A fap inhibitor, compositions and uses thereof

Abstract

The application discloses a FAP inhibitor, a composition and application thereof, relates to the field of medicinal chemistry and radiopharmaceuticals, and the FAP inhibitor has a compound shown in formula I or a pharmaceutically acceptable salt, a corresponding radioactive element marker: wherein R1 and R2 are independently selected from hydrogen, halogen or methyl; R3 is selected from hydrogen, methyl or isopropyl; R4 is selected from hydrogen or methyl; and R5 is selected from hydrogen, methyl or halogen. The FAP inhibitor combined with the corresponding radioactive element can be used for diagnosis and treatment of FAP-positive related diseases, and compared with traditional FAPI radiopharmaceuticals, the FAP inhibitor has higher uptake rate at a lesion site, higher target-to-non-target contrast, and no obvious toxic side effects.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry & radiopharmaceutical technology, in particular to a FAP inhibitor, composition and application thereof. BACKGROUND

[0002] FAP (Fibroblast activation protein-alpha) is a 97 kDa type II transmembrane serine protease that contains both dipeptidyl peptidase and endopeptidase activities and exists as a homodimer. FAP requires dimerization and glycosylation for functional activity. The dipeptidyl peptidase activity of FAP enables it to cleave neuropeptide Y, peptide YY, substance P and brain natriuretic peptide 32, while its endopeptidase activity substrates include denatured type I and III collagens, alpha-2 antiplasmin cleaving enzyme, and FGF21. Under physiological conditions, FAP is expressed at low levels in most adult tissues. However, FAP mRNA levels are elevated in different tumor types, with the highest median in pancreatic and breast cancers. In most epithelial cancers, FAP is mainly expressed in cancer-associated fibroblasts (CAFs) cells in the stroma.

[0003] In addition, FAP is also expressed in some tumor cells such as sarcoma, mesothelioma and esophageal epithelial tumors. FAP can affect tumor growth through various mechanisms, including promoting proliferation, invasion, angiogenesis, epithelial-mesenchymal transition, stem cell promotion, immunosuppression and drug resistance. Mechanistically, FAP can bind to beta-integrin, synergistically promoting tumor cell proliferation, migration and invasion. The pro-angiogenic properties of FAP are attributed to its dipeptidyl peptidase activity, which acts on its substrate neuropeptide Y, which can promote angiogenesis and promote endothelial cell migration after cleavage. In addition, the interaction of FAP with uPAR is also involved in the process of tumor cell migration and immunosuppression phenotype. The downstream signaling pathways of FAP mainly include PI3K / AKT, RAS / ERK, SHH / GLI, FAK, etc. The tumor stroma is an important participant in tumor occurrence, drug resistance, angiogenesis, invasion and metastasis, which is composed of CAF and ECM, and FAP, as a specific surface marker of CAF, plays an important role in it, and is a high-potential target for tumor diagnosis and treatment.

[0004] In view of the problems in the related art, no effective solution has been proposed so far. SUMMARY

[0005] In view of the problems in the related art, the present application proposes a FAP inhibitor, composition and application thereof to overcome the above technical problems existing in the prior art.

[0006] To this end, the specific technical solutions adopted by the present application are as follows:

[0007] According to one aspect of the present application, there is provided a FAP inhibitor having a compound as shown in Formula I or a pharmaceutically acceptable salt thereof, a corresponding radioelement label:

[0008]

[0009] wherein R1 and R2 are independently selected from hydrogen, halogen or methyl;

[0010] R3 is selected from hydrogen, methyl or isopropyl;

[0011] R4 is selected from hydrogen or methyl;

[0012] R5 is selected from hydrogen, methyl or halogen;

[0013] X1 and X2 are independently selected from carbon and nitrogen;

[0014] R6 and R7 are independently selected from hydrogen, halogen or methyl;

[0015] R8 is selected from methyl or halogen.

[0016] Further, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, trifluoroacetate, fumarate, succinate, sulfonate, maleate, acetate, phosphate or citrate.

[0017] Further, R5 is also selected from a four-membered heterocyclic ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring formed by R4 and R5.

[0018] Further, R9 is selected from:

[0019]

[0020] wherein R 11 is selected from hydrogen or methyl;

[0021] n is selected from 1-10.

[0022] Further, R 10 is selected from:

[0023]

[0024] Further, the FAP inhibitor is selected from at least one of the following compounds:

[0025]

[0026] According to yet another aspect of the present application, the FAP inhibitor is used as an active ingredient to form a FAP inhibitor pharmaceutical composition.

[0027] According to another aspect of the present application, there is also provided a use of a FAP inhibitor, i.e. a use of a FAP inhibitor in the preparation of a medicament for diagnosing glioma.

[0028] The present application has the following beneficial effects:

[0029] 1. A new choice is provided for the development of therapeutic drugs for FAP-positive related diseases by using FAP inhibitors, and the FAP inhibitors combined with corresponding radioactive elements can be used for the diagnosis and treatment of FAP-positive related diseases. Compared with traditional FAPI radioactive drugs, the FAP inhibitors have higher uptake rate at lesion sites, higher target-to-non-target contrast, and no obvious toxic side effects.

[0030] 2. The FAPI inhibitors of the present application can be used for the treatment and diagnosis of diseases such as tumors (pancreatic cancer, breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer), myocardial infarction, scar formation, osteoporosis, liver, kidney and lung fibrosis, chronic inflammation and destructive processes (rheumatoid arthritis, Crohn's disease, atherosclerotic plaques, immunoglobulin-related diseases), etc. BRIEF DESCRIPTION OF DRAWINGS

[0031] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed in the embodiments will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative labor on the basis of these drawings.

[0032] Figure 1 is the nuclear magnetic hydrogen spectrum of compound 1;

[0033] Figure 2 is the nuclear magnetic carbon spectrum of compound 1;

[0034] Figure 3 is the nuclear magnetic hydrogen spectrum of compound 2;

[0035] Figure 4 is the nuclear magnetic carbon spectrum of compound 2;

[0036] Figure 5 is the nuclear magnetic hydrogen spectrum of compound 3;

[0037] Figure 6 is the nuclear magnetic carbon spectrum of compound 3;

[0038] Figure 7 is the nuclear magnetic hydrogen spectrum of compound 4;

[0039] Figure 8 is the nuclear magnetic carbon spectrum of compound 4;

[0040] Figure 9is a contrast image of Example Compound 7 and FAPI-04 in U87 mouse tumor imaging;

[0041] Figure 10 is a biodistribution of Example Compound 7 and FAPI-04 in U87 mice;

[0042] Figure 11 is an imaging image of Example Compound 9 labeled with 99mTc in U87 tumor-bearing mice;

[0043] Figure 12 is an imaging image of Example Compound 6 labeled with 68Ga in U87 tumor-bearing mice;

[0044] Figure 13 is an imaging image of Example Compound 8 labeled with 177Lu in U87 tumor-bearing mice;

[0045] Figure 14 is an imaging image of Example Compound 14 labeled with 177Lu in U87 tumor-bearing mice;

[0046] Figure 15 is an imaging image of Example Compound 15 labeled with 18F in U87 tumor-bearing mice. DETAILED DESCRIPTION

[0047] According to one embodiment of the present application, a FAP inhibitor is provided.

[0048] The FAP inhibitor according to the embodiment of the present application has a compound as shown in Formula I or a pharmaceutically acceptable salt thereof, a corresponding radioactive element label:

[0049]

[0050] wherein R1 and R2 are independently selected from hydrogen, halogen or methyl;

[0051] R3 is selected from hydrogen, methyl or isopropyl;

[0052] R4 is selected from hydrogen or methyl;

[0053] R5 is selected from hydrogen, methyl or halogen;

[0054] X1 and X2 are independently selected from carbon and nitrogen;

[0055] R6 and R7 are independently selected from hydrogen, halogen or methyl;

[0056] R8 is selected from methyl or halogen.

[0057] In the description of the present application, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, trifluoroacetate, fumarate, succinate, sulfonate, maleate, acetate, phosphate or citrate.

[0058] In the description of the present application, R5 is also selected from a four-membered heterocyclic ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring formed by R4 and R5.

[0059] In the description of the present application, R9 is selected from:

[0060]

[0061] wherein, R 11 selected from hydrogen or methyl;

[0062] n is selected from 1-10.

[0063] In the description of the present application, R 10 selected from:

[0064]

[0065] In the description of the present application, the FAP inhibitor is selected from at least one of the following compounds (17 compounds, the number below the chemical formula is the corresponding number of the compound, for example, 1 represents compound 1):

[0066]

[0067]

[0068]

[0069] In the description of the present application, the FAP inhibitor is used as an active ingredient to form a FAP inhibitor pharmaceutical composition.

[0070] According to another embodiment of the present application, the application also provides a FAP inhibitor for use in the preparation of a drug for diagnosing tumor cells.

[0071] The FAP inhibitor includes 17 compounds, and the preparation process and properties of each compound are different. The following embodiments 1 to 17 (according to the order of selecting the FAP inhibitor from the compounds below the number to realize the corresponding matching) detail the specific preparation process and synthesis method of the 17 compounds appearing in the present application, and the properties of some compounds are shown in Table 1. Figures 1-10

[0072] Embodiment 1

[0073] Preparation of compound 1:

[0074] ​

[0075] Synthesis of compound a3:

[0076] Take a1 (175 mg, 1 mmol), a2 (132 mg, 1 mmol) dissolved in 5 mL of DMF solution, add HATU (418 mg, 1.1 mmol), DIPEA (521 μL, 3 mmol), react at room temperature for 2 h. TLC detects complete reaction, concentrate the reaction solution. Add ethyl acetate to dissolve, wash with water, saturated brine in turn, dry the organic layer with anhydrous sodium sulfate and concentrate.

[0077] Synthesis of compound a4:

[0078] Add the concentrated a3 to a DCM: TFA (10: 1) solution, react at room temperature for 1 h, concentrate the reaction solution, separate and purify by C18 reverse phase liquid chromatography, freeze-dry to obtain compound a4 (171 mg, yield 60%). MS (ESI): 190.20 [M+H] + .

[0079] Synthesis of compound a6:

[0080] Dissolve 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazin-3-quinoline carboxylic acid (a5, 1 g, 3.13 mmol) in a solution of tetrahydrofuran: water = 1:1 (100 mL), add 2M NaOH (1.75 mL), stir at room temperature until clear, add (Boc)20 (0.75 g, 3.44 mmol) and stir at room temperature overnight. When the reaction is complete, concentrate under vacuum to remove THF, adjust the pH to 7 with citric acid, white solid precipitates, suction filter, wash with water 30 mL x 3, dry under vacuum to obtain white solid 1.3 g, yield 98%.

[0081] Synthesis of compound a7:

[0082] Take a6 (419 mg, 1 mmol), a4 (287 mg, 1 mmol) dissolved in 5 mL of DMF solution, add HATU (418 mg, 1.1 mmol), DIPEA (521 μL, 3 mmol), react at room temperature for 2 h. TLC detects complete reaction, concentrate the reaction solution. Add ethyl acetate to dissolve, wash with water, saturated brine in turn, dry the organic layer with anhydrous sodium sulfate and concentrate. Wet sample, column chromatography separation and purification, obtain compound a7 (319 mg, yield 54%).

[0083] Synthesis of compound 1:

[0084] To a solution of a7 (590 mg, 1 mmol) in DCM:TFA (10:1) was added and stirred at room temperature for 1 h. The reaction was concentrated and purified by C18 reverse phase preparative HPLC. The product was lyophilized to give compound 1 (490 mg, 100% yield). MS (ESI): 491.35 [M+H] + .

[0085] 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (t, J = 5.2 Hz, 1H), 8.94 (s, 2H), 8.81 (s, 1H), 7.95 (d, J = 13.2 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 5.11 (dd, J = 9.0, 2.9 Hz, 1H), 4.54 (q, J = 7.0 Hz, 2H), 4.24 (qd, J = 17.8, 5.2 Hz, 3H), 4.09 (dt, J = 21.2, 10.3 Hz, 1H), 3.49 (dd, J = 6.7, 3.6 Hz, 4H), 3.33 (s, 4H), 2.99 - 2.73 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, DMSO-d6) δ 174.50, 168.61, 164.71, 158.30, 154.10, 151.64, 148.07, 143.84, 136.92, 122.69, 118.24, 112.33, 112.11, 110.71, 106.78, 52.05, 48.90, 47.19, 44.60, 43.22, 41.86, 36.92, 14.94.

[0086] Example 2

[0087] Preparation of compound 2:

[0088]

[0089] Synthesis of compound b2:

[0090] A solution of 1-ethyl-6,8-difluoro-7-(3-methylpiperazin-1-yl)-4-oxo-1,4- dihydroquinoline-3-carboxylic acid (b1, 1 g, 2.85 mmol) in tetrahydrofuran: water = 1:1 (100 mL) was added 2M NaOH (1.75 mL) and stirred at room temperature until clear. (Boc)20 (0.65 g, 3 mmol) was added and stirred at room temperature overnight. When the reaction was complete, THF was removed by vacuum concentration. The pH was adjusted to 7 with citric acid. White solid was precipitated and filtered under suction. The solid was washed with water (30 mL x 3) and dried under vacuum to give white solid 1.2 g in 95% yield.

[0091] Synthesis of compound b3:

[0092] b2(451 mg, 1 mmol), a4(287 mg, 1 mmol) were dissolved in 5 mL DMF solution, HATU (418 mg, 1.1 mmol), DIPEA (521 μL, 3 mmol) were added, and the reaction was carried out at room temperature for 2 h. TLC detection showed that the reaction was complete, and the reaction solution was concentrated. Ethyl acetate was added for dissolution, and water and saturated brine were sequentially added for washing. The organic layer was dried over anhydrous sodium sulfate and concentrated. Wet loading and column chromatography separation and purification were carried out to obtain compound b3(311.3 mg, yield 50%).

[0093] Synthesis of compound 2:

[0094] b3(622.6 mg, 1 mmol) was added to a DCM:TFA (10:1) solution, and the reaction was carried out at room temperature for 1 h. The reaction solution was concentrated, and compound 2(522 mg, yield 99%) was obtained by C18 reverse phase liquid chromatography separation and purification and freeze-drying. MS (ESI): 523.43 [M+H] + .

[0095] 1 HNMR (400 MHz, Chloroform-d) δ 10.46 (t, J = 5.4 Hz, 1H), 8.61 (s, 1H), 8.05-7.94 (m, 1H), 5.07 (t, J = 6.5 Hz, 1H), 4.49-4.36 (m, 2H), 4.34-4.15 (m, 2H), 4.12-3.95 (m, 2H), 3.79-3.61 (m, 1H), 3.61-3.40 (m, 6H), 3.39-3.23 (m, 1H), 2.77 (dd, J = 16.5, 8.6 Hz, 2H), 1.53 (m, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 173.54, 168.52, 164.18, 158.90, 158.57, 153.49, 150.68, 145.84, 131.90, 129.81, 127.09, 124.23, 118.72, 118.22, 115.77, 110.55, 107.80, 53.94, 53.37, 51.74, 51.46, 47.38, 44.61, 43.58, 41.92, 36.92, 16.44, 15.81.

[0096] Example 3

[0097] Preparation of compound 3:

[0098]

[0099] Synthesis of compound c2:

[0100] A solution of 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-l-yl)-l,4-dihydroquinoline-3- carboxylic acid (c2, 431.5 mg, 1 mmol) and a4 (287 mg, 1 mmol) in 5 mL of DMF was added HATU (418 mg, 1.1 mmol) and DIPEA (521 μL, 3 mmol) and stirred at room temperature for 2 h. TLC showed the reaction was completed. The reaction solution was concentrated. Ethyl acetate was added to dissolve the reaction solution. The solution was washed with water and saturated brine successively. The organic layer was dried over anhydrous sodium sulfate and concentrated. The wet sample was loaded on a column and purified by column chromatography to give compound c3 (361.6 mg, 60% yield).

[0101] Synthesis of compound c3:

[0102] A solution of 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-l-yl)-l,4-dihydroquinoline-3- carboxylic acid (c2, 431.5 mg, 1 mmol) and a4 (287 mg, 1 mmol) in 5 mL of DMF was added HATU (418 mg, 1.1 mmol) and DIPEA (521 μL, 3 mmol) and stirred at room temperature for 2 h. TLC showed the reaction was completed. The reaction solution was concentrated. Ethyl acetate was added to dissolve the reaction solution. The solution was washed with water and saturated brine successively. The organic layer was dried over anhydrous sodium sulfate and concentrated. The wet sample was loaded on a column and purified by column chromatography to give compound c3 (361.6 mg, 60% yield).

[0103] Synthesis of compound 3:

[0104] A solution of 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-l-yl)-l,4-dihydroquinoline-3- carboxylic acid (c2, 431.5 mg, 1 mmol) and a4 (287 mg, 1 mmol) in 5 mL of DMF was added HATU (418 mg, 1.1 mmol) and DIPEA (521 μL, 3 mmol) and stirred at room temperature for 2 h. TLC showed the reaction was completed. The reaction solution was concentrated. Ethyl acetate was added to dissolve the reaction solution. The solution was washed with water and saturated brine successively. The organic layer was dried over anhydrous sodium sulfate and concentrated. The wet sample was loaded on a column and purified by column chromatography to give compound c3 (361.6 mg, 60% yield). + .

[0105] 1H NMR (400 MHz, DMSO-d6) δ 10.22 (t, J = 5.2 Hz, 1H), 9.02 (s, 2H), 8.65 (s, 1H), 7.92 (d, J = 13.2 Hz, 1H), 7.54 (d, J = 7.4 Hz, 1H), 5.11 (dd, J = 9.1, 2.8 Hz, 1H), 4.24 (qd, J = 17.8, 5.2 Hz, 3H), 4.08 (dt, J = 21.2, 10.2 Hz, 1H), 3.77 (tt, J = 7.2, 4.1 Hz, 1H), 3.49 (d, J = 6.4 Hz, 4H), 3.35 (s, 4H), 2.98 - 2.74 (m, 2H), 1.31 (d, J = 6.5 Hz, 2H), 1.12 (d, J = 3.6 Hz, 2H).13C NMR (101 MHz, DMSO) δ 174.67, 168.57, 164.51, 158.75, 154.25, 151.80, 147.47, 143.54, 138.83, 122.03, 118.23, 112.07, 111.85, 110.37, 107.14, 51.73, 47.08, 44.66, 43.19, 41.87, 36.91, 35.60, 8.07.

[0106] Example 4

[0107] Preparation of compound 4:

[0108]

[0109] Synthesis of compound d2:

[0110] A solution of 8-ethyl-5-oxo-2-(piperazin-l-yl)-5,8-dihydropyrido[2,3- d]pyrimidine-6-carboxylic acid (dl, 1 g, 3.29 mmol) in tetrahydrofuran: water = 1 : 1 (100 mL) was added 2M NaOH (1.75 mL) and stirred at room temperature until clear. (Boc)20 (0.75 g, 3.44 mmol) was added and stirred at room temperature overnight. When the reaction was complete, THF was removed by vacuum concentration. The pH was adjusted to 7 with citric acid and a white solid precipitated. The solid was filtered under suction, washed with water (30 mL x 3) and dried under vacuum to give a white solid (1.5 g, 95% yield).

[0111] Synthesis of compound d3:

[0112] To a solution of d2 (403 mg, 1 mmol) and a4 (287 mg, 1 mmol) in 5 mL of DMF, HATU (418 mg, 1.1 mmol) and DIPEA (521 μL, 3 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. TLC detection showed that the reaction was completed. The reaction mixture was concentrated. Ethyl acetate was added to dissolve the mixture, which was washed with water and saturated brine successively. The organic layer was dried over anhydrous sodium sulfate and concentrated. The wet sample was loaded and purified by column chromatography to give compound d3 (281.6 mg, yield 49%).

[0113] Synthesis of compound 4:

[0114] d3 (575 mg, 1 mmol) was added to a solution of DCM: TFA (10: 1) and stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by C18 reverse phase liquid chromatography. Compound 4 (474 mg, yield 100%) was obtained by freeze-drying. MS (ESI): 475.35 [M+H] + .

[0115] 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (t, J = 5.2 Hz, 1H), 9.21 (s, 1H), 9.06 (s, 2H), 8.82 (s, 1H), 5.12 (dd, J = 9.0, 2.9 Hz, 1H), 4.39 (q, J = 7.0 Hz, 2H), 4.26 (td, J = 19.0, 18.4, 5.2 Hz, 3H), 4.19 - 4.02 (m, 5H), 3.26 (s, 4H), 2.88 (ddd, J = 35.0, 16.0, 9.4 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, DMSO) δ 175.71, 168.47, 163.86, 160.98, 160.81, 158.77, 158.45, 155.23, 149.51, 127.34, 118.21, 113.97, 111.12, 51.71, 45.76, 44.61, 42.89, 41.90, 41.13, 36.92, 14.96.

[0116] Example 5

[0117] Preparation of compound 5:

[0118]

[0119] Synthesis of compound e2:

[0120] 6-Fluoro-l-methyl-4-oxo-7-(piperazin-l-yl)-l,4-dihydro-[l,3]thiazetidine[3,2- a]quinoline-3-carboxylic acid (e1, 1g, 2.86 mmol) was dissolved in tetrahydrofuran: water = 1:1 (100 mL), 2M NaOH (1.75 mL) was added, stirred at room temperature until clear, (Boc)20 (0.65 g, 3 mmol) was added, stirred at room temperature overnight. When the reaction was complete, THF was removed by vacuum concentration, pH was adjusted to 7 with citric acid, white solid precipitated, suction filtered, washed with water 30 mL x 3, dried under vacuum to give white solid 1.2 g, yield 95%.

[0121] Synthesis of compound e3:

[0122] e2 (449 mg, 1 mmol), a4 (287 mg, 1 mmol) were dissolved in 5 mL DMF, HATU (418 mg, 1.1 mmol), DIPEA (521 μL, 3 mmol) were added, stirred at room temperature for 2 h. TLC detection showed that the reaction was complete, the reaction solution was concentrated. Ethyl acetate was added to dissolve, washed with water, saturated brine in turn, the organic layer was dried over anhydrous sodium sulfate and concentrated. Wet sample was loaded, column chromatography separation and purification, compound e3 (279.3 mg, yield 45%) was obtained.

[0123] Synthesis of compound 5:

[0124] e3 (620.7 mg, 1 mmol) was added to a solution of DCM: TFA (10: 1), stirred at room temperature for 1 h, the reaction solution was concentrated, separated and purified by C18 reverse phase liquid chromatography, freeze-dried to give compound 5 (495 mg, yield 95%). MS (ESI): 521.37 [M+H] + .

[0125] Example 6

[0126] Preparation of compound 6:

[0127]

[0128] Synthesis of compound f1:

[0129] To 1 (245 mg, 0.5 mmol), 5,8,11,14-tetraoxa-2-azaheneicosandioic acid 1-tert-butyl ester (219 mg, 0.6 mmol) in DMF was added HATU (228 mg, 0.6 mmol), DIPEA (261 μL, 1.5 mmol) and the reaction was stirred at room temperature for 2 h. TLC indicated the reaction was complete and the reaction was concentrated. The residue was dissolved in ethyl acetate and washed with water, saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in DCM:TFA (10:1) and stirred at room temperature for 1 h. The reaction was concentrated and purified by column chromatography to give compound f1 (221 mg, 60% yield).

[0130] Synthesis of compound f3:

[0131] To f1 (74 mg, 0.1 mmol), f2 (80 mg, 0.12 mmol) in DMF was added DIPEA (52 μL, 0.3 mmol) and the reaction was stirred at room temperature for 2 h. TLC indicated the reaction was complete and the reaction was concentrated. The residue was dissolved in ethyl acetate and washed with water, saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give compound f3 (105 mg, 81% yield).

[0132] Synthesis of compound 6:

[0133] To f3 (65 mg, 0.05 mmol) in DCM:TFA (10:1) was stirred at room temperature for 1 h. The reaction was concentrated and purified by C18 reverse phase preparative HPLC and lyophilized to give compound 6 (56 mg, 100% yield). MS (ESI): 1124.92 [M+H] + .

[0134] Imaging of compound 6 labeled with68Ga in U87 tumor-bearing mice is shown in Figure 12 .

[0135] Example 7

[0136] Synthesis of compound 7:

[0137]

[0138] Synthesis of compound 7:

[0139] To a solution of f1 (73.7 mg, 0.1 mmol) and g1 (26.6 mg, 0.12 mmol) in DMF, DIPEA (52 μL, 0.3 mmol) was added and the reaction was stirred at room temperature for 2 h. TLC showed the reaction was complete. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give compound 7 (77.7 mg, 89% yield). MS (ESI): 872.75 [M+H] + .

[0140] Example 8

[0141] Preparation of compound 8:

[0142]

[0143] Synthesis of compound h1:

[0144] To a solution of 1 (245 mg, 0.5 mmol) and Boc-GPGP (255.9 mg, 0.6 mmol) in DMF, HATU (228 mg, 0.6 mmol) and DIPEA (261 μL, 1.5 mmol) were added and the reaction was stirred at room temperature for 2 h. TLC showed the reaction was complete. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in DCM:TFA (10:1) and stirred at room temperature for 1 h. The reaction mixture was concentrated. The residue was purified by C18 reverse phase preparative HPLC and lyophilized to give compound h1 (259.6 mg, 65% yield).

[0145] Synthesis of compound h2:

[0146] To a solution of h1 (79.9 mg, 0.1 mmol) and f2 (80 mg, 0.12 mmol) in DMF, DIPEA (52 μL, 0.3 mmol) was added and the reaction was stirred at room temperature for 2 h. TLC showed the reaction was complete. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give compound h2 (115 mg, 85% yield).

[0147] Synthesis of compound 8:

[0148] The residue was dissolved in DCM:TFA (10:1) and stirred at room temperature for 1 h. The reaction mixture was concentrated. The residue was purified by C18 reverse phase preparative HPLC and lyophilized to give compound 8 (58.1 mg, 98% yield). MS (ESI): 1185.89 [M+H] + .

[0149] The imaging of compound 8 labeled with 177Lu in U87 tumor-bearing mice is shown in Figure Figure 13 .

[0150] Example 9

[0151] Preparation of compound 9:

[0152]

[0153] Synthesis of compound i1:

[0154] Take 1 (245 mg, 0.5 mmol), (tert-butoxycarbonyl) glycyl glycyl glycyl glycine (242 mg, 0.6 mmol) dissolved in DMF, add HATU (228 mg, 0.6 mmol), DIPEA (261 μL, 1.5 mmol), react at room temperature for 2 h. TLC detects that the reaction is complete, and the reaction solution is concentrated. Add ethyl acetate to dissolve, and sequentially wash with water, saturated brine, dry the organic layer with anhydrous sodium sulfate, and concentrate. Add to a DCM: TFA (10: 1) solution, react at room temperature for 1 h, concentrate the reaction solution, and perform wet loading and column chromatography to separate and purify to obtain compound i1 (271.5 mg, yield 70%).

[0155] Synthesis of compound 9:

[0156] Take i1 (77.5 mg, 0.1 mmol), g1 (133.2 mg, 0.12 mmol) dissolved in DMF solution, add DIPEA (52 μL, 0.3 mmol), react at room temperature for 2 h. TLC detects that the reaction is complete, and the reaction solution is concentrated. Add ethyl acetate to dissolve, and sequentially wash with water, saturated brine, dry the organic layer with anhydrous sodium sulfate, and concentrate. Perform wet loading and column chromatography to separate and purify to obtain compound 9 (74.7 mg, yield 82%). MS (ESI): 911.71 [M+H] + .

[0157] The imaging of compound 9 labeled with 99mTc in U87 tumor-bearing mice is shown in Figure Figure 11 .

[0158] Example 10

[0159] Preparation of compound 10:

[0160]

[0161] Synthesis of compound 10:

[0162] To 1 (245 mg, 0.5 mmol), f2 (401.9 mg, 0.6 mmol) was dissolved in DMF, DIPEA (52 μL, 0.3 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 h. TLC detection showed that the reaction was complete, and the reaction solution was concentrated. Ethyl acetate was added to dissolve the solution, which was washed with water and saturated brine in turn. The organic layer was dried over anhydrous sodium sulfate and concentrated. Wet sample was loaded and purified by column chromatography to obtain compound 10 (355.1 mg, yield 81%). MS (ESI): 877.74 [M+H] + .

[0163] Example 11

[0164] Preparation of compound 11:

[0165]

[0166] Synthesis of compound j1:

[0167] To 1 (245 mg, 0.5 mmol), N-Boc-3-[2-(2-aminoethoxy)ethoxy]propionic acid (166.4 mg, 0.6 mmol) was dissolved in DMF, HATU (228 mg, 0.6 mmol) and DIPEA (261 μL, 1.5 mmol) were added, and the reaction was allowed to proceed at room temperature for 2 h. TLC detection showed that the reaction was complete, and the reaction solution was concentrated. Ethyl acetate was added to dissolve the solution, which was washed with water and saturated brine in turn. The organic layer was dried over anhydrous sodium sulfate and concentrated. It was added to a DCM:TFA (10:1) solution, and the reaction was allowed to proceed at room temperature for 1 h. The reaction solution was concentrated, wet sample was loaded, and purified by column chromatography to obtain compound j1 (201.4 mg, yield 62%).

[0168] Synthesis of compound j2:

[0169] To j1 (65.0 mg, 0.1 mmol), f2 (80 mg, 0.12 mmol) was dissolved in DMF, DIPEA (52 μL, 0.3 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 h. TLC detection showed that the reaction was complete, and the reaction solution was concentrated. Ethyl acetate was added to dissolve the solution, which was washed with water and saturated brine in turn. The organic layer was dried over anhydrous sodium sulfate and concentrated. Wet sample was loaded, and purified by column chromatography to obtain compound j2 (95.1 mg, yield 79%).

[0170] Synthesis of compound 11:

[0171] j2 (60.22 mg, 0.05 mmol) was added to a DCM:TFA (10:1) solution, and the reaction was allowed to proceed at room temperature for 1 h. The reaction solution was concentrated, purified by C18 reverse phase liquid chromatography, and freeze-dried to obtain compound 11 (51.3 mg, yield 99%). MS (ESI): 1036.83 [M+H]+ .

[0172] Example 12

[0173] Preparation of compound 12:

[0174]

[0175] Synthesis of compound k1:

[0176] Take 2 (261.3 mg, 0.5 mmol), 5, 8, 11, 14-tetraoxa-2-azadodecanedioic acid 1-tert-butyl ester (219 mg, 0.6 mmol) dissolved in DMF, add HATU (228 mg, 0.6 mmol), DIPEA (261 μL, 1.5 mmol), react at room temperature for 2 h. TLC detects that the reaction is complete, concentrate the reaction solution. Add ethyl acetate to dissolve, sequentially wash with water, saturated brine, dry the organic layer with anhydrous sodium sulfate and concentrate. Add to a DCM: TFA (10:1) solution, react at room temperature for 1 h, concentrate the reaction solution, wet load, separate and purify by column chromatography to obtain compound k1 (269.4 mg, yield 70%).

[0177] Synthesis of compound k2:

[0178] Take k1 (77.0 mg, 0.1 mmol), f2 (80.4 mg, 0.12 mmol) dissolved in DMF solution, add DIPEA (52 μL, 0.3 mmol), react at room temperature for 2 h. TLC detects that the reaction is complete, concentrate the reaction solution. Add ethyl acetate to dissolve, sequentially wash with water, saturated brine, dry the organic layer with anhydrous sodium sulfate and concentrate. Wet load, separate and purify by column chromatography to obtain compound k2 (112.6 mg, yield 85%).

[0179] Synthesis of compound 12:

[0180] Add k2 (66.2 mg, 0.05 mmol) to a DCM: TFA (10:1) solution, react at room temperature for 1 h, concentrate the reaction solution, separate and purify by C18 reverse phase liquid chromatography, freeze-dried to obtain compound 12 (57.8 mg, yield 100%). MS (ESI): 1156.89 [M+H] + .

[0181] Example 13

[0182] Preparation of compound 13:

[0183]

[0184] Synthesis of compound 13:

[0185] Take k1 (77.0 mg, 0.1 mmol), g1 (26.6 mg, 0.12 mmol) dissolved in DMF solution, add DIPEA (52 μL, 0.3 mmol), react at room temperature for 2 h. TLC detects that the reaction is complete, concentrate the reaction solution. Add ethyl acetate to dissolve, sequentially wash with water, saturated brine, dry the organic layer with anhydrous sodium sulfate and concentrate. Wet sample, column chromatography separation and purification, get compound 13 (83.3 mg, yield 92%). MS (ESI): 905.76 [M+H] + .

[0186] Example 14

[0187] Preparation of compound 14:

[0188]

[0189] Synthesis of compound 11:

[0190] Take 3 (251.3 mg, 0.5 mmol), Boc-GPGP (219 mg, 0.6 mmol) dissolved in DMF, add HATU (228 mg, 0.6 mmol), DIPEA (261 μL, 1.5 mmol), react at room temperature for 2 h. TLC detects that the reaction is complete, concentrate the reaction solution. Add ethyl acetate to dissolve, sequentially wash with water, saturated brine, dry the organic layer with anhydrous sodium sulfate and concentrate. Add to DCM: TFA (10:1) solution, react at room temperature for 1 h, concentrate the reaction solution, wet sample, column chromatography separation and purification, get compound 11 (291.9 mg, yield 72%).

[0191] Synthesis of compound 12:

[0192] Take l1 (81.1 mg, 0.1 mmol), f2 (80.4 mg, 0.12 mmol) dissolved in DMF solution, add DIPEA (52 μL, 0.3 mmol), react at room temperature for 2 h. TLC detects that the reaction is complete, concentrate the reaction solution. Add ethyl acetate to dissolve, sequentially wash with water, saturated brine, dry the organic layer with anhydrous sodium sulfate and concentrate. Wet sample, column chromatography separation and purification, get compound l2 (113.3 mg, yield 83%).

[0193] Synthesis of compound 14:

[0194] Add l2 (68.3 mg, 0.05 mmol) to DCM: TFA (10:1) solution, react at room temperature for 1 h, concentrate the reaction solution, separate and purify by C18 reverse phase liquid chromatography, freeze-drying to get compound 14 (59.9 mg, yield 100%). MS (ESI): 1197.89 [M+H] + .

[0195] The imaging of compound 14 labeled with 177Lu in U87 tumor-bearing mice is shown in Figure Figure 14

[0196] Example 15

[0197] Preparation of compound 15:

[0198]

[0199] Synthesis of compound m1:

[0200] Take 5 (260.3 mg, 0.5 mmol), (tert-butoxycarbonyl) glycyl glycyl glycyl glycine (242 mg, 0.6 mmol) dissolved in DMF, add HATU (228 mg, 0.6 mmol), DIPEA (261 μL, 1.5 mmol), react at room temperature for 2 h. TLC detects that the reaction is complete, and the reaction solution is concentrated. Dissolve in ethyl acetate, wash successively with water, saturated brine, dry the organic layer over anhydrous sodium sulfate, and concentrate. Add to a DCM: TFA (10: 1) solution, react at room temperature for 1 h, concentrate the reaction solution, wet load, and purify by column chromatography to obtain compound m1 (282.0 mg, yield 70%).

[0201] Synthesis of compound m3:

[0202] Take m1 (80.6 mg, 0.1 mmol), m2 (58.2 mg, 0.12 mmol) dissolved in DMF solution, add DIPEA (52 μL, 0.3 mmol), react at room temperature for 2 h. TLC detects that the reaction is complete, and the reaction solution is concentrated. Dissolve in ethyl acetate, wash successively with water, saturated brine, dry the organic layer over anhydrous sodium sulfate, and concentrate. Wet load, and purify by column chromatography to obtain compound m3 (95.1 mg, yield 79%).

[0203] Synthesis of compound 15:

[0204] Add m3 (60.2 mg, 0.05 mmol) to a DCM: TFA (10: 1) solution, react at room temperature for 1 h, concentrate the reaction solution, purify by C18 reverse phase liquid chromatography, and freeze-dry to obtain compound 15 (54.6 mg, yield 100%). MS (ESI): 1091.46 [M+H] + .

[0205] The imaging of compound 15 labeled with 18F in U87 tumor-bearing mice is shown in Figure Figure 15

[0206] Example 16

[0207] ​​Preparation of compound 16:

[0208]

[0209] Synthesis of compound 16:

[0210] To 4 (237.3 mg, 0.5 mmol) and 5-carboxy-pyridine-2-N,N,N-trimethylammonium chloride (129 mg, 0.6 mmol) in DMF was added HATU (228 mg, 0.6 mmol) and DIPEA (261 μL, 1.5 mmol) and the reaction was stirred at room temperature for 2 h. The reaction was monitored by TLC and the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give compound 16 (159.4 mg, 50% yield). MS (ESI): 637.67 [M+H] + .

[0211] Example 17

[0212] Preparation of compound 17:

[0213]

[0214] Synthesis of compound n1:

[0215] To 1 (245.2 mg, 0.5 mmol) and 6-((tert-butoxycarbonyl)amino)hexanoic acid (138.8 mg, 0.6 mmol) in DMF was added HATU (228 mg, 0.6 mmol) and DIPEA (261 μL, 1.5 mmol) and the reaction was stirred at room temperature for 2 h. The reaction was monitored by TLC and the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in DCM:TFA (10:1) and stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by column chromatography to give compound n1 (241.5 mg, 80% yield).

[0216] Synthesis of compound n3:

[0217] To n1 (60.4 mg, 0.1 mmol) and n2 (132.4 mg, 0.12 mmol) in DMF was added DIPEA (52 μL, 0.3 mmol) and the reaction was stirred at room temperature for 2 h. The reaction was monitored by TLC and the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give compound n3 (97.2 mg, 60% yield).

[0218] Synthesis of compound 17:

[0219] n3 (81.0 mg, 0.05 mmol) was added to a DCM:TFA (10:1) solution, and reacted at room temperature for 1 hour, the reaction solution was concentrated, purified by C18 reverse phase liquid chromatography, and freeze-dried to obtain compound 17 (61.0 mg, yield 95%). MS (ESI): 542.22 [M+2 / 2] + .

[0220] In summary, by means of the above technical solutions of the present application, the FAP inhibitor is used as a new choice for the development of therapeutic drugs for FAP-positive related diseases, the FAP inhibitor combined with the corresponding radioactive element can be used for the diagnosis and treatment of FAP-positive related diseases, compared with the traditional FAPI radioactive drug, the FAP inhibitor has higher uptake rate at the lesion site, higher target and non-target contrast, and no obvious toxic side effects. The FAPI inhibitor of the present application can be used for the treatment and diagnosis of diseases such as tumors (pancreatic cancer, breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer), myocardial infarction, scar formation, osteoporosis, liver, kidney and lung fibrosis, chronic inflammation and destructive processes (rheumatoid arthritis, Crohn's disease, atherosclerotic plaques, immunoglobulin-related diseases), etc.

[0221] The above only describes the preferred embodiments of the present application and is not intended to limit the present application, and any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A FAP inhibitor, characterized in that, The FAP inhibitor has a compound as shown in Formula I or a pharmaceutically acceptable salt thereof, a corresponding radioactive element marker: wherein R1 and R2 are independently selected from hydrogen, halogen or methyl; R3 is selected from hydrogen, methyl or isopropyl; R4 is selected from hydrogen or methyl; R5 is selected from hydrogen, methyl or halogen; or R4 and R5 form a four-membered heterocyclic ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring; X1 and X2 are independently selected from carbon and nitrogen; R6 and R7 are independently selected from hydrogen, halogen or methyl; R8 is selected from methyl or halogen; R9 is selected from: wherein R is selected from hydrogen or methyl; 11 selected from hydrogen or methyl; n is selected from 1-10; R 10 selected from the group consisting of:

2. The FAP inhibitor according to claim 1, characterized in that, The pharmaceutically acceptable salt is selected from hydrochloride, sulfate, trifluoroacetate, fumarate, succinate, sulfonate, maleate, acetate, phosphate or citrate.

3. A FAP inhibitor characterized in that, The FAP inhibitor is selected from at least one of the following compounds:

4. A FAP inhibitor composition, which comprises the FAP inhibitor as described in any one of claims 1-2 as an active ingredient.

5. Use of a FAP inhibitor, the use of the FAP inhibitor as described in any one of claims 1-2 in the preparation of a medicament for diagnosing glioma.

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