1-6烷基)、-C(＝O)O(C1-6烷基)、-OC(＝O)(C1-6烷基)、-S(＝O)NH2、-S(＝O)NH(C1-6烷基)、-S(＝O)N(C1-6烷基)2、-NHS(＝O)(C1-6烷基)、-S(＝O)2NH2、-S(＝O)2NH(C1-6烷基)、-S(＝O)2N(C1-6烷基)2、-NHS(＝O)2(C1-6烷基)、-C(＝O)-苯基、-C(＝O)-5-10元杂芳基、-C(＝O)-3-7元杂环基、3-7元碳环基、3-7元杂环基、苯基或5-10元杂芳基的取代基取代；所述杂环基或杂芳基在每次出现时独立地包括一个或多个选自N、O或S的杂原子；
    当A选自
    其中，Y1、Y2、Y3和Y4各自独立地位CR8或N，且每个R8独立地为-H、卤素、-C1-6烷基、-C(＝O)NH2、-C(＝O)NH(C1-6烷基)、-C(＝O)N(C1-6烷基)2、-COOH、-NHC(＝O)N(C1-6烷基)2、-S(＝O)2NH(C1-6烷基)、-O-(C1-6烷基)、-CN或-C1-6卤代烷基；
    当A选自
    其中，Z2选自-O-，Z3选自-C(CH3)2-，Z1和Z4选自-CH2-；或者，Z2和Z3各自独立地选自-C(O)-、-N(CH3)-或-NH-，Z1和Z4选自-CH2-；
    R10选自氢或-CH3；
    当A选自
    其中，Z5、Z6、Z7和Z8各自独立地选自CR12或N，R12各自独立地选自氢、F、Cl、-CN或-OCH3；
    R11选自氢、-CH3、-CH2CH3、或-CH(CH3)2；
    当A选自
    其中，W1、W2、W3和W4各自独立地选自-CH2-、-O-、-NH-、-N(CH3)-或
    当A选自
    其中，U1选自O或S，U2选自N；
    当A选自
    其中，U5选自N，U6选自O或S；或者，U5选自CH，U6选自NH；
    当A选自
    其中，U3选自N或CH；
    R16选自Cl；
    p选自0或1；
    当A选自
    其中，U4选自N或CH；
    R13选自-CH3、-OCH3、F、Cl或-CF3；
    q选自0或1；
    当A选自
    其中，W6、W7、W8和W9各自独立地选自N或CR15；
    R14选自氢或-CH3；
    R15各自独立地选自氢、F、Cl、-CH3、-OCH3、
  2. 式(I)的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，
    其中，
    R1、R2、R3、R4和R5各自独立地为-H、-卤素、-CF3或-C1-4烷基；其中，R1、R2、R3、R4或R5中的至少两个不为H；
    A选自
    其中，R7选-H、-C1-4烷基或-(氧杂环丁烷)基；
    当A选自时：
    其中，n为0、1或2；
    Y1、Y2和Y4各自为-CH2-，且Y3为-NR9-；或Y1、Y3和Y4各自为-CH2-，且Y2为-NR9-；
    R9选自氢、-C1-6烷基、-C(＝O)(C1-6烷基)、-S(＝O)(C1-6烷基)、-S(＝O)2(C1-6烷基)、3-7元碳环基、3-7元杂环基、苯基、5-10元杂芳基；所述R9任选地被1、2、3、4、5或6个选自-C1-6烷基、-C1-6烯基、-C1-6炔基、-C1-6卤代烷基、-C1-6烷氧基、-CN、-NH2、-COOH、-NH(C1-6烷基)、-N(C1-6烷基)2、-OH、-O(C1-6烷基)、-SH、-S(C1-6烷基)、-C(＝O)(C1-6烷基)、-S(＝O)(C1-6烷基)、-S(＝O)2(C1-6烷基)、-C(＝O)NH2、-C(＝O)NH(C1-6烷基)、-C(＝O)N(C1-6烷基)2、-NHC(＝O)(C1-6烷基)、-C(＝O)O(C1-6烷基)、-OC(＝O)(C1-6烷基)、-S(＝O)NH2、-S(＝O)NH(C1-6烷基)、-S(＝O)N(C1-6烷基)2、-NHS(＝O)(C1-6烷基)、-S(＝O)2NH2、-S(＝O)2NH(C1-6烷基)、-S(＝O)2N(C1-6烷基)2、-NHS(＝O)2(C1-6烷基)、3-7元碳环基、3-7元杂环基、苯基或5-10元杂芳基的取代基取代；所述杂环基或杂芳基在每次出现时独立地包括一个或多个选自N、O或S的杂原子；
    当A选自
    其中，Y1、Y2、Y3和Y4各自独立地为CR8或N，且每个R8独立地为-H、卤素、-O-(C1-6烷基)、-CN或-C1-6卤代烷基。
  3. 根据权利要求1-2中任一项所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，
    R1、R2、R3、R4和R5各自独立地为-H、-F、-Cl、-Br或-CF3。
  4. 根据权利要求1-3中任一项所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，
    R1为-CF3、R2为-F、R3为-F、R4为-H且R5为-H，或
    R1为-CF3、R2为-F、R3为-H、R4为-H且R5为-H，或
    R1为-CF3、R2为-F、R3为-H、R4为-F且R5为-H，或
    R1为-CF3、R2为-H、R3为-F、R4为-F且R5为-H，或
    R1为-CF3、R2为-H、R3为-H、R4为-H且R5为-F，或
    R1为-CF3、R2为-H、R3为-F、R4为-H且R5为-H，或
    R1为-CF3、R2为-H、R3为-H、R4为-Cl且R5为-H，或
    R1为-CF3、R2为-Cl、R3为-H、R4为-H且R5为-H，或
    R1为-H、R2为-CF3、R3为-H、R4为-CF3且R5为-H，或
    R1为-Cl、R2为-H、R3为-H、R4为-F且R5为-H，或
    R1为-Cl、R2为-F、R3为-H、R4为-H且R5为-H，或
    R1为-CF3、R2为-H、R3为-H、R4为-F且R5为-H。
  5. 根据权利要求1-4中任一项所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，
    R1为-CF3、R2为-F、R3为-F、R4为-H且R5为-H，或
    R1为-CF3、R2为-F、R3为-H、R4为-H且R5为-H。
  6. 根据权利要求1-4中任一项所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，式(I)的化合物为如下任一式：
  7. 根据权利要求1-6中任一项所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，
    A为
    n为0或1；
    当n为0时，Y1和Y3各自为-CH2-，以及Y2是-NR9-；
    当n为1时，Y1、Y2和Y4各自为-CH2-，以及Y3是-NR9-；或Y1、Y3和Y4各自为-CH2-，以及Y2是-NR9-；
    R7是-H、-C1-4烷基或-(氧杂环丁烷)基；
    所述R9是-H、-CN、-C1-6烷基、-C1-6卤代烷基、-C3-6环烷基、-(C1-4亚烷基)-(C3-6环烷基)、-C3-6杂环基、-(C1-4亚烷基)-(C3-6杂环基)、-(C1-6亚烷基)-O(C1-3烷基)、-(C1-6亚烷基)-CF3、-C(O)-(C1-6烷基)、-C(O)2-(C1-6烷基)、-C(O)-NH2、-CH2C(O)-NH2、-C(O)-C(O)-NH2、-C(O)-CH(C1-6亚烷基)-C(O)-NH2、-CH2C(O)-NH(C1-3烷基)、-CH2C(O)-N(C1-3烷基)2、-C(O)-NH(C1-3烷基)、-C(O)-N(C1-3烷基)2、-C(O)NH-(C1-6烷基)、-C(O)-(C1-6卤代烷基)、-C(O)-(C1-6烷氧基)、-C(O)-(C1-6亚烷基)-(OC1-6烷基)、-C(O)-(C6芳基)、-C(O)-(C6杂芳基)、-C(O)-(C6杂环基)、-(C1-6亚烷基)-CO2H、-(C1-6亚烷基)-CO2(C1-6烷基)、-SO2-(C1-6烷基)、氧杂环丁烷基或
  8. 式(I)的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，
    其中，
    R1、R2、R3、R4和R5各自独立地为-H、-卤素、-CF3或-C1-4烷基；其中，R1、R2、R3、R4或R5中的至少两个不为H；其中，A选自
    R7和R9的定义同权利要求1或2。
  9. 根据权利要求8所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，
    R1、R2、R3、R4和R5各自独立地为-H、-F、-Cl、-Br或-CF3。
  10. 根据权利要求8或9所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，
    R1为-CF3、R2为-F、R3为-F、R4为-H且R5为-H，或
    R1为-CF3、R2为-F、R3为-H、R4为-H且R5为-H，或
    R1为-CF3、R2为-F、R3为-H、R4为-F且R5为-H，或
    R1为-CF3、R2为-H、R3为-F、R4为-F且R5为-H，或
    R1为-CF3、R2为-H、R3为-H、R4为-H且R5为-F，或
    R1为-CF3、R2为-H、R3为-F、R4为-H且R5为-H，或
    R1为-CF3、R2为-H、R3为-H、R4为-Cl且R5为-H，或
    R1为-CF3、R2为-Cl、R3为-H、R4为-H且R5为-H，或
    R1为-H、R2为-CF3、R3为-H、R4为-CF3且R5为-H，或
    R1为-Cl、R2为-H、R3为-H、R4为-F且R5为-H，或
    R1为-Cl、R2为-F、R3为-H、R4为-H且R5为-H。
  11. 根据权利要求1-10中任一项所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，
    R9为-H、-CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2、-C(CH3)3、-CH2CH(CH3)2、-CH2C(CH3)3、-CH2CF3、-CH2CH2CF3、-CH2OCH3、-CH2CH2OCH3、-SO2-CH3、-C(O)-CH3、-C(O)-CH2CH3、-C(O)-CH2CH2CH3、-C(O)-CH(CH3)2、-C(O)-CH2CH(CH3)2、-C(O)-C(CH3)3、-C(O)-OCH3、-C(O)-NHCH3、-C(O)-CH2OCH3、-C(O)-CH2OCH2CH3、-C(O)-CH2OCH(CH3)2、-C(O)-CH2CH2OCH3、-C(O)-CH2CH2OCH2CH3、-C(O)-CH2CH2OCH(CH3)2、-C(O)-CH2CF3、-C(O)-CH2Cl、-C(O)-CH2F、-C(O)-CH2CH2OCH3、-C(O)-CH2CH2CF3、-C(O)-CH2CH2Cl、-C(O)-CH2CH2F、
  12. 根据权利要求1或2中所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，
    A为
    其中，
    Y1、Y2、Y3和Y4各自独立地为CR8或N，
    R8在每次出现时独立地为-H、卤素、-OCH3、-CN或-CF3。
  13. 根据权利要求12所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，
    A为
  14. 根据权利要求1或2所述的化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，
    A为
  15. 一种化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，所述化合物为如下任一式：


  16. 一种化合物、其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐，其中，所述化合物为如下任一式：
  17. 一种药物组合物，包括权利要求1至16中任一项所述的化合物，其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐；和至少一种药学上可接受的赋形剂。
  18. 一种权利要求1至16中任一项所述的化合物，其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐；或权利要求17所述的药物组合物在制备治疗与RBP4的血清浓度相关的视网膜中过量累积脂褐质的疾病的药物中的用途。
  19. 根据权利要求18所述的用途，其中，所述视网膜中过量累积脂褐质的疾病为双视黄酸介导的黄斑变性，包括与年龄相关性黄斑变性、干性年龄相关性黄斑变性、斯特格氏病、Best病、成人卵黄样黄斑病变或类似斯特格氏病的黄斑营养不良；所述双视黄酸是A2E、isoA2E、A2-DHP-PE或atRALdi-PE。
  20. 一种治疗与RBP4的血清浓度相关的视网膜中过量累积脂褐质的疾病的受试者的方法，所述方法包括给予该受试者治疗有效量的权利要求1至16中任一项所述的化合物，其立体异构体、其氘代衍生物、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其氘代衍生物的可接受的盐；或权利要求17所述的药物组合物。
  21. 根据权利要求20所述的方法，其中，所述视网膜中过量累积脂褐质的疾病为双视黄酸介导的黄斑变性，包括与年龄相关性黄斑变性、干性年龄相关性黄斑变性、斯特格氏病、Best病、成人卵黄样黄斑病变或类似斯特格氏病的黄斑营养不良；所述双视黄酸是A2E、isoA2E、A2-DHP-PE或atRALdi-PE。
PCT/CN2024/133816 2023-11-24 2024-11-22 一种降低rbp4的血清浓度的化合物及用途 Pending WO2025108420A1 (zh)

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