FAP inhibitor and application

Abstract

The invention belongs to the field of medicines, and relates to an FAP inhibitor and application thereof, the FAP inhibitor is specifically a compound shown in a formula I or pharmaceutically acceptable salt, optical isomer and stereoisomer thereof, and further, the invention also comprises application of the compound and a pharmaceutical composition thereof in preparation of medicines serving as the FAP inhibitor, the traditional Chinese medicine composition can be used for preventing and treating tumors, rheumatic arthritis, non-alcoholic fatty liver and atherosclerosis.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to an FAP inhibitor and its uses, mainly including its use in the prevention and treatment of tumors, inflammatory diseases, metabolic diseases or cardiovascular diseases. Background Technology

[0002] Fibroblast activation protein (FAP) is an important biomarker on the surface of tumor-associated fibroblasts. It is highly expressed in over 90% of stromal fibroblasts in epithelial cancers and is widely distributed in many cancer types, such as sarcoma, prostate cancer, breast cancer, lung cancer, pancreatic cancer, head and neck cancer, and colorectal cancer. Studies have shown that FAP promotes tumor development and progression through multiple mechanisms, including promoting tumor angiogenesis, tumor growth, immune evasion, and assisting tumor metastasis. Furthermore, and importantly, due to its low expression levels in healthy tissues, FAP is considered a promising target for tumor diagnosis and treatment.

[0003] The FAP inhibitor talapostat (PT-100) was evaluated in Phase II clinical trials as a treatment for various cancers (PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 2004, 64, 5471-5480; Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma J. BMC Cancer 2009,9, 263). Although it showed clinical response in some trials, its subsequent development was terminated due to safety concerns caused by insufficient selectivity.

[0004] FAP is highly expressed in arthritis, atherosclerotic plaques, and fibrotic tissue. FAP hydrolyzes and breaks down substrates such as type I and type III collagen, α2-antifibrinolytic enzyme, and fibroblast growth factor, creating a pro-fibrotic environment that promotes the infiltration of immune cells, proliferation of synovial fibroblasts, and angiogenesis. It is associated with rheumatoid arthritis, non-alcoholic fatty liver disease, and the worsening of atherosclerosis.

[0005] In a diet-induced obesity model, the FAP gene knockout group showed better metabolic health compared to the wild-type control group. FAP deficiency prevented liver steatosis, glucose intolerance, and insulin resistance. Pancreatic and plasma insulin levels, pancreatic β-cell hyperplasia, serum alanine aminotransferase, and circulating cholesterol levels were all significantly reduced (Fibroblast activation protein enzyme deficiency prevents liver steatosis, insulin resistance, and glucose intolerance and increases fibroblast growthfactor-21 in diet-induced obese mice. Bio. Rxiv. (2018).).

[0006] Currently, there are relatively few FAP inhibitors used for the prevention and treatment of tumors, inflammatory diseases, metabolic diseases, or cardiovascular diseases. Therefore, it is necessary to develop more FAP inhibitors with good selectivity and strong inhibitory activity. Summary of the Invention

[0007] Objective of the Invention: To overcome the shortcomings of the prior art, this invention aims to provide a FAP inhibitor with good selectivity and inhibitory activity, and its uses. This invention provides a compound or its pharmaceutically acceptable salts, optical isomers, stereoisomers, and corresponding solvates, metabolites, cocrystals, or prodrugs and pharmaceutical compositions for the prevention and / or treatment of FAP-mediated diseases.

[0008] To achieve the above objectives, the technical solution provided by the present invention is as follows: In a first aspect, a compound of Formula I or a pharmaceutically acceptable salt, optical isomer, or stereoisomer thereof is provided: ; Wherein, ring A is arbitrarily selected from substituted saturated 4- to 7-membered alicyclic alkyl, saturated 7- to 8-membered bridged heterocyclic alkyl, optionally substituted saturated 8- to 10-membered spirocyclic alkyl, optionally substituted saturated 9-membered fused heterocyclic alkyl, wherein the number of heteroatoms on ring A is 1, 2, 3 or 4, and the heteroatoms are selected from one, two or three of N, O or S. When ring A is selected from a substituted saturated 4- to 7-membered alicyclic alkyl group, ring A may optionally be substituted with the following substituents: C 1-6 Alkyl, =O, -OH, -N(R) 1 (R) 2 ), saturated 4- to 6-membered alicyclic alkyl groups or 5- to 6-membered aromatic heterocyclic groups, wherein the C 1-6Alkyl groups, saturated 4- to 6-membered alicyclic alkyl groups, or 5- to 6-membered aromatic heteroyl groups may each be optionally substituted with one or more of the following substituents: -OH, -OR 3 halogen or C 1-6 Alkyl, wherein the R 1 R 2 Each is independently selected from H and C. 1-6 Alkyl or -S(O)2R 4 R 3 R 4 Selected from C 1-6 alkyl; When ring A is selected from an optionally substituted saturated 8- to 10-membered spirochetal alkyl group, ring A may optionally be substituted by one or more of the following substituents: C 1-6 alkyl; When ring A is selected from an optionally substituted saturated 9-membered fused heterocyclic alkyl group, ring A may optionally be selected from one or more of the following substituents: C 1-6 Alkyl or =O.

[0009] In some embodiments, when ring A is selected from optionally substituted saturated 4- to 7-membered alicyclic alkyl groups, in Formula I Partially selected from: The compound is described by formula I-1: ; Wherein A 1 Selected from -CH2- or -CH(R) 5 )-;A 2 Selected from -CH2-, -CH(R) 6 - or key; A 3 Selected from -CH2- or -CH(R) 7 )-;A 4 Selected from -CH2-, -CH(R) 5 - or key; A 5 Selected from -CH2- or the bond; Y is selected from -O-, -S-, -S(O)2-, -N(R)2-. 8 - or -CH(R) 9 )-;R 5 Selected from C 1-6 Alkyl; R 6 Selected from C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more of the following substituents: -OR 3 ;R 7 Selected from C 1-6 Alkyl or -OR 3 ;R 8 Selected from C 1-6 Alkyl, wherein the C 1-6Alkyl groups may optionally be substituted with one or more of the following substituents: -OR 3 ;R 9 Selected from -N(R) 1 (R) 2 ), saturated 4- to 6-membered alicyclic alkyl groups or 5- to 6-membered aromatic heterocyclic groups, wherein each of the saturated 4- to 6-membered alicyclic alkyl groups or 5- to 6-membered aromatic heterocyclic groups may optionally be substituted with one or more of the following substituents: - OR 3 halogen or C 1-6 Alkyl; R 1 R 2 Each is independently selected from H and C. 1-6 Alkyl or -S(O)2R 4 ;R 3 R 4 Selected from C 1-6 alkyl.

[0010] In some embodiments, the Selected from optional replacements , , , , , , , or Any one of them may optionally be substituted by one or two of the following substituents: methyl, =O, -OH, -CH2CH2OH, -CH2CH(OH)CH2OH, -CH2OCH3, or R 9 The saturated 4- to 6-membered alicyclic alkyl group or 5- to 6-membered aromatic heterocyclic group may optionally be independently selected from the following. , or Any one of them may optionally be substituted with the following substituents: chloro, methyl, or methoxy; R 10 R 11 Selected from C 1-3 alkyl.

[0011] In some embodiments, the Selected from optional replacements When, it can be substituted by one of the following substituents: The Selected from optional replacements Optionally, it can be substituted with one or two of the following substituents: -OH or The Selected from optional replacements Optionally, it can be substituted with one of the following substituents: , , or The Selected from optional replacements Optionally, it may be substituted with one or two of the following substituents: methyl, -CH2CH2OH, -CH2CH(OH)CH2OH, or -CH2OCH3; Selected from optional replacements Optionally, it may be substituted with the following substituents: methyl; Selected from optional replacements Optionally, it can be substituted with the following substituents: =O; the Selected from optional replacements Optionally, it can be substituted with the following substituents: -OH; Selected from optional replacements When it is substituted, it can be replaced by one of the following substituents: methyl.

[0012] In some embodiments, ring A for At that time, selected from: , , , , , , , , , , , , , , , , , , , , , or .

[0013] In some embodiments, when ring A is a saturated 7- to 8-membered bridged heterocyclic alkyl, an optionally substituted 8- to 10-membered spirocyclic alkyl, or an optionally substituted saturated 9-membered fused heterocyclic alkyl, the number of heteroatoms on ring A is 2, 3, or 4, and the heteroatoms are selected from one or both of N, O, or S; wherein when ring A is selected from an optionally substituted saturated 8- to 10-membered spirocyclic alkyl, ring A may optionally be substituted with the following substituents: C 1-3 Alkyl; wherein ring A is selected from an optionally substituted saturated 9-membered fused heterocyclic alkyl group, ring A may optionally be substituted with the following substituents: C 1-3 Alkyl or =O.

[0014] In some embodiments, the saturated 7- to 8-membered bridged heterocyclic alkyl group is selected from: or ; The optionally substituted 8- to 10-membered spirochetal alkyl groups are selected from: , , , , , , , , or ; The optionally substituted saturated 9-membered fused heterocyclic alkyl group is selected from: or .

[0015] In some embodiments, the optionally substituted 8- to 10-membered spirochetal alkyl group is selected from: , , , , , , , , or Any one of them may optionally be substituted with the following substituents: methyl; The optionally substituted saturated 9-membered fused heterocyclic alkyl group is selected from: or Any one of them may optionally be substituted by one of the following substituents: =O or methyl.

[0016] In some embodiments, The 8- to 10-membered spirochetal alkyl groups that are optionally substituted are selected from: , , , , , , , , or .

[0017] In some embodiments, The substituted saturated 9-membered fused heterocyclic alkyl group is selected from: or .

[0018] Furthermore, it is selected from any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0019] In a second aspect, the present invention also relates to a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt, optical isomer, stereoisomer, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0020] Thirdly, the present invention also relates to the use of the compounds described in the first aspect or pharmaceutically acceptable salts, optical isomers, stereoisomers, and solvates, metabolites, cocrystals or prodrugs thereof, or the pharmaceutical compositions described in the second aspect, in the preparation of a medicament as an FAP inhibitor.

[0021] The FAP inhibitors mentioned above are used to prevent and treat one or more of the following diseases: rheumatoid arthritis, non-alcoholic fatty liver disease, metabolic dysfunction-related steatohepatitis, atherosclerosis, myocardial infarction, and liver fibrosis.

[0022] The various terms and phrases used in this invention have their general meanings known to those skilled in the art. Nevertheless, this invention still intends to provide a more detailed description and explanation of these terms and phrases. In the event of any inconsistency between the terms and phrases mentioned and their known meanings, the meanings expressed in this invention shall prevail.

[0023] Unless otherwise stated, the terms used in the specification and claims shall have the following meanings.

[0024] As used in this invention, "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0025] As used in this invention, "C" 1-3 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 3 carbon atoms, such as 1, 2, or 3 carbon atoms. Specific examples include, but are not limited to, methyl, ethyl, propyl, or isopropyl.

[0026] As used in this invention, "C" 1-6 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc.

[0027] As used in this invention, "C" 3-12 "Cycloalkyl" refers to an aliphatic cyclic system containing 3 to 12 carbon atoms. For example, C 3-4 cycloalkyl or C 5-6 Cycloalkyl. "C" 3-12 "Cycloalkyl" includes monocyclic, fused, or bridged rings. Specific examples include, but are not limited to, cyclopropyl, cyclopentyl, or cyclohexyl.

[0028] The term "substituted" refers to a portion having a substituent that replaces a hydrogen atom or a substituted heteroatom on one or more carbons of a compound, such as hydrogen on NH or NH2. It should be understood that "substituted" or "replaced by" includes the implicit precondition that such substitution conforms to the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, i.e., a compound that does not spontaneously transform, such as through rearrangement, cyclization, elimination, etc. In some embodiments, "substituted" refers to a portion having a substituent that replaces two hydrogen atoms on the same carbon atom (such as replacing two hydrogen atoms on a single carbon with an oxo group, imino group, or thio group). As used herein, the term "substituted" is considered to include all permissible substituents in organic compounds, such as sulfur, which can be oxosubstituted as a heteroatom to form... In a broad sense, permitted substituents include acyclic and cyclic, branched and linear, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permitted substituents can be one or more and can be the same or different. Substituents include oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), etc.

[0029] As used herein, the term "heterocyclic alkyl" refers to a saturated or unsaturated cyclic group (including aromatic cyclic groups) containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocyclic groups include 3- to 8-membered heterocyclic groups and 4- to 6-membered heterocyclic groups, for example... , , , The heterocyclic group can optionally be substituted with one or more substituents (such as those described herein). Heterocyclic groups include monocyclic and polycyclic groups, wherein each ring can be selected from saturated, unsaturated, and aromatic rings. Where valence permits, the heterocyclic group can be attached to the remainder of the molecule by any atom of the heterocycle, such as a carbon or nitrogen atom of the heterocycle. Polycyclic heterocyclic groups can be fused rings, bridged rings, or spirocyclic systems. In some embodiments, the heterocyclic group is an aromatic heterocyclic group (e.g., pyrimidinyl). In some embodiments, the heterocyclic group is a heterocyclic alkyl group (e.g., morpholinyl). In an exemplary embodiment, the heterocycle (e.g., morpholinyl or piperazine) can be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Exemplary heterocyclic groups include pyrrolidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazole, indolyl, and quinolinyl. The heterocycle may be optionally substituted by one or more substituents (such as those described herein).

[0030] The term "4- to 6-membered alicyclic alkyl group" refers to a non-aromatic heterocyclic group, such as the monocyclic "heterocyclic group" defined above, containing 4-6 ring atoms (C1-C2). 4-6 The heterocyclic group (heterocyclic group) wherein one, two, three or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. The heteroatoms are preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Examples include azircyclopropane, oxacyclopropane, thiohercyclopropane, azircyclobutane, oxacyclobutane, thiohercyclobutane, pyrrolidinyl, tetrahydrofuranyl, oxacyclohexane, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxane, dithiohexyl, oxazolyl, thiazolyl, pyrazolyl, etc. It may optionally be substituted with one or more substituents (such as those described herein).

[0031] The term "5- to 6-membered aromatic heterocyclic group" refers to an aromatic monocyclic cyclic system containing a 5- to 6-membered structure, wherein one, two, three, or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, or three. Examples of aromatic heterocyclic groups include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, etc. It may optionally be substituted with one or more substituents (such as those described herein).

[0032] The term "7- to 8-membered bridged heterocyclic alkyl" refers to a cycloalkyl group in which two rings share two or more ring atoms, wherein the cyclic system contains 7-8 ring atoms, for example: , It can be optionally substituted by one or more substituents (such as those described herein).

[0033] The term "8- to 10-membered spirochetal alkyl" refers to a cycloalkyl group in which two rings share a single ring atom, and the cyclic system contains 8 to 10 ring atoms, for example: , , , , , , , , , It can be optionally substituted by one or more substituents (such as those described herein).

[0034] The term "9-membered fused heterocyclic alkyl" refers to a cycloalkyl group in which two rings share two ring atoms, and the cyclic system contains nine ring atoms, for example: , It can be optionally substituted by one or more substituents (such as those described herein).

[0035] In this invention, "optionally," "optionally," "optionally," and "optionally" mean that the events or situations described below may or may not occur, and the description includes both the occurrence and non-occurrence of things or situations. "Optionally substituted" refers to both substitution and non-substitution. "Optionally substituted by the following substituents" refers to both substitution and non-substitution.

[0036] In this invention, the definition and conventional use of stereochemistry are generally referred to in the following literature: SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984); McGraw-Hill Book Company, New York; and Elielj E. and Wilenj S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994. "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0037] In some embodiments, the compositions of this disclosure may comprise two or more enantiomers or diastereomers of the compound, wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods for producing substantially pure enantiomers are well known to those skilled in the art.

[0038] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds where hydrogen is replaced by deuterium or tritium, or where carbon is enriched. 13 C or 14 Compounds having the structure of this invention, other than carbon substitution of C, are within the scope of this disclosure. The compounds of this disclosure optionally contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds may use isotopes such as, for example, deuterium (₂H), tritium (₃H), etc. 3 H), iodine 125 ( 125 I) or carbon 14 ( 14 C) Mark. Use 2 H, 11 C 13 C 14 C 15 C 12 N、 13 N、 15 N、 16 N、 16 O、 17 O、 14 F, 15 F,16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br and 125 Isotopic substitutions of I are all considered. All isotopic variants of the compounds of this invention, whether or not they are radioactive, are covered within the scope of this invention.

[0039] "Pharmaceutically acceptable salt" means a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: salts formed by addition to inorganic acids or acids formed with organic acids; salts formed when an acidic proton present on the parent compound is replaced by a metal ion; or coordination compounds formed with organic bases.

[0040] "Pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention or their pharmaceutically acceptable salts, solvates, hydrates or prodrugs with other chemical components, such as pharmaceutically acceptable carriers.

[0041] "Solvate" refers to an association formed by one or more solvent molecules with the compounds of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. "Hydrate" refers to an association formed by solvent molecules that are water.

[0042] "Pharmaceutical carrier" refers to the inactive component in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the given compound.

[0043] The beneficial effects of this invention are: This invention discloses a compound having Formula I or a pharmaceutically acceptable salt, optical isomer, or stereoisomer thereof. The invention evaluates the affinity and selectivity of the compound for FAP by testing its inhibitory effects on the activities of FAP-related proteins, including dipeptidyl peptidase (DPP4) and proline oligopeptidase (PREP), and finds that the compound exhibits excellent FAP activity inhibition and good selectivity. Furthermore, the compound demonstrates good metabolic stability and can be used for the prevention and / or treatment of FAP-mediated diseases.

[0044] The abbreviations for the reaction reagents mentioned in this invention specification are as follows: Zn(CN)2: Zinc cyanide; Zn: Zinc; Pd(dba)3: Tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2: 1,1'-Bis(diphenylphosphino)ferrocene dichloropalladium; DMF: N,N-Dimethylformamide; LDA: Lithium diisopropylamide; THF: Tetrahydrofuran; HCl: Hydrochloric acid; MeOH: Methanol; NaOH: Sodium hydroxide; HOBt: 1-Hydroxybenzotriazole; EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; DIEA: N,N-Diisopropylethylamine; CO: Carbon monoxide; TEA: Triethylamine; CH2Cl2 / DCM: Dichloromethane; Dioxane: 1,4-Dioxane; NaOMe: Sodium methoxide; EtOAc: Ethyl acetate; MsCl: Methanesulfonyl chloride; Morpholine: Morpholine; EtOH: Ethanol; HCHO / Formalin: Formaldehyde; AcOH: Acetic acid; NaBH3CN: Sodium cyanoborohydride; NaBH(OAc)3: Sodium triacetoxyborohydride. Detailed implementation manners

[0045] The following further illustrates the present invention in conjunction with specific embodiments. These embodiments are implemented on the premise of the technical solution of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.

[0046] Example 1: Synthesis of intermediate

[0047] Intermediate 1:

[0048] To a DMF (120 mL) solution of 7-chlorothieno[3,2-b]pyridine (10.0 g, 58.9 mmol), Zn(CN)₂ (6.81 g, 57.9 mmol), Zn (960 mg, 14.7 mmol), Pd₂(dba)₃ (5.40 g, 5.90 mmol), and Pd(dppf)Cl₂ (4.31 g, 5.90 mmol) were added. The mixture was degassed under vacuum and purged with nitrogen three times. The mixture was heated to 120°C and stirred for 12 hours. The reaction was quenched with saturated sodium carbonate aqueous solution (50 mL), followed by dilution with water (50 mL) and extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to rapid silica gel column chromatography (ISCO). ® SepaFlash ® Purification was performed using a silica gel column (200 g) and hexane-ethyl acetate (0–15%, 120 mL / min) to give a yellow solid intermediate 1-1 (4.13 g, yield 43.7%). 1 H NMR (400 MHz, CDCl3)δ 8.85 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 5.6 Hz, 1H), 7.68 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 4.8 Hz, 1H). Under nitrogen protection and at -78°C, LDA (2 M, 9.36 mL) was added to a THF (10 mL) solution of intermediate 1-1 (1.00 g, 6.24 mmol), and the mixture was stirred for 0.5 hours. Then, a THF (10 mL) solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (2.25 mL, 18.7 mmol) was added, and the mixture was stirred at -78°C for another 1.5 hours. The mixture was heated to 0°C, quenched with water (15 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (8 mL × 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to rapid silica gel column chromatography (ISCO). ® SepaFlash ® Purification was performed using a silica gel column (40 g; hexane-ethyl acetate, 0–10%, 100 mL / min) to give a yellow solid intermediate 1–2 (778 mg, yield 52.1%). 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 4.8 Hz, 1H), 7.68 (s, 1H), 7.50 (d, J = 4.8Hz, 1H). Intermediate 1-2 (778 mg, 3.25 mmol) was added to hydrochloric acid / methanol (4 M, 15 mL), heated to 70°C and stirred for 12 hours. Then, hydrochloric acid / methanol (4 M, 10 mL) was added, and stirring was continued at 70°C for 17 hours. The reaction mixture was concentrated under reduced pressure to give crude yellow solid intermediate 1-3 (1.11 g). 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 4.8Hz, 1H), 7.92 (s, 1H), 7.87 (d, J = 4.8 Hz, 1H), 4.00 (s, 3H). THF (2 mL), water (1 mL), and sodium hydroxide (73.5 mg, 1.84 mmol) were added to a methanol (2 mL) solution of crude intermediates 1-3 (100 mg, 367 μmol), and the mixture was stirred at 25°C for 12 hours. The reaction mixture was adjusted to pH 7 with 1 N hydrochloric acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (WePure Biotech XP tC18, 100×30 mm, 7 μm; [H2O(10 mM NH4HCO3)-ACN], 1%–30%) to give intermediate 1 (43.0 mg, 56.8% yield) as a white solid. MS (ESI) was then used. + ): m / z 258.0, 260.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J =4.8 Hz, 1H), 7.64 (s, 1H), 7.62 - 7.59 (m, 1H). Intermediate 2:

[0049] To a THF (2 mL) solution of intermediate 1 (20.0 mg, 77.5 μmol), DIEA (40.5 μL, 232 μmol), (2S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-onitrile hydrochloride (17.5 mg, 77.5 μmol), HOBt (15.7 mg, 116 μmol), and EDCI (22.3 mg, 116 μmol) were added, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (WePure Biotech XPt C18, 150×30 mm, 7 μm; [H2O(10 mM NH4HCO3)-ACN], 20%–50%) to give a white solid, comparative compound 2 (16.3 mg, 48.8% yield). MS (ESI) + ): m / z 429.0, 431.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.53(br t, J = 6.0 Hz, 1H), 8.85 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 5.2 Hz, 1H), 7.83 (s, 1H), 5.12 (dd, J = 2.4, 9.2 Hz, 1H), 4.36 - 4.09 (m, 4H), 3.01 -2.75 (m, 2H). To a mixed solution of dioxane (2 mL) and water (0.4 mL) of comparative compound 2 (30.0 mg, 69.9 μmol), triethylamine (29.2 μL, 210 μmol) and Pd(dppf)Cl2·CH2Cl2 (8.56 mg, 10.5 μmol) were added. The mixture was degassed under vacuum and purged with CO (50 Psi) three times. The mixture was then heated to 80°C and stirred for 2 hours under a CO (50 Psi) atmosphere. The reaction mixture was diluted with water (2 mL) and washed with ethyl acetate (2 mL × 3). The aqueous phase was collected and purified by preparative HPLC (WePure Biotech XPtC18, 100 × 30 mm, 7 μm; [H2O(10 mM NH4HCO3)-ACN], 1%–30%) to give intermediate 2 (10.0 mg, 36.3% yield) as a white solid. MS (ESI) was then used. + ): m / z 395.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 9.42 (br t, J = 5.2 Hz, 1H), 8.90 (d, J = 4.8 Hz, 1H), 8.06 - 7.84 (m, 2H), 5.13 (dd, J = 2.4, 9.2 Hz, 1H), 4.39 - 4.08 (m, 4H), 2.95 - 2.80 (m, 2H). Intermediate 3:

[0050] To a methanol (10 mL) solution of N-Boc-piperidin-4-methylformamidinium (1.00 g, 4.40 mmol), NaOMe (500 mg, 9.26 mmol) and 3-dimethylamino-2-methylpropenal (600 mg, 5.30 mmol) were added, and the mixture was heated to 70°C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (5 mL), extracted with ethyl acetate (5 mL × 2), the organic phases were combined, washed with saturated brine (10 mL × 2), and dried over sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to rapid silica gel column chromatography (ISCO). ® SepaFlash ® Silicone pillars Purification was performed on 20.0 g (hexane-ethyl acetate, 0-28%) to give a colorless oily intermediate 3-1 (300 mg, yield 24.6%). 1 H NMR (400 MHz, CDCl3) δ 8.52 (s,2H), 4.32 - 4.12 (m, 2H), 3.01 (tt, J = 3.6, 11.6 Hz, 1H), 2.87 (br t, J =10.8 Hz, 2H), 2.30 (s, 3H), 1.98 (br d, J = 12.8 Hz, 2H), 1.86 - 1.74 (m,2H), 1.48 (s, 9H). Intermediate 3-1 (60.0 mg, 216 μmol) was added to hydrochloric acid / ethyl acetate (1 mL, 4 M) and stirred at 25°C for 14 hours. The reaction mixture was concentrated under reduced pressure to give intermediate 3 hydrochloride (35.0 mg, 75.7% yield) as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 9.06 - 8.67 (m, 2H), 8.62 (s, 2H), 3.31 (br d, J =12.4 Hz, 2H), 3.17 - 3.08 (m, 1H), 3.06 - 2.96 (m, 2H), 2.25 (s, 3H), 2.14 -2.05 (m, 2H), 1.98 - 1.91 (m, 2H). Intermediate 4:

[0051] Under nitrogen protection and at -70°C, TEA (825 μL, 5.93 mmol) and MsCl (270 μL, 3.49 mmol) were added to a DCM (5 mL) solution of N-Boc-3-methylaminoacetidine (500 mg, 2.68 mmol), and the mixture was stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate aqueous solution (5 mL), and the mixture was extracted with DCM (3 mL × 3). The organic phases were combined, washed with brine (10 mL), and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to rapid silica gel column chromatography (ISCO). ® SepaFlash ® Purification was performed using a silica gel column (12.0 g) and hexane-ethyl acetate (0–70%) to give a white solid intermediate 4-1 (400 mg, 56.4% yield). 1 H NMR (400 MHz, DMSO-d6) δ 4.52 - 4.43 (m, 1H), 4.07 - 4.00 (m, 2H), 3.99 - 3.92 (m, 2H), 2.86 (s, 3H), 2.82 (s, 3H), 1.38 (s, 9H). Intermediate 4-1 (200 mg, 757 μmol) was added to hydrochloric acid / ethyl acetate (4 M, 2 mL) and stirred at 25°C for 2 hours. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (10 mL), and dried under vacuum to give a white solid intermediate 4 hydrochloride (120 mg, yield 79.0%). 1 H NMR (400 MHz, DMSO-d6) δ 9.05 - 8.59 (m, 2H), 4.69- 4.58 (m, 1H), 4.24 - 4.13 (m, 2H), 4.12 - 4.00 (m, 2H), 2.93 (s, 3H), 2.85(s, 3H). Intermediate 5:

[0052] N-Boc-6-oxo-3-azabicyclo-3-10-hexane (1.00 g, 5.40 mmol) and morpholine (949 μL, 10.8 mmol) were dissolved in ethanol (10 mL), and the mixture was stirred at 75°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to rapid silica gel column chromatography (ISCO). ® SepaFlash ® Purification was performed using a silica gel column (40.0 g); hexane-ethyl acetate: 0-100% → ethyl acetate-methanol: 0-10%) to give a yellow solid intermediate 5-1 (1.20 g, yield 81.6%). 1 H NMR (400MHz, CDCl3) δ 4.30 (q, J = 6.4 Hz, 1H), 3.70 (t, J = 4.8 Hz, 5H), 3.66 - 3.54(m, 1H), 3.26 (br d, J = 4.0 Hz, 1H), 3.18 (br dd, J = 6.0, 10.8 Hz, 1H), 2.82 (br s, 1H), 2.66 (br d, J = 10.8 Hz, 2H), 2.55 - 2.44 (m, 2H), 1.44 (s, 9H). Intermediate 5-1 (600 mg, 2.20 mmol) was dissolved in hydrochloric acid / ethyl acetate (4 M, 6 mL), and the mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL) and dried under vacuum to give an off-white solid intermediate 5 hydrochloride (380 mg, yield 82.6%). 1 H NMR (400 MHz, DMSO-d6) δ 10.16 - 9.65(m, 2H), 4.89 - 4.74 (m, 1H), 4.08 - 3.64 (m, 8H), 3.40 - 3.02 (m, 5H). Intermediate 6:

[0053] To a methanol (3 mL) solution of 300 mg (1.31 mmol) of 8-Boc-5-oxa-2,8-diazaspiro[3,5]nonane, formaldehyde (120 μL, 1.61 mmol, 37.0%), sodium borohydride cyanide (826 mg, 13.1 mmol), and acetic acid (7.52 μL, 131 μmol) were added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (WePureBiotech XP tC18, 100×30 mm, 7 μm; [H2O(10 mM NH4HCO3)-ACN], 15%–45%) to give a colorless oily intermediate 6-1 (177 mg, 55.6% yield). 1 H NMR (400 MHz, DMSO-d6) δ 3.53 - 3.47(m, 4H), 3.29 - 3.25 (m, 4H), 3.10 (br d, J = 1.6 Hz, 2H), 2.45 (s, 3H), 1.41(s, 9H). Intermediate 6-1 (50.0 mg, 206 μmol) was added to hydrochloric acid / ethyl acetate (1 mL, 4 M) and stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a colorless colloidal intermediate 6 hydrochloride (45.0 mg, 100% yield). 1 HNMR (400 MHz, DMSO-d6) δ 9.74 (br dd, J = 3.2, 13.6 Hz, 2H), 4.52 - 4.43 (m,1H), 4.17 - 4.02 (m, 2H), 3.99 - 3.82 (m, 3H), 3.37 - 3.25 (m, 2H), 3.06 (brs, 2H), 2.86 (brs, 3H). Intermediate 7:

[0054] 25 oAt C, propionide-D-glyceraldehyde (500 mg, 3.84 mmol) and N-Boc-piperazine (700 mg, 3.76 mmol) were dissolved in DCM (5 mL) and stirred for 10 minutes. NaBH(OAc)3 (1.63 g, 7.68 mmol) was added, and stirring continued for 50 minutes. The reaction was quenched with water (10 mL), and the aqueous phase was extracted with DCM (10 mL). The organic phases were combined, washed with saturated sodium bicarbonate aqueous solution (20 mL × 2), and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to rapid silica gel column chromatography (ISCO). ® ;SepaFlash ® Purification was performed using a silica gel column (12.0 g; hexane-ethyl acetate: 0-25%) to give a colorless oily intermediate 7-1 (660 mg, yield 57.2%). 1 H NMR (400 MHz, CDCl3) δ 4.34 - 4.24 (m, 1H), 4.08 (dd, J= 6.4, 8.0 Hz, 1H), 3.61 (dd, J = 7.2, 7.6 Hz, 1H), 3.45 (br t, J = 4.8 Hz, 4H), 2.60 - 2.39 (m, 6H), 1.46 (s, 9H), 1.42 (s, 3H), 1.36 (s, 3H). Intermediate 7-1 (50.0 mg, 166 μmol) was dissolved in hydrochloric acid / ethyl acetate (4 M, 1 mL) solution, 25 o The mixture was stirred at C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a white solid intermediate 7 hydrochloride (15.0 mg, yield 56.2%). MS (ESI) + ): m / z 161.2 [M+H] + . Intermediate 8:

[0055] Following the synthesis method of intermediate 8, intermediate 8 was synthesized using propylene-L-glyceraldehyde as a raw material.

[0056] Intermediate 9:

[0057] Formaldehyde (229 μL, 3.08 mmol, 37%) and acetic acid (14.30 μL, 250 μmol) were added to a methanol (5 mL) solution of 1-Boc-2(R)-methoxymethylpiperidine (500 mg, 2.17 mmol), and the mixture was stirred at 25°C for 10 min. Then, sodium borohydride cyanide (300 mg, 4.77 mmol) was added, and the mixture was stirred at 25°C for 11 h 50 min. The pH of the reaction solution was adjusted to 7 with DIEA. The resulting mixture was purified by preparative HPLC (WePure Biotech XP tC18, 100×30 mm, 7 μm; [H2O(10 mM NH4HCO3)-ACN], 25%–55%) to give a yellow oily intermediate 9-1 (300 mg, 56.6% yield). MS (ESI) + ): m / z 245.1 [M+H] + . Intermediate 9-1 (300 mg, 1.23 mmol) was added to a hydrochloric acid / ethyl acetate solution (4 M, 3 mL) and stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a white solid intermediate 9 hydrochloride (180 mg, 67.5% yield). MS (ESI) + ): m / z 145.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.61 - 11.44 (m,1H), 10.53 - 9.60 (m, 2H), 3.86 (br d, J = 7.6 Hz, 1H), 3.69 - 3.35 (m, 9H),3.30 - 3.11 (m, 2H), 2.82 (s, 3H). Intermediate 10:

[0058] Following the synthetic method for intermediate 9, intermediate 10 was synthesized from 1-Boc-2(S)-methoxymethylpiperidine. MS (ESI) + ): m / z 145.0 [M+H] + . Intermediate 11:

[0059] Following the synthetic method for intermediate 3, intermediate 11 was synthesized using N-Boc-piperidin-4-methylammonium phosphate and 2-chloro-1,3-bis(dimethylamino)trimethylenehexafluorophosphate as starting materials. MS (ESI)+ ): m / z 198.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 9.42 (br s, 1H), 9.21 (br s, 1H), 8.92 (s, 2H), 3.31 (m, 2H), 3.20 (m, 1H), 3.03 (m, 2H), 2.18-1.90 (m, 4H).

[0060] Example 2: Synthesis of the compound

[0061] Synthesis of Compound 1

[0062] To a THF (0.5 mL) solution of intermediate 2 (8.00 mg, 20.3 μmol), N-methylpiperazine (2.25 μL, 20.3 μmol), DIEA (10.6 μL, 60.9 μmol), HOBt (3.29 mg, 24.3 μmol), and EDCI (4.67 mg, 24.3 μmol) were added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Phenomenex Gemini-NX, 150 × 30 mm, 5 μm; [H₂O(10 mM NH₄HCO₃)-ACN]; 10%–40%) to give compound 1 (5.20 mg, 53.8% yield) as a white solid. MS (ESI) + ): m / z 477.0 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 9.55 - 9.45 (m, 1H), 8.94 (d, J = 4.8 Hz, 1H), 8.06- 8.00 (m, 1H), 7.80 (s, 1H), 5.12 (dd, J = 2.4, 9.2 Hz, 1H), 4.39 - 4.08 (m,4H), 3.70 - 3.59 (m, 4H), 3.00 - 2.76 (m, 2H), 2.37 (br s, 4H), 2.21 (s, 3H). Synthesis of compounds 2-37: Following the synthetic route of compound 1, the raw materials and spectral data are shown in Table 1.

[0063] Table 1 Synthesis of compounds 2-37

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070] Example 3: Protein-level FAP enzyme activity assay

[0071] Using H-Gly-Pro-pNA (CAS: 103213-34-9) as a substrate, the enzymatic activities of human FAP and DPP4 proteins (purchased from Shanghai Kaika Biotechnology) on their hydrolysis were measured. Using Z-Gly-Pro-pNA (CAS: 65022-15-3) as a substrate, the enzymatic activities of human PREP protein (purchased from Bai'ao Technology Co., Ltd.) on its hydrolysis were measured. The inhibitory effects of the compounds on the activities of these different enzymes (i.e., IC50 determination) were determined. 50 The affinity and selectivity of compounds for FAP were evaluated using a multi-component assay (ICP-A). First, a mixture of purified protein-level enzymes and a series of compounds was incubated at room temperature for 1 h. The reaction system could contain FAP (2 μg / mL, 100 mM Tris buffer, 100 mM NaCl, pH 7.4), DPP4 (0.25 μg / mL, 100 mM Tris buffer, pH 8.0), or PREP (1 μg / mL, 25 mM Tris buffer, 250 mM NaCl, 1 mM DTT, pH 7.5), for a total volume of 50 μL. Next, 50 μL of substrate working solution containing 2.5 mM H-Gly-Pro-pNA or 0.25 mM Z-Gly-Pro-pNA was added, and the mixture was incubated at 37°C for 1 h. The volume of DMSO in the reaction system was 1%. The absorbance at 405 nm was measured using a Multiskan FC microplate reader. 50 The values ​​were fitted using GraphPadPrism.

[0072] Table 2 Results of the inhibitory effect of compounds on enzyme activity

[0073]

[0074] This invention evaluates the affinity and selectivity of compounds for FAP by testing their enzymatic activity against the hydrolysis of substrates catalyzed by FAP and its family proteins DPP4 and PREP. Specifically, it tests the inhibitory activity of compounds on the increase in the 405 nm spectral signal caused by substrate hydrolysis, obtaining data on the inhibitory activity of the compounds. The stronger the affinity of the compound for FAP, DPP4, and PREP, the stronger the inhibitory effect on enzyme activity, the less substrate hydrolysis, and the smaller the increase in the 405 nm spectral signal. The data on the inhibition rates of the compounds are shown in Table 2. The results show that the compound has excellent inhibitory activity against FAP enzyme activity, but weak or no inhibitory effect on PREP and DPP4 enzyme activity, thus exhibiting good selectivity. Tarapote (PT-100) has a weak inhibitory effect on FAP enzyme activity and a strong inhibitory effect on DPP-4 and PREP enzyme activity, showing no selectivity. The comparative compound showed good selectivity for FAP and DPP-4, but poor selectivity for PREP, with its inhibitory effect on PREP enzyme activity even stronger than that on FAP. The compounds of this invention can be used as FAP inhibitors for the prevention and treatment of diseases such as rheumatoid arthritis, non-alcoholic fatty liver disease, metabolic dysfunction-related steatohepatitis, atherosclerosis, myocardial infarction, and liver fibrosis.

[0075] Synthesis of Comparative Compound 1 and Comparative Compound 2: Comparative compound 1:

[0076] Following the synthetic method of Comparative Compound 2, Comparative Compound 1 was synthesized using thieno[3,2-b]pyridine-7-carboxylic acid and (2S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-nitrile hydrochloride as starting materials. MS (ESI) + ): m / z 351.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (br t, J = 6.0 Hz, 1H), 8.87 (d, J =4.8 Hz, 1H), 8.23 ​​(d, J = 5.6 Hz, 1H), 7.95 (d, J = 4.8 Hz, 1H), 7.61 (d, J =4.8 Hz, 1H), 5.13 (dd, J = 2.8, 9.6 Hz, 1H), 4.33 - 4.13 (m, 4H), 2.97 - 2.81(m, 2H). Comparative compound 2: For the specific synthesis route, see intermediate 2.

[0077] Example 4: Liver microsomal stability test Microsomes (10 μL, 6.3 mg / mL) were diluted with 80 μL of 0.1 M phosphate buffer (containing 3.3 mM MgCl2), and then 90 μL of 1.1 μM phosphate buffer solution of the test compound or blank phosphate buffer solution was added. The prepared reaction solution was preheated at 37°C for 5 minutes. NADPH (1.75 mg) was dissolved in 210 μL of 0.1 M phosphate buffer (containing 3.3 mM MgCl2), and 10 μL of NADPH solution was added to the above reaction solution to start the reaction. The reaction time was set to 0, 10, 30, and 60 minutes, respectively. The reaction was terminated by adding 300 μL of cold acetonitrile (containing 50 nM NCF60) at the specified time points. After centrifugation at 4000 rpm for 20 minutes to precipitate the protein, 200 μL of the supernatant was added to 200 μL of 0.1% formic acid water for LC / MS / MS analysis. Plot the natural logarithm of the ratio of the compound peak area to the NCF60 peak area against time and calculate the slope of the curve, as shown in Table 3.

[0078] Table 3. Results of the stability of the compounds in liver microsomes

[0079] The above description is merely an optional embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A compound as shown in Formula I, or a pharmaceutically acceptable salt, optical isomer, or stereoisomer thereof: ； in, Ring A is arbitrarily selected from substituted saturated 4- to 7-membered alicyclic alkyl, saturated 7- to 8-membered bridged heterocyclic alkyl, optionally substituted saturated 8- to 10-membered spirocyclic alkyl, optionally substituted saturated 9-membered fused heterocyclic alkyl, wherein the number of heteroatoms on ring A is 1, 2, 3 or 4, and the heteroatoms are selected from one, two or three of N, O or S. When ring A is selected from a substituted saturated 4- to 7-membered alicyclic alkyl group, ring A may optionally be substituted with the following substituents: C 1-6 Alkyl, =O, -OH, -N(R) 1 (R) 2 ), saturated 4- to 6-membered alicyclic alkyl groups or 5- to 6-membered aromatic heterocyclic groups, wherein the C 1-6 Alkyl groups, saturated 4- to 6-membered alicyclic alkyl groups, or 5- to 6-membered aromatic heteroyl groups may each be optionally substituted with one or more of the following substituents: -OH, -OR 3 halogen or C 1-6 Alkyl, wherein the R 1 R 2 Each is independently selected from H and C. 1-6 Alkyl or -S(O)2R 4 R 3 R 4 Selected from C 1-6 alkyl; When ring A is selected from an optionally substituted saturated 8- to 10-membered spirochetal alkyl group, ring A may optionally be substituted by one or more of the following substituents: C 1-6 alkyl; When ring A is selected from an optionally substituted saturated 9-membered fused heterocyclic alkyl group, ring A may optionally be selected from one or more of the following substituents: C 1-6 Alkyl or =O.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, optical isomer, or stereoisomer, characterized in that, When ring A is selected from optionally substituted saturated 4- to 7-membered alicyclic alkyl groups, in Formula I Partially selected from: The compound is described by formula I-1: ； Wherein A 1 Selected from -CH2- or -CH(R) 5 )-;A 2 Selected from -CH2-, -CH(R) 6 - or key; A 3 Selected from -CH2- or -CH(R) 7 )-;A 4 Selected from -CH2-, -CH(R) 5 - or key; A 5 Selected from -CH2- or the bond; Y is selected from -O-, -S-, -S(O)2-, -N(R)2-. 8 - or -CH(R) 9 )-;R 5 Selected from C 1-6 Alkyl; R 6 Selected from C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more of the following substituents: -OR 3 ;R 7 Selected from C 1-6 Alkyl or -OR 3 ;R 8 Selected from C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with one or more of the following substituents: -OR 3 ;R 9 Selected from -N(R) 1 (R) 2 ), saturated 4- to 6-membered alicyclic alkyl groups or 5- to 6-membered aromatic heterocyclic groups, wherein each of the saturated 4- to 6-membered alicyclic alkyl groups or 5- to 6-membered aromatic heterocyclic groups may optionally be substituted with one or more of the following substituents: - OR 3 halogen or C 1-6 Alkyl; R 1 R 2 Each is independently selected from H and C. 1-6 Alkyl or -S(O)2R 4 ;R 3 R 4 Selected from C 1-6 alkyl.

3. The compound according to any one of claims 1-2, or its pharmaceutically acceptable salt, optical isomer, or stereoisomer, characterized in that, The Selected from optional replacements , , , , , , , or Any one of them may optionally be substituted by one or two of the following substituents: methyl, =O, -OH, -CH2CH2OH, -CH2CH(OH)CH2OH, -CH2OCH3, Or R 9 The saturated 4- to 6-membered alicyclic alkyl group or 5- to 6-membered aromatic heterocyclic group may optionally be independently selected from the following. , or Any one of them may optionally be substituted with the following substituents: chloro, methyl, or methoxy; R 10 R 11 Selected from C 1-3 alkyl.

4. The compound according to claim 3, or its pharmaceutically acceptable salt, optical isomer, or stereoisomer, characterized in that, The Selected from optional replacements When, it can be substituted by one of the following substituents: The Selected from optional replacements Optionally, it can be substituted with one or two of the following substituents: -OH or The Selected from optional replacements Optionally, it can be substituted with one of the following substituents: , , or The Selected from optional replacements Optionally, it may be substituted with one or two of the following substituents: methyl, -CH2CH2OH, -CH2CH(OH)CH2OH, or -CH2OCH3; Selected from optional replacements Optionally, it may be substituted with the following substituents: methyl; Selected from optional replacements Optionally, it can be substituted with the following substituents: =O; the Selected from optional replacements Optionally, it can be substituted with the following substituents: -OH; Selected from optional replacements When it is substituted, it can be replaced by one of the following substituents: methyl.

5. The compound according to claim 4, or its pharmaceutically acceptable salt, optical isomer, or stereoisomer, characterized in that, Ring A for At that time, selected from: , , , , , , , , , , , , , , , , , , , , , or .

6. The compound according to claim 1, or its pharmaceutically acceptable salt, optical isomer, or stereoisomer, characterized in that, When ring A is a saturated 7- to 8-membered bridged heterocyclic alkyl, an optionally substituted 8- to 10-membered spirocyclic alkyl, or an optionally substituted saturated 9-membered fused heterocyclic alkyl, the number of heteroatoms on ring A is 2, 3, or 4, and the heteroatoms are selected from one or both of N, O, or S; wherein when ring A is selected from an optionally substituted saturated 8- to 10-membered spirocyclic alkyl, ring A may optionally be substituted with the following substituents: C 1-3 Alkyl; wherein ring A is selected from an optionally substituted saturated 9-membered fused heterocyclic alkyl group, ring A may optionally be substituted with the following substituents: C 1-3 Alkyl or =O.

7. The compound according to claim 6, or its pharmaceutically acceptable salt, optical isomer, or stereoisomer, characterized in that, The saturated 7- to 8-membered bridged heterocyclic alkyl groups are selected from: or ; The optionally substituted 8- to 10-membered spirochetal alkyl groups are selected from: , , , , , , , , or ; The optionally substituted saturated 9-membered fused heterocyclic alkyl group is selected from: or .

8. The compound according to any one of claims 6-7, or its pharmaceutically acceptable salt, optical isomer, or stereoisomer, characterized in that, The optionally substituted 8- to 10-membered spirochetal alkyl groups are selected from: , , , , , , , , or Any one of them may optionally be substituted with the following substituents: methyl; The optionally substituted saturated 9-membered fused heterocyclic alkyl group is selected from: or Any one of them may optionally be substituted by one of the following substituents: =O or methyl.

9. The compound according to claim 8, or its pharmaceutically acceptable salt, optical isomer, or stereoisomer, characterized in that, The 8- to 10-membered spirochetal alkyl groups that are optionally substituted are selected from: , , , , , , , , or .

10. The compound according to claim 8, or its pharmaceutically acceptable salt, optical isomer, or stereoisomer, characterized in that, The substituted saturated 9-membered fused heterocyclic alkyl group is selected from: or .

11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, optical isomer, or stereoisomer thereof, wherein the compound is selected from any one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 12. A pharmaceutical composition comprising the compound according to any one of claims 1-11 or a pharmaceutically acceptable salt, optical isomer, stereoisomer, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

13. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, optical isomer, stereoisomer thereof, and a solvate, metabolite, cocrystal, or prodrug thereof, or a pharmaceutical composition according to claim 12, in the preparation of a medicament as an FAP inhibitor.

14. The use according to claim 13, wherein the FAP inhibitor is used to prevent and treat any one or more of the following diseases: rheumatoid arthritis, non-alcoholic fatty liver disease, metabolic dysfunction-related steatohepatitis, atherosclerosis, myocardial infarction, and liver fibrosis.

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