Phenyl-substituted heterocyclic compound, preparation method therefor and use thereof

Abstract

Provided are a phenyl-substituted heterocyclic compound, a preparation method therefor, and a use thereof. Specifically, provided is a compound represented by formula I, or a pharmaceutically acceptable salt thereof. The provided phenyl-substituted heterocyclic compound can effectively inhibit RBP4, and has prospects for use in the treatment of RBP4-related diseases.

Description

A phenyl-substituted heterocyclic compound, its preparation method and application

[0001] Cross-references to related applications

[0002] This application claims priority to Chinese Patent Application No. 2024118412404, filed on December 13, 2024, entitled "A phenyl-substituted heterocyclic compound and its preparation method and application thereof," the contents of which are incorporated herein by reference in their entirety and are part of the original description of this publication.

[0003] This application claims priority to Chinese Patent Application No. 202511402383X, filed on September 28, 2025, entitled "A phenyl-substituted heterocyclic compound and its preparation method and application thereof," the contents of which are incorporated herein by reference in their entirety and are part of the original description of this publication. Technical Field

[0004] This disclosure relates to a phenyl-substituted heterocyclic compound, its preparation method, and its application. Background Technology

[0005] Age-related macular degeneration (AMD) is an age-related structural change in the macula. Patients are mostly over 50 years old, with bilateral involvement occurring sequentially or simultaneously, and progressive vision loss severely impacting their quality of life. RBP4, a key protein for transporting retinol in the body, is synthesized by the liver and transports retinol from the liver to the eye via the bloodstream. It is a key target for treating Stargardt's disease and AMD, and inhibiting RBP4 holds promise for treating these diseases. Summary of the Invention

[0006] The technical problem to be solved by this disclosure is to overcome the deficiency of the limited variety of RBP4 inhibitors in the prior art, and to provide a phenyl-substituted heterocyclic compound, its preparation method and application.

[0007] This disclosure solves the above-mentioned technical problems through the following technical solution:

[0008] This disclosure provides a pharmaceutically acceptable salt of a compound as shown in Formula I, a deuterated compound thereof, or any of the foregoing (referring to the compound as shown in Formula I or its deuterated compound):

[0009] Among them, R 1 R 2 R 3 R4 and R 5 Each is independently H, deuterium, halogen, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl or C 1-4 Halogenated alkyl groups;

[0010] X is CR 7 Or N; R 7 For H, deuterium, OH, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl or C 1-4 Halogenated alkyl groups;

[0011] R 6 For one or more R 6-2 The substituted phenyl group or "a 5-6 membered heteroaryl group selected from one, two or three of N, O and S, with one, two or three heteroatoms";

[0012] When X is CR 7 At that time, R 6-1 and R 6-2 Deuterium and C are independently distinguished. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or "a 4-6 membered heterocyclic alkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms";

[0013] When X is N, R 6-1 and R 6-2 Deuterium and C are independently distinguished. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or "a 4-6 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms"; or, two adjacent R 6-1 Or two adjacent R 6-2 Together with the intermediary atoms they are connected to, they form C 3-6 A carbon ring, "a 4-6 membered heterocycle selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or a ring surrounded by one or more R... 6-1-1 Replacement C 3-6 Carbon rings or "by one or more R" 6-1-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, forming a 4-6 membered heterocycle.

[0014] R 6-1-1 and R6-1-2 Deuterium and C are independently distinguished. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 deuterated alkoxy group, -L 1 -R 6-1-1-1 , cyano, C 3-6 Cycloalkyl, "a 4-6 membered heterocycloalkyl group selected from one, two, or three heteroatoms selected from N, O, and S, with one, two, or three heteroatoms", or consisting of one or more R... 6-1-1-2 Replacement C 1-4 alkyl;

[0015] R 6-1-1-2 Independently for -L 2 -R 6-1-1-2-1 Halogen, C 1-4 Alkyl, carboxyl, cyano, "a 4-6 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", C 3-6 cycloalkyl, -CONR a R b C 1-4 Halogenated alkoxy or C 1-4 Alkoxy;

[0016] L 1 and L 2 Independently -S-, -CO-, -CO-O-, -O-CO-, -SO2-, -CONR c -or NR d -;

[0017] R 6-1-1-1 and R 6-1-1-2-1 Independent of H, deuterium, and C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 6-10 Aryl, "5-6 membered heteroaryl with one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms" or "4-6 membered heterocyclic alkyl with one, two or three heteroatoms selected from N, O and S";

[0018] R a R b R c and R d Independent of H, deuterium, and C 1-4 Deuterated alkyl or C 1-4 alkyl.

[0019] In some embodiments, in compounds represented by Formula I, their deuterated compounds, or pharmaceutically acceptable salts thereof, certain groups may be defined as follows, and other groups may be defined as described in any embodiment of this disclosure (hereinafter referred to as "in some embodiments"), wherein the "C" 1-4 Alkyl, substituted C 1-4 Alkyl group, -CO-C 1-4 The "C" in "alkyl" 1-4 "alkyl" is independently methyl or ethyl; for example, methyl.

[0020] In some implementations, the C 1-4 The deuterated alkyl group is independently a deuterated methyl or a deuterated ethyl; for example, CD3.

[0021] In some implementations, the halogen is independently F, Cl, Br, or I; for example, F.

[0022] In some implementations, the C 1-4 The alkyl halide is independently C10. 1-4 Fluorinated alkyl groups; for example, CF3.

[0023] In some implementations, the C 1-4 The haloalkoxy group is independently C 1-4 Fluoroalkyl groups; for example, OCF3.

[0024] In some implementations, the C 1-4 Alkyl groups are independently methoxy or ethoxy; for example, methoxy.

[0025] In some implementations, the C 1-4 The deuterated alkoxy group is independently a deuterated methoxy or a deuterated ethoxy group; for example, OCD3.

[0026] In some embodiments, the heteroatom of the "5-6 membered heteroaryl group selected from one, two or three of N, O and S, with one, two or three heteroatoms" is independently N; the number of heteroatoms can be independently two or three.

[0027] In some embodiments, the phrase "a 5-6 membered heteroaryl group whose heteroatoms are selected from one, two, or three of N, O, and S, and whose heteroatoms number one, two, or three" is independently defined as "a 5 membered heteroaryl group whose heteroatoms are selected from one, two, or three of N, O, and S, and whose heteroatoms number one, two, or three".

[0028] In some embodiments, the phrase "a 5-6 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" is independently defined as...

[0029] In some embodiments, the heteroatom of the 4-6 membered heterocyclic alkyl group is independently O; for example...

[0030] In some implementations, the two adjacent R 6-1 Or two adjacent R 6-2 The C formed together with the intermediary atoms they are connected to 3-6 Carbon rings and "by one or more R" 6-1-1 Replacement C 3-6 The "C" in "carbon ring" 3-6 The "carbon ring" can be independently a C3 carbon ring, a C4 carbon ring, a C5 carbon ring, or a C6 carbon ring.

[0031] In some implementations, the two adjacent R 6-1 Or two adjacent R 6-2 The "4-6 membered heterocycles, consisting of one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms" formed together with the intermediary atoms they are connected to, and "enclosed by one or more R..." 6-1-2 The substituted heteroatom is selected from one, two or three of N, O and S. The heteroatom in the "4-6 membered heterocycle" with one, two or three heteroatoms is independently O or N; the number of heteroatoms can be one.

[0032] In some implementations, the two adjacent R 6-1 Or two adjacent R 6-2 The "4-6 membered heterocycles, consisting of one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms" formed together with the intermediary atoms they are connected to, and "enclosed by one or more R..." 6-1-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S. The "4-6 membered heterocycle" in "4-6 membered heterocycle with one, two, or three heteroatoms" is independently a 6 membered heterocycle.

[0033] In some implementations, the two adjacent R 6-1 Or two adjacent R 6-2 The "4-6 membered heterocycles, consisting of one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms" formed together with the intermediary atoms they are connected to, and "enclosed by one or more R..." 6-1-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three. The "4-6 membered heterocycle" in "4-6 membered heterocycle" is independently defined as...

[0034] In some implementations, the C 3-6The cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; for example, cyclopropyl.

[0035] In some implementation schemes, R 1 R 2 R 3 R 4 and R 5 Each can be independently H, halogen, or C. 1-4 Haloalkyl. Preferably, R 1 R 2 R 3 R 4 and R 5 Two or more of them are not H; more preferably, R 1 R 2 and R 3 Each independently is either halogen or C 1-4 Halogenated alkyl; R 4 and R 5 For H.

[0036] In some implementations, X is N.

[0037] In some implementations, X is CR 7 .

[0038] In some implementation schemes, R 6 For one or more R 6-1 The substituted heteroatom is a 5-6 membered heteroaryl group selected from one, two or three of N, O and S, with one, two or three heteroatoms.

[0039] In some implementation schemes, R 7 For H.

[0040] In some implementations, when X is CR 7 At that time, R 6-1 Independently for C 1-4 Alkyl, C 1-4 The alkoxy group or "a 4-6 membered heterocyclic alkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms".

[0041] In some implementations, when X is N, R 6-1 Independently for C 1-4 Alkyl group; or, two adjacent R groups. 6-1 Together with the intermediary atoms they are attached to, they form "4-6 membered heterocycles selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "a ring bounded by one or more R atoms". 6-1-2The substituted heteroatoms are selected from one, two, or three of N, O, and S, and are 4-6 membered heterocycles with one, two, or three heteroatoms.

[0042] In some implementation schemes, R 6-1-1 and R 6-1-2 Each independently is -L 1 -R 6-1-1-1 Or by one or more R 6-1-1-1 Replacement C 1-4 alkyl.

[0043] In some implementations, L 1 and L 2 Independently -CO-.

[0044] In some implementations, when two adjacent R 6-1 Or two adjacent R 6-2 Together with the intermediary atoms they are connected to, they form C 3-6 A carbon ring, "a 4-6 membered heterocycle selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or a ring surrounded by one or more R... 6-1-1 Replacement C 3-6 Carbon rings or "by one or more R" 6-1-2 When the substituted heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, forming a 4-6 membered heterocycle, R... 6 for Ring A is the C 3-6 A carbon ring, "a 4-6 membered heterocycle selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or a ring surrounded by one or more R... 6-1-1 Replacement C 3-6 Carbon rings or "by one or more R" 6-1-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, forming a 4-6 membered heterocycle. Preferably, R... 6 for Y 1 and Y 4 CH2; Y 2 and Y 3 Independent of O, NH or NR 6-1-2 .

[0045] In some implementation schemes, R a R b R c and R d Independently H or C 1-4 alkyl.

[0046] In some implementations, when X is CR7 At that time, the R 6-1 and R 6-2 Each independently Methyl or methoxy.

[0047] In some implementations, when X is N, the R 6-1 and R 6-2 Each is independently a methyl group, or two adjacent R groups. 6-1 Or two adjacent R 6-2 Together with the intermediary atoms they are connected to form

[0048] In some implementations, the R 6-1-1 and R 6-1-2 Each independently

[0049] In some implementation schemes, structural units for For example

[0050] In some implementations, when X is CR 7 At that time, R 6 for

[0051] In some implementations, when X is N, R 6 for

[0052] In some embodiments, the compound as shown in Formula I is

[0053] This disclosure also provides a method for preparing a compound as shown in Formula I, comprising the following steps:

[0054] In the presence of a solvent, a base and a condensing agent, the compound shown in Formula II and the compound shown in Formula III undergo a condensation reaction to produce the compound shown in Formula I.

[0055] X, R 1 R 2 R 3 R 4 R 5 and R 6 The definition is as described in any of the preceding items.

[0056] The solvent is a conventional solvent for this type of reaction in the art, such as DCM or DMF.

[0057] In some embodiments, the condensing agent is BOP or HATU.

[0058] In some embodiments, the base is N,N-diisopropylethylamine.

[0059] This disclosure also provides a pharmaceutical composition comprising:

[0060] (1) The compound of formula I as described in any one of the claims of this disclosure, or a pharmaceutically acceptable salt thereof; and

[0061] (2) Pharmaceutically acceptable excipients.

[0062] This disclosure also provides for the use of any of the compounds of Formula I as described in this disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions as described above, wherein the use is selected from:

[0063] (1) Preparation of RBP4 inhibitors;

[0064] (2) Prepare drugs for the treatment or prevention of RBP4-related diseases; said RBP4-related diseases include, but are not limited to, age-related macular degeneration.

[0065] In some embodiments, the RBP4 inhibitor can be used in mammalian organisms or in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of RBP4 inhibition effects.

[0066] Unless otherwise specified, the terms used in this disclosure have the following meanings:

[0067] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-4 "Including C1, C2, C3, C4, C1-C4, C1-C3, C1-C2, C2-C4, C2-C3 and C3-C4 alkyl groups."

[0068] The term "multiple" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0069] When any variable (e.g., R) 6-1 When a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0070] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0071] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (e.g., C1 to C4). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, etc.

[0072] The term “halogenated alkyl” refers to an alkyl group that has been substituted with one or more halogens, where “halogen” is the halogen as defined above and “alkyl” is the alkyl group as defined above.

[0073] The term “deuterated alkyl” refers to an alkyl group that has been substituted with one or more deuterium atoms, where “alkyl” is the alkyl group defined above.

[0074] The term "alkoxy" refers to the group R. X -O-, where R X It is an alkyl group as defined above.

[0075] The term “haloalkoxy” refers to an alkoxy group substituted with one or more halogens, where “halogen” is the halogen as defined above and “alkoxy” is an alkyl group as defined above.

[0076] The term "cycloalkyl" refers to a saturated monocyclic cyclic group consisting only of carbon atoms and having a specified number of carbon atoms (e.g., C3 to C6). Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0077] The term "carbocyclic ring" refers to a saturated or unsaturated, non-aromatic (not conforming to Hückel's rule) monocyclic group consisting only of carbon atoms, having a specified number of carbon atoms (e.g., C3 to C6).

[0078] The term "heterocyclic alkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 4 to 6), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatoms (1, 2 or 3 of N, O and S), which is monocyclic and saturated.

[0079] The term "heterocycle" refers to a cyclic group having a specified number of ring atoms (e.g., 4 to 6), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatoms (1, 2 or 3 of N, O and S), which is a saturated or unsaturated non-aromatic (not conforming to Hückel's rule) monocyclic group.

[0080] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 6), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatoms (1, 2 or 3 of N, O and S), which is monocyclic and aromatic (conforming to Hückel's rule).

[0081] Those skilled in the art will understand that, in accordance with the conventions used in the art, the structural formulas of the groups described in this disclosure are... This refers to the fact that the corresponding group is connected to other segments or groups in the compound through this site. In the embodiments of this disclosure, a single dash "-" may be added before the substituent to indicate that the named substituent is connected to the parent part by a single bond. The "-" at the end of the group indicates that the group is connected to other segments in the molecule through this site.

[0082] When the linking groups listed in the embodiments of this disclosure do not specify their linking direction, the linking direction is the same as the reading order from left to right. Examples are given below. The linker group L1 is -CD-, and -CD- connects ring A and ring B in the same direction as the reading order from left to right to form... and does not constitute Specifically in this disclosure, R 6-1-1 -L 1 -R 6-1-1-1 At that time, L 1 The -CO-O- designation indicates that the carbonyl C in -CO-O- is linked to the parent compound via a single bond, and the oxygen in -CO-O- is linked to the R... 6-1-1-1 The oxygen in -CO-O- is linked to the parent bond via a single bond.

[0083] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.

[0084] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. It includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009) for details.

[0085] The term “treatment” refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that triggers the disease; or (3) slowing the development of one or more biological manifestations of a disease.

[0086] The term "prevention" refers to reducing the risk of developing a disease.

[0087] The positive and progressive effect of this disclosure is that the phenyl-substituted heterocyclic compounds provided by this disclosure can effectively inhibit RBP4 and are expected to be used to treat RBP4-related diseases. Attached Figure Description

[0088] To more clearly illustrate the technical solutions of the embodiments of this disclosure, the accompanying drawings used in the embodiments will be briefly described below. It should be understood that the following drawings only show some embodiments of this disclosure and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0089] Figure 1 shows the HMBC diagram for 004-SM9. Detailed Implementation

[0090] To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions in the embodiments of this disclosure will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0091] Preparation of P1 in Example 1

[0092] 1.1 Synthesis of N-methoxy-N-methyltetrahydrofuran-3-carboxamide (001-SM2)

[0093] Take a 100mL round-bottom flask, add a magnetic stir bar, 2.3g tetrahydrofuran-3-carboxylic acid (1), 9.0g BOP, and 30mL dichloromethane. While stirring, add 9mL N,N-diisopropylethylamine dropwise. A slight exothermic reaction can be observed, and condensed dichloromethane droplets form on the flask wall as the dichloromethane refluxes. Install a gas delivery tube at the flask opening and continue stirring for 1 hour. Weigh 2.0g N,O-dimethylhydroxylamine and add it to the system; exothermic reaction can be observed again. After stirring the system overnight, add 10mL saturated saline solution for extraction. Extract the aqueous phase three times with dichloromethane (20mL x 3). Combine the organic phases and dry with anhydrous magnesium sulfate. Filter and remove the solvent under reduced pressure. Column chromatography yielded 3.2 g of product N-methoxy-N-methyltetrahydrofuran-3-carboxamide (2), with eluent of PE:EtOAc:Et3N = 200:40:1, yield of 91%, and the product was a colorless liquid.

[0094] 1 H NMR (400MHz, CDCl3) δ4.05(td,J=8.4,3.2Hz,1H),3.93-3.77(m,3H),3.71(s,3H),3.42(quint,J=8.4Hz,1H),3.21(s,3H),2.29-2.00(m,2H).

[0095] 1.2 Synthesis of 3-Tetrahydrofuranylethyl ketone (001-SM3)

[0096] Take a 100mL round-bottom flask, add a magnetic stir bar, 3.2g of N-methoxy-N-methyltetrahydrofuran-3-carboxamide (2), and purge the system with N2 three times to form an N2 atmosphere. Add 30mL of anhydrous THF, cool to -20℃ in an ice-salt bath, add 6.3mL of ethyl Grignard reagent (EtMgBr, 3M), stir for 1h, and then return to room temperature and stir overnight. After the reaction is complete, add 1mL of saturated ammonium chloride solution to quench the reaction, remove the solvent under reduced pressure, add 5mL of 1M hydrochloric acid and 20mL of ethyl acetate. Extract the system three times (20mL x 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Column chromatography separates 1.87g of product 3-tetrahydrofuranylethyl ketone (3), eluent: PE:EtOAc = 10:1, yield: 72%, the product is a colorless liquid.

[0097] 1H NMR (400MHz, CDCl3) δ3.96 (t, J = 8.4Hz, 1H), 3.91-3.85 (m, 2H), 3.84-3.78 (m, 1H) ,3.29-3.17(m,1H),2.61-2.41(m,2H),2.19-2.02(m,2H),1.09(t,J=7.3Hz,3H).

[0098] 1.3 Synthesis of ethyl 2-methyl-3-oxo-3-(3-tetrahydrofuranyl)propionate (001-SM4)

[0099] Take a 100mL round-bottom flask, add a magnetic stir bar, 1.87g of 3-tetrahydrofuranyl ethyl ketone (3), purge the system with N2 three times to form an N2 atmosphere, add 30mL of anhydrous THF, cool to -78℃ in a liquid nitrogen-ethyl acetate bath, add 30mL of LiHMDS (1M), stir for 1h, add 3mL of diethyl oxalate, continue stirring for 1h, and then return to room temperature and stir overnight. After the reaction is complete, add 1mL of 1M hydrochloric acid solution to quench the reaction, remove the solvent under reduced pressure, add 20mL of saturated saline and 20mL of ethyl acetate. Extract the system three times (20mL x 3), combine the organic phases, dry with anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Column chromatography separates 690mg of crude ethyl 2-methyl-3-oxo-3-(3-tetrahydrofuranyl)propionate (4), eluent: PE:EtOAc = 5:1, yield: 24%, the product is a pale yellow liquid.

[0100] 1.4 Synthesis of ethyl 4-methyl-5-(3-tetrahydrofuranyl)-1H-pyrazole-3-carboxylate (001-SM5)

[0101] The liquid obtained in 1.3 (4) was removed from the solvent under reduced pressure and stored in a 100 mL pear-shaped flask. 10 mL of anhydrous ethanol was added, and 0.4 mL of hydrazine hydrate (80%) and 0.4 mL of glacial acetic acid were added with stirring. The mixture was stirred at room temperature for 5 h and then heated under reflux for 3 h. After the reaction was completed, the solvent was removed from the solvent under reduced pressure. 10 mL of saturated saline and 20 mL of ethyl acetate were added to the system, and the mixture was extracted 3 times (20 mL x 3). The organic phases were combined and dried with anhydrous sodium sulfate. After filtration, the solvent was removed from the solvent under reduced pressure. Column chromatography was used to separate 352 mg of ethyl 4-methyl-5-(3-tetrahydrofuranyl)-1H-pyrazole-3-carboxylate (5). Eluent: PE:EtOAc = 2:1, yield: 45%, product was a pale yellow liquid.

[0102] 1H NMR(400MHz, CDCl3)δ10.82(br s,1H),4.39(q,J=7.1Hz,2H),4.16-4.01(m,2H),3.93(dt,J=8.4,7.3Hz,1H),3.87(dd,J=8.4,6.6H z,1H),3.55-3.44(m,1H),2.38-2.28(m,1H),2.27(s,3H),2.23-2.12(m,1H),1.39(t,J=7.1Hz,3H).

[0103] 13 C NMR (101MHz, CDCl3) δ160.9,150.5,133.8,117.8,72.3,68.1,60.8,36.3,31.9,14.3,8.6.

[0104] Synthesis of 1,5-methyl-5-(3-tetrahydrofuranyl)-1H-pyrazole-3-carboxylic acid (001-SM6)

[0105] Take 53 mg of the liquid (5) obtained in 1.4 and add it to a 25 mL pear-shaped flask. Add 5 mL of 10% NaOH aqueous solution and stir for 3 h. Add 1 M hydrochloric acid to adjust the pH to 1. Add 10 mL of ethyl acetate to the system and extract 3 times (10 mL x 3). Combine the organic phases and dry with anhydrous sodium sulfate. After filtration, remove the solvent under reduced pressure to obtain 35 mg of product 4-methyl-5-(3-tetrahydrofuranyl)-1H-pyrazole-3-carboxylic acid (6). Yield: 70%. The product is a white solid.

[0106] 1 H NMR(400MHz,Acetone-d6)δ10.88(br s,2H),4.07(t,J=7.9Hz,1H),3.96(td,J=8.1,5.0Hz,1H),3.88-3.81(m,1H),3.76(t,J= 7.8Hz,1H),3.53(quint,J=7.7Hz,1H),2.36-2.23(m,4H),2.17(dq,J=12.1,7.8Hz,1H).

[0107] 1.6 Synthesis of (4-(2,3-difluoro-4-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl) methyl ketone

[0108] Take 107 mg of the solid (6) obtained in step 1.5, add it to a 50 mL pear-shaped flask, add 236 mg of BOP and 5 mL of dichloromethane, and add 0.13 mL of N,N-diisopropylethylamine while stirring. Stir for one hour. Dissolve 140 mg of ethyl 4-(2,3-difluoro-4-(trifluoromethyl)phenyl)piperidine in 5 mL of dichloromethane and add it dropwise to the system. Stir overnight. After reacting overnight, wash the system three times with saturated brine (10 mL x 3). Dry the organic phase with anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure to obtain the crude product. The hexamethylphosphonamide in the crude product is still difficult to remove after three column chromatographys. Finally, recrystallize 19 mg of the product (4-(2,3-difluoro-4-(trifluoromethyl)phenyl)piperidine-1-yl)(4-methyl-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl) methyl ketone (P1) by recrystallization from 3 mL of ethyl acetate and 15 mL of n-pentane. Yield: 8%, product is a white solid.

[0109] 1 H NMR(400MHz,Chloroform-d)δ10.52(br s,1H),7.70-7.30(m,2H),7.27-7.07(m,1H),5.12-4.10(m,4H),4.08(td,J=8.4,5.6Hz,1H),4.02-3.87(m,3H),3 .54(dt,J=8.5,5.6Hz,1H),3.29-2.80(m,3H),2.45-2.31(m,1H),2.15(s,3H),2.12-2.00(m,1H),1.96-1.46(m,5H contain peak of water).

[0110] 19 F NMR (376MHz, Chloroform-d) δ -53.60 (d, J = 33.2Hz), -59.01 (d, J = 194.6Hz), -137.28 (dq, J = 18.7, 33.2Hz), -137.83 (d, J = 20.6Hz).

[0111] HRMS(ESI+)Calcd.for C 21 H 23 F5N3O2 + [M+H] + :444.1705; Experimental value:444.1730.

[0112] Synthesis of Example 2P2

[0113] 2.1 Synthesis of 1-(tetrahydro-4H-pyran-4-ylidene)propyl-2-one (002-SM3)

[0114] 1.23 g (22 mmol, 1.1 equiv.) of potassium hydroxide was added to a 100 mL round-bottom flask (with a magnetic stir bar), along with 20 mL of ethanol and 5 mL of water as solvents. Then, 1.85 mL (20 mmol, 1.0 equiv.) of tetrahydropyranone (002-SM1) and 4.23 mL (22 mmol, 1.1 equiv.) of diethyl acetone phosphonate (002-SM2) were slowly added sequentially. The mixture was then stirred at room temperature for 5 h. After the reaction was complete, the solvent ethanol was removed under reduced pressure, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue was purified by column chromatography to give 2.38 g of 1-(tetrahydro-4H-pyran-4-yl)propyl-2-one (002-SM3), a colorless liquid, in 85% yield. (This step produced only one compound, therefore the product was not characterized).

[0115] Data for 1-(tetrahydro-4H-pyran-4-ylidene)propyl-2-one (002-SM3):

[0116] Colorless liquid, yield: 85%. f =0.42 (PE / EtOAc = 5:1, v / v).

[0117] 2.2 Synthesis of 1-(tetrahydro-2H-pyran-4-)propyl-2-one (002-SM4)

[0118] A 50 mL pear-shaped flask (with a magnetic inlet) was flame-dried, and 181 mg (1.7 mmol, 10 mol%) of palladium on carbon was added. The system was charged and purged with N2 three times to create an N2 atmosphere. Then, the nitrogen balloon was quickly replaced with a hydrogen balloon to create an H2 atmosphere. Next, 2.38 g (16.9 mmol) of palladium was dissolved in 10 mL of ethyl acetate and transferred to a pear-shaped flask under a hydrogen atmosphere. The mixture was then stirred for 1 h at room temperature under a hydrogen atmosphere. After the reaction was complete, the palladium on carbon was removed by filtration with diatomaceous earth, and the organic phase was evaporated to dryness to obtain the target product 1-(tetrahydro-2H-pyran-4-)propyl-2-one (002-SM4).

[0119] Characterization data of 1-(tetrahydro-2H-pyran-4-)propyl-2-one (002-SM4)

[0120] Colorless liquid, yield >99%. f =0.32 (PE / EtOAc = 5:1, v / v). 1H NMR (400MHz, CDCl3) δ3.92 (dd, J=11.4, 3.8Hz, 2H, OCH2), 3.41 (td, J=11.9, 1.8Hz, 2H, OCH2), 2.14 (s, 3H, CH3), 2.07 (ddd, J=8.1, 5.8, 2.7Hz, 1H, CH), 1.61 (ddd, J=13.0, 4.0, 2.0Hz, 2H), 1.33-1.25 (m, 2H).

[0121] 2.3 Synthesis of ethyl 4-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate (002-SM6)

[0122] In a 100 mL round-bottom flask (with a magnetic stir bar), 2.99 g (21.0 mmol, 2.0 equiv.) of 1-(tetrahydro-2H-pyran-4-)propyl-2-one (002-SM4), 1.12 mL (10.5 mmol, 1.0 equiv.) of ethyl diazonate (002-SM5) and 90 μL (1.1 mmol, 0.1 equiv.) of tetrahydropyrrole were added sequentially. Then, 10 mL of DMSO was added as a solvent to the reaction mixture, and the reaction system was stirred at room temperature for 24 h. After the reaction was complete, the system was diluted with 20 mL of ethyl acetate, then washed with water (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and the residue was purified by column chromatography to give 1.13 g of the target product, ethyl 4-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate (002-SM6), with a yield of 45%. (This step produced only one compound, therefore the product was not characterized).

[0123] Data for ethyl 4-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate (002-SM6):

[0124] Brown liquid, yield: 45%. f =0.58 (DCM / MeOH = 20:1, v / v).

[0125] 2.4 Synthesis of 4-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylic acid (002-SM7)

[0126] In a 100 mL round-bottom flask (with a magnetic stir bar), 1.07 g (4.5 mmol, 1.0 equiv.) of ethyl 4-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylic acid (002-SM6) and 900 mg (22.5 mmol, 5.0 equiv.) of sodium hydroxide solid were added sequentially. Then, 20 mL of dioxane and 20 mL of water were added as solvents. The system was then transferred to an oil bath at 100 °C and heated with stirring for 16 h. After the reaction was completed, the system was cooled to room temperature, and the solvent dioxane was removed by rotary evaporation. The pH of the aqueous solvent system was then adjusted to 1 with 2 M HCl solution, and a brown powdery solid gradually precipitated out. After filtration, 583 mg of the pure target product 4-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylic acid (002-SM7) was obtained.

[0127] Characterization data for 4-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylic acid (002-SM7):

[0128] Brown powdery solid, yield: 62%. f =0.12 (DCM / MeOH = 5:1, v / v). 1 H NMR(400MHz,DMSO-d6)δ12.89(s,1H,COOH),3.91(dd,J=11.4,2.5Hz,2H,OCH2),3.41(td,J=11.7,2.4Hz,2H ,OCH2),2.88(tt,J=11.7,4.1Hz,1H,CH),2.16(s,3H,CH3),1.72(td,J=11.8,3.7Hz,2H),1.67-1.61(m,2H).

[0129] 2.5 Synthesis of the target compound (P2)

[0130] A 25 mL round-bottom flask (with a magnetic stir bar) was flame-dried to remove water. Then, 103 mg (0.49 mmol, 1.0 equiv.) of 4-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylic acid (002-SM7), 105 mg (0.49 mmol, 1.2 equiv.) of condensing agent HATU, and 65 μL (0.49 mmol, 1.2 equiv.) of N,N-diisopropylethylamine were added sequentially. The system was charged with N2 three times to create an N2 atmosphere. Then, 2 mL of anhydrous DMF was added as a solvent, and the mixture was stirred at room temperature for 30 min. Next, 109 mg (0.41 mmol, 1.0 equiv.) of 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine (002-SM8) was dissolved in 1 mL of anhydrous DMF and transferred to the reaction system. The mixture was stirred at room temperature for 6 h. After the reaction, the solvent DMF was removed by depressurization using an oil pump. The residue was first roughly purified by column chromatography using n-pentane / acetone as eluent. During the purification process, some product decomposition was observed. The crude product was then collected, and the byproduct HOAt of HATU was removed by thin-layer chromatography. Finally, the residue was further purified by column chromatography to obtain 40 mg of the target product (P2), with a yield of 21%, as a white solid, meeting the requirements for final purity. f =0.65 (DCM / MeOH=100:7, v / v).

[0131] Nuclear magnetic resonance spectroscopy was performed using a Bruker 400M instrument. 1 H NMR(400MHz,Methanol-d4)δ7.53(q,J=8.8Hz,1H,ArH),7.40(d,J=8.9Hz,1H,ArH),4 .84-4.77(m,1H,NCH2),4.10(brs,1H,NCH2),4.03(dd,J=11.3,3.7Hz,2H,OCH2),3.56 (td,J=11.8,2.1Hz,2H,OCH2),3.29-3.15(m,2H,OCH2),3.03(tt,J=12.4,4.0Hz,1H,C H),2.92(m,1H,CH)2.08(s,3H,CH3),1.88(qd,J=12.6,4.4Hz,4H),1.81-1.73(m,4H).

[0132] HRMS (ESI) calculated value C 22 H 25 F5N3O2 + :458.1861; Experimental value:458.1862.

[0133] Synthesis of P3 in Example 3

[0134] 3.1 Synthesis of ethyl 4,5-dimethyl-1H-pyrazole-3-carboxylate (003-SM3)

[0135] Take a clean 50 mL round-bottom flask, add a magnetic stir bar and 20 mL of dimethyl sulfoxide (DMSO), followed by 1.79 mL (20 mmol, 2.0 equiv.) of butanone (003-SM1), 82 μL (1 mmol, 0.1 equiv.) of pyrrolidine, and 1.05 mL (10 mmol, 1.0 equiv.) of ethyl azide (003-SM2). Stir at room temperature for 7 days. After the reaction is complete, remove the solvent by vacuum distillation. The crude product is separated by column chromatography to give 237 mg of ethyl 4,5-dimethyl-1H-pyrazole-3-carboxylate (003-SM3), a pale yellow liquid, with a yield of 14%.

[0136] Characterization data of ethyl 4,5-dimethyl-1H-pyrazole-3-carboxylate (003-SM3) (NMR data are in the appendix):

[0137] Pale yellow liquid, 237 mg (1.4 mmol scale), yield 14%, R f =0.54 (DCM / MeOH=10:1, v / v). 1 H NMR (400MHz, CDCl3) δ (ppm) δ4.38 (q, J = 7.2Hz, 1H, CH2), 2.25 (s, 3H, CH3), 2.23 (s, 3H, CH3), 1.40 (t, 3H, CH3 in Et).

[0138] 3.2 Synthesis of 4,5-dimethyl-1H-pyrazole-3-carboxylic acid (003-SM4)

[0139] A clean 100 mL round-bottom flask was prepared, a magnetic stir bar was added, and 237 mg (1.4 mmol) of ethyl 4,5-dimethyl-1H-pyrazole-3-carboxylate (003-SM3) was added. Then, 25 mL of 1 mol / L sodium hydroxide aqueous solution and an equal volume of dioxane were added. The mixture was heated under reflux for 3 h. After the reaction was complete, most of the dioxane was removed by rotary evaporation. 1 mol / L hydrochloric acid aqueous solution was added until the system became acidic. The mixture was extracted with ethyl acetate (25 mL x 3), and then the product was further purified by recrystallization to obtain 35 mg of 3,5-dimethyl-pyrazole-4-carboxylic acid (003-SM4) as a white solid, with a yield of 18%. The low yield may be due to significant losses during purification. The NMR spectrum of the product showed only two methyl peaks, making structural identification somewhat difficult. Comparison with standard spectra confirmed it to be 4,5-dimethyl-1H-pyrazole-3-carboxylic acid (003-SM4).

[0140] Characterization data of 4,5-dimethyl-1H-pyrazole-3-carboxylic acid (003-SM4) (NMR data are in the appendix):

[0141] White solid, 35 mg (0.25 mmol scale), yield 18%, R f =0.43 (DCM / MeOH=10:1, v / v). 1 H NMR(400MHz, DMSO-d6)δ(ppm)δ2.28(s,3H,CH3),2.23(s,3H,CH3).

[0142] 3.3 Synthesis of the target compound (P3)

[0143] a) EDCI abbreviation

[0144] In a 25 mL round-bottom flask, add 120 mg (0.86 mmol, 1.2 equiv.) 3,5-dimethyl-pyrazole-4-carboxylic acid (003-SM1), 190 mg (0.72 mmol, 1.0 equiv.) 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine (003-SM2), 275 mg (1.43 mmol, 2.0 equiv.) 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and 49 mg (0.36 mmol, 0.5 equiv.) 1-hydroxybenzotriazole (HOBt). Purge with nitrogen three times, then add 12 mL of dichloromethane. Stir the mixture at room temperature for 8 h under nitrogen protection. After the reaction is complete, dissolve the mixture in 6 mL of dichloromethane, then wash with water (6 mL x 3). The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The crude product was subjected to column chromatography to obtain 75 mg of the target compound (P3), with a yield of 27%. The product was a white solid compound (containing impurities), and it was not purified after recrystallization. f =0.77 (DCM / MeOH / Et3N=100:10:1, v / v).

[0145] Next, we tried different condensation reagents and used 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) as the condensation agent and N,N-diisopropylethylamine (DIPEA) as the base to prepare the target product (P3) with high purity. The specific steps are as follows.

[0146] b) HATU abbreviation

[0147] In a 25 mL round-bottom flask, add 48 mg (0.34 mmol, 1.0 equiv.) 3,5-dimethyl-pyrazole-4-carboxylic acid (003-SM4), 91 mg (0.34 mmol, 1.0 equiv.) 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine (003-SM5), and 156 mg (0.41 mmol, 1.2 equiv.) 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU). Purge with nitrogen three times, then add 12 mL of [unclear text - possibly a typo, should be 12 mL]. Ultra-dry DMF (N,N-dimethylformamide) was added under nitrogen protection with 72 μL (0.41 mmol, 1.2 equiv.) of N,N-diisopropylethylamine (DIPEA). The mixture was stirred at room temperature for 12 h. At the 6th h, 24 mg (0.17 mmol, 0.5 equiv.) of 3,5-dimethyl-pyrazole-4-carboxylic acid (003-SM4) and 78 mg (0.2 mmol, 0.6 equiv.) of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) were added. After the reaction was complete, the solvent was evaporated to dryness, and the mixture was recrystallized with ethyl acetate. The resulting solid was further separated using a large plate (CH2Cl2:MeOH:EtOH = 100:10 1). R was taken as the solid. f =0.7-0.8% silica gel was eluted with methanol to remove the compound, and then recrystallized again with ethyl acetate to give 52 mg of the target compound (P3), with a yield of 36% (purity ~90%). The product was a white solid compound, which was recrystallized from acetone and n-hexane to give 28 mg of pure product (97%). R f =0.77 (DCM / MeOH / Et3N=100:10:1, v / v).

[0148] 1 H NMR (400MHz, Acetone-d6) δ (ppm): 11.77 (br s, 1H, NH), 7.63 (q, J = 8.8Hz, 1H, ArH), 7.49 (dd, J = 8.4, 3.2Hz, 1H, ArH), 4.66 (br s, 2H in piperidine), 3.26 (m, 1H in piperidine),3.12(br s,1H in piperidine),2.81(s,1H in piperidine,CH),2.22(s,3H,CH3),2.05(s,3H,CH3),1.78(m,4H in piperidine).

[0149] HRMS(ESI): m / z calculated value C 18 H19 F5N3O + [M+H] + :388.1443, Experimental value:388.1447.

[0150] Example 4: Synthesis of P4

[0151] 4.1 Synthesis of ethyl 1,5-dimethyl-1,2,4-triazol-3-carboxylate (004-SM9)

[0152] Add 1.00 g (6.4 mmol, 1.0 equiv.) of ethyl 5-methyl-4H-1,2,4-triazole-3-carboxylate (004-SM8) to a 100 mL round-bottom flask (with a magnetic stir bar), and add 12 mL of dry THF as a solvent. Stir in an ice-water bath at 0 °C. Then slowly add 250 mg-280 mg NaH (60%) (6.4-7.1 mmol, 1.0-1.1 equiv.). After 40 min, slowly add 0.39 mL of CH3I (6.4 mmol, 1.0 equiv.). After 10 min, remove the ice-water bath and stir at room temperature for 24 h. After the reaction was complete, the system was placed in an ice-water bath, and the reaction was quenched by adding saturated NH4Cl. THF was then removed by vortexing, followed by extraction with H2O (5 mL x 3) and ethyl acetate (10 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue was purified by column chromatography to give 0.68 g of ethyl 1,5-dimethyl-1,2,4-triazol-3-carboxylate (004-SM9), a yellow solid with a yield of 62%.

[0153] Data for ethyl 1,5-dimethyl-1,2,4-triazol-3-carboxylate (004-SM9):

[0154] Yellow solid, yield: 62%. f =0.19(DCM / CH3OH=50:1,v / v).

[0155] 1 H NMR (400MHz, CDCl3) δ4.37 (q, J = 7.1Hz, 1H), 3.83 (s, 2H), 2.44 (s, 2H), 1.34 (t, 3H).

[0156] The HMBC results are shown in Figure 1.

[0157] 4.2 Synthesis of 1,5-dimethyl-1,2,4-triazol-3-carboxylic acid (004-SM12)

[0158] 50 mg (0.3 mmol, 1.0 equiv.) of ethyl 1,5-dimethyl-1,2,4-triazol-3-carboxylic acid (004-SM9) was added to a 10 mL Sclenk tube (with a magnetic stir bar), followed by 0.5 mL of CH3OH solution. The tube was placed in an ice-water bath at 0 °C, and then 0.52 mL of 2 M / L KOH (aq.) was added. The tube was stoppered, and a balloon was attached to the support. After stirring for 10 min, the ice-water bath was removed, and the tube was placed in an oil bath at 70 °C for 1 h. After the reaction was complete, five drops of H2O were added, and the CH3OH was removed by rotary evaporation. Then, 13 drops of 2 M / L HCl were added, and the pH was adjusted to 1. The mixture was evaporated to dryness. The resulting white solid was sonicated repeatedly with small amounts of acetonitrile, and the liquid was evaporated by rotary evaporation to obtain 17 mg of 1,5-dimethyl-1,2,4-triazol-3-carboxylic acid (004-SM12), a white solid with a yield of 40%.

[0159] Data for 1,5-dimethyl-1,2,4-triazol-3-carboxylic acid (004-SM12):

[0160] White solid, yield: 40%. f =0.28(CH3OH).

[0161] 4.3 Take a 25 mL round-bottom flask (with a magnetic stir bar) and add 100 mg (0.38 mmol, 1.0 equiv.) 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine (004-SM7), 64 mg (0.45 mmol, 1.2 equiv.) 1,5-dimethyl-1,2,4-triazol-3-carboxylic acid (004-SM12) (the synthesis of 004-SM12 is described in 4.2), and 171 mg (0.45 mmol, 1.2 equiv.) 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) in sequence. Stopper the flask and purge with nitrogen three times. Then add 5 mL of dry DMF as a solvent. Next, add 78 μL of N,N-diisopropylethylamine (DIPEA) (0.45 mmol, 1.2 equiv.) to the system and stir at room temperature for 7 h. After the reaction was complete, DMF was removed by rotary evaporation. The residue was extracted with saturated NaCl (1 mL x 3) and ethyl acetate (2 mL x 3), and the organic phase was collected. After drying with anhydrous sodium sulfate, the solvent was removed by concentration. The residue was separated by column chromatography and then purified by recrystallization to give 10 mg of product P4 (yield 14%) as a white solid. f =0.05 (DCM / MeOH=50:1, v / v).

[0162] 1H NMR(400MHz,Chloroform-d)δ7.32(q,J=8.8Hz,1H),7.22-7.12(m,1H),4.91(d,J=13Hz,1H),4.75(d, J=13Hz,1H),3.86(s,3H),3.21(q,J=13Hz,2H),2.82(t,J=13Hz,1H),2.49(s,3H),1.91-1.71(m,4H).

[0163] HRMS (ESI) + Calculated value C 17 H 18 F5N4O + [M+1] + :389.1396; Experimental value:389.1395

[0164] 19 F NMR (376MHz, CDCl3) δ-53.6 (d, J=33.3Hz, 3F), -137.4 (dq, J=19.6, 33.3Hz, 1F), -137.90 (d, J=19.6Hz, 1F).

[0165] Synthesis of Example 5P5

[0166] 5.1 Synthesis of methyl 2-(2-(2-ethoxy-2-oxoethyl)hydrazine)propionate (005-SM3)

[0167] A 20 mL solution of MeOH:H₂O = 3:1 was added to a 50 mL round-bottom flask (with a magnetic stir bar), followed by 2.04 g (20.0 mmol, 1.0 equiv.) of methyl 2-oxopropionate (005-SM2). Then, 1.64 g (20.0 mmol, 1.0 equiv.) of sodium acetate and 3.08 g (20.0 mmol, 1.0 equiv.) of ethyl hydrazine carbamate hydrochloride (005-SM1) were added sequentially. The reaction mixture was then stirred at room temperature for 16 h. After the reaction was complete, the methanol was removed by vacuum concentration, and the mixture was diluted with water (5 mL). The solution was extracted with dichloromethane (10 mL x 3), and the organic phase was collected. After drying with anhydrous sodium sulfate, the organic phase was evaporated to dryness to obtain crude methyl 2-(2-(2-ethoxy-2-oxoethyl)hydrazineyl)propionate (005-SM3), which required no further purification.

[0168] Data for methyl 2-(2-(2-ethoxy-2-oxoethyl)hydrazine)propionate (005-SM3):

[0169] Yellow oily liquid, yield >99%.f =0.88 (DCM / MeOH = 20:1, v / v).

[0170] 5.2 Synthesis of methyl 4-hydroxy-5-methyl-1H-pyrazole-3-carboxylate (005-SM4)

[0171] Add 80 mL of anhydrous methanol to a 250 mL dry round-bottom flask (with a magnetic stir bar). Slowly add 1.2 g of Na under an ice-water bath to generate a sodium methoxide (54 mmol, 2.7 equiv.) methanol solution. Then add 4.0 g (20.0 mmol, 1.0 equiv.) of methyl 4-hydroxy-5-methyl-1H-pyrazole-3-carboxylate (005-SM4). Stir the system at 70 °C for 4 h. After the reaction is complete and the system has returned to room temperature, concentrate under reduced pressure to remove methanol, and dilute with water (15 mL). Slowly add 2 M HCl dropwise to the reaction system under an ice-water bath until pH = 7. Extract with ethyl acetate (15 mL x 5), collect the organic phase, dry with anhydrous sodium sulfate, and then evaporate the organic phase to obtain 1.0 g of crude methyl 4-hydroxy-5-methyl-1H-pyrazole-3-carboxylate (005-SM4). No purification is required; it can be directly added to the next step.

[0172] Data for methyl 4-hydroxy-5-methyl-1H-pyrazole-3-carboxylate (005-SM4):

[0173] Pale yellow solid powder, yield: 32%. f =0.28 (PE / EtOAc = 1:1, v / v).

[0174] 5.3 Synthesis of methyl 4-methoxy-3-methyl-1H-pyrazole-5-carboxylate (005-SM5)

[0175] Add 10 mL of DCM to a dried 50 mL round-bottom flask (with a magnetic stirrup). Then, under ice-water bath conditions, add 1.0 g (6.4 mmol, 1.0 equiv.) of methyl 4-hydroxy-5-methyl-1H-pyrazole-3-carboxylate (005-SM4) and 1.37 g (6.4 mmol, 1.0 equiv.) of N... 1 N 1 N 8 N 8The mixture was stirred for 30 min with tetramethylnaphthalene-1,8-diamine, and then 946.5 mg (6.4 mmol, 1.0 equiv.) of trimethyloxonium tetrafluoride boron salt was slowly added to the flask. The reaction mixture was stirred at room temperature for 12 h. The solution was diluted with DCM (5 mL) and filtered. The filtrate was quenched with KHSO4 (1 M) (10 mL x 2), then washed with saturated NaCl solution (15 mL x 3), and the organic phase was collected. After drying with anhydrous sodium sulfate, the solvent was removed by concentration. The residue was purified by column chromatography to give 620 mg of methyl 4-methoxy-3-methyl-1H-pyrazole-5-carboxylate (005-SM5) as a pale yellow solid powder, with a yield of 57%. f =0.85 (PE / EtOAc = 1:1, v / v).

[0176] 5.4 Synthesis of 4-methoxy-5-methyl-1H-pyrazole-3-carboxylic acid (005-SM6)

[0177] 2 mL of MeOH was added to a 25 mL round-bottom flask (with a magnetic stir bar) to dissolve 620 mg (3.6 mmol, 1.0 equiv.) of 4-methoxy-5-methyl-1H-pyrazole-3-carboxylic acid (005-SM6). 6.3 mL (12.6 mmol, 3.5 equiv.) of 2M KOH solution was added under ice-water bath conditions, and the reaction mixture was stirred at 70 °C for 5 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove methanol, and 2M HCl was slowly added dropwise under ice-water bath conditions until the pH reached 1. A white solid precipitated, and 478 mg of 4-methoxy-5-methyl-1H-pyrazole-3-carboxylic acid (005-SM6) white solid powder was obtained by filtration, with a yield of 85%. f =0.26(DCM / MeOH / CH3COOH=100:10:1,v / v).

[0178] 5.5 Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methoxy-5-methyl-1H-pyrazol-3-yl) methyl ketone (P5)

[0179] In a 25 mL dry round-bottom flask (with a magnetic stir bar), add 56.2 mg (0.36 mmol, 1.0 equiv.) of 4-methoxy-5-methyl-1H-pyrazole-3-carboxylic acid (005-SM6) and 163.5 mg (0.43 mmol, 1.2 equiv.) of HATU. Purge and release N2 three times. Under a nitrogen atmosphere, add 108 mg (0.36 mmol, 1.0 equiv.) of 4-(3,4-difluoro-2-trifluoromethylphenyl)piperidine (005-SM7) dissolved in 2 mL of DMF. After stirring for 30 min, add 72 μL (0.43 mmol, 1.2 equiv.) of DIPEA. Stir the reaction mixture at room temperature for 8 h. After the reaction was complete, the DMF was removed by concentration under reduced pressure. The residue was purified by column chromatography to obtain 86 mg of crude (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methoxy-5-methyl-1H-pyrazol-3-yl) methyl ketone (P5), which was then purified by PTLC to obtain 55 mg of pure white solid powder. f =0.78 (DCM / MeOH = 10:1, v / v).

[0180] Nuclear magnetic resonance spectroscopy was performed using a Bruker 400M instrument. 1 H NMR (400MHz, CDCl3-d) δ (ppm): 7.97 (br s, 1H, NH), 7.36 (q, J = 9.2Hz, 1H, ArH), 7.21 (dd, J = 9.2, 4.6Hz, 1H, ArH), 4.40 (d, J = 13.3Hz, 2H in Piperazine), 3.76 (s, 3H in OCH3),3.29-3.13(m,1H in Piperazine),3.03(t,J=12.0Hz,2H in Piperazine),2.05(s,3H in Pyrazole),1.94-1.74(m,4H in Piperazine).

[0181] HRMS (ESI) + Calculated value C 18 H 19 F5N3O2 + [M+H] + :404.1392; Experimental value:404.1397.

[0182] Synthesis of Example 6P6

[0183] 6.1 Synthesis of tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (006-SM3)

[0184] Dry a 25 mL three-necked round-bottom flask (with a magnetic condenser) connected to a spherical condenser with a flame. Add 343 mg (1.84 mmol, 1.2 equiv.) of tert-butyl piperazine-1-carboxylate (006-SM2). Purge the system with N2 three times to create an N2 atmosphere. Add 10 mL of anhydrous toluene, and then add 226 μL (1.53 mmol, 1.0 equiv.) of 1-bromo-3,4-difluoro-2-(trifluoromethyl)benzene (006-SM1). Subsequently, under a nitrogen atmosphere and at room temperature, 95 mg (0.15 mmol, 0.1 equiv.) of 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP) and 294 mg (3.06 mmol, 2.0 equiv.) of sodium tert-butoxide were added to the stirred system, followed by the addition of 17 mg (5 mol%) of palladium acetate. The system was then transferred to an oil bath at 110 °C and heated with stirring for 6 h. After the reaction was complete, the reaction system was cooled to room temperature, and the mixture was filtered under reduced pressure. The residue was washed with ethyl acetate, and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give 460 mg of tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (006-SM3), a colorless liquid with a yield of 82%.

[0185] Characterization data for tert-butyl piperazine-1-carboxylate (006-SM3):

[0186] Colorless liquid, 460 mg (1.53 mmol scale), yield 82%. f =0.69 (PE / EA = 5:1, v / v). 1 H NMR (400MHz, CDCl3) δ (ppm) δ7.30 (q, J = 8.8Hz, 1H, ArH), 7.01-6.94 (m, 1H, ArH), 3.55 (br s, 4H in Piperazine), 2.84 (br s, 4H in Piperazine), 1.48 (s, 9H in t-Bu).

[0187] 6.2 Synthesis of 1-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperazine (006-SM4)

[0188] 55 mg (0.15 mmol, 1.0 equiv.) of tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (006-SM3) was added to a 10 mL reaction tube, followed by 1 mL of a solution of dichloromethane:trifluoroacetic acid in a volume ratio of 5:1. The system was stirred at room temperature for 1 h. After the reaction was complete, saturated sodium bicarbonate solution was slowly added dropwise to the reaction system until the solution became weakly alkaline. The mixture was extracted with dichloromethane (5 mL x 3), and the organic phase was collected. After drying with anhydrous sodium sulfate, the organic phase was evaporated to dryness to obtain the corresponding crude product 1-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperazine (006-SM4), which can be directly added to the next step without purification (this step is a simple deBoc reaction, and the product has not been characterized).

[0189] Data for (3,4-difluoro-2-(trifluoromethyl)phenyl)piperazine (006-SM4):

[0190] Colorless liquid, yield >99%. f =0.41 (DCM / MeOH = 10:1, v / v).

[0191] 6.3 Synthesis of the target compound (P6)

[0192] In a 10 mL reaction tube, 40 mg (0.15 mmol, 1.0 equiv.) 1-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperazine (006-SM4), 28 mg (0.16 mmol, 1.1 equiv.) 1,4,6,7-tetrahydropyran[4,3-c]pyrazole-3-carboxylic acid (006-SM5), 114 mg (0.3 mmol, 2.0 equiv.) condensing agent HATU, and 65 μL (0.75 mmol, 2.5 equiv.) N,N-diisopropylethylamine were added sequentially. Then, 2.5 mL of anhydrous DMF was added to the reaction tube as a solvent. The reaction system was stirred at room temperature until the starting materials were completely consumed. After the reaction was complete, a large amount of DMF was removed by rotary evaporation. The residue was dissolved in 10 mL of dichloromethane, then washed with water (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue was purified by column chromatography to give 31 mg of the target product (P6), with a yield of 50%. Recrystallization (pure EtOAc) yielded the final pure product, a white solid, meeting the requirements. f =0.66 (DCM / MeOH=10:1, v / v).

[0193] Nuclear magnetic resonance spectroscopy was performed using a Bruker 400M instrument. 1H NMR (400MHz, DMSO-d6) δ (ppm): 13.01 (br s, 1H, NH), 7.74 (q, J = 9.6Hz, 1H, ArH), 7.34 (dd, J = 9.6, 4.0Hz, 1H, ArH), 4.66 (s, 2H, OCH2), 4.27 (br s, 2H in Piperazine), 3.80 (t, J=5.6Hz, 3H, in OCH2CH2 and Piperazine), 3.69 (br s, 1H in Piperazine), 2.91 (app t, J=5.0Hz, 4H in Piperazine), 2.71 (t, J=5.6Hz, 2H, CH2).

[0194] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 161.81 (CO), 148.69 (N-ArC), 147.99 (dd, 1 J CF =260.28, 2 J CF =18.58Hz), 147.09(dd, 1 J CF =245.33, 2 J CF =13.03Hz),141.30(NHC),136.48(NC),122.96(q, 1 J CF =275.73Hz), 121.26(d, 2 J CF =17.57Hz),120.22,116.92,114.12(q, 3 J CF =4.75Hz),63.71(OCH2),62.98(OCH2),53.62,53.31,46.32,42.14,21.78(CH2 in CH2CH2).

[0195] HRMS (ESI) + Calculated value C 18 H 18 F5N4O2 + [M+1] + :417.1345; Experimental value:417.1366.

[0196] Synthesis of Example 7P7

[0197] 7.1 Synthesis of methyl 2-(2-(2-ethoxy-2-oxoethyl)hydrazine)propionate (007-SM3).

[0198] A 20 mL solution of MeOH:H₂O = 3:1 was added to a 100 mL round-bottom flask (with a magnetic stir bar), followed by 2.04 g (20.0 mmol, 1.0 equiv.) of methyl 2-oxopropionate (007-SM2). Then, 1.64 g (20.0 mmol, 1.0 equiv.) of sodium acetate and 3.08 g (20.0 mmol, 1.0 equiv.) of ethyl hydrazine hydrochloride (007-SM1) were added sequentially. The reaction mixture was then stirred at room temperature for 16 h. After the reaction was complete, the methanol was removed by vacuum concentration, and the mixture was diluted with water (5 mL). The solution was extracted with dichloromethane (10 mL x 3), and the organic phase was collected. After drying with anhydrous sodium sulfate, the organic phase was evaporated to dryness to obtain crude methyl 2-(2-(2-ethoxy-2-oxoethyl)hydrazineyl)propionate (007-SM3), which required no further purification.

[0199] Data for methyl 2-(2-(2-ethoxy-2-oxoethyl)hydrazine)propionate (007-SM3):

[0200] Yellow oily liquid, yield >99%. f =0.88 (DCM / MeOH = 20:1, v / v).

[0201] 7.2 Synthesis of methyl 4-hydroxy-5-methyl-1H-pyrazole-3-carboxylate (007-SM4)

[0202] Add 80 mL of anhydrous methanol to a 250 mL dry round-bottom flask (with a magnetic stir bar). Slowly add 1.2 g of Na under an ice-water bath to generate a sodium methoxide (54 mmol, 2.7 equiv.) methanol solution. Then add 4.0 g (20.0 mmol, 1.0 equiv.) of methyl 4-hydroxy-5-methyl-1H-pyrazole-3-carboxylate (007-SM4). Stir the system at 70 °C for 4 h. After the reaction is complete and the system has returned to room temperature, concentrate under reduced pressure to remove methanol, and dilute with water (15 mL). Slowly add 2 M HCl dropwise to the reaction system under an ice-water bath until pH = 7. Extract with ethyl acetate (15 mL x 5), collect the organic phase, dry with anhydrous sodium sulfate, and then evaporate the organic phase to obtain 1.0 g of crude methyl 4-hydroxy-5-methyl-1H-pyrazole-3-carboxylate (007-SM4). No purification is required; it can be directly added to the next step.

[0203] Data for methyl 4-hydroxy-5-methyl-1H-pyrazole-3-carboxylate (007-SM4):

[0204] Pale yellow solid powder, yield: 32%. f =0.28 (PE / EtOAc = 1:1, v / v).

[0205] 7.3 Synthesis of methyl 4-methoxy-3-methyl-1H-pyrazole-5-carboxylate (007-SM5)

[0206] Add 10 mL of DCM to a dried 50 mL round-bottom flask (with a magnetic stirrup). Then, under ice-water bath conditions, add 1.0 g (6.4 mmol, 1.0 equiv.) of methyl 4-hydroxy-5-methyl-1H-pyrazole-3-carboxylate (007-SM4) and 1.37 g (6.4 mmol, 1.0 equiv.) of N... 1 N 1 N 8 N 8 The mixture was stirred for 30 min with tetramethylnaphthalene-1,8-diamine, and then 946.5 mg (6.4 mmol, 1.0 equiv.) of trimethyloxonium tetrafluoride boron salt was slowly added to the flask. The reaction mixture was stirred at room temperature for 12 h. The solution was diluted with DCM (5 mL) and filtered. The filtrate was quenched with KHSO4 (1 M) (10 mL x 2), and then washed with saturated NaCl solution (15 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue was purified by column chromatography to give 620 mg of methyl 4-methoxy-3-methyl-1H-pyrazole-5-carboxylate (007-SM5) as a pale yellow solid powder, with a yield of 57%. f =0.85 (PE / EtOAc = 1:1, v / v). 1 H NMR (400MHz, CDCl3) δ (ppm): 6.91 (s, 1H, NH), 3.97 (s, 3H, CH3), 3.96 (s, 3H in OCH3), 2.20 (s, 3H in Pyrazole).

[0207] 7.4 Synthesis of 4-methoxy-5-methyl-1H-pyrazole-3-carboxylic acid (007-SM6)

[0208] 2 mL of MeOH was added to a 25 mL round-bottom flask (with a magnetic stir bar) to dissolve 620 mg (3.6 mmol, 1.0 equiv.) of 4-methoxy-5-methyl-1H-pyrazole-3-carboxylic acid (007-SM6). 6.3 mL (12.6 mmol, 3.5 equiv.) of 2M KOH (aq.) was added under ice-water bath conditions, and the reaction mixture was stirred at 70 °C for 5 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove methanol, and then 2M HCl was slowly added dropwise under ice-water bath conditions until pH = 1. A white solid precipitated, and after filtration, 478 mg of 4-methoxy-5-methyl-1H-pyrazole-3-carboxylic acid (007-SM6) white solid powder was obtained, with a yield of 85%. f =0.26(DCM / MeOH / CH3COOH=100:10:1,v / v). 1 H NMR (400MHz, DMSO-d6) δ (ppm): 3.85 (s, 3H in OCH3), 2.04 (s, 3H in Pyrazole).

[0209] 7.5 Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperazin-1-yl)(4-methoxy-5-methyl-1H-pyrazol-3-yl)methyl ketone (P7)

[0210] In a dry 25 mL round-bottom flask (with a magnetic stir bar), add 40.5 mg (0.26 mmol, 1.0 equiv.) of 4-methoxy-5-methyl-1H-pyrazole-3-carboxylic acid (007-SM6) and 117.8 mg (0.31 mmol, 1.2 equiv.) of HATU. Purge and release N2 three times. Under a nitrogen atmosphere, add 69.2 mg (0.26 mmol, 1.0 equiv.) of 41-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperazine (007-SM7) dissolved in 2.0 mL of DMF. After stirring for 30 min, add 54 μL (0.31 mmol, 1.2 equiv.) of DIPEA. Stir the reaction mixture at room temperature for 7 h. After the reaction was complete, the DMF was removed by concentration under reduced pressure. The residue was purified by column chromatography to obtain 54 mg of crude (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperazin-1-yl)(4-methoxy-5-methyl-1H-pyrazol-3-yl) methyl ketone (P7), which was then purified by PTLC to obtain 36 mg of pure white solid powder. f =0.75 (DCM / MeOH = 10:1, v / v).

[0211] 1H NMR (400MHz, Methanol-d4) δ (ppm): 7.52 (q, J=9.6Hz, 1H, ArH), 7.24 (ddd, J=9.6, 4.0, 2.0Hz 1H, ArH), 3.75 (br s, 4H in Piperazine), 3.75 (s, 3H in OCH3)2.99(t,J=5.0Hz,4H in Piperazine),2.14(s,3H in Pyrazole).

[0212] HRMS (ESI) + Calculated value C 17 H 18 F5N4O2 + [M+H] + :405.1344; Experimental value:405.1347.

[0213] Synthesis of Example 8P8

[0214] 8.1 Synthesis of P8-1

[0215] In a dry 25 mL round-bottom flask, 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperazine (006-SM4; 150 mg, 0.57 mmol, 1.0 equiv., its synthesis is described in Example 6), 6H-pyrazole[3,4-C]1,4,5,7-tetrahydropyridine-3,6-carboxylic acid 6-(1,1-dimethylethyl) ester (LBS-SM6; CAS: 821785-76-6.182 mg, 0.68 mmol, 1.2 equiv.), and HATU (258 mg, 0.68 mmol, 1.2 equiv.) were added sequentially, substituted with N2 three times, dissolved in 5 mL of ultra-dry DMF, and diisopropylethylamine (DIPEA, 0.12 mL, 1.2 equiv.). The reaction was carried out at 25℃ for 6 hours. After the reaction was completed, DMF was removed under reduced pressure. The product was dissolved in 10 mL of DCM, washed with water (10 mL x 3), dried over anhydrous Na2SO4 to remove the solvent, and separated by column chromatography (eluent DCM / MeOH = 60:1 to 20:1, gradient elution) to give product P8-1 (white solid; 170 mg, 0.33 mmol, 59%; Rf = 0.7 (DCM / MeOH = 10:1, v / v)).

[0216] 1H NMR(400MHz, CDCl3)δ7.33(q,J=8.6Hz,1H,ArH),7.16(q,J=8.6,1H,ArH),4.60(m,4H,NCH2),3.66(s,2H,NCH2),3.29-3.01(m,2H, NCH2,),2.72(t,J=5.3Hz,2H,=CH-CH2),1.88(d,J=11.8Hz,2H,CH2),1.75(d,J=9.6Hz,2H,CH2),1.49(s,9H,CH3).MS(H+):516.49.

[0217] 8.2 Synthesis of P8-2

[0218] Add P8-1 (170 mg, 0.33 mmol) to a 25 mL dry round-bottom flask, dissolve it in 3 mL of 1,4-dioxane, and slowly add 3 mL of 4 M HCl solution of 1,4-dioxane. React at 25 °C for 1.5 hours until a white turbidity appears. After the reaction is complete, remove the solvent under reduced pressure to obtain a white solid. Dissolve the solid in 5 mL of DCM, adjust the pH to 7-8 with saturated NaHCO3 solution, dry with Na2SO4, and evaporate the organic solvent under reduced pressure to obtain the product P8-2 (white solid, 136 mg, 0.33 mmol, 100%).

[0219] 8.3 Synthesis of the target compound (P8)

[0220] Add P8-2 (132 mg, 0.32 mmol, 1.0 equiv.) to a dry 25 mL round-bottom flask, replace with N2 three times, dissolve in 10 mL DCM, inject triethylamine (Et3N, 136 μL, 0.98 mmol, 3.0 equiv.), stir for 1 hour, then slowly add acetyl chloride (23 μL, 0.33 mmol, 1.0 equiv.) under an ice-water bath, react at 0 °C for 35 min, quench the reaction with 1 mL methanol, stir for 5 minutes, remove the solvent under reduced pressure, dissolve in 5 mL DCM, wash with H2O (10 mL x 3), collect the organic phase, dry with anhydrous Na2SO4 to remove the solvent, separate by column chromatography (eluent DCM / MeOH / NH4OH = 100:2:1), to give product P8. (56 mg; Rf = 0.65 (DCM / MeOH / NH4OH = 100:10:1)).

[0221] 1H NMR(400MHz,MeOD)δ7.53(q,J=8.6Hz,1H,ArH),7.39(q,J=8.6Hz,1H,ArH),4.72(m,4H,NCH2),3.86-3.80(m,1 H,NCH),3.76(t,J=5.3Hz,1H,NCH),3.25-2.73(m,4H,NCH2,=C-CH2),2.20(s,3H,CH3),1.95-1.73(m,4H,CH2).

[0222] Synthesis of Example 9P9

[0223] 9.1 Synthesis of P9-1

[0224] In a 25 mL three-necked round-bottom flask (with a magnetic stirrer) equipped with a spherical condenser, 343 mg (1.84 mmol, 1.2 equiv.) of piperazine-1-carboxylic acid tert-butyl ester was added. The mixture was charged and discharged with N2 three times, followed by the addition of 10 mL of anhydrous toluene, and then 226 μL (1.53 mmol, 1.0 equiv.) of 1-bromo-3-fluoro-2-(trifluoromethyl). Subsequently, 95 mg (0.15 mmol, 0.1 equiv.) of 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) and 294 mg (3.06 mmol, 2.0 equiv.) of sodium tert-butoxide were added to the stirred system. Then, 17 mg (5 mol%) of palladium acetate was added to the solution, and the mixture was stirred in an oil bath at 110 °C for 6 h. After cooling to room temperature, the mixture was filtered under reduced pressure, washed with ethyl acetate, concentrated, and the residue was purified by column chromatography to give 460 mg of 4-(3-fluoro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (P9-1), a colorless liquid with a yield of 82%. 400 mg (1.52 mmol / L).

[0225] 1 H NMR (400MHz, CDCl3) δ (ppm) δ7.30 (q, J=8.8Hz, 1H, ArH), 7.01-6.94 (m, 2H, ArH), 3.55 (br s, 4H in Piperazine), 2.84 (br s, 4H in Piperazine), 1.48 (s, 9H in t-Bu).MS+:349.33.

[0226] 9.2 Synthesis of P9-2

[0227] Add 55 mg (0.15 mmol, 1.0 equiv.) tert-butyl 4-(3-fluoro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (P9-1) to a 10 mL reaction tube, followed by 1 mL of a solution of dichloromethane:trifluoroacetic acid in a volume ratio of 5:1. Stir the system at room temperature for 1 h. After the reaction is complete, slowly add saturated sodium bicarbonate solution dropwise to the reaction system until it becomes weakly alkaline. Extract with dichloromethane (5 mL x 3), collect the organic phase, dry it with anhydrous sodium sulfate, and then evaporate the organic phase to obtain the corresponding crude product 1-(3-fluoro-2-(trifluoromethyl)phenyl)piperazine (P9-2), which can be directly added to the next step without purification.

[0228] 9.3 Synthesis of P9-3

[0229] In a dry 25 mL round-bottom flask, add 4-(3-fluoro-2-(trifluoromethyl)phenyl)piperazine P9-2 (146 mg, 0.56 mmol, 1.0 equiv.), 6H-pyrazole [3,4-C]1,4,5,7-tetrahydropyridine-3,6-carboxylic acid 6-(1,1-dimethylethyl) ester (LBS-SM6; CAS: 821785-76-6.182 mg, 0.68 mmol, 1.2 equiv.), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU; 258 mg, 0.68 mmol, 1.2 equiv.), purged three times with N2, dissolved in 5 mL of ultra-dry DMF, and diisopropylethylamine (DIPEA, 0.12 mL, 1.2 equiv.). The reaction was carried out at 25°C for 6 hours. DMF was removed under reduced pressure. The product was dissolved in 10 mL of DCM, washed with water (10 mL x 3), dried over anhydrous Na2SO4 to remove the solvent, and separated by column chromatography (eluent DCM / MeOH = 60:1 to 20:1, gradient elution) to give product P9-3 (white solid; 160 mg, 0.32 mmol).

[0230] 1 H NMR (400MHz, CDCl3) δ7.33 (q, J=8.6Hz, 1H, ArH), 7.16 -7.10(q,2H,ArH),4.60(m,4H,NCH2),3.66(s,2H,NCH2),3.29-3.01(m,2H,NCH2),2.72(t,J=5.3Hz,2H ,=CH-CH2),1.88(d,J=11.8Hz,2H,CH2),1.75(d,J=9.6Hz,2H,CH2),1.49(s,9H,CH3).MS(H+):498.49.

[0231] Synthesis of 9.4P9-4

[0232] Add P9-3 (160 mg, 0.33 mmol) to a 25 mL dry round-bottom flask, dissolve it in 3 mL of 1,4-dioxane, add 3 mL of 4 M HCl solution of 1,4-dioxane dropwise, react at 25 °C for 1 hour, remove the solvent under reduced pressure to obtain a white solid, dissolve it in 5 mL of DCM, adjust the pH to 7-8 with saturated NaHCO3 solution, dry with Na2SO4, and evaporate the organic solvent under reduced pressure to obtain the product P9-4 (white solid, 130 mg, 0.33 mmol, 100%).

[0233] 9.5 Synthesis of the target compound (P9)

[0234] Add P9-4 (132 mg, 0.32 mmol, 1.0 equiv.) to a dry 25 mL round-bottom flask, replace with N2 three times, dissolve in 10 mL DCM, then inject triethylamine (Et3N, 136 μL, 0.98 mmol, 3.0 equiv.) using a microsyringe, stir for half an hour, then slowly add acetyl chloride (23 μL, 0.33 mmol, 1.0 equiv.) under an ice-water bath, react at 0 °C for 35 min, quench the reaction with 1 mL methanol, stir for 5 minutes, remove the solvent under reduced pressure, dissolve in 5 mL DCM, and add H2O (10 mL x 3) Wash and collect the organic phase, dry with anhydrous Na2SO4 to remove the solvent, and separate by column chromatography (eluent DCM / MeOH / NH4OH = 100:2:1) to obtain product P9 (50 mg, 35%; Rf = 0.65 (DCM / MeOH / NH4OH = 100:10:1, v / v / v)).

[0235] 1 H NMR (400MHz, MeOD) δ7.53 (q, J=8.6Hz, 1H, ArH), 7.39 -7.30(q,J=8.6Hz,2H,ArH),4.72(m,4H,NCH2),3.86-3.80(m,1H,NCH),3.76(t,J=5.3Hz,1H, NCH),3.25-2.73(m,4H,NCH2,=C-CH2),2.20(s,3H,CH3),1.95-1.73(m,4H,CH2).MS+:440.41.

[0236] Example 1: RBP4 Inhibition Effect Test

[0237] Laboratory animals: Mice; Species and strain: ICR SPF grade; Sex and age: Male, 8 weeks old;

[0238] Compounds P3, P4, and P6 prepared in Examples 3, 4, and 6 were dissolved in PBS + 5% DMSO to prepare compound solutions.

[0239] Mice that had been fasted for 8 hours were administered the above-mentioned compound solution via gavage, with a blank control group of mice (administered physiological saline). The dosage was 3 mg / kg. Plasma samples were collected from the animals at 0, 5, and 8 hours after administration (three parallel experiments were conducted). The samples were placed in ordinary centrifuge tubes or coagulation-promoting tubes for 30 minutes, centrifuged at 1000g, and 50-100 μL of serum was collected and stored at -80°C for biochemical analysis within 3 days. The RBP4 protein content in mouse plasma was measured to determine the efficacy of the compound. The results are shown in the table below.

[0240] In the table above, a negative inhibition rate indicates that the RBP4 protein content in plasma has increased compared to before drug administration.

[0241] Example 2: Liver microsomal stability test

[0242] P3, P4, P6 and verapamil hydrochloride prepared in Examples 3, 4 and 6 were dissolved in DMSO to form working solutions.

[0243] Add 358 μL of 0.5587 mg / mL microparticle solution and 40 μL of 8.334 mg / mL NADPH solution to a 96-well incubation plate. Vortex at 800 rpm for 10 seconds, then pre-incubate at 37°C for 10 minutes. The negative sample is prepared with 40 μL of PBS solution. After pre-incubation, add 2 μL of the compound working solution to each well to start the reaction. After mixing, remove 50 μL of the reaction mixture from each well at 0.5, 15, 30, 45, and 60 minutes and add it to 200 μL of internal standard stop solution to terminate the reaction. The reaction is carried out at 37°C in a water bath at 60 rpm. After mixing by vortexing at 800 rpm for 3-5 minutes, centrifuge at 3220 g for 30 minutes at 4°C. Take 100 μL of supernatant and mix it with 100 μL of ultrapure water (the ratio of supernatant to ultrapure water can be adjusted according to the sample chromatographic peak shape and signal response) and use it for liquid chromatography-mass analysis.

[0244] The internal standard method was used, and the ratio of the sample peak area to the internal standard peak area was used to calculate the remaining percentage (with the ratio of the sample peak area to the internal standard peak area at 0.5 minutes being 100%).

[0245] Plot the natural logarithm of the remaining percentage against the incubation time. The slope of the straight line is the elimination rate constant k. Calculate the half-life t1 / 2 and the clearance rate Clint using the following formulas.

[0246] The results are shown in the table below.

[0247] *t1 / 2" > 184.79" and CLint "< 7.50" are reported when the remaining cpds% > 80 after 60 minutes.

[0248] Example 3: CYP Inhibition Experiment

[0249] 25 nL of the 2 mM test compound (P3 and P6 provided in Examples 3 and 6) or 125 nL of the positive control compound (see Table 1) was transferred to an incubation plate, and then a 22.375 μL master solution was prepared according to Table 2. The final concentration of the test compound was 10 μM, and the final concentrations of the positive control compounds were shown in Table 1. DMSO was used as the solvent. All experiments were repeated.

[0250] Table 1 Preparation of positive control compounds

[0251] Table 2 Preparation of the main solution

[0252] Table 3. Preparation of substrates

[0253] The mixture was preheated at 37°C for 15 minutes. The reaction was then initiated by adding 2.5 μL of 10 mM NADPH solution (final concentration 1 mM), and the entire reaction was carried out at 37°C.

[0254] At specified time points, 50 μL of pre-cooled quenching solution (containing methanol internal standards (100 nM Tolbutamide, 200 nM Labetalol, 100 nM Ketoprofen, 200 nM Imipramine) was added to stop the reaction (Phenacetin: 20 min; Bupropion: 20 min; Diclofenac: 5 min; (s)-Mephenytoin: 20 min; Bufuralol: 20 min; Testosterone: 10 min). The mixture was centrifuged at 3220 g for 45 min at 4 °C. Then, 40 μL of the supernatant was transferred to a new 384-well plate, and 40 μL of water was added for LC-MS / MS analysis.

[0255] Data analysis. The formation of metabolites was analyzed using LC-MS / MS. The inhibition rate percentage (%) was calculated by the decrease in the ratio of metabolite peak area to the solvent control group. Residual activity percentage = (average ratio of test compound or inhibitor / average ratio of solvent control group) x 100%. Inhibition rate percentage = 100% - residual activity percentage.

[0256] The results are shown in Table 4.

[0257] Table 4. Results of CYP450 enzyme inhibition

[0258] Test Example 4: Oral Compound Metabolism Experiment

[0259] The P3, P6 and positive control (Lbs-008) prepared in Examples 3 and 6 were dissolved in PBS and 10% DMSO to form compound solutions, respectively.

[0260] ICR, SPF, male, 8-week-old mice were used for the assay. Specifically, mice were fasted for 8 hours before administration, and then orally administered the above-mentioned compound solution via gavage (hereinafter referred to as PO) at a concentration of 3 mg / kg. Fasting was resumed 2 hours after administration. The changes in plasma drug concentrations of the compound were measured after oral administration, with sampling points at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, and 8.0 h, n = 3.

[0261] The results are shown in Table 5.

[0262] Table 5. Oral p-values ​​of compounds in mice

[0263] Test Example 5: Animal Experiment

[0264] Animals: SPF grade SD rats; female, weighing 200-220g.

[0265] Experimental methods: SD rats were fasted for 8 hours before being administered the drug, and then resumed eating 2 hours later. The administration methods were: gavage, 1.0 mg / kg and 10 mg / kg.

[0266] Blood collection time points: 0h, 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 8.0h, 12.0h, 24.0h, n = 3 / sex. At the specified time, collect 700μL of whole blood from the animal and place it in an EDTA anticoagulant tube. Centrifuge immediately after collection (4℃, 3000xg, 10 minutes) to separate the plasma.

[0267] Collect 4 plasma samples: 25 μL / sample, 2 samples (including one backup), for drug concentration detection; 100 μL / sample, 2 samples (including one backup), for RBP4 protein detection, and store frozen at -80 degrees Celsius.

[0268] The results are shown in Table 6.

[0269] Table 6. Oral p-values ​​of compounds in rats

[0270] As shown in Table 6, P6 rats had high oral exposure, which was significantly better than the control drug Lbs-008.

[0271] The above description is merely a preferred embodiment of this disclosure and is not intended to limit this disclosure. Various modifications and variations can be made to this disclosure by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this disclosure should be included within the scope of protection of this disclosure. Industrial applicability

[0272] This disclosure provides heterocyclic compounds with phenyl substituted structures that can effectively inhibit RBP4 and are expected to be used to treat RBP4-related diseases.

Claims

1. A compound of formula I, a deuterated compound thereof, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that, Among them, R 1 R 2 R 3 R 4 and R 5 Each is independently H, deuterium, halogen, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl or C 1-4 Halogenated alkyl groups; X is CR 7 Or N; R 7 For H, deuterium, OH, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl or C 1-4 Halogenated alkyl groups; R 6 For one or more R 6-2 Substituted phenyl or substituted with one or more R 6-1 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and are 5-6 membered heteroaryl groups with one, two, or three heteroatoms. When X is CR 7 At that time, R 6-1 and R 6-2 Deuterium and C are respectively independent. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 The deuterated alkoxy group or "a 4-6 membered heterocyclic alkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms"; When X is N, R 6-1 and R 6-2 Deuterium and C are respectively independent. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or "a 4-6 membered heterocycle with one, two, or three heteroatoms selected from N, O, and S"; or, two adjacent R 6-1 Or two adjacent R 6-2 Together with the intermediary atoms they are connected to, they form C 3-6 A carbon ring, "a 4-6 membered heterocycle selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", and surrounded by one or more R... 6-1-1 Replacement C 3-6 Carbon rings or "by one or more R" 6-1-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, forming a 4-6 membered heterocycle. R 6-1-1 and R 6-1-2 Deuterium and C are respectively independent. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy, -L 1 -R 6-1- 1-1 , cyano, C 3-6 Cycloalkyl, "a 4-6 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or containing one or more R... 6-1-1-2 Replacement C 1-4 alkyl; R 6-1-1-2 Independently for -L 2 -R 6-1-1-2-1 Deuterium, halogens, C 1-4 Alkyl, C 1-4 Deuterated alkyl, carboxyl, cyano, "a 4-6 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", C 3-6 cycloalkyl, -CONR a R b C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy or C 1-4 Alkoxy; L 1 and L 2 Independently -S-, -CO-, -CO-O-, -O-CO-, -SO2-, -CONR c -or NR d -; R 6-1-1-1 and R 6-1-1-2-1 Independent of H, deuterium, and C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 6-10 Aryl, "a 5-6 membered heteroaryl group selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 heteroatoms" or "a 4-6 membered heterocyclic alkyl group selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 heteroatoms"; R a R b R c and R d Independent of H, deuterium, and C 1-4 Deuterated alkyl or C 1-4 alkyl.

2. The compound of formula I as claimed in claim 1, its deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that, It meets one or more of the following conditions: (1) The "C" 1-4 Alkyl and substituted C 1-4 The "C" in "alkyl" 1-4 "alkyl" is independently methyl or ethyl; preferably methyl; (2) The halogen is independently F, Cl, Br or I; preferably F; (3) The C 1-4 The alkyl halide is independently C10. 1-4 Fluorinated alkyl group; preferably CF3; (4) The C 1-4 The alkoxy group is independently methoxy or ethoxy; preferably methoxy. (5) The heteroatom in the phrase "a 5-6 membered heteroaryl group selected from one, two or three of N, O and S, with one, two or three heteroatoms" is independently N; the number of heteroatoms can be independently two or three. (6) The phrase “a 5-6 membered heteroaryl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S and whose heteroatoms number 1, 2 or 3” is independently defined as “a 5 membered heteroaryl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S and whose heteroatoms number 1, 2 or 3”. (7) The heteroatom of the 4-6 membered heterocyclic alkyl group is O; preferably... (8) The two adjacent R 6-1 Or two adjacent R 6-2 The "4-6 membered heterocycles, consisting of one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms" formed together with the intermediary atoms they are connected to, and "enclosed by one or more R..." 6-1-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S. The heteroatoms in the "4-6 membered heterocycle" with one, two, or three heteroatoms are independently O or N; the number of heteroatoms can be one independently. (9) The two adjacent R 6-1 Or two adjacent R 6-2 The "4-6 membered heterocycles, consisting of one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms" formed together with the intermediary atoms they are connected to, and "enclosed by one or more R..." 6-1-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and the "4-6 membered heterocycle" in "4-6 membered heterocycle with one, two, or three heteroatoms" is a 6 membered heterocycle; (10) The two adjacent R 6-1 Or two adjacent R 6-2 The C formed together with the intermediary atoms they are connected to 3-6 Carbon rings and "by one or more R 6-1-1 Replacement C 3-6 The "C" in "carbon ring" 3-6 The carbon ring can be independently a C3 carbon ring, a C4 carbon ring, a C5 carbon ring, or a C6 carbon ring; (11) The C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; preferably cyclopropyl. (12)X is CR 7 ; (13) The C 1-4 The haloalkoxy group is independently C 1-4 Fluorinated alkyl group; preferably OCF3; (14) The C 1-4 The deuterated alkyl group is independently a deuterated methyl or a deuterated ethyl; preferably CD3; (15) The C 1-4 The deuterated alkoxy group is independently a deuterated methoxy or a deuterated ethoxy group; preferably OCD3.

3. The compound of formula I as claimed in claim 1, its deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that, It meets one or two of the following conditions: (1) The phrase "a 5-6 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" independently constitutes... (2) The two adjacent R 6-1 Or two adjacent R 6-2 The "4-6 membered heterocycles, consisting of one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms" formed together with the intermediary atoms they are connected to, and "enclosed by one or more R..." 6-1-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three. The "4-6 membered heterocycle" in the phrase "4-6 membered heterocycle" is independently...

4. The compound of formula I as claimed in claim 1, its deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that, It meets one or more of the following conditions: (1)R 1 R 2 R 3 R 4 and R 5 Each can be independently H, halogen, or C. 1-4 Haloalkyl; preferably, R 1 R 2 R 3 R 4 and R 5 Two or more of them are not H; more preferably, R 1 R 2 and R 3 Each independently is either halogen or C 1-4 Halogenated alkyl; R 4 and R 5 For H; (2)R 6 For one or more R 6-1 The substituted heteroatom is "a 5-6 membered heteroaryl group selected from one, two or three of N, O and S, with one, two or three heteroatoms"; (3)R 7 For H; (4) When X is CR 7 At that time, R 6-1 Independently for C 1-4 Alkyl, C 1-4 Alkoxy or "a 4-6 membered heterocyclic alkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms"; (5) When X is N, R 6-1 Independently for C 1-4 Alkyl group; or, two adjacent R groups. 6-1 Together with the intermediary atoms they are attached to, they form "4-6 membered heterocycles selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "a ring formed by one or more R..." 6-1-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, forming a 4-6 membered heterocycle. Preferably, when two adjacent R 6-1 Together with the intermediary atoms they are attached to, they form "4-6 membered heterocycles selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "a ring formed by one or more R..." 6-1-2 When the substituted heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, forming a 4-6 membered heterocycle, R... 6 for Ring A is "a 4-6 membered heterocycle with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, or three", and is surrounded by one or more R... 6-1-1 Replacement C 3-6 Carbon rings or "by one or more R" 6-1-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, forming a 4-6 membered heterocycle; more preferably, R 6 for Y 1 and Y 4 CH2; Y 2 and Y 3 Independent of O, NH or NR 6-1-2 ; (6)R 6-1-1 and R 6-1-2 Each independently is -L 1 -R 6-1-1-1 Or by one or more R 6-1-1-1 Replacement C 1-4 alkyl; (7)L 1 and L 2 Independently -CO-; (8) X is N; (9)R a R b R c and R d Independently H or C 1-4 alkyl.

5. The compound of formula I as claimed in claim 1, its deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that, It meets one or more of the following conditions: (1) When X is CR 7 At that time, the R 6-1 and R 6-2 Each independently Methyl or methoxy; (2) When X is N, the R 6-1 and R 6-2 Each is independently a methyl group, or two adjacent R groups. 6-1 Or two adjacent R 6-2 Together with the intermediary atoms they are connected to form (3) The R 6-1-1 and R 6-1-2 Each independently (4) Structural Unit for Preferred 6. The compound of formula I as claimed in claim 1, its deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that, It meets one or more of the following conditions: (1) When X is CR 7 At that time, R 6 for (2) When X is N, R 6 for 7. The compound of formula I as claimed in claim 1, its deuterated compound, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that, It is 8. A method for preparing a compound as shown in Formula I, characterized in that, It includes the following steps: In the presence of a solvent, a base and a condensing agent, the compound shown in Formula II and the compound shown in Formula III undergo a condensation reaction to produce the compound shown in Formula I. X, R 1 R 2 R 3 R 4 R 5 and R 6 The definition is as described in any one of claims 1-7.

9. The preparation method according to claim 8, characterized in that, It meets one or more of the following conditions: (1) The solvent is DCM or DMF; (2) The condensing agent is BOP or HATU; (3) The base is N,N-diisopropylethylamine.

10. A pharmaceutical composition, characterized in that, It includes: (1) The compound of formula I as described in any one of claims 1-7, or a pharmaceutically acceptable salt thereof; and (2) Pharmaceutically acceptable excipients.

11. Use of a compound of Formula I as described in any one of claims 1-7, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 10, wherein the use is selected from: (1) Preparation of RBP4 inhibitors; and (2) Prepare a drug for the treatment or prevention of RBP4-related diseases, including age-related macular degeneration.

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