A compound for reducing serum concentration of rbp4 and use

Abstract

The present application relates to a compound for reducing serum concentration of RBP4, a stereoisomer, a deuterated derivative, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of a stereoisomer or an acceptable salt of a deuterated derivative, and a method for preparing the compound, a composition and use thereof.

Description

A compound for reducing serum concentration of RBP4 and its use

[0001] This application claims the prior application No. PCT / CN2023 / 133891, filed on November 24, 2023, entitled “A compound for reducing the serum concentration of RBP4 and its use”, the prior application No. PCT / CN2023 / 134874, filed on November 29, 2023, entitled “A compound for reducing the serum concentration of RBP4 and its use”, the prior application No. PCT / CN2023 / 141113, filed on December 22, 2023, entitled “A compound for reducing the serum concentration of RBP4 and its use”, the prior application No. PCT / CN2023 / 143407, filed on December 29, 2023, entitled “A compound for reducing the serum concentration of RBP4 and its use”, the prior application No. PCT / CN2023 / 143408, filed on January 24, 2024, entitled “A compound for reducing the serum concentration of RBP4 and its use” The present invention claims priority from the prior application No. PCT / CN2024 / 070370 filed on March 3, 2024, with the International Bureau application number PCT / CN2024 / 070370, entitled “A compound for reducing the serum concentration of RBP4 and its use”, the prior application No. PCT / CN2024 / 080774 filed on March 8, 2024, with the invention number PCT / CN2024 / 080774, entitled “A compound for reducing the serum concentration of RBP4 and its use”, the prior application No. PCT / CN2024 / 098922 filed on June 13, 2024, with the invention number PCT / CN2024 / 124934 filed on October 15, 2024, with the invention number PCT / CN2024 / 124934, entitled “A compound for reducing the serum concentration of RBP4 and its use”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] 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. Background Art

[0003] Retinol-binding protein 4 (RBP4) is the only plasma transporter that transports vitamin A from the liver to peripheral tissues. Because 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).

[0004] Multiple studies have elucidated the role of RBP4 in the pathogenesis of cardiovascular disease (CVD), obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and insulin resistance in type 2 diabetes mellitus (T2DM) (see N. Engl. J. Med., 354 (2006), pp. 2552-2563; Adv. Nutr., 6 (2015), pp. 748-762; Nature, 436 (2005), pp. 356-362; Circulation, 127 (2013), pp. 1938-1947; Lipid Health Dis., 16 (2017), p. 180).

[0005] RBP4 is also believed to be involved in the development 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 (2018), 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). In the treatment of the above diseases, studies have been conducted to reduce the expression of RBP4 by directly antagonizing or inhibiting its level.

[0006] Although RBP4 is primarily synthesized in the liver, with approximately 20% synthesized in adipose tissue (see J. Lipid Res., 30 (1989), pp. 171-180), it has been recognized as a biomarker for insulin resistance and metabolism. RBP4 is known as an adipokine involved in energy metabolism, insulin signaling, 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; Diabetologia, 59 (2016), pp. 354-362). In addition to its role as a selective retinol transporter, a recent study has shown that RBP4 is also involved in fatty acid transport (see Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 1863 (2018), pp. 458-466). In addition, many studies have reported that RBP4 levels are elevated 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).

[0007] Research is also exploring the role of RBP4 in atrophic (dry) AMD and STGD. AMD and STGD are slowly progressive neurodegenerative diseases that can lead to blindness. Excessive accumulation of lipofuscin in the retinal pigment epithelium (RPE) is considered to be the cause of these diseases. Elevated lipofuscin levels inhibit the normal function of the RPE, thereby promoting its degeneration. The lack of RPE metabolic support subsequently leads to photoreceptor death (see Exp. Eye Res., 80 (2005), pp. 595-606; Faseb. J., 18 (2004), pp. 562-564). Therefore, in order to prolong RPE effects and photoreceptor lifespan, the concentration of lipofuscin should be reduced. Lipofuscin toxicity is mainly mediated by A2E, one of its diretinol components.

[0008] Therefore, the reduction of RBP4 levels will affect the expression of specific genes and subsequent biological functions. A recent paper discussed the biological functions of RBP4 and its pathological relevance in human diseases (see Front. Physiol., 12 (2021), p. 659977). There is also a need to develop compounds with excellent RBP4-lowering effects. Summary of the Invention

[0009] In one aspect, the present application provides a compound for reducing the serum concentration of RBP4. Specific examples are as follows:

[0010] In a first aspect, 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,

[0011] in,

[0012] R1, R2, R3, R4 and R5 are each independently -H, -halogen, -CF3 or -C 1-4 Alkyl; wherein at least two of R1, R2, R3, R4 or R5 are not H;

[0013] A is

[0014] α, β, χ, and δ are each independently absent or present, and when present each is a bond;

[0015] X is C or N;

[0016] Z1 is N;

[0017] Z2 is O, S, N or NR7,

[0018] R7 is -H, -C 1-4 Alkyl or -(oxetane) group;

[0019] Q is a substituted or unsubstituted heterobicyclic ring; preferably, Q is a substituted or unsubstituted 5-, 6-, or 7-membered ring structure.

[0020] In some embodiments, R1, R2, R3, R4 and R5 are each independently -H, -F, -Cl, -Br or -CF3.

[0021] In some embodiments of the present application, among the compounds described in the first aspect of the present application, their stereoisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts of their stereoisomers, or their acceptable salts of their deuterated derivatives,

[0022] R1 is -CF3, R2 is -F, R3 is -F, R4 is -H and R5 is -H, or

[0023] R1 is -CF3, R2 is -F, R3 is -H, R4 is -H and R5 is -H, or

[0024] R1 is -CF3, R2 is -F, R3 is -H, R4 is -F and R5 is -H, or

[0025] R1 is -CF3, R2 is -H, R3 is -F, R4 is -F and R5 is -H, or

[0026] R1 is -CF3, R2 is -H, R3 is -H, R4 is -H and R5 is -F, or

[0027] R1 is -CF3, R2 is -H, R3 is -F, R4 is -H and R5 is -H, or

[0028] R1 is -CF3, R2 is -H, R3 is -H, R4 is -Cl and R5 is -H, or

[0029] R1 is -CF3, R2 is -Cl, R3 is -H, R4 is -H and R5 is -H, or

[0030] R1 is -H, R2 is -CF3, R3 is -H, R4 is -CF3 and R5 is -H, or

[0031] R1 is -Cl, R2 is -H, R3 is -H, R4 is -F and R5 is -H, or

[0032] R1 is -Cl, R2 is -F, R3 is -H, R4 is -H, and R5 is -H.

[0033] In some embodiments of the present application, among the compounds described in the first aspect of the present application, their stereoisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts of their stereoisomers, or their acceptable salts of their deuterated derivatives,

[0034] R1 is -CF3, R2 is -F, R3 is -F, R4 is -H and R5 is -H, or

[0035] R1 is -CF3, R2 is -F, R3 is -H, R4 is -H and R5 is -H.

[0036] In some embodiments of the present application, among the compounds described in the first aspect of the present application, their stereoisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts of their stereoisomers, or their acceptable salts of their deuterated derivatives,

[0037] In some embodiments of the present application, among the compounds described in the first aspect of the present application, their stereoisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts of their stereoisomers, or their acceptable salts of their deuterated derivatives,

[0038] A is

[0039] wherein when α is present, then Z1 and Z2 are N, X is N, β is present, and χ and δ are not present; and

[0040] When α is absent, then Z1 is N, Z2 is NR7, X is C, β and δ are present, and χ is absent.

[0041] In some embodiments of the present application, among the compounds described in the first aspect of the present application, their stereoisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts of their stereoisomers, or their acceptable salts of their deuterated derivatives,

[0042] A is

[0043] n is an integer from 0 to 2;

[0044] R7 is -H, -C 1-4 Alkyl or -(oxetane) group;

[0045] α, β, χ, δ, ε, and κ are each independently absent or present, and when present are each a bond;

[0046] Z1 is N;

[0047] Z2 is O, S, N or NR7,

[0048] X is C or N; and

[0049] Y1, Y2, Y3 and each occurrence of Y4 are each independently CR8, CH2 or NR9;

[0050] in,

[0051] R8 is -H, halogen, -OCH3, -CN or -CF3; and

[0052] R9 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 Heterocyclic), -(C 1-4 alkylene)-(C 3-6 Heterocyclic), -(C 1-6 Alkylene)-O(C 1-3 Alkyl), -(C 1-6 Alkylene)-CF3, -C(O)-(C 1-6 alkyl), -C(O)2-(C 1-6 alkyl), -C(O)-NH2, -C(O)-NH(C 1-3alkyl), -C(O)-N(C 1-3 Alkyl)2, -C(O)NH-(C 1-6 alkyl), -C(O)-(C 1-6 Halogenated alkyl), -C(O)-(C 1-6 Alkoxy), -C(O)-(C 1-6 Alkylene)-(OC 1-6 alkyl), -C(O)-(C6 aryl), -C(O)-(C6 heteroaryl), -C(O)-(C6 heterocyclyl), -(C 1-6 Alkylene)-CO2H, -(C1 -6 Alkylene)-CO2(C 1-6 Alkyl) or -SO2-(C 1-6 alkyl).

[0053] The second aspect of the present application provides a compound of formula (I), its stereoisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers or its deuterated derivatives,

[0054] in,

[0055] R1, R2, R3, R4 and R5 are each independently -H, -halogen, -CF3 or -C 1-4 Alkyl; wherein at least two of R1, R2, R3, R4 or R5 are not H;

[0056] A is selected from

[0057] Among them, R7 is -H, -C 1-4 Alkyl or -(oxetane) group;

[0058] When A is selected from hour:

[0059] Where n is 0, 1 or 2;

[0060] Y1, Y2 and Y4 are each -CH2-, and Y3 is -NR9-; or Y1, Y3 and Y4 are each -CH2-, and Y2 is -NR9-; or Y1, Y2 and Y4 are each -CH2-, and Y3 is -O- or -S(=O)2-; or Y1, Y3 and Y4 are each -CH2-, and Y2 is -O- or -S(=O)2-;

[0061] R9 is selected from hydrogen, -C 1-6 Alkyl, -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C1-6 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, 5-10 membered heteroaryl; said R9 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, -NH2, -COOH, -NH(C 1-6 alkyl), -N(C1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -O(C 1-6 deuterated alkyl), -SH, -S(C 1-6 alkyl), =O, -C(=O)(C 1-6 alkyl), -C(=O)(C 1-6 Alkoxy), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)NH2, -C(=O)-C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -C(=O)O(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -C(=O)-phenyl, -C(=O)-5-10 membered heteroaryl, -C(=O)-3-7 membered heterocyclyl, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl or 5-10 membered heteroaryl; said heterocyclyl or heteroaryl independently including one or more heteroatoms selected from N, O or S at each occurrence;

[0062] When A is selected from

[0063] wherein Y1, Y2, Y3 and Y4 are each independently CR8 or N, and each R8 is independently -H, halogen, -C 1-6 Alkyl, -C(=O)NH2, -C(=O)NH(C1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -COOH, -NHC(=O)N(C 1-6 Alkyl)2, -S(=O)2NH(C 1-6 Alkyl), -O-(C 1-6 alkyl), -CN or -C 1-6 alkyl halide;

[0064] When A is selected from

[0065] wherein Z2 is selected from -O-, Z3 is selected from -C(CH3)2-, and Z1 and Z4 are selected from -CH2-; or, Z2 and Z3 are each independently selected from -C(O)-, -N(CH3)- or -NH-, and Z1 and Z4 are selected from -CH2-;

[0066] R 10 Selected from hydrogen or -CH3;

[0067] When A is selected from

[0068] wherein Z5, Z6, Z7 and Z8 are each independently selected from CR 12 or N, R 12 Each independently selected from hydrogen, F, Cl, -CN or -OCH3;

[0069] R 11 Selected from hydrogen, -CH3, -CH2CH3, or -CH(CH3)2;

[0070] When A is selected from

[0071] Wherein, W1, W2, W3 and W4 are each independently selected from -CH2-, -O-, -NH-, -N(CH3)- or

[0072] When A is selected from

[0073] wherein U1 is selected from O or S, and U2 is selected from N;

[0074] When A is selected from

[0075] wherein U5 is selected from N, U6 is selected from O or S; or, U5 is selected from CH, U6 is selected from NH;

[0076] When A is selected from

[0077] wherein U3 is selected from N or CH;

[0078] R 16 Selected from Cl;

[0079] p is selected from 0 or 1;

[0080] When A is selected from

[0081] wherein U4 is selected from N or CH;

[0082] R 13 Selected from -CH3, -OCH3, F, Cl or -CF3;

[0083] q is selected from 0 or 1;

[0084] When A is selected from

[0085] Wherein, W6, W7, W8 and W9 are each independently selected from N or CR 15 ;

[0086] R 14 Selected from hydrogen or -CH3;

[0087] R 15 Each independently selected from hydrogen, F, Cl, -CH3, -OCH3,

[0088] 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.

[0089] Wherein, R1, R2, R3, R4 and R5 are each independently -H, -halogen, -CF3 or -C 1-4 Alkyl; wherein at least two of R1, R2, R3, R4 or R5 are not H;

[0090] A is selected from

[0091] Wherein, R7 is -H, -C 1-4 Alkyl or -(oxetane) group;

[0092] When A is selected from hour:

[0093] n is 0, 1 or 2, preferably 0 or 1; Y1, Y2 and Y4 are each -CH2-, and Y3 is -NR9-; or

[0094] Y1, Y3 and Y4 are each -CH2-, and Y2 is -NR9-;

[0095] R9 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 R9 is optionally replaced by 1, 2, 3, 4, 5 or 6 members selected from -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 1-6 Alkynyl, -C 1-6 Haloalkyl, -C 1-6 Alkoxy, -CN, -NH2, -COOH, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -C(=O)O(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl or 5-10 membered heteroaryl; said heterocyclyl or heteroaryl independently includes one or more heteroatoms selected from N, O or S at each occurrence;

[0096] When A is selected from

[0097] in,

[0098] Y1, Y2, Y3 and Y4 are each independently CR8 or N, and

[0099] Each R8 is independently -H, halogen, -O-(C 1-3 alkyl), -CN or -C 1-3 Halogenated alkyl.

[0100] In some embodiments, 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,

[0101] R1, R2, R3, R4 and R5 are each independently -H, -F, -Cl, -Br or -CF3; the definitions of other groups are as defined in the second aspect or the third aspect of this application.

[0102] In some embodiments, 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,

[0103] R1 is -CF3, R2 is -F, R3 is -F, R4 is -H and R5 is -H, or

[0104] R1 is -CF3, R2 is -F, R3 is -H, R4 is -H and R5 is -H, or

[0105] R1 is -CF3, R2 is -F, R3 is -H, R4 is -F and R5 is -H, or

[0106] R1 is -CF3, R2 is -H, R3 is -F, R4 is -F and R5 is -H, or

[0107] R1 is -CF3, R2 is -H, R3 is -H, R4 is -H and R5 is -F, or

[0108] R1 is -CF3, R2 is -H, R3 is -F, R4 is -H and R5 is -H, or

[0109] R1 is -CF3, R2 is -H, R3 is -H, R4 is -Cl and R5 is -H, or

[0110] R1 is -CF3, R2 is -Cl, R3 is -H, R4 is -H and R5 is -H, or

[0111] R1 is -H, R2 is -CF3, R3 is -H, R4 is -CF3 and R5 is -H, or

[0112] R1 is -Cl, R2 is -H, R3 is -H, R4 is -F and R5 is -H, or

[0113] R1 is -Cl, R2 is -F, R3 is -H, R4 is -H and R5 is -H, or

[0114] R1 is -CF3, R2 is -H, R3 is -H, R4 is -F and R5 is -H; the definitions of other groups are as defined in the second aspect or the third aspect of the present application.

[0115] In some embodiments, 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,

[0116] R1 is -CF3, R2 is -F, R3 is -F, R4 is -H and R5 is -H, or

[0117] R1 is -CF3, R2 is -F, R3 is -H, R4 is -H and R5 is -H; the definitions of other groups are as defined in the second aspect or the third aspect of the present application.

[0118] In some embodiments, 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, is any of the following formulas:

[0119] The definitions of other groups are the same as those in the second or third aspect of the present application.

[0120] In some embodiments, 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,

[0121] A is selected from n is 0 or 1, and

[0122] When n is 0, Y1 and Y3 are each -CH2-, and Y2 is -NR9-;

[0123] When n is 1, Y1, Y2 and Y4 are each -CH2-, and Y3 is -NR9-; or Y1, Y3 and Y4 are each -CH2-, and Y2 is -NR9-; R9 is selected from hydrogen, -C 1-6 Alkyl, -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6alkyl), -S(=O)2(C 1-6 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, 5-10 membered heteroaryl; said R9 is optionally replaced 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, -NH2, -COOH, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), -C(=O)(C 1-3 alkyl), -S(=O)(C 1-3 alkyl), -S(=O)2(C 1-3 alkyl), -C(=O)NH2, -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl)2, -NHC(=O)(C 1-3 alkyl), -C(=O)O(C 1-3 alkyl), -C(=O)-(C 1-3 Alkylene)-(OC 1-3 alkyl), -OC(=O)(C 1-3 alkyl), -S(=O)NH2, -S(=O)NH(C 1-3 alkyl), -S(=O)N(C 1-3 Alkyl)2, -NHS(=O)(C 1-3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-3 alkyl), -S(=O)2N(C 1-3 alkyl)2, -NHS(=O)2(C 1-3 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl or 5-10 membered heteroaryl; said heterocyclyl or heteroaryl independently includes one or more heteroatoms selected from N, O or S at each occurrence; said R9 is preferably -H, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-6 Cycloalkyl, -(C1 -4 alkylene)-(C 3-6 Cycloalkyl), -C 3-6 Heterocyclic group, -(C 1-4 alkylene)-(C 3-6 Heterocyclic), -(C 1-6Alkylene)-O(C 1-3 Alkyl), -(C 1-6 Alkylene)-CF3, -C(O)-(C 1-6 alkyl), -C(O)2-(C 1-6 alkyl), -C(O)-NH2, -CH2C(O)-NH2, -C(O)-C(O)-NH2, -C(O)-CH(C 1-6 Alkylene)-C(O)-NH2, -CH2C(O)-NH(C 1-3 alkyl), -CH2C(O)-N(C 1-3 Alkyl)2, -C(O)-NH(C 1-3 alkyl), -C(O)-N(C 1-3 Alkyl)2, -C(O)NH-(C1 -6 alkyl), -C(O)-(C 1-6 Halogenated alkyl), -C(O)-(C 1-6 Alkoxy), -C(O)-(C 1-6 Alkylene)-(OC 1-6 alkyl), -C(O)-(C6 aryl), -C(O)-(C6 heteroaryl), -C(O)-(C6 heterocyclyl), -(C 1-6 Alkylene)-CO2H, -(C 1-6 Alkylene)-CO2(C 1-6 Alkyl), --SO2-(C 1-6 alkyl), oxetane or

[0124] R7 is -H, -C 1-4 Alkyl or -(oxetane) group.

[0125] In some embodiments, 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,

[0126] A is

[0127] in,

[0128] n is 0;

[0129] R7 is -H, -C 1-4 Alkyl or -(oxetane) group;

[0130] Y1 and Y3 are each -CH2-, and Y2 is -NR9-;

[0131] R9 is -H, -CN, -C1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-6 Cycloalkyl, -(C 1-4 alkylene)-(C 3-6 Cycloalkyl), -(C 1-4 alkylene)-(C 3-6 Heterocyclic), -(C 1-6 Alkylene)-O(C 1-3 Alkyl), -(C 1-6 Alkylene)-CF3, -C(O)-(C 1-6 alkyl), -C(O)2-(C 1-6 alkyl), -C(O)-NH2, -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 Halogenated alkyl), -C(O)-(C 1-6 Alkoxy), -C(=O)-(C 1-6 Alkylene)-(OC 1-3 alkyl), -C(O)-(C6 aryl), -C(O)-(C6 heteroaryl), -C(O)-(C6 heterocyclyl), -(C 1-6 Alkylene)-CO2H, -(C 1-6 Alkylene)-CO2(C 1-6 Alkyl) or -SO2-(C 1-6 alkyl).

[0132] In some embodiments, 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,

[0133] A is

[0134] in,

[0135] n is 1;

[0136] R7 is -H, -C 1-4 Alkyl or -(oxetane) group;

[0137] Y1, Y2 and Y4 are each -CH2-, and Y3 is -NR9-;

[0138] R9 is -H, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-6 Cycloalkyl, -(C1-4 alkylene)-(C 3-6 Cycloalkyl), -(C 3-6 Heterocyclic), -(C1 -4 alkylene)-(C 3-6 Heterocyclic), -(C 1-6 Alkylene)-O(C 1-3 Alkyl), -(C 1-6 Alkylene)-CF3, -C(O)-(C 1-6 alkyl), -C(O)2-(C 1-6 alkyl), -C(O)-NH2, -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 Halogenated alkyl), -C(O)-(C 1-6 Alkoxy), -C(=O)-(C 1-6 Alkylene)-(OC 1-3 alkyl), -C(O)-(C6 aryl), -C(O)-(C6 heteroaryl), -C(O)-(C6 heterocyclyl), -(C 1-6 Alkylene)-CO2H, -(C1 -6 Alkylene)-CO2(C 1-6 Alkyl) or -SO2-(C 1-6 alkyl).

[0139] In some embodiments, 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,

[0140] A is

[0141] in,

[0142] n is 1;

[0143] R7 is -H, -C 1-4 Alkyl or -(oxetane) group;

[0144] Y1, Y3 and Y4 are each -CH2-, and Y2 is -NR9-;

[0145] R9 is -H, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-6 Cycloalkyl, -(C 1-4 alkylene)-(C 3-6Cycloalkyl), -(C 3-6 Heterocyclic), -(C1 -4 alkylene)-(C 3-6 Heterocyclic), -(C 1-6 Alkylene)-O(C 1-3 Alkyl), -(C 1-6 Alkylene)-CF3, -C(O)-(C 1-6 alkyl), -C(O)2-(C 1-6 alkyl), -C(O)-NH2, -CH2C(O)-NH2, -C(O)-C(O)-NH2, -C(O)-CH(C 1-6 Alkylene)-C(O)-NH2, -CH2C(O)-NH(C 1-3 alkyl), -CH2C(O)-N(C 1-3 Alkyl)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 Halogenated alkyl), -C(O)-(C 1-6 Alkoxy), -C(=O)-(C 1-6 Alkylene)-(OC 1-3 alkyl), -C(O)-(C6 aryl), -C(O)-(C6 heteroaryl), -C(O)-(C6 heterocyclyl), -(C 1-6 Alkylene)-CO2H, -(C 1-6 Alkylene)-CO2(C 1-6 alkyl), -SO2-(C 1-6 alkyl) or

[0146] 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:

[0147] R1, R2, R3, R4 and R5 are each independently -H, -halogen, -CF3 or -C 1-4 Alkyl; wherein at least two of R1, R2, R3, R4 or R5 are not H;

[0148] A is selected from

[0149] The definitions of R7 and R9 are the same as those in the second aspect or the third aspect of the present application.

[0150] In some embodiments, 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,

[0151] R1, R2, R3, R4 and R5 are each independently -H, -F, -Cl, -Br or -CF3; the definitions of other groups are as defined in the second aspect or the third aspect of this application.

[0152] In some embodiments, 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,

[0153] R1 is -CF3, R2 is -F, R3 is -F, R4 is -H and R5 is -H, or

[0154] R1 is -CF3, R2 is -F, R3 is -H, R4 is -H and R5 is -H, or

[0155] R1 is -CF3, R2 is -F, R3 is -H, R4 is -F and R5 is -H, or

[0156] R1 is -CF3, R2 is -H, R3 is -F, R4 is -F and R5 is -H, or

[0157] R1 is -CF3, R2 is -H, R3 is -H, R4 is -H and R5 is -F, or

[0158] R1 is -CF3, R2 is -H, R3 is -F, R4 is -H and R5 is -H, or

[0159] R1 is -CF3, R2 is -H, R3 is -H, R4 is -Cl and R5 is -H, or

[0160] R1 is -CF3, R2 is -Cl, R3 is -H, R4 is -H and R5 is -H, or

[0161] R1 is -H, R2 is -CF3, R3 is -H, R4 is -CF3 and R5 is -H, or

[0162] R1 is -Cl, R2 is -H, R3 is -H, R4 is -F and R5 is -H, or

[0163] R1 is -Cl, R2 is -F, R3 is -H, R4 is -H and R5 is -H; the definitions of other groups are as defined in the second aspect or the third aspect of the present application.

[0164] In some embodiments, 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,

[0165] 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, -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,

[0166] In some embodiments, in the compound described in the second, third or fourth aspect of the present application, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its acceptable salt of the deuterated derivative, 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,

[0167] In some embodiments, in the compound described in the second, third or fourth aspect of the present application, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its acceptable salt of the deuterated derivative, R9 is -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,

[0168] In some embodiments, in the compound described in the second, third or fourth aspects of the present application, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer or its acceptable salt of the deuterated derivative, 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)-C H2OCH3, -C(O)-CH2OCH2CH3, -C(O)-CH2OCH(CH3)2, -C(O)-CH2CF3, -C(O)-CH2Cl, -C(O)-CH2F, -C(O)-CH2CH2 OCH3, -C(O)-CH2CH2OCH2CH3, -C(O)-CH2CH2OCH(CH3)2, -C(O)-CH2CH2CF3, -C(O)-CH2CH2Cl, -C(O)-CH2CH2F,

[0169] In some embodiments, 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,

[0170] R7 is -H, -CH3, -CH2CH3, -CH(CH3)2 or

[0171] In some embodiments, 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,

[0172] A is

[0173] in,

[0174] Y1, Y2, Y3 and Y4 are each independently CR8 or N,

[0175] R8, at each occurrence, is independently -H, halogen, -OCH3, -CN or -CF3.

[0176] In some embodiments, 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,

[0177] A is

[0178] In some embodiments, in 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 its stereoisomer or its deuterated derivative, A is

[0179] 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:

[0180] 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:

[0181] 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:

[0182] In an eighth aspect, 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:

[0183] 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:

[0184] On the other hand, the present application provides a pharmaceutical composition comprising a compound 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.

[0185] On the other hand, the present application provides a compound described in any of the above 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 use of the pharmaceutical composition described herein in the preparation of a medicament for treating a disease in which lipofuscin accumulates excessively in the retina and is associated with the serum concentration of RBP4; 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, or atRALdi-PE.

[0186] In another aspect, 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 according to 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 according to 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, or atRALdi-PE.

[0187] On the other hand, the present application provides a compound described in any of the above 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 treating a disease in which lipofuscin accumulates excessively in the retina and is associated with the serum concentration of RBP4; 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, or atRALdi-PE.

[0188] definition

[0189] Unless otherwise indicated, the term "halogen" is used interchangeably herein to refer to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include -F, -Cl, and -Br.

[0190] Unless otherwise indicated, the term "alkyl" as used herein includes saturated monovalent hydrocarbon groups having straight or branched chains. For example, 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. Similarly, C 1-6 C in the alkyl group 1-6 It is defined to identify a group having a straight or branched chain arrangement of 1, 2, 3, 4, 5 or 6 carbon atoms.

[0191] Unless otherwise indicated, the term "haloalkyl" as used herein refers to an alkyl group substituted with one or more (1, 2, 3, 4, 5 or 6) halogens (-F, -Cl or -Br). In some embodiments, a haloalkyl group is an interchangeable -C 1-6 Halogenated alkyl or halogenated C 1-6 Alkyl, where -C 1-6 Halogenated alkyl or halogenated C 1-6 C in the alkyl group 1-6 In some embodiments, -C 1-6 Haloalkyl is -C 1-3 In some embodiments, -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 -CF3.

[0192] The term "alkylene" refers to a difunctional group obtained by removing an additional hydrogen atom from an alkyl group as defined above. For example, methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)- or -CH2-CH(CH3)-).

[0193] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds, typically 2 to 20 carbon atoms in length. For example, "-C 2-6 "Alkenyl" contains 2 to 6 carbon atoms. For example, alkenyl includes, but is not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0194] The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds, typically 2 to 20 carbon atoms in length. For example, "-C 2-6 The term "alkynyl" refers to a group containing 2 to 6 carbon atoms. For example, representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0195] The term "alkoxy" refers to oxygen ethers formed from the aforementioned alkyl groups, including but not limited to -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CH2OCH3, -CH2CH2OCH3.

[0196] Unless otherwise indicated, the term "haloalkoxy" as used herein refers to an alkoxy group substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In certain embodiments, a haloalkoxy group is interchangeably -C 1-6 Haloalkoxy or halogenated C 1-6 Alkoxy, wherein -C 1-6 Halogenated alkoxy or halogenated C 1-6 C in alkoxy 1-6 Indicates that the total carbon atoms of the alkoxy group are 1 to 6. In certain embodiments, -C 1-6 Haloalkoxy is -C 1-3 In certain embodiments, -C 1-6 Haloalkoxy is substituted by 1, 2, 3, 4, 5 or 6 -F (methoxy, ethoxy, propoxy or isopropoxy); preferably -C 1-3 Haloalkoxy is -OCF3.

[0197] Unless otherwise indicated, the term "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.

[0198] Unless otherwise indicated, the term "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. Preferably, the heterocycle is a three- to ten-membered ring that is fully saturated or has one or more degrees of unsaturation. The present definition of heterocycle includes multiple degrees of substitution (preferably one, two, or three degrees of substitution). Examples of such 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.

[0199] Unless otherwise indicated, the term "heteroaryl" as used herein refers to an aromatic ring system containing carbon and at least one heteroatom. A heteroaryl or heteroaromatic ring can be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl can have 1 to 4 heteroatoms in its ring, while a polycyclic heteroaryl can contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings can contain fused rings, spirocycles, or bridged rings. For example, a bicyclic heteroaryl is a polycyclic heteroaryl. A bicyclic heteroaryl ring can contain 8 to 12 atoms. A monocyclic heteroaryl ring can contain 5 to 8 atoms (carbon atoms and heteroatoms). Examples of 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.

[0200] The term "carbocyclyl" refers to a substituted or unsubstituted monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring system containing only carbon atoms. Preferably, 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, and the like.

[0201] The term "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.

[0202] In the present application, when a ring is substituted with one or more substituents, it means that each substituent can be substituted independently on each ring atom of the ring, including but not limited to a ring carbon atom or a ring nitrogen atom. In addition, when the ring is polycyclic, such as a fused ring, a bridged ring or a spiro ring, each substituent can be substituted independently on each ring atom of the polycyclic ring.

[0203] The term "oxo" refers to an oxygen atom and the carbon atom to which it is attached forming an group.

[0204] In this application, the term "composition" is intended to encompass a product comprising a specific amount of a specific ingredient, as well as any product produced directly or indirectly by a combination of a specific amount of a specific ingredient. Therefore, pharmaceutical compositions containing the present application compound as an active ingredient and methods for preparing the present application compound are also part of this application. Moreover, some crystalline forms of the compound may exist in the form of polymorphs and are therefore included in this application. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of this application.

[0205] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present application is acidic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic bases and organic bases. When the compound of the present application is basic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic acid, 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, and especially at least 98% pure (% by weight).

[0206] The present application includes within its scope prodrugs of the compounds of the present application. Typically, such 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" should include treating 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 in, for example, "Prodrug Design" ("Design of Prodrugs", ed. 25 H. Bundgaard, Elsevier, 1985).

[0207] The definition of 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 invention to provide chemically stable compounds that can be readily synthesized by techniques known in the art and the methods illustrated herein.

[0208] 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.

[0209] This 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 used to prepare 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.

[0210] The term "stereoisomer" as used herein refers to isomers resulting from differences in spatial arrangement of atoms or groups of atoms in a molecule in the same order of interconnection. This includes configurational isomers and conformational isomers. Configurational isomers further include geometric isomers and optical isomers. Optical isomers primarily include enantiomers and diastereomers. This application encompasses all possible stereoisomers of the compound.

[0211] Certain compounds provided herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about 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, enriched atropisomers of each, or nonspecific mixtures of each. If the barrier to rotation about a single bond is high enough and the interconversion between conformations is slow enough, separation of atropisomers may be permitted.

[0212] This application is intended to include all isotopes of atoms present in the compounds of this application. Isotopes are atoms having the same atomic number but different mass numbers. As a general example and not limitation, 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 commonly represented as D (deuterium) and T (tritium). In this application, CD3 represents a methyl group in which all hydrogen atoms are deuterium. Carbon isotopes include 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using an appropriate isotopically labeled reagent instead of a non-labeled reagent.

[0213] Unless otherwise indicated, the term "deuterated derivative" as used herein refers to a compound having the same chemical structure as a reference compound, but in which one or more hydrogen atoms have been 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 herein, although such variation is small and insignificant. Therefore, unless otherwise indicated, when referring to a "deuterated derivative" of a compound disclosed herein, at least one hydrogen has been replaced by deuterium at a level well above its natural isotopic abundance (typically about 0.015%). In some embodiments, the deuterated derivatives disclosed herein have an isotopic enrichment factor per deuterium atom 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).

[0214] When the compounds of the present application exist in tautomers, the present application includes any possible tautomers and pharmaceutically acceptable salts and mixtures thereof, unless otherwise specifically stated.

[0215] The pharmaceutical composition of the present application comprises a compound of the present application (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optional other therapeutic ingredients or adjuvants. Although the most suitable approach in any given case will depend on the specific host, and the nature and severity of the disease (the active ingredient is being applied for the treatment of the disease), the composition includes compositions suitable for oral, rectal, topical 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.

[0216] In practice, according to conventional pharmaceutical formulation techniques, the compound of the present application or its prodrug or metabolite or pharmaceutically acceptable salt can be combined as an active ingredient with a drug carrier and a drug carrier to form a close mixture. Depending on the formulation form required for the route of administration, for example, the carrier can take 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 ingredient. In addition, 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. In addition to the above-mentioned common dosage forms, 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. Typically, such methods include the step of combining the active ingredient with a carrier constituting one or more essential ingredients. Typically, 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.

[0217] Therefore, 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.

[0218] The pharmaceutical carrier used can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oil, alcohol, flavorings, preservatives, colorants, etc. can be used to form oral liquid preparations such as suspensions, elixirs, and solutions; while carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc. can be used to form oral solid preparations such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units due to their ease of administration, which utilize solid pharmaceutical carriers. Alternatively, tablets can be coated using standard aqueous or non-aqueous techniques.

[0219] Tablets containing the compositions 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, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation for oral administration to humans may contain from about 0.5 mg to about 5 g of the active agent mixed with an appropriate and convenient amount of carrier material, which may comprise from 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.

[0220] The pharmaceutical compositions of the present application suitable for parenteral administration can be prepared as solutions or suspensions 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 oils. In addition, preservatives can be included to prevent the harmful growth of microorganisms.

[0221] The pharmaceutical compositions of the present application suitable for injection include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for ease of injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, it is best to preserve it to prevent contamination by microorganisms such as bacteria and fungi. The carrier may 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 suitable mixtures thereof.

[0222] 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. In addition, the composition can be in a form suitable for transdermal devices. Utilizing the compound shown in the present application formula (I) or a pharmaceutically acceptable salt thereof, these preparations can be prepared by conventional processing methods. For example, a cream or ointment can be 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 the desired consistency.

[0223] The pharmaceutical composition of the present application can be a form suitable for rectal administration, wherein the carrier is a solid. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in this area. Suppositories can be formed easily by first mixing the composition with a softening or melting carrier, then cooling and molding in a mold.

[0224] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may suitably include one or more additional carrier components, such as diluents, buffers, flavorings, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other adjuvants may be included to make the preparation isotonic with the blood of the intended recipient. Compositions containing the compound or its pharmaceutically acceptable salt may also be prepared in the form of powders or liquid concentrates.

[0225] Generally, dosage levels of about 0.001 mg / kg to about 150 mg / kg of body weight per day are useful for treating the aforementioned conditions, or about 0.05 mg to about 7 g per patient per day. For example, dosages of about 0.001 to 50 mg of the compound per kg of body weight per day, or about 0.05 mg to about 3.5 g per kg of body weight per day, may be effective for treating age-related macular degeneration, dry (atrophic) age-related macular degeneration, Stargardt disease, Best disease, adult vitelliform maculopathy, or macular dystrophies similar to Stargardt disease. However, it should be understood that 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.

[0226] Unless the context indicates otherwise, when a value is expressed as "about X" or "approximately X", the specified value of X is to be understood to be accurate to ±10%, preferably ±5%, ±2%.

[0227] These and other aspects will become apparent from the following written description of the application. BRIEF DESCRIPTION OF THE DRAWINGS

[0228] The drawings described herein are used to provide further understanding of the present application and constitute a part of the present application. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute improper limitations on the present application.

[0229] FIG1 is a hydrogen NMR spectrum of compound 1 synthesized in Example 1 of the present application;

[0230] FIG2 is a graph showing the comparison of the RBP4 reduction rates of compound 17 of the present application and a control compound (at a dose of 1 mg / kg) at different time points;

[0231] FIG3 is a graph showing the comparison of the RBP4 reduction rates of the present compound 17 and the control compound (at a dose of 5 mg / kg) at different time points. DETAILED DESCRIPTION

[0232] The compounds of the present invention 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 skilled 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.

[0233] The following examples are provided to better illustrate the present application. Unless otherwise specified, all parts and percentages are by weight and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:

[0234] Example 1

[0235] 3,4-difluoro-2-trifluoromethyl-bromodiphenyl (835 mg, 3.2 mmol), Pd(PPh3)4 (370 mg, 0.32 mmol) and K2CO3 aqueous solution (2.6 mL, 2 M, 5.2 mmol) were added to 1,4-dioxane (dry solvent, 40 mL) of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (989 mg, 3.2 mmol). Under a nitrogen atmosphere, the resulting reaction mixture was stirred at 80 ° C overnight, quenched with water, and extracted with EtOAc. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by silica gel column chromatography (using V 石油醚 / V 乙酸乙酯 =20 / 1 elution) to obtain yellow liquid compound 1-1 (834.8 mg, 71.5% yield). LCMS: m / z=364.0 [M+H] + .

[0236] A solution of compound 1-1 (832 mg, 2.29 mmol) in HCl / 1,4-dioxane (32 mmol, 4 M, 8 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain the crude hydrochloride salt of compound 1-2, which was used directly in the next reaction without purification. LCMS: m / z = 264.4 [M+H] + .

[0237] At room temperature, EDCI (527 mg, 2.748 mmol), HOBt (371 mg, 2.748 mmol) and DIEA (1.2 mL, 6.87 mmol) were added to a solution of 6H-pyrazole [3, 4-C] 1,4,5,7-tetrahydropyridine-3,6-carboxylic acid 6- (1,1-dimethylethyl) ester (612 mg, 2.29 mmol) and the hydrochloride (2.29 mmol) of compound 1-2 in DMF (dry solvent, 20 mL). The resulting reaction mixture was stirred at room temperature overnight, quenched with water, and extracted with EtOAc. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by silica gel column chromatography (using V DCM / V MeOH=30 / 1 elution) to obtain a light yellow liquid compound 1-3 (793 mg, 67.5% yield). LCMS: m / z=513.3 [M+H] + .

[0238] A solution of compound 1-3 (789 mg, 1.54 mmol) in HCl / 1,4-dioxane (21.56 mmol, 4 M, 5.4 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain the crude hydrochloride salt of compound 1-4, which was used directly in the next reaction without purification. LCMS: m / z = 413.4 [M+H] + .

[0239] At 0 ° C, acetic anhydride (30 μL, 0.315 mmol) diluted with DCM (dry, 1 mL) was slowly added to a solution of the hydrochloride of compound 1-4 (0.35 mmol) and Et3N (0.15 mL, 1.05 mmol) in DCM (5 mL). The resulting reaction mixture was stirred at 0 ° C for 30 minutes, quenched with water, and extracted with EtOAc. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (using V DCM / V MeOH =20 / 1) to give a crude product. The crude product was purified by Prep-HPLC (C18 column, eluted with CH3CN / H2O) to give a white solid compound 1 (32.1 mg, 20.2% yield). LCMS: m / z = 455.3 [M+H] + FIG1 is a hydrogen NMR spectrum of compound 1 synthesized in Example 1 of the present application.

[0240] 1 H 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).

[0241] Example 2

[0242] 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(PPh3)4 (1.733 g, 1.5 mmol), and 12 mL of K2CO3 (2 M 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 Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc=20 / 1, volume ratio) to obtain the pure product compound 3-1 (4.5684 g, 88% yield) as a colorless liquid. LCMS: m / z=346.02[M+H] + .

[0243] Compound 3-1 (2.072 g, 6 mmol) was added to a reaction flask, and then 21 mL of HCl (84 mmol, 4 M solution in 1,4-dioxane) was slowly added to the reaction flask. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure to obtain a crude white solid, compound 3-2, which was used directly in the next step. LCMS: m / z = 246.30 [M+H] + .

[0244] 6H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylic acid (1.604 g, 6 mmol) and compound 3-2 (6 mmol) were weighed, anhydrous DMF (50 mL) was added to dissolve, followed by EDCI (1.382 g, 7.2 mmol), HOBt (973 mg, 7.2 mmol) and DIEA (3.1 mL, 18 mmol). The resulting mixture was stirred at room temperature overnight. The resulting mixture was then quenched with water and extracted with EtOAc. The organic solution was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH=30 / 1, volume ratio) to give compound 3-3 (2.7094 g, 91% yield) as a light yellow solid. LCMS: m / z=495.5[M+H] + .

[0245] Compound 3-3 (2.67 g, 5.4 mmol) was added to a reaction flask, and then 19 mL of HCl (75.6 mmol, 4 M 1,4-dioxane) was slowly added to the reaction flask. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain the crude product, compound 3-4, as a pale yellow solid. The crude product was used directly in the next step. LCMS: m / z = 395.3 [M+H] +.

[0246] Weigh compound 3-4 (3.1mmol), add anhydrous MeCN (15mL) to dissolve, add Et3N (1.29mL, 9.3mmol) and 1-bromo-2-methoxyethane (0.29mL, 3.1mmol). The mixture is stirred at 80°C overnight. The resulting mixture is then quenched with water and extracted with EtOAc. The organic solution is dried over anhydrous Na2SO4 and concentrated. The crude product is purified by silica gel column chromatography (DCM / MeOH=20 / 1, volume ratio) to obtain pure product compound 3 (760.2mg, 54% yield) as a white solid.

[0247] Example 3

[0248] To a DCM (5mL) solution of compound 3-4 (137mg, 0.34mmol) was added 3-oxetanes (30 μL, 0.51mmol) and HOAc (0.12mL, 2.04mmol). The resulting mixture was stirred at room temperature overnight. Then, sodium triacetoxyborohydride (144mg, 0.68mmol) was added to the reaction system and the resulting mixture was stirred at room temperature for 24 hours. The resulting mixture was then quenched with saturated sodium bicarbonate and extracted with DCM. The organic solution was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH=20 / 1, volume ratio) to give compound 4 (16mg, 10.5% yield) as a white solid.

[0249] Example 4

[0250] Compound 3-4 (310 mg, 0.721 mmol) was weighed and dissolved in anhydrous DCM (2 mL). Methoxyacetyl chloride (86 mg, 0.793 mmol) and Et3N (0.12 mL, 0.865 mmol) were added sequentially to the system under an ice bath. The reaction was maintained at this temperature for 4 hours. The reaction system was quenched with water and extracted with EtOAc. The organic solution was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, volume ratio) to obtain the pure product as a white solid (260 mg, 77% yield).

[0251] Example 5

[0252] {4-[3,4-difluoro-2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridin-1-yl}(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (Compound 1-4, 135 mg, 0.3 mmol) was added to anhydrous MeCN (5 mL) to dissolve, and Et3N (0.13 mL, 0.9 mmol) and 2-bromoacetamide (62 mg, 0.45 mmol) were added to the system. The resulting mixture was stirred at 80 ° C for 2 hours. The resulting mixture was then quenched with water and extracted with EtOAc. The organic solution was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH=10 / 1, volume ratio) to give a white solid pure product compound 10 (110.7 mg, 78.5%).

[0253] Example 6

[0254] At room temperature, EDCI (68 g, 354.16 mmol), HOBt (47.8 g, 354.16 mmol) and DIEA (94 g, 729.15 mmol) were added sequentially to a DMF (600 mL) solution of compound 1-2 (54.8 g, 208.33 mmol) and 1,4,6,7-tetrahydropyrano[4,3-C]pyrazole-3-carboxylic acid (35 g, 208.33 mmol). The reaction system was stirred at room temperature for 12 h. LCMS detection showed that the reaction was complete. The reaction system was added to 4 L of water under ice bath, and a large amount of solid precipitated. The mixture was stirred for 45 minutes and filtered to collect the solid. The resulting solid was added to 3 L of methanol solution, slurried, filtered, and the solid was collected. The product was pumped dry for 4 hours to give a white solid product (56 g, 65% yield).

[0255] Example 7

[0256] At room temperature, compound 1-4 (150 mg, 0.36 mmol) and (3R)-3-[(methylsulfonyl)oxy]-2-pyrrolidone (59.8 mg, 0.36 mmol) were dissolved in 3 mL of acetonitrile solution, and DIEA (129.3 mg, 1.08 mmol) was subsequently added dropwise. The reaction system was heated to 80° C. and stirred overnight. The resulting reaction mixture was cooled to room temperature, quenched with water, and extracted with EtOAc. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (using V DCM / V MeOH =20 / 1 elution) to give compound 18 (53 mg, 29.4% yield) as a pale yellow liquid.

[0257] The compounds in Table 1 below were synthesized using the above procedures or similar procedures employing the corresponding intermediates or reactants.

[0258] Table 1 Synthesized compounds

[0259] Control compound

[0260] The following compounds were synthesized with reference to Example 19 of CN111393434B as a control:

[0261] 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone.

[0262] 1. Detection of RBP4 content in plasma

[0263] Experimental Methods: 7- to 8-week-old ICR male mice were acclimated for 3 to 7 days and randomly divided into groups (4 mice per group). They were fasted for 12 hours before testing. On the day of the test, orbital venous blood samples were collected before dosing (0-hour values ​​were used as initial levels), and plasma was isolated. Subsequently, the test compound (solvent: 5% DMSO + 10% cyclodextrin) was administered orally at a dose of 1 mg / kg or 5 mg / kg. A control group (5% DMSO + 10% cyclodextrin) was also administered orally. Orbital venous blood samples were collected at 5, 8, 10, 12, and 24 hours after compound administration, and plasma was isolated. Plasma RBP4 (Retinol Binding Protein 4, Plasma) ELISA kit (immunoway, KE1574) was used to measure RBP4 levels. The percentage of reduction was calculated, with the maximum percentage reduction between 5 and 24 hours selected. The reduction rate of RBP4 content in mouse plasma at different sampling time points = (initial RBP4 content - RBP4 content at sampling point) / initial RBP4 content. The maximum reduction rate of RBP4 content in mouse plasma by each compound is shown in Table 2 below. The results are shown in Table 2.

[0264] Table 2 Plasma RBP4 reduction levels of different compounds

[0265] 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 Figure 2 , and the comparison results at a dose of 5 mg / kg are shown in Figure 3 .

[0266] The results showed that after a single oral dose of 1 mg / kg or 5 mg / kg, the compound of the present application could significantly reduce the plasma RBP4 content compared with the control group.

[0267] 2. Antagonistic activity test

[0268] Test method:

[0269] Test compound solution: Each compound was diluted to 10 different concentrations in a 3-fold gradient starting at 100 μM.

[0270] Working solution: buffer containing 10 mM Tris-HCl pH 7.5, 1 mM DTT, 0.05% NP-40, and 6% glycerol.

[0271] The reaction composition includes the following components: 2 μL hFc-RBP4 (MCE, HY-P72031) (62.5 nM, diluted in working solution), 1 μL Retinol (Sigma, A2056-25MG) (retinol, 5 μM, diluted in working solution), 2 μL his-TTR (SinoBioloqical, 12091-H08H) (10 nM, diluted in working solution) and 5 μL Anti-His-Tb (Cisbio, 61HISTLB) & Anti-IgG-XL665 (Cisbio, 61HFCXLB) working solution (antibodies are diluted with working solution to a 2× mixture).

[0272] Incubation reaction process: Transfer 100 nL of the test compound solution to a 384-well reaction plate (set up in duplicate wells for each concentration), add each component of the reaction composition in sequence, and then incubate at 25°C for 60 minutes. Read the HTRF signal 665 / 620 ratio using a BMG microplate reader.

[0273] Data processing: Inhibition percentage of compound (%inh) = 100 × (average value of high control - value of test well) / (average value of high control - average value of low control). IC values ​​of compounds were fitted from nonlinear regression equation by XLfit 5.5.0. 50 and HillSlope. The results are shown in Table 3.

[0274] Table 3 RBP4-TTR interaction antagonistic activity of different compounds

[0275] The results showed that compared with the control compound, the compound of the present application could significantly antagonize the RBP4-TTR interaction.

[0276] 3. Pharmacokinetic Studies

[0277] Experimental Methods: Three ICR mice (male) were used for each compound, for a total of five groups. Mice were treated with a single dose of 10 mg / kg or 5 mg / kg (oral administration). For each mouse, blood samples were collected at 0.25, 0.5, 1, 2, 4, and 8 hours after administration. Whole blood samples were placed in a tube containing EDTA-K2, inverted several times, and then centrifuged at 6000 rpm at 4°C for 15 minutes to obtain plasma. The concentration of the compound in the plasma samples was determined using LC-MS / MS. The results are shown in Table 4.

[0278] Table 4 Pharmacokinetic results of different compounds

[0279] 4. Liver Microsome Stability

[0280] Test method:

[0281] Preparation of compound working solution: Prepare 10 mM DMSO stock solutions of the test substance and control compound verapamil (i.e., Varapamil), and dilute them to 200 μM working solution with acetonitrile before the experiment. The final concentration of the test substance and verapamil is 1 μM.

[0282] Prepare phosphate buffer: Weigh 7.098 g of disodium hydrogen phosphate and add 500 mL of pure water. Dissolve by ultrasonication to obtain a disodium hydrogen phosphate solution. Weigh 3.400 g of potassium dihydrogen phosphate and add 250 mL of pure water. Dissolve by ultrasonication to obtain a potassium dihydrogen phosphate solution. Mix the disodium hydrogen phosphate solution and potassium dihydrogen phosphate solution and adjust the pH to 7.4 ± 0.2.

[0283] Preparation of 10mM NADPH: Weigh an appropriate amount of NADPH (reduced coenzyme II) and freshly prepare a 10mM working solution with phosphate buffered saline for a final concentration of 1mM.

[0284] 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 minutes.

[0285] Table 5 Configuration of incubation system

[0286] Add 2 μL of the positive control or test compound working solution to the 358 μL incubation system and vortex to mix thoroughly. All samples were prepared in duplicate. Add 40 μL of 10 mM NADPH to the system and vortex to mix thoroughly. Start the reaction timer. Take 50 μL of the above suspension at 0.5 min, 5 min, 10 min, 15 min, 30 min, and 60 min, add 400 μL of acetonitrile (containing 100 ng / mL dexamethasone) stop solution, and vortex to mix thoroughly. Centrifuge at 4700 rpm and 4°C for 15 minutes to precipitate the protein. Transfer 100 μL of the supernatant to the sample plate, add 100 μL of pure water and mix thoroughly. Use for UPLC-MS / MS analysis. The results are shown in Table 6.

[0287] Table 6 Liver microsome stability results

[0288] The results showed that most of the compounds in this application had good metabolic stability, especially in human liver microsomes. In addition, the clearance rate of some compounds in this application in human liver microsomes was less than 10 μL / min / mg, indicating good drug-forming properties.

[0289] It will be appreciated that if any prior art publication is referred to in this application; such reference does not constitute an admission that the publication is part of the common general knowledge in the art in any country.

[0290] All publications, patents, patent applications, and published patent applications cited herein are hereby incorporated by reference in their entirety.

[0291] Although the foregoing invention has been described in considerable detail by way of illustration and example for the purpose of clear understanding, it is obvious to those skilled in the art that some subtle changes and modifications may be implemented. Therefore, the description and example should not be construed as limiting the scope of this application.

Claims

1. 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, in, R1, R2, R3, R4 and R5 are each independently -H, -halogen, -CF3 or -C 1-4 alkyl; wherein at least two of R1, R2, R3, R4 or R5 are not H; A is selected from Among them, R7 is -H, -C 1-4 Alkyl or -(oxetane) group; When A is selected from hour: Where n is 0, 1 or 2; Y1, Y2 and Y4 are each -CH2-, and Y3 is -NR9-; or Y1, Y3 and Y4 are each -CH2-, and Y2 is -NR9-; or Y1, Y2 and Y4 are each -CH2-, and Y3 is -O- or -S(=O)2-; or Y1, Y3 and Y4 are each -CH2-, and Y2 is -O- or -S(=O)2-; R9 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 R9 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, -NH2, -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), =O, -C(=O)(C 1-6 alkyl), -C(=O)(C 1-6 Alkoxy), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)NH2, -C(=O)-C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 Alkyl)2, -NHC(=O)(C 1-6 alkyl), -C(=O)O(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 Alkyl)2, -NHS(=O)2(C 1-6 The substituents are -C(=O)-alkyl, -C(=O)-phenyl, -C(=O)-5-10 membered heteroaryl, -C(=O)-3-7 membered heterocyclyl, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl or 5-10 membered heteroaryl; wherein the heterocyclyl or heteroaryl independently includes one or more heteroatoms selected from N, O or S at each occurrence; When A is selected from wherein Y1, Y2, Y3 and Y4 are each independently CR8 or N, and each R8 is independently -H, halogen, -C 1-6 Alkyl, -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -COOH, -NHC(=O)N(C 1-6 Alkyl)2, -S(=O)2NH(C 1-6 Alkyl), -O-(C 1-6 alkyl), -CN or -C 1-6 Haloalkyl; When A is selected from wherein Z2 is selected from -O-, Z3 is selected from -C(CH3)2-, and Z1 and Z4 are selected from -CH2-; or, Z2 and Z3 are each independently selected from -C(O)-, -N(CH3)- or -NH-, and Z1 and Z4 are selected from -CH2-; R 10 Selected from hydrogen or -CH3; When A is selected from wherein Z5, Z6, Z7 and Z8 are each independently selected from CR 12 or N, R 12 Each independently selected from hydrogen, F, Cl, -CN or -OCH3; R 11 Selected from hydrogen, -CH3, -CH2CH3, or -CH(CH3)2; When A is selected from Wherein, W1, W2, W3 and W4 are each independently selected from -CH2-, -O-, -NH-, -N(CH3)- or When A is selected from wherein U1 is selected from O or S, and U2 is selected from N; When A is selected from wherein U5 is selected from N, and U6 is selected from O or S; or, U5 is selected from CH, and U6 is selected from NH; When A is selected from wherein U3 is selected from N or CH; R 16 Selected from Cl; p is selected from 0 or 1; When A is selected from wherein U4 is selected from N or CH; R 13 Selected from -CH3, -OCH3, F, Cl or -CF3; q is selected from 0 or 1; When A is selected from Wherein, W6, W7, W8 and W9 are each independently selected from N or CR 15 ; R 14 Selected from hydrogen or -CH3; R 15 Each independently selected from hydrogen, F, Cl, -CH3, -OCH3, 2. 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, in, R1, R2, R3, R4 and R5 are each independently -H, -halogen, -CF3 or -C 1-4 alkyl; wherein at least two of R1, R2, R3, R4 or R5 are not H; A is selected from Among them, R7 is -H, -C 1-4 Alkyl or -(oxetane) group; When A is selected from hour: Where n is 0, 1 or 2; Y1, Y2 and Y4 are each -CH2-, and Y3 is -NR9-; or Y1, Y3 and Y4 are each -CH2-, and Y2 is -NR9-; R9 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 R9 is optionally substituted by 1, 2, 3, 4, 5 or 6 selected from -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 1-6 Alkynyl, -C 1-6 Haloalkyl, -C 1-6 Alkoxy, -CN, -NH2, -COOH, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 Alkyl)2, -NHC(=O)(C 1-6 alkyl), -C(=O)O(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 Alkyl)2, -NHS(=O)2(C 1-6 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl or 5-10 membered heteroaryl; said heterocyclyl or heteroaryl independently comprises one or more heteroatoms selected from N, O or S at each occurrence; When A is selected from Wherein, Y1, Y2, Y3 and Y4 are each independently CR8 or N, and each R8 is independently -H, halogen, -O-(C 1-6 alkyl), -CN or -C 1-6 Halogenated alkyl.

3. The compound according to any one of claims 1 to 2, 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: R1, R2, R3, R4 and R5 are each independently -H, -F, -Cl, -Br or -CF3.

4. The compound according to any one of claims 1 to 3, 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: 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 and R5 is -H, or R1 is -Cl, R2 is -H, R3 is -H, R4 is -F and R5 is -H, or R1 is -Cl, R2 is -F, R3 is -H, R4 is -H and R5 is -H, or R1 is -CF3, R2 is -H, R3 is -H, R4 is -F and R5 is -H.

5. The compound according to any one of claims 1 to 4, 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: 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.

6. The compound according to any one of claims 1 to 4, 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 of formula (I) is any of the following:

7. The compound according to any one of claims 1 to 6, 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: A is n is 0 or 1; When n is 0, Y1 and Y3 are each -CH2-, and Y2 is -NR9-; When n is 1, Y1, Y2 and Y4 are each -CH2-, and Y3 is -NR9-; or Y1, Y3 and Y4 are each -CH2-, and Y2 is -NR9-; R7 is -H, -C 1-4 Alkyl or -(oxetane) group; R9 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 Heterocyclic group, -(C 1-4 Alkylene)-(C 3-6 Heterocyclic group), -(C 1-6 Alkylene)-O(C 1-3 Alkyl), -(C 1-6 Alkylene)-CF3, -C(O)-(C 1-6 alkyl), -C(O)2-(C 1-6 alkyl), -C(O)-NH2, -CH2C(O)-NH2, -C(O)-C(O)-NH2, -C(O)-CH(C 1-6 Alkylene)-C(O)-NH2, -CH2C(O)-NH(C 1-3 alkyl), -CH2C(O)-N(C 1-3 Alkyl)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 1-6 Alkoxy), -C(O)-(C 1-6 Alkylene)-(OC 1-6 alkyl), -C(O)-(C6 aryl), -C(O)-(C6 heteroaryl), -C(O)-(C6 heterocyclyl), -(C 1-6 Alkylene)-CO2H, -(C 1-6 Alkylene)-CO2(C 1-6 Alkyl), -SO2-(C 1-6 Alkyl), oxetane or 8. 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, in, R1, R2, R3, R4 and R5 are each independently -H, -halogen, -CF3 or -C 1-4 alkyl; wherein at least two of R1, R2, R3, R4 or R5 are not H; wherein A is selected from R7 and R9 are as defined in claim 1 or 2.

9. The compound according to claim 8, 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: R1, R2, R3, R4 and R5 are each independently -H, -F, -Cl, -Br or -CF3.

10. The compound according to claim 8 or 9, 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: 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 and R5 is -H, or R1 is -Cl, R2 is -H, R3 is -H, R4 is -F and R5 is -H, or R1 is -Cl, R2 is -F, R3 is -H, R4 is -H and R5 is -H.

11. The compound according to any one of claims 1 to 10, 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: 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, <h2 style=";text-align:left;direction:ltr">-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、<h2 style=";text-align:left;direction:ltr"> -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. The compound according to claim 1 or 2, 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: A is in, Y1, Y2, Y3 and Y4 are each independently CR8 or N, R8 at each occurrence is independently -H, halogen, -OCH3, -CN or -CF3.

13. The compound according to claim 12, 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: A is 14. The compound according to claim 1 or 2, 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: A is 15. 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:

16. 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:

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, 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.

18. Use of a compound according to any one of claims 1 to 16, 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 according to claim 17 in the preparation of a medicament for treating a disease in which lipofuscin is excessively accumulated in the retina and which is associated with the serum concentration of RBP4.

19. The use according to claim 18, wherein The disease in which lipofuscin accumulates excessively in the retina is a retinoic acid-mediated macular degeneration, including age-related macular degeneration, dry age-related macular degeneration, Stargardt's disease, Best's disease, adult vitelliform maculopathy or macular dystrophy similar to Stargardt's disease; the retinoic acid is A2E, isoA2E, A2-DHP-PE or atRALdi-PE.

20. A method for treating a subject with a disease in which there is excessive accumulation of lipofuscin in the retina associated with serum concentrations of RBP4, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 16, 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 according to claim 17.

21. The method according to claim 20, wherein: The disease in which lipofuscin accumulates excessively in the retina is a retinoic acid-mediated macular degeneration, including age-related macular degeneration, dry age-related macular degeneration, Stargardt's disease, Best's disease, adult vitelliform maculopathy or macular dystrophy similar to Stargardt's disease; the retinoic acid is A2E, isoA2E, A2-DHP-PE or atRALdi-PE.

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