FAP inhibitor and application

Abstract

The invention belongs to the field of medicine, and relates to an FAP inhibitor and application, the FAP inhibitor is specifically a compound shown as a formula I or pharmaceutically acceptable salt, optical isomer and stereoisomer thereof, and further, the invention also comprises application of the compound in medicines for diagnosing and / or treating tumors, immune diseases or inflammatory diseases, # imgabs0 #.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a FAP inhibitor and its uses, mainly including uses for diagnosing and / or treating tumors, immune diseases or inflammatory diseases. Background Art

[0002] Fibroblast activation protein (FAP) is one of the important markers on the surface of tumor-associated fibroblasts. It is highly expressed in the stromal fibroblasts of more than 90% of 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 the occurrence and development of tumors by promoting angiogenesis in tumor tissues, promoting tumor growth, achieving immune escape, and assisting tumor metastasis. In addition, and more importantly, because FAP is expressed at low levels in healthy tissues, FAP is considered a promising target in the field of tumor diagnosis and treatment.

[0003] Furthermore, FAP is highly expressed in arthritis, atherosclerotic plaques, and fibrotic tissue. FAP hydrolyzes and cleaves substrates such as type 1 and type III collagen, α2-antiplasmin, and fibroblast growth factor, creating a pro-fibrotic environment that promotes immune cell infiltration, synovial fibroblast proliferation, and angiogenesis. This is associated with the exacerbation of rheumatoid arthritis, non-alcoholic fatty liver disease, and atherosclerosis. Therefore, FAP inhibitors could be used for the diagnosis and treatment of cancer, rheumatoid arthritis, non-alcoholic fatty liver disease, and atherosclerosis.

[0004] There are currently few types of FAP inhibitors, so it is necessary to develop more FAP inhibitors with good selectivity and better inhibitory activity. Summary of the Invention

[0005] Objective of the Invention: To overcome the shortcomings of the prior art, the present invention aims to provide a FAP inhibitor with excellent selectivity and inhibitory activity, and its uses. The present invention provides a compound or pharmaceutically acceptable salt, optical isomer, stereoisomer thereof, as well as corresponding solvates, metabolites, cocrystals, prodrugs, and pharmaceutical compositions for the diagnosis and / or treatment of FAP-mediated diseases.

[0006] To achieve the above objectives, the present invention provides the following technical solutions:

[0007] In a first aspect, a compound as shown in Formula I or a pharmaceutically acceptable salt, optical isomer, or stereoisomer thereof is provided:

[0008]

[0009] wherein W is selected from -CONH-, -NHCO-;

[0010] R1 is selected from H, halogen, hydroxyl, C 1-3 Alkoxy, C 1-3 alkyl;

[0011] Ring A is selected from wherein X and Y are independently selected from F and NR2R3; R4 is selected from H, halogen, and cyano;

[0012] R2 and R3 are each independently selected from L is selected from C 1-5 Alkylene or bond; K1 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR5 or a bond; K2 is selected from AA or a bond; Z is selected from H, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 Alkyl; wherein R5 is selected from H, C 1-4 Alkyl, Boc or wherein AA is selected from amino acid residues selected from glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; Ring A1 and Ring A2 are independently selected from a naphthalene ring, a benzene ring, and a pyridine ring.

[0013] Optionally, R2 is selected from H, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 Alkyl, preferably H, C 1-4 Alkyl; R3 is selected from L is selected from C 1-5 Alkylene or bond; K1 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR5 or a bond; K2 is selected from AA or a bond; Z is selected from H, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 Alkyl; wherein R5 is selected from H, C 1-4 Alkyl, Boc or wherein AA is selected from amino acid residues selected from glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; Ring A1 and Ring A2 are independently selected from a naphthalene ring, a benzene ring, and a pyridine ring.

[0014] Further, R3 is selected from L is selected from C 1-5 Alkylene or bond; K1 is selected from O, S, NR5 or bond; K2 is selected from AA or a bond; Z is selected from H, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 Alkyl; wherein R5 is selected from H, C 1-4 Alkyl, Boc or wherein AA is selected from amino acid residues selected from glycine, phenylalanine, arginine, N ω ,N ω - dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; Ring A1 and Ring A2 are independently selected from a naphthalene ring, a benzene ring, and a pyridine ring;

[0015] Preferably, R3 is selected from L is selected from C 1-5 Alkylene or bond; K1 is selected from O, S, NR5 or bond; K2 is selected from AA or a bond; Z is selected from H, C 3-6 Cycloalkyl, C 1-4 Alkyl; wherein R5 is selected from H, C 1-4 Alkyl, Boc or wherein AA is selected from amino acid residues selected from glycine, phenylalanine, arginine, N ω ,N ω - dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; Ring A1 and Ring A2 are independently selected from a naphthalene ring, a benzene ring, and a pyridine ring;

[0016] More preferably, R3 is selected from L is selected from C 1-5 Alkylene or bond; K1 is selected from O, S, NR5 or bond; K2 is selected from AA or a bond; Z is selected from H, C 3-6 Cycloalkyl, C 1-4 Alkyl; wherein R5 is selected from H, Boc or wherein AA is selected from amino acid residues selected from glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; Ring A1 and Ring A2 are independently selected from a naphthalene ring, a benzene ring, and a pyridine ring, and Ring A1 and Ring A2 are preferably a naphthalene ring.

[0017] Optionally, R1 is selected from H, C 1-3Alkoxy, preferably H and methoxy.

[0018] Optionally, the amino acid is selected from glycine, phenylalanine, arginine, N ω ,N ω - dimethylarginine, citrulline, histidine or lysine, preferably arginine.

[0019] Optionally, Ring A is selected from

[0020] The compound of formula I can be and / or Represents; wherein R4 is selected from H, halogen, cyano, preferably H, halogen.

[0021] Optionally, Ring A is selected from

[0022] The compound of formula I can be and / or express.

[0023] Furthermore, the above compound is selected from any of the following compounds:

[0024]

[0025] 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 thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0026] In a third aspect, the present invention also relates to the use of the compound described in the first aspect or its pharmaceutically acceptable salts, optical isomers, stereoisomers, and solvates, metabolites, cocrystals or prodrugs, or the pharmaceutical composition described in the second aspect in the preparation of drugs as FAP inhibitors.

[0027] The diseases for which the above-mentioned FAP inhibitors are used to diagnose and / or treat are any one or more of rheumatoid arthritis, non-alcoholic fatty liver disease, atherosclerosis, myocardial infarction, liver fibrosis, pulmonary fibrosis, renal fibrosis, sarcoma, glioblastoma, ovarian cancer, breast cancer, cervical cancer, lung cancer, pancreatic cancer, mesothelioma, skin cancer, colorectal cancer, bladder cancer, gastric cancer, endometrial cancer or thyroid cancer.

[0028] The various terms and phrases used in the present invention have general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases herein. If the mentioned terms and phrases are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail.

[0029] Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0030] As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.

[0031] As used in the present invention, "C 1-3 "Alkyl" refers to a straight or branched chain 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.

[0032] As used in the present invention, "C 1-3 "Alkoxy" refers to a C 1-3 Examples of the group obtained by connecting a carbon atom on an alkyl group to an oxygen atom include, but are not limited to, methoxy, ethoxy, or propoxy.

[0033] As used in the present invention, "C 1-4 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms, such as 1, 2, 3 or 4 carbon atoms. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0034] As used in the present invention, "C 1-5 "Alkylene" refers to a straight or branched chain alkylene group having 1 to 5 carbon atoms, such as 1, 2, 3, 4 or 5 carbon atoms. Specific examples include, but are not limited to, methylene, ethylene, propylene, isopropylene or n-butylene.

[0035] As used in the present invention, "C 3-6 "Cycloalkyl" refers to an aliphatic ring system containing 3 to 6 ring carbon atoms. For example, C 3-4 Cycloalkyl or C 5-6 Cycloalkyl. "C 3-6 "Cycloalkyl" includes monocyclic, fused or bridged rings. Specific examples include, but are not limited to, cyclopropyl, cyclopentyl or cyclohexyl.

[0036] As used herein, "4- to 6-membered heterocycloalkyl" refers to an aliphatic ring system containing 4 to 6 ring atoms (at least one of which is a heteroatom, such as N, O, S, etc.). Specific examples include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl.

[0037] As used in the present invention, It is an α-aminoacetic acid analogue, wherein R is a corresponding substituent.

[0038] As used herein, "Boc" means tert-butyloxycarbonyl.

[0039] In the present invention, "optionally", "optional", "optionally", and "optional" mean that the event or situation described subsequently may or may not occur, and the description includes that the thing or situation may or may not occur, and the description includes both situations where the thing or situation occurs and does not occur.

[0040] In the present invention, the definition and convention of stereochemistry are generally used with reference to the following literature: SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., ^ Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0041] "Stereoisomers" are compounds that have identical chemical constitutions but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0042] "Pharmaceutically acceptable salt" means a salt of a compound of the invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic or 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.

[0043] A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and other chemical components, such as a pharmaceutically acceptable carrier.

[0044] "Solvate" refers to an association formed between one or more solvent molecules and a compound of the present 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 when the solvent molecule is water.

[0045] "Pharmaceutically acceptable carrier" refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to organisms and does not interfere with the biological activity and properties of the administered compound.

[0046] Beneficial effects of the present invention:

[0047] The present invention discloses a compound represented by Formula I, or a pharmaceutically acceptable salt, optical isomer, or stereoisomer thereof. The present invention evaluates the affinity and selectivity of the compound for FAP by testing its inhibitory effects on the activities of FAP and its family proteins, dipeptidyl peptidase (DPP4) and proline oligopeptidase (PREP). The compound was found to have excellent FAP activity inhibition and good selectivity. Furthermore, the compound has good metabolic stability and can be used to diagnose and / or treat FAP-mediated diseases.

[0048] The abbreviations of the reaction reagents involved in the present specification are as follows:

[0049] DMF: N,N-dimethylformamide;

[0050] DIEA: N,N-diisopropylethylamine;

[0051] DCM: dichloromethane;

[0052] (COCl)2: oxalyl chloride;

[0053] Tf2O: trifluoromethanesulfonic anhydride;

[0054] NCS: N-chlorosuccinimide;

[0055] Dioxane: dioxane;

[0056] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;

[0057] HOBT or HOBt: 1-hydroxybenzotriazole;

[0058] EDCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide;

[0059] BF3OEt: Boron trifluoride diethyl ether;

[0060] t-BuONO: tert-butyl nitrite;

[0061] K2S2O5: potassium metabisulfite;

[0062] NFSI: N-fluorobis(benzenesulfonamide);

[0063] THF: tetrahydrofuran;

[0064] TEA: triethylamine;

[0065] TFA: trifluoroacetic acid;

[0066] HCTU: O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate;

[0067] LiOH·H2O: lithium hydroxide monohydrate;

[0068] ACN: acetonitrile;

[0069] AcOH: acetic acid;

[0070] BnSH: benzyl mercaptan;

[0071] Pd2(dba)3: trisdibenzylideneacetone dipalladium. DETAILED DESCRIPTION

[0072] The present invention will be further illustrated below with reference to specific examples. These examples are implemented based on the technical solutions of the present invention. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0073] Example 1: Synthesis of intermediates

[0074] Synthesis of intermediate 1:

[0075]

[0076] To a solution of cyclopropylamine (126.76 mg, 2.22 mmol) in DCM (5 mL) were added DIEA (477.46 mg, 3.69 mmol) and 5-(chlorosulfonyl)-1-naphthoic acid (0.5 g, 1.85 mmol). The reaction was stirred at 25°C for 12 hours. LC-MS showed that the compound 5-(chlorosulfonyl)-1-naphthoic acid was completely consumed. 1N hydrochloric acid was added to the reaction mixture to adjust the pH to 1. A solid precipitated, which was filtered, washed with water (5 mL), and dried to give a crude pale yellow solid of Intermediate 1 (138 mg).

[0077] Synthesis of intermediates 2 to 5: Intermediates 2 to 5 were synthesized by referring to the synthesis method of intermediate 1, as shown in Table 1.

[0078] Table 1 Synthesis of Intermediates 2 to 5

[0079]

[0080]

[0081] Synthesis of Intermediates 6 and 7:

[0082]

[0083] Under nitrogen, 2-hydroxy-1-naphthoic acid (10.0 g, 53.1 mmol) was added portionwise to HSO₃Cl (50 mL) at 0°C. The ice bath was removed, and the reaction mixture was warmed to 20°C and stirred for 12 hours. The mixture was quenched with ice water (200 mL) at 0°C to precipitate a solid, which was collected by filtration, rinsed with water (10 mL x 3), and dried under reduced pressure to afford the crude product of Intermediate 6-1 (15.0 g) as an off-white solid in a 98.6% yield. 1 H NMR (400MHz, DMSO-d6) δ8.35(d,J=9.2Hz,1H),8.09(d,J=1.6Hz,1H),8.05(d,J=9.2Hz,1H),7.74(dd,J=1.6,9.2Hz,1H),7.21(d,J=9.2Hz,1H).

[0084] To a DCM solution (150 mL) of the crude intermediate 6-1 (15.0 g, 52.3 mmol) and cyclopropylamine (3.58 g, 62.8 mmol, 4.35 mL) was added DIEA (20.3 g, 157 mmol, 27.3 mL), and the mixture was stirred at 20° C. for 2 hours. The residue was concentrated under reduced pressure and purified by flash silica gel column chromatography ( 120g Silica gel column; 0-100% ethyl acetate / hexane → 0-30% methanol / ethyl acetate gradient, 100 mL / min) to give yellow oily intermediate 6 (16.0 g) in a yield of 99.3%. 1 HNMR (400MHz, DMSO-d6) δ9.72(d,J=9.2Hz,1H),8.99-8.85(m,2H),8.11(d,J=2.0Hz,1H),7.85(d,J=9.2Hz,1H),7.72(d,J =2.4Hz,1H),7.63(dd,J=2.0,9.2Hz,1H),7.01(d,J=8.8Hz,1H),2.11-2.03(m,1H),0.46-0.39(m,2H),0.38-0.32(m,2H).

[0085] To an acetone solution (20 mL) of intermediate 6 (2.00 g, 6.51 mmol) was added potassium carbonate (3.60 g, 26.0 mmol). Under nitrogen protection, at 20°C, MeI (2.77 g, 19.5 mmol, 1.22 mL) was added dropwise. The reaction mixture was heated to 60°C under nitrogen protection and stirred for 12 hours. Filtered, the filter cake was rinsed with ethyl acetate (5 mL * 3). The filtrates were combined and concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography ( 20.0g The product was purified by silica gel column (0-20% ethyl acetate / hexane gradient, 120 mL / min) to give a pale yellow solid intermediate 7-1 (550 mg) in a yield of 25.2%. 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.37(d,J=9.2Hz,1H),8.00(s,1H),7.86-7.78(m,2H),7.69(d,J=9.2Hz,1H),3.98(s,3H),3.95(s,3H),2.11(br d,J=1.6Hz,1H),0.49-0.42(m,2H),0.38-0.32(m,2H).

[0086] To a mixed solution of intermediate 7-1 (550 mg, 1.64 mmol) in MeOH (4 mL) and water (1 mL) was added sodium hydroxide (197 mg, 4.92 mmol), the mixture was heated to 60°C and stirred for 12 hours. The mixture was concentrated under reduced pressure, and the resulting residue was acidified to pH = 2 with 1N hydrochloric acid to precipitate a solid. The solid was collected by filtration, rinsed with water (3 mL), and dried under reduced pressure to obtain intermediate 7 (430 mg) as a white solid in an 89.8% yield. 1 H NMR (400MHz, DMSO-d6) δ8.46 (s, 1H), 8.30 (d, J = 8.8Hz, 1H), 7.97 (br d,J=2.4Hz,1H),7.89-7.82(m,2H),7.66(d,J=9.2Hz,1H),3.97(s,3H),2.13(td,J=3.2,6.4Hz,1H),0.52-0.41(m,2H),0.39-0.31(m,2H).

[0087] Synthesis of intermediate 8:

[0088]

[0089] 6-Hydroxynaphthoic acid (1.00 g, 5.31 mmol) was dissolved in DCM (40 mL). DMF (40.9 μL, 531 μmol) and (COCl) (809 mg, 6.38 mmol) were added sequentially, and the mixture was stirred at 25°C for 1 hour. Methanol (10 mL) was then added, and the mixture was stirred at 25°C for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography to afford intermediate 8-1 (350 mg) as a yellow solid in a 32.6% yield.

[0090] Intermediate 8-1 (350 mg, 1.73 mmol) was dissolved in DCM (3 mL) and cooled to -78°C under N2 protection. DIEA (904 μL, 5.19 mmol) and trifluoromethanesulfonic anhydride (343 μL, 2.08 mmol) were added and the reaction was stirred for 1 hour. LC-MS showed that Intermediate 8-1 was completely consumed. The reaction mixture was diluted with aqueous ammonium chloride (5 mL). The aqueous phase was extracted with DCM (5 mL x 2). The organic layers were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography to obtain Intermediate 8-2 (408 mg) as a white solid in a 70.5% yield. 1 H NMR (400MHz, DMSO-d6) δ8.93(d,J=9.6Hz,1H),8.35(d,J=8.4Hz,1H),8.30-8.23(m,2H),7.79-7.72(m,2H),3.95(s,3H).

[0091] Intermediate 8-2 (350 mg, 1.05 mmol), DIEA (547 μL, 3.14 mmol), BnSH (293 μL, 2.50 mmol), Pd2(dba)3 (95.9 mg, 105 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (60.6 mg, 105 μmol) were dissolved in dioxane (4 mL). The atmosphere was degassed and replaced with N2 three times. The mixture was then heated to 100°C under N2 protection and stirred for 12 hours. LC-MS showed that intermediate 8-2 was completely consumed. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain intermediate 8-3 (320 mg) as a yellow oil in a 99.1% yield. 1 H NMR (400MHz, DMSO-d6) δ8.65 (brd, J=9.0Hz, 1H), 8.14-8.03 (m, 2H), 7.96 (br s,1H),7.64-7.53(m,2H),7.48-7.39(m,3H),7.33-7.28(m,2H),4.39(br s,2H),3.92(d,J=2.8Hz,3H).

[0092] To a mixed solution of intermediate 8-3 (320 mg, 1.04 mmol) in AcOH (2 mL), THF (0.4 mL), and water (0.4 mL) at 0°C was added NCS (554 mg, 4.15 mmol). The mixture was heated to 25°C and stirred for 1 hour. LC-MS showed complete consumption of intermediate 8-3. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 mL*3). The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to afford intermediate 8-4 (120 mg) as a colorless oil in a 40.6% yield. 1 H NMR (400MHz, DMSO-d6) δ8.70(d,J=8.8Hz,1H),8.29-8.21(m,2H),8.17-8.11(m,1H),7.84(dd,J=1.6,8.8Hz,1H),7.62(t,J=7.6Hz,1H),3.94(s,3H).

[0093] Intermediate 8-4 (120 mg, 421 μmol) was dissolved in DCM (1 mL), and DIEA (147 μL, 843 μmol) and cyclopropylamine (35 μL, 506 μmol) were added. The reaction was stirred at 25°C for 0.5 h. LC-MS showed complete consumption of intermediate 8-4. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to afford intermediate 8-5 (100 mg) as a colorless gel in a 77.7% yield.

[0094] To a mixed solution of Intermediate 8-5 (100 mg, 327 μmol) in THF (1 mL) and water (1 mL) was added LiOH·H2O (68.7 mg, 1.64 mmol). The mixture was heated to 70°C and stirred for 2 hours. LC-MS showed complete consumption of Intermediate 8-5. The reaction mixture was adjusted to pH 1 by adding 1N hydrochloric acid, filtered, and the filter cake was washed with water (5 mL) and dried to afford Intermediate 8 (90.0 mg) as a white solid in a yield of 94.5%. MS (ESI-): m / z 290.1 [MH] - .

[0095] Synthesis of intermediate 9:

[0096]

[0097] To a solution of 8-bromo-1-naphthoic acid (10.0 g, 39.8 mmol) in DCM (100 mL) was added DMF (306 μL, 3.98 mmol) and (COCl) 2 (4.18 mL, 47.8 mmol) at 0°C under nitrogen protection. After stirring for 1 hour, MeOH (20 mL) was added dropwise. The ice bath was removed and stirring was continued at 20°C for 1 hour. The residue was concentrated under reduced pressure and subjected to flash silica gel column chromatography ( 40.0g Purification by silica gel column, 0-5% ethyl acetate / hexane, 120 mL / min) afforded intermediate 9-1 (8.80 g) as a colorless oil in a yield of 83.3%. 1 H NMR (400MHz, DMSO-d6) δ8.16(dd,J=1.2,8.0Hz,1H),8.09(d,J=8.0Hz,1H),7.97(dd,J=1 .2,7.6Hz,1H),7.72-7.68(m,1H),7.66-7.60(m,1H),7.50(t,J=8.0Hz,1H),3.90(s,3H).

[0098] Under nitrogen, Intermediate 9-1 (6.0 g, 22.6 mmol) was added portionwise to HSO3Cl (18 mL) at 0°C and stirred at 20°C for 24 hours. The mixture was quenched by the addition of ice water (10 mL) to precipitate a solid. The solid was collected by filtration, rinsed with water (3 mL x 3), and dried under reduced pressure to afford a crude brown solid of Intermediate 9-2 (6.40 g).

[0099] To a solution of intermediate 9-2 (6.40 g) in DCM (32 mL) was added DIEA (3.41 g, 26.4 mmol) and 3-methoxypropan-1-amine (1.18 g, 13.2 mmol) at 0°C, and the mixture was stirred at 20°C for 2 hours. The residue was concentrated under reduced pressure and purified by flash silica gel column chromatography ( 40.0g Purification by silica gel column, 0-33% ethyl acetate / hexane, 80 mL / min) afforded intermediate 9-3 (2.00 g) as a yellow oil with a two-step yield of 27.3%. 1 H NMR (400MHz, DMSO-d6) δ8.87(dd,J=2.0,8.0Hz,1H),8.15(d,J=8.0Hz,1H),8.05(d,J=8.0Hz,1H),7. 88-7.80(m,2H),3.92(s,3H),3.13(t,J=6.0Hz,2H),3.00(s,3H),2.84(t,J=6.8Hz,2H),1.52(m,2H).

[0100] To a mixed solution of intermediate 9-2 (2.00 g, 2.4 mmol) in methanol (10 mL) and water (2 mL) was added sodium hydroxide (200 mg, 5.00 mmol), stirred at 60°C for 12 hours, and then additional sodium hydroxide (400 mg, 10.0 mmol) was added. The temperature was raised to 80°C and stirring was continued for 48 hours. The mixture was concentrated under reduced pressure, and the resulting residue was acidified with 1N hydrochloric acid to pH = 2 to precipitate a solid. The solid was collected by filtration and rinsed with water (2 mL * 3), and dried under reduced pressure to obtain intermediate 9 (1.27 g) as a yellow solid in a yield of 65.7%. 1 H NMR (400MHz, DMSO-d6) δ13.76-13.09(m,1H),8.83(br d,J=8.0Hz,1H),8.26-8.09(m,2H),8.08-8.01(m,1H),7.87-7.78(m,2H),3.14(br t,J=6.0Hz,2H),3.00(s,3H),2.89-2.79(m,2H),1.52(m,2H).

[0101] Synthesis of intermediate 10:

[0102]

[0103] Under nitrogen, 2-hydroxy-1-naphthoic acid (10.0 g, 53.1 mmol) was added portionwise to HSO₃Cl (50 mL) at 0°C and stirred at 20°C for 12 hours. The reaction mixture was quenched with ice water (200 mL), resulting in the precipitation of a solid. The solid was collected by filtration, rinsed with water (10 mL x 3), and dried under reduced pressure to afford the crude product of Intermediate 10-1 (15.0 g) as an off-white solid.

[0104] To a solution of the crude intermediate 10-1 (15.0 g) in DCM (150 mL) were added cyclopropylamine (3.58 g, 62.8 mmol) and DIEA (27.3 mL, 157 mmol), and the mixture was stirred at 20° C. for 2 hours. The residue was concentrated under reduced pressure and purified by flash silica gel column chromatography ( 120g The residue was purified by silica gel column (0-100% ethyl acetate / hexane → 0-30% methanol / ethyl acetate, 100 mL / min) to give the crude intermediate 10-2 (16.0 g) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ9.72(d,J=9.2Hz,1H),8.99-8.85(m,2H),8.11(d,J=2.0Hz,1H),7.85(d,J=9.2Hz,1H),7.72(d,J =2.4Hz,1H),7.63(dd,J=2.0,9.2Hz,1H),7.01(d,J=8.8Hz,1H),2.11-2.03(m,1H),0.46-0.39(m,2H),0.38-0.32(m,2H).

[0105] At 20°C, under nitrogen protection, potassium carbonate (3.60g, 0.21mol) and MeI (9.76mL, 0.16mol) were added to an acetone solution (160mL) of the crude intermediate 10-2 (16.0g, 6.51mmol), and the mixture was heated to 60°C and stirred for 12 hours. The mixture was filtered and the filter cake was rinsed with ethyl acetate (5mL*3). The filtrates were combined and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography ( 20.0 grams Purification was performed on a silica gel column (eluting with a gradient of 0-20% ethyl acetate / commercial hexane at 120 mL / min) to afford intermediate 10-3 (4.38 g) as a pale yellow solid with a three-step yield of 16.4%. 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.37(d,J=9.2Hz,1H),8.00(s,1H),7.86-7.78(m,2H),7.69(d,J=9.2Hz,1H),3.98(s,3H),3.95(s,3H),2.11(br d,J=1.6Hz,1H),0.49-0.42(m,2H),0.38-0.32(m,2H).

[0106] To a mixed solution of intermediate 10-3 (550 mg, 1.64 mmol) in THF (4 mL), water (1 mL), and MeOH (4 mL) was added sodium hydroxide (197 mg, 4.92 mmol), and the mixture was heated to 60°C and stirred for 38 hours. The mixture was concentrated under reduced pressure, and the resulting residue was acidified to pH = 2 with 1N hydrochloric acid to precipitate a solid. The solid was collected by filtration, rinsed with water (3 mL), and dried under reduced pressure to obtain intermediate 10 (430 mg) as a white solid in an 81.6% yield. 1H NMR (400MHz, DMSO-d6) δ8.46 (s, 1H), 8.30 (d, J = 8.8Hz, 1H), 7.97 (br d,J=2.4Hz,1H),7.89-7.82(m,2H),7.66(d,J=9.2Hz,1H),3.97(s,3H),2.13(td,J=3.2,6.4Hz,1H),0.52-0.41(m,2H),0.39-0.31(m,2H).

[0107] Example 2: Synthesis of compounds

[0108] Synthesis of compound 1:

[0109]

[0110] To a solution of 5-amino-1-naphthoic acid (280 mg, 1.50 mmol) in THF (6 mL) were added EDCI (573 mg, 2.99 mmol), TEA (625 μL, 4.49 mmol), HOBt (404 mg, 2.99 mmol), and 2S-(2-aminoacetyl)-4,4-difluoro-2-cyanopyrrole (337 mg, 1.50 mmol) in sequence. The mixture was stirred at 15° C. for 1 hour. LC-MS showed that 5-amino-1-naphthoic acid was completely consumed. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 2:3) to give Compound 1-1 (302 mg) as a yellow solid in a yield of 56.3%.

[0111] To a solution of compound 1-1 (100 mg, 279 μmol) in acetonitrile (2 mL) were added boron trifluoride-diethyl ether (51.5 μL, 419 μmol) and t-BuONO (34.5 mg, 335 μmol), and the mixture was stirred at 15°C for 1 hour. Potassium metabisulfite (155 mg, 698 μmol), NFSI (132 mg, 419 μmol), water (0.03 mL), and AcOH (0.06 mL) were then added under N2 conditions. The mixture was heated to 50°C and stirred for 10 hours. LC-MS showed that compound 1-1 was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative reverse phase chromatography (column: Waters Xbridge BEH C 18 100*30mm, 10μm; mobile phase: [water (10mM NH4HCO3)-ACN], 30%-60% ACN) to obtain yellow solid compound 1 (14.0mg), yield 11.4%. MS (ESI-): m / z 424.0 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ9.13-9.06(m,1H),8.92(d,J=8.4Hz,1H),8.57-8.49(m,2H), 8.02-7.88(m,3H),5.19(dd,J=2.0,9.2Hz,1H),4.45-4.10(m,4H),3.00-2.80(m,2H).

[0112] Synthesis of compound 2:

[0113]

[0114] To a DMF (2 mL) solution of intermediate 2 (100 mg, 377 μmol) and 2S-(2-aminoacetyl)-4,4-difluoro-2-cyanopyrrole (163 mg, 452 μmol) were added HOBt (102 mg, 754 μmol), triethylamine (158 μL, 1.13 mmol) and EDCI (145 mg, 754 μmol), and the mixture was stirred at 20° C. for 2 hours. LC-MS results showed that intermediate 2 was completely consumed. The reaction mixture was subjected to preparative reverse phase chromatography (chromatographic column: Phenomenex Genimi NX C 18 150*40mm, 5μm; mobile phase: [water (10mMNH4HCO3)-ACN]; gradient: 15% to 45% ACN) to obtain white solid compound 2 (56.1mg), yield 34.1%. MS (ESI+): m / z 437.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.98(br t,J=5.6Hz,1H),8.77-8.72(m,1H),8.62(d,J=8.4Hz,1H),8.15(d,J=7.2Hz,1H),7.88-7.81(m,1H),7.78-7.69(m,3H),5.18(br d,J=9.2Hz,1H),4.39-4.27(m,1H),4.38-4.06(m,3H),2.99-2.78(m,2H),2.43(s,3H).

[0115] Synthesis of compounds 3-9: Compounds 3-9 were synthesized by referring to the synthesis method of compound 2, as shown in Table 2.

[0116] Table 2 Synthesis of compounds 3 to 9

[0117]

[0118]

[0119]

[0120] Synthesis of compound 10:

[0121]

[0122] Under nitrogen protection, DPPA (556 μL, 2.57 mmol) and TEA (717 μL, 5.15 mmol) were added to a toluene solution (10 mL) of intermediate 1 (500 mg, 1.72 mmol), stirred at 25 ° C for 2 hours, and then ethanol (902 μL, 15.45 mmol) was added, heated to 70 ° C and stirred for 2 hours. After that, ethanol (3 mL) and potassium hydroxide (867 mg, 15.45 mmol) were added, and stirring was continued at 70 ° C for 4 hours. Water (10 mL) was added to dilute the reaction mixture, extracted with ethyl acetate (5 mL * 3), the organic layer phases were combined, washed with brine (5 mL), dried over sodium sulfate, filtered, the filtrate was collected and concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography ( 5.0g The residue was purified by silica gel column, 0-20% ethyl acetate / hexane, 120 mL / min) to obtain compound 10-1 (150 mg) as a brown oil in a yield of 33.3%.

[0123] To a solution of monomethyl malonate (72 μL, 686 μmol) and compound 10-1 (150 mg, 572 μmol) in dichloromethane (2 mL) were added HATU (326 mg, 858 μmo) and DIEA (199 μL, 1.14 mmol), and the mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (4 mL*3), and the organic phases were combined, dried over sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography ( 5.0g The residue was purified by silica gel column (0-30% ethyl acetate / hexane, 100 mL / min) to obtain yellow oily compound 10-2 (100 mg) in a yield of 48.3%.

[0124] To a mixed solution of compound 10-3 (100 mg, 276 μmol) in MeOH (1.6 mL) and water (0.4 mL) was added sodium hydroxide (110 mg, 2.76 mmol), and the mixture was heated to 60°C and stirred for 36 hours. The mixture was concentrated under reduced pressure, and the resulting residue was acidified to pH = 2 with 1N hydrochloric acid to precipitate a solid. The solid was collected by filtration, rinsed with water (2 mL), and dried under reduced pressure to afford compound 10-3 (80 mg) as a white solid in an 83.4% yield.

[0125] To a solution of compound 10-3 (80 mg, 230 μmol) and (2S)-4,4-difluoro-pyrrolidine-2-carbonitrile hydrochloride (46.6 mg, 276 μmol) in DMF (0.5 mL) were added DIEA (80 μL, 460 μmol), HOBt (46.5 mg, 344 μmol), and EDCI (66.1 mg, 344 μmol). The mixture was stirred at 20°C for 12 hours. The reaction mixture was purified by pre-HPLC (column: WePureBiotech XP tC18100*30 mm, 7 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 30% to 60% ACN, 8 min) to afford compound 10 (55.5 mg) as a white solid in a yield of 52.3%. MS (ESI+): m / z 463.1 [M+H] + ; 1 HNMR (400MHz, DMSO-d6) δ10.48-10.38(m,1H),8.53(d,J=8.6Hz,1H),8.40(d,J=8.6Hz,1H),8.35-8.26(m,1H),8.24(d,J=6.8Hz,1H) ,7.79-7.65(m,3H),5.16(dd,J=2.4,9.2Hz,1H),4.39-4.08(m,4H),3.28(s,2H),2.08(m,1H),0.42-0.35(m,2H),0.30-0.20(m,2H).

[0126] Synthesis of compounds 11-13:

[0127]

[0128] To a solution of compound 5 (330.0 mg, 583 μmol) in DCM (1 mL) was added TFA (0.3 mL, 4.04 mmol), and the mixture was stirred at 20°C for 0.5 h. The mixture was concentrated under reduced pressure, and the resulting residue was purified by pre-HPLC (column: Phenomenex Luna C1875*30 mm, 3 μm; mobile phase: [water (0.1% TFA)-ACN]; gradient: 5% to 35% ACN, 8 min) to afford the trifluoroacetate salt of compound 5-1 as a white solid (98.0 mg) in a yield of 29.9%.

[0129] Compound 5-1 trifluoroacetate (53.5 μmol), α-aminoacetic acid analog (64.2 μmol), HCTU (33.2 mg, 80.3 μmol), DIEA (28 μL, 161 μmol), and HOBt (723 mg, 5.35 μmol) were added to DMF (0.5 mL) in sequence and stirred at 20° C. for 1 hour. The reaction mixture was purified by pre-HPLC (column: WePure Biotech XP tC18100*30 mm, 7 μm; mobile phase: [H2O(10 mMNH4HCO3)-ACN]; gradient: 50% to 80% ACN, 8.0 min) to give 11-1 to 13-1.

[0130] The white solid obtained in the previous step was dissolved in DCM (1.5 mL), and TFA (0.5 mL) was added. The mixture was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure, and the resulting residue was purified by pre-HPLC (Phenomenex Luna C1875*30 mm, 3 μm column; mobile phase: [water (0.1% TFA)-ACN]; gradient: 15% to 45% ACN, 8.0 min) to afford compounds 11-13 as white solids (see Table 3 for details. Note: In the above synthetic route, when the R substituent has a Boc group, R' represents the substituent in the de-Boc structure. When R does not have a Boc group, the substituents R and R' are the same).

[0131] Table 3 Synthesis of compounds 11 to 13

[0132]

[0133]

[0134] Synthesis of compound 14:

[0135]

[0136] To a solution of naphthalene-1-carboxylic acid (1.84 mg, 10.7 μmol) and compound 5-1 (5.63 mg, 10.0 μmol) in DMF (0.1 mL) were added DIEA (5.2 μL, 30.0 μmol), HOBt (134 μg, 0.10 μmol), and HCTU (6.10 mg, 15.0 μmol), and the mixture was stirred at 20°C for 1 hour. The reaction mixture was purified by pre-HPLC (column: WePure Biotech XP tC18100*30 mm, 7 μm; mobile phase: H2O (10 mM NH4HCO3)-ACN; gradient: 45% to 90% ACN over 8.0 min) to afford compound 14 (1.2 mg) as a white solid in a yield of 16.0%. MS (ESI +):m / z 620.2[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),8.62(d,J=8.4Hz,1H),8.53(t,J=5.6Hz,1H),8.46(d,J=8.4Hz,1H),8.27(br d,J=7.2Hz,2H),8.24-8.19(m,1H),8.07-7.99(m,2H),7.86-7.81(m,1H),7.78(dt,J=3.6,8.0Hz,2H),7.63-7 .54(m,4H),5.17(dd,J=2.4,9.2Hz,1H),4.38-4.09(m,4H),3.90-3.81(m,3H),3.43-3.40(m,2H),3.10(m,2H).

[0137] Synthesis of Compound 15 and Compound 16: Compound 15 and Compound 16 were synthesized by referring to the synthesis method of Compound 10, as shown in Table 4.

[0138] Table 4 Synthesis of Compound 15 and Compound 16

[0139]

[0140] Synthesis of comparative example (1374770-21-4): Reference patent EP2804859B1,

[0141]

[0142] To a solution of 1-naphthoic acid (20.0 mg, 116 μmol) in DMF (0.5 mL) were added 2S-(2-aminoacetyl)-4,4-difluoro-2-cyanopyrrole (28.8 mg, 128 μmol), DIEA (40.5 μL, 232 μmol), HOBt (23.5 mg, 174 μmol), and EDCI (33.4 mg, 174 μmol) in sequence. The mixture was stirred at 20°C for 12 hours. The reaction mixture was purified by pre-HPLC (column: WePureBiotech XP tC18100*30 mm, 7 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 30% to 60% ACN over 8.0 min) to afford the comparative compound (15.6 mg) as a white solid in a 38.9% yield. MS (ESI+): m / z 344.1 [M+H] + ; 1HNMR(400MHz,DMSO-d6)δ8.84(br t,J=5.6Hz,1H),8.39-8.33(m,1H),8.03(d,J=8.2Hz,1H),8.00-7.96(m,1H),7.67-7.62(m,1H),7.60-7.54(m,3H), 5.17(dd,J=2.8,9.2Hz,1H),4.37-4.24(m,1H),4.20(dd,J=6.0,11.6Hz,2H),4.16-4.08(m,1H),3.00-2.77(m,2H).

[0143] Example 3: Evaluation of enzyme activity inhibition at the pure protein level

[0144] The enzyme activity of the hydrolysis of H-Gly-Pro-pNA (CAS: 103213-34-9) and human FAP and DPP4 proteins (purchased from Shanghai Kaijia Biotechnology Co., Ltd.) was measured. The enzyme activity of the hydrolysis of Z-Gly-Pro-pNA (CAS: 65022-15-3) and human PREP protein (purchased from Baiaode Co., Ltd.) was measured. The inhibitory effect of the compounds on the above-mentioned different enzyme activities (i.e., the IC 50 The affinity and selectivity of the compound for FAP were evaluated by ELISA. First, the mixture of pure protein level enzyme and a series of compounds was incubated at room temperature for 1 hour. The reaction system contained FAP (2μg / mL, 100mM Tris buffer, 100mM NaCl, pH 7.4), DPP4 (0.25μg / mL, 100mM Tris buffer, pH 8.0), and PREP (2μg / mL, 100mM Trisbuffer, 100mM NaCl, pH 6.0), with a total volume of 50μL. Secondly, 50μL of substrate solution containing substrate H-Gly-Pro-pNA 2.5mM or Z-Gly-Pro-pNA 0.25mM was added and incubated at 37°C for 0.5h. The DMSO volume in the reaction system was 1%. The absorbance at 405nm was measured using Multiskan FC on the ELISA plate. IC 50 Values were fitted using GraphPad Prism.

[0145] Table 5 Inhibitory activity data of compounds on enzymes

[0146]

[0147] The present invention evaluates the affinity and selectivity of compounds for FAP by testing their enzymatic activity against substrate hydrolysis catalyzed by FAP and its family proteins, DPP4 and PREP. Specifically, the compounds are tested for inhibition of the increase in 405 nm spectral signal caused by substrate hydrolysis, yielding data on their inhibitory activity against the enzyme. Stronger affinity for FAP, DPP4, or PREP indicates stronger inhibition, while less substrate hydrolysis indicates a smaller increase in 405 nm spectral signal. The inhibitory activity data for specific compounds are shown in Table 5. These results demonstrate that the compounds of the present invention exhibit excellent FAP enzymatic activity inhibition, but no significant inhibition of DPP4 or PREP enzymatic activity, demonstrating good selectivity. The compounds of the present invention can be used as FAP inhibitors for the diagnosis and / or treatment of diseases such as rheumatoid arthritis, non-alcoholic fatty liver disease, atherosclerosis, myocardial infarction, liver fibrosis, pulmonary fibrosis, renal fibrosis, sarcoma, glioblastoma, ovarian cancer, breast cancer, cervical cancer, lung cancer, pancreatic cancer, mesothelioma, skin cancer, colorectal cancer, bladder cancer, gastric cancer, endometrial cancer or thyroid cancer.

[0148] The above descriptions are merely optional embodiments of the present invention and are 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 in the scope of protection of the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, optical isomer, or stereoisomer thereof: in, W is selected from -CONH-, -NHCO-; R1 is selected from H, halogen, hydroxyl, C 1-3 Alkoxy, C 1-3 alkyl; Ring A is selected from wherein X and Y are independently selected from F and NR2R3; R4 is selected from H, halogen, and cyano; R2 and R3 are each independently selected from L is selected from C 1-5 Alkylene or bond; K1 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR5 or a bond; K2 is selected from AA or a bond; Z is selected from H, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 Alkyl; wherein R5 is selected from H, C 1-4 Alkyl, Boc or wherein AA is selected from amino acid residues selected from glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; Ring A1 and Ring A2 are independently selected from a naphthalene ring, a benzene ring, and a pyridine ring.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, optical isomer, or stereoisomer, wherein: Said R2 is selected from H, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 Alkyl, preferably H, C 1-4 Alkyl; said R3 is selected from L is selected from C 1-5 Alkylene or bond; K1 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR5 or a bond; K2 is selected from AA or a bond; Z is selected from H, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 Alkyl; wherein R5 is selected from H, C 1-4 Alkyl, Boc or wherein AA is selected from amino acid residues selected from glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; Ring A1 and Ring A2 are independently selected from a naphthalene ring, a benzene ring, and a pyridine ring.

3. The compound according to claim 2 or its pharmaceutically acceptable salt, optical isomer, or stereoisomer, wherein: The R3 is selected from L is selected from C 1-5 Alkylene or bond; K1 is selected from O, S, NR5 or bond; K2 is selected from AA or a bond; Z is selected from H, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 Alkyl; wherein R5 is selected from H, C 1-4 Alkyl, Boc or wherein AA is selected from amino acid residues selected from glycine, phenylalanine, arginine, N ω ,N ω - dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; Ring A1 and Ring A2 are independently selected from a naphthalene ring, a benzene ring, and a pyridine ring; Preferably, said R3 is selected from L is selected from C 1-5 Alkylene or bond; K1 is selected from O, S, NR5 or bond; K2 is selected from AA or a bond; Z is selected from H, C 3-6 Cycloalkyl, C 1-4 Alkyl; wherein R5 is selected from H, C 1-4 Alkyl, Boc or wherein AA is selected from amino acid residues selected from glycine, phenylalanine, arginine, N ω ,N ω - dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; Ring A1 and Ring A2 are independently selected from a naphthalene ring, a benzene ring, and a pyridine ring; More preferably, said R3 is selected from L is selected from C 1-5 Alkylene or bond; K1 is selected from O, S, NR5 or bond; K2 is selected from AA or a bond; Z is selected from H, C 3-6 Cycloalkyl, C 1-4 Alkyl; wherein R5 is selected from H, Boc or wherein AA is selected from amino acid residues selected from glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; Ring A1 and Ring A2 are independently selected from a naphthalene ring, a benzene ring, and a pyridine ring.

4. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt, optical isomer, or stereoisomer thereof, characterized in that: The R1 is selected from H, C 1-3 Alkoxy.

5. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt, optical isomer, or stereoisomer thereof, characterized in that: The amino acids are selected from glycine, phenylalanine, arginine, N ω ,N ω - dimethylarginine, citrulline, histidine or lysine, preferably arginine.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, optical isomer, or stereoisomer thereof, characterized in that: The ring A is selected from 7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, optical isomer, or stereoisomer thereof, characterized in that: The ring A is selected from 8. The compound according to claim 1 or its pharmaceutically acceptable salt, optical isomer, or stereoisomer, wherein: The compound is selected from any of the following compounds:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, optical isomer, stereoisomer thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

10. Use of the compound according to any one of claims 1 to 8 or its pharmaceutically acceptable salt, optical isomer, stereoisomer, and solvate, metabolite, cocrystal or prodrug thereof, or the pharmaceutical composition according to claim 9 in the preparation of a medicament as a FAP inhibitor.

11. The use according to claim 10, wherein the disease for diagnosis and / or treatment of the FAP inhibitor is any one or more of rheumatoid arthritis, non-alcoholic fatty liver disease, atherosclerosis, myocardial infarction, liver fibrosis, pulmonary fibrosis, renal fibrosis, sarcoma, glioblastoma, ovarian cancer, breast cancer, cervical cancer, lung cancer, pancreatic cancer, mesothelioma, skin cancer, colorectal cancer, bladder cancer, gastric cancer, endometrial cancer or thyroid cancer.

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