Complement factor B inhibitor as well as medicinal composition and application thereof

Abstract

The invention provides a complement factor B inhibitor compound, pharmaceutically acceptable salts thereof, a medicinal composition thereof and application of the complement factor B inhibitor compound in preparation of medicines related to complement factor B. The compound has a structural formula shown in a formula (I), and experimental results show that the compound has good complement factor B inhibitory activity, good in-vivo C3a level inhibition rate, bioavailability and safety. Particularly, the polypeptide has more remarkable binding capacity with target protein. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a complement factor B inhibitor compound and a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and an application thereof in preparing a complement factor B-related drug. Background Art

[0002] Complement is a serum protein that exists in human and vertebrate serum and tissue fluid. It is heat-resistant and has enzyme activity after activation, and can mediate immune and inflammatory responses. It can be activated by antigen-antibody complexes or microorganisms, causing pathogenic microorganisms to be lysed or phagocytosed. It can be activated through three independent and overlapping pathways, namely the classical pathway, the bypass pathway, and the lectin pathway.

[0003] The complement system is an important component of the innate immune system and is activated through three independent and overlapping pathways, namely the classical pathway, the alternative pathway, and the lectin pathway. During complement activation, a series of positive feedbacks are used to exert powerful biological effects and participate in the occurrence and development of diseases. C3 convertase is an important component of the first three pathways, and produces a series of complement protein fragments and membrane attack complexes (MACs) through the complement activation cascade reaction. C3 convertase cleaves C3 to generate C5 convertase, which then cleaves C5 to generate C5a and C5b. C5b combines with C6, C7, C8, and C9 to form C5b-9, namely MAC. Abnormalities in the complement pathway can cause the lysis of the body's inherent normal cells, leading to the occurrence of diseases.

[0004] Complement factor B is a heat-labile β-globulin that can be cleaved by factor D into two fragments, Ba and Bb. Bb combines with C3b to form the C3 convertase of the alternative pathway. Factor B is an important component of the complement alternative activation pathway, also known as C3 activator precursor. It can be used as a suitable target for inhibiting the complement activation pathway.

[0005] A series of complement factor B inhibitors have been disclosed, including CN105579444A, CN114057758A, WO2022256586, WO2023278698, WO2023020566 or WO2023139534, etc.

[0006] Although a series of complement factor B inhibitor compounds have been disclosed, there is still a need to develop new compounds with richer structural types, better efficacy and greater safety. After continuous efforts, the present invention designs compounds having a structure shown in general formula (I), and finds that compounds having such a structure exhibit excellent effects and good safety. Summary of the invention

[0007] The object of the present invention is to provide a compound capable of inhibiting complement factor B or its tautomer or stereoisomer, deuterated product, pharmaceutically acceptable salt, prodrug, and its use in the preparation of drugs for treating diseases related to complement factor B activity or expression.

[0008] The present invention provides a compound represented by formula (I), or its tautomer, and a pharmaceutically acceptable salt thereof.

[0009]

[0010] in,

[0011] is a single bond or a double bond;

[0012] Y is selected from CR a R b ;

[0013] R a , R b Each is independently selected from hydrogen or absent;

[0014] or R a , R b Together with the carbon atom to which it is attached, it forms a double bond;

[0015] R1 is selected from -COOH, -CN, R2 and R3 are each independently selected from H, deuterium, halogen, -C 1-6 alkyl;

[0016] Or R2 and R3 together form an imino group;

[0017] Or R2, R3 together with the carbon atom to which they are attached form a 3 to 8-membered cycloalkyl group;

[0018] R4 is selected from -C 1-6 Alkyl or H;

[0019] L is selected from a bond, O, NH;

[0020] R5 is selected from -C(=O)NR c R d 、-S(O) t -C 1-6 Alkyl, -S(O) t -3 to 8 membered cycloalkyl, C 1-6 Alkyl, 3 to 8 membered cycloalkyl, wherein the alkyl is optionally further substituted by one or more substituents selected from halogen, deuterium, and alkoxy;

[0021] R c , R d Each independently selected from hydrogen or C1-6 alkyl;

[0022] W is selected from NR e , CR f R g ;

[0023] R e Selected from -C(=O)NH-3 to 8-membered cycloalkyl or -C(=O)-3 to 8-membered cycloalkyl;

[0024] R f , R g Each is independently selected from hydrogen, deuterium, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, -C 1-6 Alkyl, -TS(O) t -X, -NHC(=O)-C 1-6 Alkyl-NR c R d , -SC(=O)-3 to 8-membered cycloalkyl, -O-3 to 8-membered heterocyclic group, -OC 1-6 Alkyl, guanidinyl; wherein the alkyl, cycloalkyl and heterocyclic groups may be optionally further substituted by one or more substituents selected from halogen, deuterium, alkyl, alkoxy and -OH;

[0025] T is selected from a bond, O, -NH-, -N(CH3)-, C 1-6 alkyl;

[0026] X is selected from C 1-6 Alkyl, 3 to 8 membered cycloalkyl or NR c R d ; wherein the alkyl group may be further substituted by one or more halogen, deuterium, 3 to 8 membered cycloalkyl;

[0027] or R f , R g Together with the carbon atom to which it is attached, it forms a 3- to 8-membered heterocyclic group, which may be further selected from C 1-6 Alkyl, -S(O) t -C 1-3 Alkyl, -S(O) t -C 3-6 Cycloalkyl, -S(O) t -NH-C 1-3 Alkyl, -C(=O)-C 1-3 The alkyl group is substituted by one or more substituents; t is selected from 0, 1, 2;

[0028] Wherein, the compound of general formula (I) is not selected from the following compounds

[0029]

[0030] In one embodiment provided by the present invention, the compound has a structure shown in the following formula (II):

[0031]

[0032] R h Selected from C 1-6 Alkyl, -S(O) t -C 1-3 Alkyl, -S(O) t -C 3-6 Cycloalkyl, -S(O) t -NH-C 1-3 Alkyl, -C(=O)-C 1-3 alkyl.

[0033] In one embodiment provided by the present invention, the compound has a structure shown in the following formula (III):

[0034]

[0035] T is selected from a bond, O, -NH-, -N(-CH3)-, C 1-6 alkyl;

[0036] X is selected from C 1-6 Alkyl, 3 to 8 membered cycloalkyl or NR c R d ; The alkyl group may be further substituted by one or more halogens, deuterium, or 3 to 8-membered cycloalkyl groups;

[0037] R c Selected from H;

[0038] R d Selected from C 1-6 alkyl.

[0039] Preferably, T is selected from a bond, -NH-; X is selected from C 1-6 Alkyl, 3 to 8 membered cycloalkyl; the alkyl may be further substituted by one or more halogen, deuterium, 3 to 8 membered cycloalkyl. Further preferably, the 3 to 8 membered cycloalkyl is selected from cyclopropyl.

[0040] In one embodiment provided by the present invention, the compound has a structure shown in the following formula (IV):

[0041]

[0042] R2 and R3 are each independently selected from deuterium, fluorine, -C 1-6 alkyl.

[0043] In one embodiment provided by the present invention, the compound has a structure shown in the following formula (V):

[0044]

[0045] R i is selected from 3 to 8 membered cycloalkyl or -NH-3 to 8 membered cycloalkyl.

[0046] In one embodiment provided by the present invention, the compound has a structure shown in the following formula (VI):

[0047]

[0048] L is selected from a bond, NH;

[0049] R5 is selected from -S(O) t -C 1-6 Alkyl, -(C=O)NR c R d 、-OC 1-6 Alkyl, wherein the -OC 1-6 The alkyl group in the alkyl group is further substituted by one or more substituents selected from F, deuterium, and alkoxy.

[0050] Preferably, the compound is selected from any one of the structures shown below:

[0051]

[0052]

[0053]

[0054]

[0055] Another aspect of the present invention provides a pharmaceutical composition, which comprises a compound as described in the above formula (I), or its tautomer, and a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and / or excipients.

[0056] Another aspect of the present invention provides the use of the compound as described in the above formula (I), or its tautomer, or its pharmaceutically acceptable salt or the pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing diseases or disorders mediated by activation of the complement alternative pathway, preferably in the preparation of a medicament for treating and / or preventing diseases or disorders mediated by complement factor B.

[0057] The compound of the present invention has good complement factor B inhibitory activity, good inhibition rate of C3a level in vivo, bioavailability and safety. In particular, it has more significant binding ability with the target protein and obvious inhibitory activity on the complement alternative pathway in human serum. DETAILED DESCRIPTION

[0058] Example 1

[0059] Synthesis of 4-[(2S,4S)-4-cyclopropanesulfonamido-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (Compound 3)

[0060]

[0061] Step 1: Synthesis of benzyl (2R, 4R)-2-(4-cyanophenyl)-4-(triaza-1-yl)piperidine-1-carboxylate (3-2) Under nitrogen protection, DIAD (5.05 g, 25.0 mmol) was dissolved in THF (25 mL), and compound 3-1 (1.68 g, 5.0 mmol) and PPh3 (2.75 mg, 10.5 mmol) were added in an ice-water bath. After stirring for 15 min, DPPA (3.43 mg, 12.5 mmol) was slowly added. After the addition was completed, the reaction was warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =6:1) to obtain compound 3-2 (1.72 g, yellow oil).

[0062] Step 2: Synthesis of benzyl (2R, 4R)-4-amino-2-(4-cyanophenyl)piperidine-1-carboxylate (3-3)

[0063] Under nitrogen protection, compound 3-2 (1.72 g, 4.76 mmol) was dissolved in THF (17 mL) and H2O (1.7 mL), PPh3 (2.50 g, 9.52 mmol) was added to the reaction solution, and stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (V 二氯甲烷 :V 甲醇 =10:1) to obtain compound 3-3 (0.6 g, yellow oil).

[0064] Step 3: Synthesis of (benzyl (2R, 4R) -2- (4-cyanophenyl) -4-cyclopropanesulfonamide piperidine-1-carboxylate (3-4) Compound 3-3 (268.1 mg, 0.8 mmol) was dissolved in DCM (3.0 mL), and Et3N (161.9 mg, 1.6 mmol), DMAP (14.7 mg, 0.12 mmol) and cyclopropylsulfonyl chloride (224.9 mg, 1.6 mmol) were added in sequence, and stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =2:1) ​​was purified to give compound 3-4 (291 mg, yellow oil).

[0065] Step 4: Synthesis of 4-[(2R, 4R)-1-[(benzyloxy)carbonyl]-4-cyclopropanesulfonylaminopiperidin-2-yl]benzoic acid (3-5) Compound 3-4 (87.8 mg, 0.2 mmol), isopropanol (0.25 mL), H2O (0.75 mL), THF (0.5 mL), Ba(OH)2·H2O (132.6 mg, 0.7 mmol) were added to the reaction flask in sequence, heated to 100°C, and stirred for 20 hours. The reaction mixture was adjusted to pH = 2-3 with 1M dilute hydrochloric acid, extracted with ethyl acetate (3 mL×3), and the organic phase was collected and concentrated to obtain compound 3-5 (97.3 mg, white solid).

[0066] Step 5: Synthesis of benzyl (2R, 4R)-4-cyclopropanesulfonamide-2-[4-(methoxycarbonyl)phenyl]piperidine-1-carboxylate (3-6) DMF (1 mL), potassium carbonate (44.2 mg, 0.32 mmol), iodomethane (45.4 mg, 0.32 mmol) and compound 3-5 (97.3 mg, 0.21 mmol) were mixed in a reaction flask and stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =2:1) ​​was purified to give compound 3-6 (71.6 mg, yellow solid).

[0067] Step 6: Synthesis of methyl 4-[(2R, 4R)-4-cyclopropanesulfonylaminopiperidin-2-yl]benzoate (3-7)

[0068] Compound 3-6 (71.6 mg, 0.15 mmol) was dissolved in methanol (1.0 mL) and THF (1.0 mL), and 5% Pd / C (7.2 mg, 10% loading) was added. The hydrogen was replaced 3 times, and the reaction was stirred overnight at room temperature under hydrogen protection. Filter, decompress and spin-dry the filtrate, and the crude product was purified by column chromatography (V 二氯甲烷 :V 甲醇 =10:1) to obtain compound 3-7 (52.1 mg, yellow oil).

[0069] Step 7: Synthesis of tert-butyl 4-{[(2S,4S)-4-cyclopropanesulfonylamino-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (3-9)

[0070] Compound 3-8 (80 mg, crude product), compound 3-7 (50.7 mg, 0.15 mmol) and DIPEA (42.7 mg, 0.33 mmol) were added to a DCM (1.5 mL) mixture and reacted at 0° C. for 1.5 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =4:1) to obtain compound 3-9 (64.1 mg, yellow solid).

[0071] Step 8: Synthesis of 4-[(2S,4S)-4-cyclopropanesulfonamido-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (3)

[0072] Compound 3-9 (64.1 mg, 0.1 mmol) was dissolved in methanol (3.0 mL), THF (1.5 mL) and H2O (1.0 mL), lithium hydroxide (13.3 mg, 0.35 mmol) was added, and the mixture was stirred at 70°C overnight. The mixture was concentrated under reduced pressure, and the residue was separated and purified by HPLC (ACN:H2O=0%-100%) to obtain compound 3 (20 mg, white solid). [M+H] + :498.20.

[0073] 1 H NMR (400MHz, Methanol-d4) δ8.26 (d, J=8.0Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 7.37 (d, J=3.1Hz , 1H), 6.80 (s, 1H), 6.38 (d, J=3.2Hz, 1H), 4.39 (d, J=12.7Hz, 1H), 4.28 (d, J=12.8Hz, 1H), 4 .01 (s, 1H), 3.80 (s, 3H), 3.65 (td, J=12.6, 5.1Hz, 1H), 3.46 (m, 1H), 3.37 (s, 2H), 2.73-2.6 2 (m, 1H), 2.53 (s, 3H), 2.39 (t, J=5.6Hz, 2H), 2.16 (s, 2H), 1.13 (m, 2H), 1.11-1.01 (m, 2H).

[0074] Example 2

[0075] Synthesis of 3-{4-[(2S,4S)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]phenyl}-2H-6,2,4-benzothiazole-1,1-dione (Compound 4)

[0076]

[0077] Step 1: Synthesis of benzyl (2S, 4S)-4-ethoxy-2-(4-formylphenyl)piperidine-1-carboxylate (4-2)

[0078] Compound 4-1 (728.0 mg, 2.0 mmol) was dissolved in DCM (20 mL), replaced with nitrogen 3 times, cooled to 0°C, and DIBAL-H (2 mL, 3.0 mmol) was slowly added. The mixture was stirred at 0°C for 2 hours. Water (50 mL) was slowly added to quench the reaction mixture, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined and dried. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =1:1) to give compound 4-2 (600 mg, yellow oil).

[0079] Step 2: Synthesis of benzyl (2S, 4S)-2-[4-(1,1-dioxo-2H-6,2,4-benzothiazol-3-yl)phenyl]-4-ethoxypiperidine-1-carboxylate (4-4)

[0080] Compound 4-2 (600 mg, 3.0 mmol), compound 4-3 (1.34 g, 3.6 mmol), Cu(OAc)2 (72.0 mg, 0.36 mmol) and DMSO (15 mL) were added to the reaction flask, oxygen was replaced 3 times, and the mixture was heated to 110°C and stirred for 16 hours under oxygen protection. Water (150 mL) and ethyl acetate (150 mL) were added to the reaction mixture, followed by extraction with ethyl acetate (150 mL×2), and the organic phase was collected and dried. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =1:1) to give compound 4-4 (450 mg, yellow solid).

[0081] Step 3: Synthesis of 3-{4-[(2S,4S)-4-ethoxypiperidin-2-yl]phenyl}-2H-benzothiazole-1,1-dione (4-5)

[0082] Compound 4-4 (450 mg, 0.87 mmol) was dissolved in methanol (5 mL) and THF (5 mL), and 5% Pd / C (45 mg, 10% loading) was added under nitrogen protection, and hydrogen was replaced 3 times. The reaction was stirred at room temperature overnight. Filtered, concentrated and dried, and the residue was purified by column chromatography (V 二氯甲烷 :V 甲醇 =20:1) to obtain compound 4-5 (417 mg, brown oil).

[0083] Step 4: Synthesis of tert-butyl 4-{[(2S,4S)-2-[4-(1,1-dioxo-2H-benzothiazol-3-yl)phenyl]-4-ethoxypiperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (4-7)

[0084] Compound 4-5 (61.8 mg, 0.2 mmol) and compound 4-6 (38.5 mg, 0.1 mmol) were dissolved in DMF (1.5 mL), Cs2CO3 (97.7 mg, 0.3 mmol) and KI (16.6 mg, 0.1 mmol) were added, and the reaction was stirred at room temperature overnight. Water (5 mL) was added, and ethyl acetate (5 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =2:3) was purified to give compound 4-7 (31.3 mg, yellow solid).

[0085] Step 5: Synthesis of 3-{4-[(2S,4S)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]phenyl}-2H-6,2,4-benzothiazole-1,1-dione (4)

[0086] Compound 4-7 (31.3 mg, 0.048 mmol) was dissolved in methanol (1.2 mL), THF (0.6 mL) and H2O (0.4 mL), and LiOH (6.5 mg, 0.17 mmol) was added, and the mixture was reacted at 70°C overnight. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (V 二氯甲烷 :V 甲醇 =10:1) to obtain compound 4 (8.0 mg, white solid). [M+H] + :559.23.

[0087] 1H NMR (400MHz, DMSO-d6) δ12.20 (s, 1H), 10.82 (s, 1H), 8.13-8.05 (m, 2H), 7.86 (dd, J=8.0, 1.4Hz, 1H), 7.80 (d , J=7.9Hz, 2H), 7.73 (t, J=7.8Hz, 1H), 7.64 (d, J=8.2Hz, 1H), 7.49 (t, J=7.6Hz, 1H), 7.26 (s, 1H), 6.67 (s, 1H ), 6.49 (s, 1H), 3.74 (s, 3H), 3.63-3.55 (m, 3H), 3.46 (d, J = 7.1Hz, 2H), 3.27 (d, J = 11.9Hz, 1H), 2.43 (s, 3H), 2.34 (t, J=12.8Hz, 1H), 1.86 (d, J=13.9Hz, 1H), 1.80-1.67 (m, 2H), 1.56-1.45 (m, 2H), 1.18 (t, J=8.0Hz, 3H).

[0088] Example 3

[0089] Synthesis of 4-[(2S,4S)-4-(ethylsulfonyl)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (Compound 6)

[0090]

[0091] Step 1: Synthesis of benzyl (2S, 4S)-4-(acetylsulfanyl)-2-(4-cyanophenyl)piperidine-1-carboxylate (6-3)

[0092] PPh3 (4.6 g, 17.8 mmol) was dissolved in THF (40 mL), cooled to 0°C, DIAD (3.6 g, 17.8 mmol) was added and stirred for 1 h, and compound 6-1 (3 g, 8.9 mmol) and compound 6-2 (1.3 g, 17.8 mmol) were added to the reaction solution. After stirring at 0°C for 1 h, the mixture was returned to room temperature overnight. The reaction was complete when detected by TLC. The reaction solution was concentrated and purified by column chromatography (V 正己烷 :V 乙酸乙酯 =5:1) to obtain compound 6-3 (2.7 g, brown oil) with a yield of 77.1%.

[0093] Step 2: Synthesis of benzyl (2S, 4S)-2-(4-cyanophenyl)-4-(ethylsulfanyl)piperidine-1-carboxylate (6-4)

[0094] Compound 6-3 (500 mg, 1.27 mmol), iodoethane (296 mg, 1.9 mmol) and potassium carbonate (351.9 mg, 2.55 mmol) were dissolved in methanol (8 mL) and stirred at room temperature overnight. After the reaction was completed by TLC, the mixture was filtered and concentrated. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =5:1) was purified to give compound 6-4 (0.38 g, brown oil) with a yield of 78.8%.

[0095] Step 3: Synthesis of benzyl (2S, 4S)-2-(4-cyanophenyl)-4-(ethylsulfonyl)piperidine-1-carboxylate (6-5)

[0096] Compound 6-4 (380 mg, 1 mmol) was dissolved in DCM (1 mL), and m-CPBA (344 mg, 2 mmol) was added at 0°C and reacted at room temperature for 4 hours. After the reaction was completed as monitored by LCMS, an aqueous sodium carbonate solution was added to the reaction solution and extracted with DCM (3 mL×3). The organic phase was dried and concentrated with anhydrous sodium sulfate, and the crude product was purified by column chromatography (eluent: V 正己烷 :V 乙酸乙酯 =3:1) was purified to give compound 6-5 (0.18 g, brown oil) with a yield of 43.6%.

[0097] Step 4: Synthesis of methyl 4-[(2S,4S)-4-(ethylsulfonyl)piperidin-2-yl]benzoate (6-6)

[0098] Compound 6-5 (320 mg, 0.77 mmol) was dissolved in methanol (1 mL), concentrated sulfuric acid (1 mL) and water (1 mL) were added, and stirred at 80°C overnight. After TLC detection, the reaction was completed, the temperature was lowered to 0°C, 2M sodium hydroxide aqueous solution was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate (5 mL×3), and the organic phase was dried by spin drying. Compound 6-6 (100 mg, white solid) was obtained, which was used directly in the next step without further purification.

[0099] Step 5: Synthesis of tert-butyl 4-{[(2S,4S)-4-(ethylsulfonyl)-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (6-8)

[0100] Compound 6-6 (70 mg, 0.22 mmol), compound 6-7 (68 mg, 0.22 mmol) and tetraisopropyl titanate (62 mg, 0.22 mmol) were dissolved in THF (3 mL) and stirred at 70°C overnight. NaBH(OAc)3 (46 mg, 0.22 mmol) was added to room temperature, and the temperature was raised to 70°C for reaction for 1 h. Water (5 mL) was added to quench the reaction, and ethyl acetate (5 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =3:1) was purified to give compound 6-8 (66 mg, brown solid) with a yield of 51.5%.

[0101] Step 6: Synthesis of 4-[(2S,4S)-4-(ethylsulfonyl)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (6)

[0102] Compound 6-8 (60 mg, 0.1 mmol) was dissolved in a mixed solvent of methanol (1.5 mL) and water (0.5 mL), and lithium hydroxide (17 mg, 0.5 mmol) was added, and the mixture was stirred at 70°C overnight. LCMS detected that the reaction was complete, the reaction solution was spin-dried, and water (3 mL) and ethyl acetate (3 mL) were added to extract the organic phase impurities. The aqueous phase was adjusted to pH = 5 with 1N HCl, extracted with DCM (5 mL), and the organic phase was concentrated and dried to obtain a crude product as a light brown oil. Ether was added to the mixture to obtain compound 6 (22 mg, off-white solid, purity: 95%), with a yield of 46.8%. [M+H] + :471.19.

[0103] 1 H NMR (400MHz, DMSO) δ12.79 (s, 1H), 10.85 (s, 1H), 7.95 (d, J = 8.0Hz, 2H), 7.63 (d, J = 8.0Hz, 2H ), 7.28 (t, J = 4.0Hz, 1H), 6.68 (s, 1H), 6.46 (t, J = 4.0Hz, 1H), 3.94-3.91 (m, 1H), 3.77-3.74 (m , 4H), 3.54 (d, J = 12.0Hz, 1H), 3.29-3.27 (m, 2H), 3.15 (q, J = 16.0Hz, 1H), 2.68-2.62 (m, 2H), 2.43 (s, 3H), 2.33-2.26 (m, 1H), 2.20-2.07 (m, 2H), 1.76-1.72 (m, 1H), 1.20 (t, J=8.0Hz, 3H).

[0104] Example 4

[0105] Synthesis of 4-[(2S,4S)-4-[(cyclopropylmethyl)sulfanyl]-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (Compound 7)

[0106]

[0107] Step 1: Synthesis of tert-butyl 5-methoxy-7-methyl-1H-indole-1-carboxylate (7-2)

[0108] Compound 7-1 (8 g, 49.63 mmol), di-tert-butyl dicarbonate (16.3 g, 74.45 mmol), triethylamine (6.03 g, 59.56 mmol) and DMAP (607 mg, 4.97 mmol) were added to dichloromethane (200 mL) solvent and dissolved, and stirred at 25 ° C for 16 hours. After the reaction, the reaction solution was quenched with saturated ammonium chloride solution, extracted three times with dichloromethane (200 mL), and the organic phases were combined, washed with water (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure and column chromatography (V 正己烷 :V 乙酸乙酯 =20:1) was purified to give compound 7-2 (14.0 g, light yellow oil) with a yield of 96%.

[0109] Step 2: Synthesis of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (7-3)

[0110] At 20°C, oxalyl chloride (8.2 g, 64.33 mmol) was added to a solution of N-methylformanilide (8.7 g, 64.33 mmol) in dichloromethane (100 mL), and the reaction was stirred for 14 h at 20°C under a nitrogen atmosphere. The reaction solution was transferred to a constant pressure dropping funnel and slowly added dropwise to a solution of compound 7-2 (14 g, 53.61 mmol) in dichloromethane (500 mL) at -14°C. The reaction solution was stirred for 3 h at -14°C under a nitrogen atmosphere. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate (200 mL), then washed with saturated brine (200 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =20:1-10:1) was purified to give compound 7-3 (9.7 g, white solid) with a yield of 62.6%.

[0111] 1H NMR (400MHz, CDCl3) δ10.65 (s, 1H), 7.65 (d, J=4.0Hz, 1H), 7.49 (d, J=4.0Hz, 1H), 6.76 (s, 1H), 3.98 (s, 3H), 3.70 (s, 3H), 1.65 (s, 9H).

[0112] Step 3: Synthesis of tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (7-4)

[0113] Under nitrogen protection, compound 7-3 (9.7 g, 33.55 mmol) was added to methanol (100 mL) to dissolve, cooled to 0 ° C, sodium borohydride (3.17 g, 83.88 mmol) was added in batches and reacted for 2 h. After the reaction, the reaction was quenched with water (100 mL), extracted with ethyl acetate (100 mL × 3), and then washed with saturated sodium chloride solution (100 mL), and the mixed organic phase was dried and spin-dried. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =10:1) to give 7-4 (9.2 g) with a yield of 94.2%.

[0114] Step 4: Synthesis of tert-butyl 4-(bromomethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (7-5)

[0115] Under nitrogen protection, compound 7-4 (3.42 g, 11.74 mmol) was dissolved in dichloromethane (30 mL), dibromotriphenylphosphine (5.4 g, 12.92 mmol) was added at 0°C, and stirred at 0°C for 2 hours. After the reaction, the reaction solution of compound 7-5 was obtained, and the next step was directly carried out. Step 5: Synthesis of tert-butyl 4-{[(2S, 4S)-4-hydroxy-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (7-7)

[0116] Compound 7-6 (2.3 g, 9.78 mmol) and DIPEA (2.78 g, 21.52 mmol) were added to the reaction solution containing compound 7-5 (4.14 g, 11.74 mmol) in the previous step, and the mixture was stirred evenly. The mixture was stirred at room temperature for 16 h. After the reaction, water (50 mL) was added for washing, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =2:1) ​​to obtain compound 7-7 (5 g, light yellow viscous oil), with a yield of 83.89%, [M+H] + :509.26.

[0117] Step 6: Synthesis of tert-butyl 4-{[(2S,4S)-4-(acetylsulfanyl)-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (7-8)

[0118] Under nitrogen protection at 0°C, triphenylphosphine (2.06 g, 7.87 mmol) and DIAD (1.59 g, 7.87 mmol) were dissolved in tetrahydrofuran (30 mL), stirred at 0°C for 1 h, compound 7-7 (2 g, 3.93 mmol) and thioacetic acid (600 mg, 7.87 mmol) were added, and stirred at room temperature for 16 h. After the reaction, water (50 mL) was added, extracted with ethyl acetate (100 mL), and then washed with saturated sodium chloride solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography (eluent: V 正己烷 :V 乙酸乙酯 =10:1) to obtain compound 7-8 (1.3 g, white solid) with a yield of 58.34%, [M+H] + :567.25.

[0119] Step 7: Synthesis of tert-butyl 4-{[(2S,4S)-4-[(cyclopropylmethyl)sulfanyl]-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (7-9)

[0120] Under nitrogen protection, compound 7-8 (500 mg, 883 μmol) was dissolved in methanol (5 mL), bromomethylcyclopropane (178 mg, 1.33 mmol) and potassium carbonate (366 mg, 2.65 mmol) were added, and stirred at room temperature for 16 h. After the reaction, methanol (10 mL) was added, filtered and dried, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =20:1) to obtain compound 7-9 (200 mg, transparent viscous oil), with a yield of 39.17%, [M+H] + :579.28.

[0121] Step 8: Synthesis of 4-[(2S,4S)-4-[(cyclopropylmethyl)sulfanyl]-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (7)

[0122] Compound 7-9 (200 mg, 0.346 mmol) was dissolved in a mixture of tetrahydrofuran and water (2 mL) at a ratio of 5:1, stirred at 70 °C for 1 h, and isopropanol (5 mL) and lithium hydroxide (83 mg, 3.46 mmol) were added to stir evenly, and stirred at 70 °C for 16 h. After the reaction, the pH of the reaction solution was adjusted to neutral (pH = 7-8), and it was dissolved in acetonitrile, methanol and water (20 mL). The crude product was prepared by reverse phase medium pressure to obtain compound 7 (110 mg, white solid), with a yield of 68.5%, a purity of 96.6%, [M+H] + :465.21.

[0123] 1 H NMR (400MHz, Methanol-d4) δ8.25 (d, J=8.0Hz, 2H), 7.78 (d, J=8.0Hz, 2H), 7.36 (d, J=4.0Hz, 1H) , 6.80 (s, 1H), 6.40 (d, J=4.0Hz, 1H), 4.38-4.30 (m, 2H), 3.79 (s, 3H), 3.72-3.65 (m, 1H), 3.56 (s, 1H), 3.48 (d, J=16.0Hz, 1H), 3.37 (s, 1H), 2.65-2.58 (m, 3H), 2.53 (s, 3H), 2.41-2.32 (m, 1H), 2.2 6-2.21 (m, 1H), 2.06 (d, J=16.0Hz, 1H), 1.07-1.01 (m, 1H), 0.63-0.59 (m, 2H), 0.29-0.26 (m, 2H).

[0124] Example 5

[0125] Synthesis of 4-[(2S,4S)-4-[2-(dimethylamino)acetamido]-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (Compound 8)

[0126]

[0127] Step 1: Synthesis of tert-butyl 5-methoxy-4-{[(2S,4R)-2-[4-(methoxycarbonyl)phenyl]-4-(triaza-1-yl)piperidin-1-yl]methyl}-7-methyl-1H-indole-1-carboxylate (8-2)

[0128] DIAD (533 mg, 2.64 mmol) was dissolved in THF (40 mL) and cooled to -5 °C. PPh3 (463 mg, 1.77 mmol) and compound 8-1 (450 mg, 0.88 mmol) were added. After stirring for 0.5 h, DPPA (486 mg, 1.77 mmol) was added and then returned to room temperature overnight. The reaction was complete when detected by TLC. The reaction solution was concentrated and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =5:1) to obtain compound 8-2 (350 mg, brown oil) with a yield of 74.6%.

[0129] Step 2: Synthesis of tert-butyl 4-{[(2S,4S)-4-amino-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (8-3)

[0130] Compound 8-2 (320 mg, 0.6 mmol) and PPh3 (157.4 mg, 0.6 mmol) were dissolved in a mixed solution of THF (5 mL) and water (0.5 mL) and stirred at room temperature overnight. After the reaction was completed by TLC, the reaction solution was concentrated. The crude product was purified by high pressure preparative chromatography (acetonitrile / water containing 0.5% TFA) to obtain compound 8-3 (200 mg) with a yield of 65.7%.

[0131] Step 3: Synthesis of tert-butyl 4-{[(2S,4S)-4-[2-(dimethylamino)acetamido]-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (8-5)

[0132] Compound 8-4 (39 mg, 0.38 mmol) was dissolved in DMF (1 mL), HATU (187 mg, 0.49 mmol) and DIEA (70 mg, 0.54 mmol) were added and stirred at room temperature for 1 hour, and compound 8-3 (100 mg, 0.19 mmol) was added and stirred overnight. After the reaction was complete as monitored by TLC, water (8 mL) was added, and ethyl acetate (5 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by high pressure preparative chromatography (acetonitrile / water containing 0.5% TFA) to obtain compound 8-5 (80 mg, light brown solid) with a yield of 71.4%.

[0133] Step 4: Synthesis of 4-[(2S,4S)-4-[2-(dimethylamino)acetamido]-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (8-6)

[0134] Compound 8-5 (320 mg, 0.77 mmol) was dissolved in isopropanol (2 mL) and water (0.4 mL) and stirred at 70°C overnight. The raw material remained 20%, and the temperature was raised to 80°C and the reaction was continued for 6 h. After TLC detection, 2M HCl aqueous solution was added to adjust the pH to 5, concentrated and dried, and the crude product was purified by high pressure preparative chromatography (acetonitrile / water containing 0.5% TFA) to obtain compound 8 (12 mg, white solid, purity 96%), with a yield of 35.4%, [M+H] + :479.26.

[0135] 1 H NMR (400MHz, DMSO) δ8.26 (d, J=8.0Hz, 2H), 7.78 (d, J=8.0Hz, 1H), 7.36 (d, J=4.0Hz, 1H) , 6.81 (s, 1H), 6.38 (d, J = 4.0Hz, 1H), 4.83 (d, J = 12.0Hz, 1H), 4.40 (d, J = 12.0Hz, 1H), 4.3 2(s, 1H), 4.23(d, J=12.0Hz, 1H), 4.14(s, 2H), 3.79(s, 3H), 3.65-3.59(m, 1H), 3.54-3. 49(m, 4H), 3.37(s, 3H), 3.01(s, 6H), 2.53(s, 3H), 2.47-2.39(m, 1H), 2.24-2.16(m, 1H).

[0136] Example 6

[0137] Synthesis of 4-[(2S,4S)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-4-(trifluoromethanesulfonylamino)piperidin-2-yl]benzoic acid (Compound 10)

[0138]

[0139] Step 1: Synthesis of tert-butyl 5-methoxy-4-{[(2S,4S)-2-[4-(methoxycarbonyl)phenyl]-4-(trifluoromethanesulfonylamino)piperidin-1-yl]methyl}-7-methyl-1H-indole-1-carboxylate (10-2)

[0140] Compound 8-3 (120 mg, 0.23 mmol) was dissolved in DCM (40 mL) and cooled to -5 °C. Compound 10-1 (86 mg, 0.3 mmol) was added and stirred for 2 h. After TLC detection, the reaction was complete. Water (50 mL) was added and extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (V 正己烷 :V乙酸乙酯 =1:1) to give compound 10-2 (180 mg, brown oil).

[0141] Step 2: Synthesis of 4-[(2S,4S)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-4-(trifluoromethanesulfonylamino)piperidin-2-yl]benzoic acid (10)

[0142] Compound 10-2 (320 mg, 0.77 mmol) was dissolved in methanol (3 mL) and water (1 mL), supplemented with lithium hydroxide (37.6 mg, 1.57 mmol), and stirred at 70°C overnight. After the reaction was completed by TLC, 2M HCl aqueous solution was added to adjust the pH to 5, concentrated, and the crude product was purified by high pressure preparative chromatography (acetonitrile / water containing 0.5% TFA) to obtain compound 10 (60 mg, white solid, purity: 97%). [M+H] + :526.15.

[0143] 1 H NMR (400MHz, Methanol-d4) δ8.23 (d, J=8.0Hz, 2H), 7.74 (d, J=8.0Hz, 2H), 7.36 (d, J=3.2Hz, 1H), 6.80 (s, 1H), 6.38 (s, 1H), 4.84 (d, J=11.6Hz, 1H), 4.3 8(d, J=12.8Hz, 1H), 4.27 (d, J=12.8Hz, 1H), 3.80 (s, 3H), 3.61 (d, J=12.4Hz , 2H), 3.44 (d, J=12.4Hz, 1H), 3.37 (s, 2H), 2.68 (s, 3H), 2.43-2.30 (m, 2H).

[0144] Example 7

[0145] Synthesis of 4-[(2S,4S)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-4-[(methylsulfamoyl)amino]piperidin-2-yl]benzoic acid (Compound 11)

[0146]

[0147] Step 1: Synthesis of tert-butyl 5-methoxy-4-{[(2S,4S)-2-[4-(methoxycarbonyl)phenyl]-4-[(methylsulfamoyl)amino]piperidin-1-yl]methyl}-7-methyl-1H-indole-1-carboxylate (11-2)

[0148] Compound 8-3 (150 mg, 0.3 mmol) was dissolved in DCM (40 mL), and compound 11-1 (46 mg, 0.35 mmol), DIEA (77 mg, 0.6 mmol), and DMAP (8 mg, 0.06 mmol) were added, and stirred overnight. After TLC detection, the reaction was complete. Water (50 mL) was added, and dichloromethane (30 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =1:1) was purified to give compound 11-2 (100 mg, brown oil).

[0149] Step 2: Synthesis of 4-[(2S,4S)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-4-[(methylsulfamoyl)amino]piperidin-2-yl]benzoic acid (11)

[0150] Compound 11-2 (320 mg, 0.77 mmol) was dissolved in methanol (3 mL) and water (1 mL), and lithium hydroxide (37.6 mg, 1.57 mmol) was added, and stirred at 70°C overnight. After the reaction was completed by TLC, 2M HCl aqueous solution was added to adjust the pH to 5, and the mixture was concentrated under reduced pressure. The crude product was purified by high pressure preparative chromatography (acetonitrile / water containing 0.5% TFA) to obtain compound 11 (65 mg, white solid, purity 98%). [M+H] + :487.19.

[0151] 1 H NMR (400MHz, Methanol-d4) δ8.26 (d, J=8.0Hz, 2H), 7.76 (d, J=7.9Hz, 2H), 7.37 (d, J=3.1Hz, 1H), 6.81 (s, 1H), 6.39 (d, J=3.1Hz, 1H), 4.87 (d, J=12.0Hz, 1H), 4. 38 (d, J=12.8Hz, 1H), 4.29 (d, J=12.8Hz, 1H), 3.80 (s, 3H), 3.73-3.61 (m, 2H), 3. 45(d, J=13.0Hz, 1H), 3.37(s, 2H), 2.68(s, 3H), 2.54(s, 3H), 2.45-2.29(m, 2H).

[0152] Example 8

[0153] Synthesis of 4-[(2S,4S)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-4-(methylsulfamoyl)piperidin-2-yl]benzoic acid (Compound 12)

[0154]

[0155] Step 1: Synthesis of benzyl (2S, 4S)-4-(chlorosulfonyl)-2-(4-cyanophenyl)piperidine-1-carboxylate (12-1)

[0156] NCS (903 mg, 5.07 mmol) was dissolved in acetonitrile (5 mL) and 2N HCl (1 mL), and compound 6-3 (500 mg, 1.26 mmol) was added at 10°C and stirred for 2 h. The reaction was complete after TLC detection. The reaction solution was concentrated and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =5:1) to obtain compound 12-1 (420 mg, brown oil), [M+H] + :418.1, yield 79.8%.

[0157] Step 2: Synthesis of benzyl (2S, 4S)-2-(4-cyanophenyl)-4-(methylsulfamoyl)piperidine-1-carboxylate (12-2)

[0158] Compound 12-1 (410 mg, 0.98 mmol) was dissolved in THF (5 mL), methylamine hydrochloride (131 mg, 1.96 mmol) and triethylamine (0.29 g, 2.94 mmol) were added, and stirred at room temperature overnight. After the reaction was completed by TLC detection, water (10 mL) was added, and ethyl acetate (8 mL × 3) was extracted, the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =5:1) to obtain compound 12-2 (215 mg, brown oil) with a yield of 53.9%.

[0159] Step 3: Synthesis of methyl 4-[(2S,4S)-4-(methylsulfamoyl)piperidin-2-yl]benzoate (12-3)

[0160] Compound 12-2 (320 mg, 0.77 mmol) was dissolved in methanol (1 mL) and concentrated sulfuric acid (1 mL) and water (1 mL) were added. Stir at 80°C overnight. After TLC detection, the reaction was completed, the temperature was lowered to 0°C, 2M sodium hydroxide aqueous solution was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate. The organic phase was dried by spin drying. The crude compound 12-3 (100 mg) was obtained and used directly in the next step without further purification.

[0161] Step 4: Synthesis of tert-butyl 5-methoxy-4-{[(2S,4S)-2-[4-(methoxycarbonyl)phenyl]-4-(methylsulfamoyl)piperidin-1-yl]methyl}-7-methyl-1H-indole-1-carboxylate (12-4)

[0162] Compound 12-3 (68 mg, 0.22 mmol), compound 6-7 (63 mg, 0.22 mmol) and tetraisopropyl titanate (62 mg, 0.22 mmol) were dissolved in THF (3 mL) and stirred at 70 °C overnight. NaBH(OAc)3 (46 mg, 0.22 mmol) was added to the room temperature, and the temperature was raised to 70 °C for 1 h. Water (10 mL) was added to the reaction solution, and ethyl acetate (8 mL × 3) was used for extraction. The organic phases were combined, saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =3:1) was purified to give compound 12-4 (66 mg, brown solid) with a yield of 51.5%.

[0163] Step 5: Synthesis of 4-[(2S,4S)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-4-(methylaminosulfonyl)piperidin-2-yl]benzoic acid (12)

[0164] Compound 12-4 (58 mg, 0.1 mmol) was dissolved in a mixed solvent of methanol (1.5 mL) and water (0.5 mL), and lithium hydroxide (17 mg, 0.5 mmol) was added and stirred at 70°C overnight. The reaction solution was spin-dried, and water (3 mL) and ethyl acetate (3 mL) were added to extract the organic phase impurities. The aqueous phase was adjusted to pH = 5 with 1N HCl, extracted with DCM (5 mL), and the organic phase was concentrated and dried to obtain a crude product as a light brown oil. Ether was added to the mixture to obtain compound 12 (22 mg, off-white solid, purity: 95%), with a yield of 46.8%. [M+H] + :472.18.

[0165] 1H NMR (400MHz, DMSO) δ12.79 (s, 1H), 10.85 (s, 1H), 7.95 (d, J = 8.0Hz, 2H), 7.63 (d, J = 8.0Hz, 2H ), 7.28 (t, J = 4.0Hz, 1H), 6.68 (s, 1H), 6.46 (t, J = 4.0Hz, 1H), 3.94-3.91 (m, 1H), 3.77-3.74 (m , 4H), 3.54 (d, J=12.0Hz, 1H), 3.29-3.27 (m, 1H), 3.15 (q, J=16.0Hz, 1H), 2.68-2.62 (m, 2H), 2.43 (s, 3H), 2.33-2.26 (m, 1H), 2.20-2.07 (m, 2H), 1.76-1.72 (m, 1H), 1.20 (t, J=8.0Hz, 3H).

[0166] Example 9

[0167] Synthesis of 4-[(2S,4S)-4-cyclopropylmethanesulfonyl-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (Compound 13)

[0168]

[0169] Step 1: Synthesis of tert-butyl 4-{[(2S,4S)-4-[(cyclopropylmethyl)sulfanyl]-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (13-1)

[0170] Under nitrogen protection, compound 7-8 (250 mg, 441 μmol) was dissolved in methanol (3 mL), bromomethylcyclopropane (89 mg, 0.661 mmol) and potassium carbonate (182 mg, 1.323 mmol) were added, and stirred at room temperature for 16 h. After the reaction, methanol (5 mL) was added, filtered and dried, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =20:1 to 10:1) to obtain compound 13-1 (220 mg, white solid) with a yield of 86.26%, [M+H] + :579.28.

[0171] Step 2: Synthesis of tert-butyl 4-{[(2S,4S)-4-cyclopropylmethanesulfonyl-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (13-2)

[0172] Compound 13-1 (220 mg, 0.380 mmol) was added to a mixed solution of isopropanol and water (V 异丙醇 :V 水 =3:1, 2mL), potassium peroxymonosulfonate (421mg, 0.684mmol) was added and stirred at room temperature for 1h. After the reaction, the reaction mixture was filtered, the pH of the filtrate was adjusted to neutral (pH=6-7) with sodium bicarbonate, the isopropanol was removed by rotation, the crude product was extracted with ethyl acetate (5mL), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =10:1 to 5:1) to obtain compound 13-2 (70 mg) with a yield of 30%, [M+H] + :611.27.

[0173] Step 3: Synthesis of 4-[(2S,4S)-4-cyclopropylmethanesulfonyl-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (13)

[0174] Compound 13-2 (70 mg, 0.115 mmol) was dissolved in a mixed solution (2 mL) of methanol: water = 5:1, and lithium hydroxide (27.5 mg, 1.147 mmol) was added to stir evenly, and stirred at 70 ° C for 16 h. After the reaction, the pH of the reaction solution was adjusted to neutral (pH = 7-8) with 2 mol / L hydrochloric acid solution, and it was dissolved in acetonitrile, methanol and water (10 mL). The crude product was directly passed through a high pressure preparative chromatography column to obtain 13 (20 mg, white solid), with a yield of 35%, [M+H] + :497.20.

[0175] 1 H NMR (400MHz, Methanol-d4) δ8.27 (d, J=8.0Hz, 2H), 7.80 (d, J=8.0Hz, 2H), 7.37 (d, J=4 .0Hz, 1H), 6.81 (s, 1H), 6.38 (d, J=4.0Hz, 1H), 4.42-4.39 (m, 1H), 4.32-4.29 (m, 1H), 3 .81(s, 3H), 3.73(s, 2H), 3.56(d, J=12.0Hz, 1H), 3.37(s, 2H), 3.26(m, 1H), 2.81(m, 2H ), 2.65 (m, 2H), 2.54 (s, 3H), 1.32 (s, 1H), 0.73 (d, J=8.0Hz, 2H), 0.46 (d, J=8.0Hz, 2H).

[0176] Example 10

[0177] Synthesis of 4-{2-ethyl-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2,7-diazaspiro[3.5]nonan-6-yl}benzoic acid (Compound 14)

[0178]

[0179] Step 1: Synthesis of 2-ethyl-6-[4-(methoxycarbonyl)phenyl]-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester (14-2)

[0180] Compound 14-1 (140 mg, 0.355 mmol) was dissolved in dichloromethane (2 mL), iodoethane (165.3 mg, 1.06 mmol) and triethylamine (108 mg, 1.06 mmol) were added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was washed with water (10 mL), the aqueous phase was extracted with dichloromethane (30 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =1:1) was purified to give compound 14-2 (149 mg, yellow oil).

[0181] Step 2: Synthesis of methyl 4-{2-ethyl-2,7-diazaspiro[3.5]nonan-6-yl}benzoate (14-3)

[0182] Compound 14-2 (144 mg, 0.341 mmol) was dissolved in methanol (2 mL), 5% Pd / C (100 mg) was added, and the reaction was stirred at room temperature for 3 h under hydrogen protection and 15 psi pressure. After the reaction was completed, the mixture was filtered, the filter cake was washed with methanol (10 mL), and the filtrate was dried to obtain compound 14-3 (80 mg, white solid).

[0183] Step 3: Synthesis of tert-butyl 4-({2-ethyl-6-[4-(methoxycarbonyl)phenyl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (14-4)

[0184] Compound 14-3 (136 mg, 0.439 mmol) and compound 9-12 (63.4 mg, 0.220 mmol) were dissolved in DMF (4 mL), followed by the addition of CS2CO3 (215 mg, 0.660 mmol) and potassium iodide (37 mg, 0.220 mmol), and the reaction was stirred at room temperature for 16 h. After the reaction was completed, water (20 mL) was added, and ethyl acetate (30 mL x 2) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯=1:1) was purified to give compound 14-4 (100 mg, white solid).

[0185] Step 4: Synthesis of 4-{2-ethyl-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2,7-diazaspiro[3.5]nonan-6-yl}benzoic acid (14)

[0186] Compound 14-4 (89.3 mg, 0.159 mmol) was dissolved in a mixed solution of methanol and water (2 mL, V 甲醇 :V 水 =5:1), lithium hydroxide (37.6 mg, 1.57 mmol) was added, and the reaction was stirred at 70°C for 16 h. After the reaction, the reaction solution was adjusted to a neutral pH with 1M hydrochloric acid, methanol was removed, water (10 mL) was added, and ethyl acetate (30 mL x 2) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by medium pressure chromatography to obtain compound 14 (66 mg, transparent oil), with a yield of 81.3%.

[0187] 1 H NMR (400MHz, Methanol-d4) δ8.14 (d, J=8.0Hz, 2H), 7.48 (d, J=4.0Hz, 2H), 7.11 (s, 1H ), 6.77 (s, 1H), 6.37 (s, 1H), 4.61 (s, 1H), 4.20-4.17 (m, 1H), 4.07 (d, J=8.0Hz, 1H), 3. 98 (d, J=8.0Hz, 1H), 3.86 (d, J=8.0Hz, 1H), 3.77 (s, 3H), 3.72 (s, 2H), 3.37 (s, 2H), 2. 65-2.58 (m, 2H), 2.51 (s, 3H), 2.29 (s, 2H), 2.10 (d, J=28.0Hz, 2H), 0.90-0.89 (m, 3H).

[0188] Embodiment 11

[0189] Synthesis of (4-[(2S,4S)-1-[dideuterium(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-4-ethoxypiperidin-2-yl]benzoic acid (Compound 15)

[0190]

[0191] Step 1: Synthesis of 5-methoxy-7-methylindole-4-carbaldehyde-d(15-1)

[0192] Compound 7-2 (750.00 mg, 2.87 mmol) was dissolved in DCM (7.0 mL) and cooled to -15°C. A solution of deuterated Weissmeier reagent (500.00 mg, 3.73 mmol) in DCM (7.0 mL) was then added and the reaction was allowed to rise to room temperature overnight. TLC showed that the reaction of the raw material was complete and new spots were generated. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =5:1-1:1) was purified to give compound 15-1 (370.00 mg, white solid).

[0193] Step 2: Synthesis of (5-methoxy-7-methyl-1H-indol-4-yl)methanol-d2-ol (15-2)

[0194] Compound 15-1 (330.00 mg, 1.14 mmol) was dissolved in methanol (10 mL), sodium borodeuteride (119.3 mg, 2.85 mmol) was added at 0°C, and the mixture was stirred at room temperature for reaction. TLC showed that the reaction of the raw material was complete and new spots were generated. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =5:1-1:1) was purified to give compound 15-2 (286 mg, colorless oil).

[0195] Step 3: Synthesis of 4-(bromomethyl-d2)-5-methoxy-1H-indole (15-3)

[0196] Compound 15-2 (129.00 mg, 0.44 mmol) was dissolved in DCM (4.0 mL), cooled to 0°C, and then dibromotriphenylphosphine (196.00 mg, 0.48 mmol) was added. The mixture was reacted at 0°C overnight, and the solvent was removed under reduced pressure to obtain compound 15-3 (200 mg). The crude product was directly used in the next step.

[0197] Step 4: Synthesis of tert-butyl 4-{[(2S,4S)-4-ethoxy-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]difluoromethyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (15-5)

[0198] A mixture of compound 15-3 (200 mg, 0.64 mmol), compound 15-4 (167.9 mg, 0.64 mmol) and DIPEA (140.0 mg, 0.78 mmol) in DCM (4.0 mL) was reacted at 0°C for 1.5 h, the solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =5:1-1:1) to give compound 15-5 (172.00 mg, yellow oil).

[0199] Step 5: Synthesis of 4-[(2S,4S)-1-[dideuterium(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-4-ethoxypiperidin-2-yl]benzoic acid (15-6)

[0200] Compound 15-5 (172.00 mg, 0.32 mmol) was dissolved in methanol (9.0 mL), THF (4.5 mL) and H2O (3.0 mL), and LiOH (42.5 mg, 1.12 mmol) was added. The mixture was stirred at 70°C overnight, and the solvent was concentrated. The crude product was purified by high pressure preparative chromatography (ACN:H2O=50:1-0:1, H2O containing 0.5% TFA) to give compound 15 (40.00 mg, white solid), [M+H] + :425.18.

[0201] 1 H NMR (400MHz, Methanol-d4) δ8.25 (d, J=8.0Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 7.36 (d, J=3.1Hz, 1H), 6.79 (s, 1H), 6.39 (d, J=3.2Hz, 1H), 3.89-3.8 2 (m, 1H), 3.78 (s, 3H), 3.62 (tdd, J=14.4, 10.9, 7.9Hz, 4H), 3.33 (p, J=1 .6Hz, 4H), 2.34-2.20(m, 2H), 2.14-1.92(m, 2H), 1.33(t, J=7.0Hz, 3H).

[0202] Example 12

[0203] Synthesis of 4-[2-(ethanesulfonyl)-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2,7-diazaspiro[3.5]nonan-6-yl]benzoic acid (Compound 16)

[0204]

[0205] Step 1: Synthesis of 2-(ethanesulfonyl)-6-[4-(methoxycarbonyl)phenyl]-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester (16-1)

[0206] Compound 14-1 (140 mg, 0.355 mmol) was dissolved in dichloromethane (2 mL), ethylsulfonyl chloride (136 mg, 1.06 mmol) and triethylamine (108 mg, 1.06 mmol) were added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was washed with water (10 mL), the aqueous phase was extracted with dichloromethane (30 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =1:1) was purified to give compound 16-1 (170 mg, yellow oil).

[0207] Step 2: Synthesis of methyl 4-[2-(ethanesulfonyl)-2,7-diazaspiro[3.5]nonan-6-yl]benzoate (16-2)

[0208] Compound 16-1 (166 mg, 0.341 mmol) was dissolved in methanol (2 mL), 5% Pd / C (100 mg) was added, and the reaction was stirred at room temperature for 3 h under hydrogen protection and 15 psi pressure. After the reaction was completed, the mixture was filtered, the filter cake was washed with methanol (10 mL), and the filtrate was dried to obtain compound 16-2 (80 mg, white solid).

[0209] Step 3: Synthesis of tert-butyl 4-{[2-(ethanesulfonyl)-6-[4-(methoxycarbonyl)phenyl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (16-3)

[0210] Compound 16-2 (136 mg, 0.439 mmol) and compound 9-12 (77 mg, 0.220 mmol) were dissolved in DMF (4 mL), followed by the addition of Cs2CO3 (215 mg, 0.660 mmol) and potassium iodide (37 mg, 0.220 mmol), and the reaction was stirred at room temperature for 16 h. After the reaction was completed, water (20 mL) was added, and ethyl acetate (30 mL x 2) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =1:1) was purified to give compound 16-3 (100 mg, white solid).

[0211] Step 4: Synthesis of 4-[2-(ethanesulfonyl)-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2,7-diazaspiro[3.5]nonan-6-yl]benzoic acid (16)

[0212] Compound 16-3 (100 mg, 0.159 mmol) was dissolved in a solution of methanol and water (2 mL, V 甲醇:V 水 =5:1), lithium hydroxide (37.6 mg, 1.57 mmol) was added, and the reaction was stirred at 70°C for 16 h. After the reaction, the reaction solution was adjusted to a neutral pH with 1M hydrochloric acid, methanol was removed, water (10 mL) was added, and ethyl acetate (30 mL x 2) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by medium pressure chromatography to obtain compound 16 (66 mg, transparent oil), with a yield of 80.38%.

[0213] 1 H NMR (400MHz, Methanol-d4) δ8.14 (d, J=8.0Hz, 2H), 7.48 (d, J=4.0Hz, 2H), 7.11 (s, 1H ), 6.77 (s, 1H), 6.37 (s, 1H), 4.61 (s, 1H), 4.20-4.17 (m, 1H), 4.07 (d, J=8.0Hz, 1H), 3. 98 (d, J=8.0Hz, 1H), 3.86 (d, J=8.0Hz, 1H), 3.77 (s, 3H), 3.72 (s, 2H), 3.37 (s, 2H), 2. 65-2.58 (m, 2H), 2.51 (s, 3H), 2.29 (s, 2H), 2.10 (d, J=28.0Hz, 2H), 0.90-0.89 (m, 3H).

[0214] Example 13

[0215] Synthesis of 4-{2-acetyl-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2,7-diazaspiro[3.5]nonan-6-yl}benzoic acid (Compound 17)

[0216]

[0217] Step 1: Synthesis of 2-acetyl-6-[4-(methoxycarbonyl)phenyl]-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester (17-1)

[0218] Compound 14-1 (140 mg, 0.355 mmol) was dissolved in dichloromethane (2 mL), iodoethane (165.3 mg, 1.06 mmol) and triethylamine (108 mg, 1.06 mmol) were added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was washed with water (10 mL), the aqueous phase was extracted with dichloromethane (30 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography (eluent: V 正己烷 :V 乙酸乙酯 =1:1) to obtain compound 17-1 (149 mg, yellow oil).

[0219] Step 2: Synthesis of methyl 4-[2-(acetyl)-2,7-diazaspiro[3.5]nonan-6-yl]benzoate (17-2)

[0220] Compound 17-1 (149 mg, 0.341 mmol) was dissolved in methanol (2 mL), 5% Pd / C (100 mg) was added, and the reaction was stirred at room temperature for 3 h under hydrogen protection and 15 psi pressure. After the reaction was completed, the mixture was filtered, the filter cake was washed with methanol (10 mL), and the filtrate was dried to obtain compound 17-2 (80 mg, white solid).

[0221] Step 3: Synthesis of tert-butyl 4-{[2-(acetyl)-6-[4-(methoxycarbonyl)phenyl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (17-3)

[0222] Compound 17-2 (136 mg, 0.439 mmol) and compound 9-12 (66.5 mg, 0.220 mmol) were dissolved in DMF (4 mL), followed by the addition of Cs2CO3 (215 mg, 0.660 mmol) and potassium iodide (37 mg, 0.220 mmol), and the reaction was stirred at room temperature for 16 h. After the reaction was completed, water (20 mL) was added, and ethyl acetate (30 mL x 2) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =1:1) was purified to give compound 17-3 (100 mg, white solid).

[0223] Step 4: Synthesis of 4-{2-acetyl-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2,7-diazaspiro[3.5]nonan-6-yl}benzoic acid (17)

[0224] Compound 17-3 (91.6 mg, 0.159 mmol) was dissolved in a solution of methanol and water (2 mL, V 甲醇 :V 水 =5:1), lithium hydroxide (37.6 mg, 1.57 mmol) was added, and the reaction was stirred at 70°C for 16 h. After the reaction, the reaction solution was adjusted to a neutral pH with 1M hydrochloric acid, methanol was removed, water (10 mL) was added, and ethyl acetate (30 mL x 2) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by medium pressure chromatography to obtain compound 17 (66 mg, transparent oil), with a yield of 80.51%.

[0225] 1H NMR (400MHz, Methanol-d4) δ8.15 (d, J=8.0Hz, 2H), 7.46 (d, J=4.0Hz, 2H), 7.14 (s, 1H), 6.75 (s, 1H), 6.34 (s, 1H), 4.65 (s, 1H), 4.20-4.18 (m, 1H), 4.09 (d, J=8 .0Hz, 1H), 3.96 (d, J=8.0Hz, 1H), 3.85 (d, J=8.0Hz, 1H), 3.79 (s, 3H), 3.74 (s, 2 H), 3.37 (s, 2H), 2.53 (s, 3H), 2.29 (s, 2H), 2.19 (d, J=28.0Hz, 2H), 2.06 (s, 3H).

[0226] Embodiment 14

[0227] Synthesis of 4-{7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2-(methylsulfamoyl)-2,7-diazaspiro[3.5]nonan-6-yl}benzoic acid (Compound 18)

[0228]

[0229] Step 1: Synthesis of 6-[4-(methoxycarbonyl)phenyl]-2-(methylsulfamoyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester (18-1)

[0230] Compound 14-1 (140 mg, 0.355 mmol) was dissolved in dichloromethane (2 mL), and N-methylsulfamoyl chloride (137 mg, 1.06 mmol) and triethylamine (108 mg, 1.06 mmol) were added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was washed with water (10 mL), and the aqueous phase was extracted with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =1:1) to obtain compound 18-1 (170 mg, yellow oil).

[0231] Step 2: Synthesis of methyl 4-[2-(methylsulfamoyl)-2,7-diazaspiro[3.5]nonan-6-yl]benzoate (18-2)

[0232] Compound 18-1 (166 mg, 0.341 mmol) was dissolved in methanol (2 mL), 5% Pd / C (100 mg) was added, and the reaction was stirred at room temperature for 3 h under hydrogen protection and 15 psi pressure. After the reaction was completed, the mixture was filtered, the filter cake was washed with methanol (10 mL), and the filtrate was dried to obtain compound 18-2 (80 mg, white solid).

[0233] Step 3: Synthesis of tert-butyl 5-methoxy-4-({6-[4-(methoxycarbonyl)phenyl]-2-(methylsulfamoyl)-2,7-diazaspiro[3.5]non-7-yl}methyl)-7-methyl-1H-indole-1-carboxylate (18-3)

[0234] Compound 9-12 (136 mg, 0.439 mmol) and compound 18-2 (77 mg, 0.220 mmol) were dissolved in DMF (4 mL), followed by the addition of Cs2CO3 (215 mg, 0.660 mmol) and potassium iodide (37 mg, 0.220 mmol), and the reaction was stirred at room temperature for 16 h. After the reaction was completed, water (20 mL) was added, and ethyl acetate (30 mL x 2) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =1:1) was purified to give compound 18-3 (100 mg, white solid).

[0235] Step 4: Synthesis of 4-{7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2-(methylsulfamoyl)-2,7-diazaspiro[3.5]nonan-6-yl}benzoic acid (18)

[0236] Compound 18-3 (100 mg, 0.159 mmol) was dissolved in a solution of methanol and water (2 mL, V 甲醇 :V 水 =5:1), lithium hydroxide (37.6 mg, 1.57 mmol) was added, and the reaction was stirred at 70°C for 16 h. After the reaction, the reaction solution was adjusted to a neutral pH with 1M hydrochloric acid, methanol was removed by vortexing, water (10 mL) was added, and ethyl acetate (30 mL x 2) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and vortexed to dryness, and the crude product was purified by medium pressure chromatography to obtain compound 18 (66 mg, transparent oil), with a yield of 80.38%.

[0237] 1H NMR (400MHz, Methanol-d4) δ8.15 (d, J=8.0Hz, 2H), 7.49 (d, J=4.0Hz, 2H), 7.12 ( s, 1H), 6.76 (s, 1H), 6.35 (s, 1H), 4.61 (s, 1H), 4.20-4.17 (m, 1H), 4.07 (d, J=8.0H z, 1H), 3.98 (d, J=8.0Hz, 1H), 3.86 (d, J=8.0Hz, 1H), 3.77 (s, 3H), 3.72 (s, 2H), 3 .37(s, 2H), 2.67(s, 3H), 2.65-2.59(m, 2H), 2.53(s, 3H), 2.12(d, J=28.0Hz, 2H).

[0238] Embodiment 15

[0239] Synthesis of 4-[(2S,4S)-4-ethanesulfonamido-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (Compound 20)

[0240]

[0241] Step 1: Synthesis of tert-butyl 4-{[(2S,4S)-4-ethanesulfonamido-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (20-1)

[0242] Compound 8-3 (150 mg, 0.3 mmol) was dissolved in DCM (40 mL), and ethylsulfonyl chloride (46 mg, 0.35 mmol), DIEA (77 mg, 0.6 mmol), and DMAP (8 mg, 0.06 mmol) were added. The mixture was stirred at room temperature overnight. After TLC detection, the reaction was complete. Water (50 mL) was added and extracted with dichloromethane (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =3:1-1:1) was purified to give compound 20-1 (100 mg, brown oil).

[0243] Step 2: Synthesis of 4-[(2S,4S)-4-ethanesulfonamido-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (20)

[0244] Compound 20-1 (320 mg, 0.77 mmol) was dissolved in methanol (3 mL) and water (1 mL), and LiOH (32.3 mg, 1.35 mmol) was added, and stirred at 70°C overnight. After the reaction was completed by TLC, 2M HCl aqueous solution was added to adjust the pH to 5, and the mixture was concentrated under reduced pressure. The crude product was purified by high pressure preparative chromatography (mobile phase: acetonitrile / water containing 0.5% TFA) to obtain compound 20 (65 mg, white solid, purity: 98%). [M+H] + :487.19.

[0245] 1 H NMR (400MHz, Methanol-d4) δ8.26 (d, J=8.0Hz, 2H), 7.76 (d, J=7.9Hz, 2H), 7.37 (d, J=3.1Hz, 1H), 6.81 (s, 1H), 6.39 (d, J=3.1Hz, 1H), 4.87 (d, J=12.0Hz, 1H), 4.38 (d, J =12.8Hz, 1H), 4.29 (d, J = 12.8Hz, 1H), 3.80 (s, 3H), 3.73-3.61 (m, 2H), 3.45 (d, J = 1 3.0Hz, 1H), 3.37(s, 2H), 2.68(m, 2H), 2.54(s, 3H), 2.45-2.29(m, 2H), 1.13(m, 3H).

[0246] Example 16

[0247] Synthesis of N-(cyclopropanesulfonyl)-4-[(2S,4S)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzamide (Compound 21)

[0248]

[0249] Under ice water, compound 21-1 (33.8 mg, 0.08 mmol), compound 21-2 (30 mg, 0.11 mmol), compound 21-3 (20 mg, 0.11 mmol), DIEA (30 mg, 0.24 mmol), DMAP (10 mg, 0.08 mmol) and dichloromethane (10 mL) were added to a 100 mL single-mouth bottle in sequence and stirred at room temperature overnight. The reaction mixture was directly concentrated under reduced pressure, and the crude product was purified by high-pressure preparative chromatography (mobile phase: acetonitrile / water containing 0.5% TFA) to obtain compound 21 (10 mg, white solid, purity: 97%). [M+H] + :526.23.

[0250] 1H NMR (400MHz, Methanol-d4) δ8.19 (d, J=7.9Hz, 2H), 7.67 (d, J=7.8Hz, 2H), 7.36 (d, J=3. 2Hz, 1H), 6.76 (s, 1H), 6.38 (s, 1H), 4.72-4.63 (s, 1H), 4.63 (s, 1H), 4.34 (d, J=12.6Hz, 1 H), 4.18 (d, J=12.7Hz, 1H), 3.83 (s, 1H), 3.77 (s, 3H), 3.62 (q, J=7.0Hz, 3H), 3.57-3.46 ( m, 2H), 2.62 (s, 3H), 2.36 (s, 2H), 2.05 (m, 1H), 1.30 (t, J=8.0Hz, 3H), 1.17-0.93 (m, 4H).

[0251] Embodiment 17

[0252] Synthesis of 4-[(2S,4S)-4-(ethylsulfanyl)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (Compound 22)

[0253]

[0254] Step 1: Synthesis of tert-butyl 4-{[(2S,4S)-4-(ethylsulfanyl)-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (22-1)

[0255] Under nitrogen protection, compound 7-8 (500 mg, 883 μmol) was dissolved in methanol (5 mL), iodoethane (207.4 mg, 1.33 mmol) and potassium carbonate (366 mg, 2.65 mmol) were added, and stirred at room temperature for 16 h. After the reaction, methanol (10 mL) was added, filtered and dried, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =20:1-3:1) was purified to give compound 22-1 (200 mg, colorless transparent viscous oil).

[0256] Step 2: Synthesis of 4-[(2S,4S)-4-(ethylsulfanyl)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (22)

[0257] Compound 22-1 (200 mg, 0.372 mmol) was dissolved in a mixed solution of tetrahydrofuran and water (2 mL, V 四氢呋喃 :V 水=5:1), stirred at 70°C for 1h, added isopropanol (5mL) and lithium hydroxide (83mg, 3.46mmol) to make it evenly stirred, and stirred at 70°C for 16h. After the reaction, the pH of the reaction solution was adjusted to neutral (pH=7-8), and concentrated under reduced pressure. The crude product was purified by medium pressure preparative chromatography to obtain compound 22 (110mg, white solid), with a yield of 68.5%, a purity of 96.6%, [M+H] + :439.20.

[0258] 1 H NMR (400MHz, DMSO-d6) δ12.76 (s, 1H), 10.84 (s, 1H), 7.93 (d, J = 8.0Hz, 2H), 7.61 (d, J = 8.0Hz, 2H), 7.26 (t, J=4.0Hz, 1H), 6.65 (s, 1H), 6.43 (t, J=4.0Hz, 1H), 3.95-3.92 (m, 1H), 3.77-3.74 (m, 4H), 3.54 (d, J = 12.0Hz, 1H), 3.29-3.27 (m, 2H), 3.15 (q, J = 16.0Hz, 1H), 2.63-2.60 (m, 2H) , 2.43 (s, 3H), 2.33-2.26 (m, 1H), 2.20-2.03 (m, 2H), 1.72-1.70 (m, 1H), 1.10 (t, J=8.0Hz, 3H).

[0259] Embodiment 18

[0260] Synthesis of 4-[(2S,4S)-4-(D5-ethyl)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (Compound 23)

[0261]

[0262] Step 1: Synthesis of benzyl (2S, 4S)-2-(4-cyanophenyl)-4-(D5-ethyl)piperidine-1-carboxylate (23-2)

[0263] Compound 23-1 (500 mg, 1.27 mmol) and iodoethane-D5 (296 mg, 1.9 mmol) were dissolved in methanol (8 mL) and stirred at room temperature overnight. After the reaction was completed by TLC, the mixture was filtered and concentrated. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =5:1) to obtain compound 23-2 (0.38 g, brown oil) with a yield of 78.6%.

[0264] Step 2: Synthesis of methyl 4-[(2S,4S)-4-(D5-ethyl)piperidin-2-yl]benzoate (23-3)

[0265] Compound 23-2 (320 mg, 0.77 mmol) was dissolved in methanol (1 mL) and concentrated sulfuric acid (1 mL) and water (1 mL) were added. Stir at 80°C overnight. After TLC detection, the reaction was completed, the temperature was lowered to 0°C, 2M sodium hydroxide aqueous solution was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. Compound 23-3 (100 mg, white solid) was obtained and used directly in the next step without further purification.

[0266] Step 3: 4-{[(2S,4S)-4-(D5-ethyl)-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (23-4)

[0267] Compound 23-3 (70 mg, 0.22 mmol), compound 6-7 (68 mg, 0.22 mmol) and tetraisopropyl titanate (62 mg, 0.22 mmol) were dissolved in THF (3 mL) and stirred at 70 ° C overnight. After cooling to room temperature, NaBH (OAc) 3 (46 mg, 0.22 mmol) was added, and the temperature was raised to 70 ° C for 1 h. Water (10 mL) was added to the reaction solution, and ethyl acetate (10 mL × 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =5:1-1:1) was purified to give compound 23-4 (66 mg, brown solid) with a yield of 51.5%.

[0268] Step 4: Synthesis of 4-[(2S,4S)-4-(D5-ethyl)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (23)

[0269] Compound 23-4 (60 mg, 0.1 mmol) was dissolved in a mixed solvent of methanol (1.5 mL) and water (0.5 mL), and lithium hydroxide (17 mg, 0.5 mmol) was added, and stirred at 70°C overnight. The reaction solution was spin-dried, and water (10 mL) and ethyl acetate (5 mL) were added to extract the organic phase impurities. The aqueous phase was adjusted to pH = 5 with 1N HCl, extracted with DCM (5 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product as a light brown oil. Ether was added to the slurry to obtain compound 22 (22 mg, off-white solid, purity: 95%), with a yield of 46.8%. [M+H] +:428.26.

[0270] 1 H NMR (400MHz, Methanol-d4) δ8.17 (d, J=7.9Hz, 2H), 7.66 (d, J=7.8Hz, 2H), 7. 34(d, J=3.2Hz, 1H), 6.78(s, 1H), 6.33(s, 1H), 4.72-4.62(s, 1H), 4.63(s, 1H) ), 4.35 (d, J = 12.6Hz, 1H), 4.18 (d, J = 12.7Hz, 1H), 3.83 (s, 1H), 3.75 (s, 3H), 3.59-3.46 (m, 1H), 2.79-2.46 (m, 1H), 2.53 (s, 3H), 2.25 (s, 2H), 2.07 (m, 1H).

[0271] Embodiment 19

[0272] Synthesis of 4-[(2S)-4-(cyclopropylcarbamoyl)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperazin-2-yl]benzoic acid (Compound 24)

[0273]

[0274] Step 1: Synthesis of tert-butyl (2S)-2-(4-cyanophenyl)piperazine-1-carboxylate (24-2)

[0275] Compound 24-1 (5.0 g, 26.7 mmol) was dissolved in dichloromethane (50 mL), and di-tert-butyl dicarbonate (5.8 g, 26.7 mmol) and triethylamine (4.05 g, 40.05 mmol) were slowly added, and the reaction was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was extracted with water (100 mL), and the aqueous phase was extracted with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography (eluent: V 正己烷： V 乙酸乙酯 =3:1-1:1) was purified to give compound 24-2 (5.0 g, yellow oil).

[0276] Step 2: Synthesis of tert-butyl (2S)-2-(4-cyanophenyl)-4-(cyclopropylcarbamoyl)piperazine-1-carboxylate (24-3)

[0277] Compound 24-2 (5.0 g, 17.40 mmol) was dissolved in dichloromethane (100 mL), and cyclopropylamine (0.99 g, 17.40 mmol), CDI (3.1 g, 19.1 mmol) and triethylamine (3.4 g, 34.8 mmol) were slowly added, and the reaction was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was extracted with water (100 mL), and the aqueous phase was extracted with dichloromethane (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography (V 正己烷： V 乙酸乙酯 =3:1-1:1) was purified to give compound 24-3 (2.0 g, yellow oil).

[0278] Step 3: Synthesis of 4-[(2S)-1-[(tert-butoxy)carbonyl]-4-(cyclopropylcarbamoyl)piperazin-2-yl]benzoic acid (24-4)

[0279] Compound 24-3 (2.0 g, 5.4 mmol) was dissolved in isopropanol (20 mL), water (30 mL) and tetrahydrofuran (20 mL), and Ba(OH)2·H2O (3.06 g, 16.2 mmol) was slowly added, and the reaction was stirred at 100°C for 12 h. After the reaction, the reaction solution was adjusted to pH = 2-3 with 1N hydrochloric acid aqueous solution, extracted with ethyl acetate (50 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography (V 正己烷： V 乙酸乙酯 =3:1-1:1) was purified to give compound 24-4 (1.5 g, yellow oil).

[0280] Step 4: Synthesis of tert-butyl (2S)-4-(cyclopropylcarbamoyl)-2-[4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (24-5)

[0281] Compound 24-4 (1.5 g, 3.7 mmol) was dissolved in DMF (15 mL), potassium carbonate (0.93 g, 6.74 mmol) and iodomethane (0.79 g, 5.56 mmol) were slowly added, and the reaction was stirred at room temperature for 12 h. After the reaction was completed, water (150 mL) was added, and ethyl acetate (50 mL × 3) was extracted, and the organic phases were combined, and the organic phases were washed with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (V 正己烷： V 乙酸乙酯 =3:1-1:1) was purified to give compound 24-5 (1.0 g, yellow oil).

[0282] Step 5: Synthesis of methyl (4-[(2S)-4-(cyclopropylcarbamoyl)piperazin-2-yl]benzoate (24-6)

[0283] Compound 24-5 (1.0 g, 2.5 mmol) was dissolved in dichloromethane (10 mL), and a methanol solution of hydrochloric acid (2 mL, 4 N) was slowly added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, water (50 mL) was added, and the solution was adjusted to pH 9-11 with a sodium hydroxide solution (1 N), and extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with water (50 mL × 3), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (V 正己烷： V 乙酸乙酯 =3:1-0:1) to obtain compound 24-6 (0.2 g, yellow oil). Step 6: Synthesis of tert-butyl 4-{[(2S)-4-(cyclopropylcarbamoyl)-2-[4-(methoxycarbonyl)phenyl]piperazin-1-yl]methyl}-5-methoxy-7-methyl-1H-indole-1-carboxylate (24-7)

[0284] Compound 9-12 (408 mg, 1.3 mmol) and compound 24-6 (200 mg, 0.66 mmol) were dissolved in DMF (10 mL), followed by the addition of Cs2CO3 (645 mg, 1.98 mmol) and potassium iodide (111 mg, 1.98 mmol), and the reaction was stirred at room temperature for 16 h. After the reaction was completed, water (50 mL) was added, and ethyl acetate (30 mL x 2) was extracted, and the organic phases were combined, and the organic phases were washed with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (V 正己烷： V 乙酸乙酯 =3:1-1:1) was purified to give compound 24-7 (100 mg, white solid).

[0285] Step 7: Synthesis of 4-[(2S)-4-(cyclopropylcarbamoyl)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperazin-2-yl]benzoic acid (24)

[0286] Compound 24-7 (92 mg, 0.159 mmol) was dissolved in a mixed solution of methanol and water (2 mL, V 甲醇 :V 水 =5:1), lithium hydroxide (37.6 mg, 1.57 mmol) was added, and the reaction was stirred at 70°C for 16 h. After the reaction, the reaction solution was adjusted to a neutral pH with 1M hydrochloric acid, methanol was removed, water (10 mL) was added, and ethyl acetate (30 mL x 2) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying, and the crude product was purified by medium pressure chromatography to obtain compound 24 (61 mg, transparent oil), with a yield of 83.56%. [M+H] +:463.23.

[0287] 1 H NMR (400MHz, Methanol-d4) δ8.28 (d, J=8.0Hz, 2H), 7.81 (d, J=8.0Hz, 2H), 7.34 (d, J=4.0Hz, 1H), 6.83 (s, 1H), 6.36 (d, J=4.0Hz, 1H), 4.41-4.39 (m, 2H), 4.32-4 .29 (m, 1H), 3.81 (s, 3H), 3.56 (d, J = 12.0Hz, 1H), 3.37 (s, 2H), 2.81 (m, 1H), 2.65 (m, 2H), 2.54 (s, 3H), 1.32 (s, 1H), 0.73 (d, J=8.0Hz, 2H), 0.46 (d, J=8.0Hz, 2H).

[0288] Embodiment 20

[0289] Synthesis of 4-{(2S)-4-cyclopropanecarbonyl-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperazin-2-yl}benzoic acid (Compound 25)

[0290]

[0291] Step 1: Synthesis of tert-butyl ((2S)-2-(4-cyanophenyl)-4-cyclopropanecarbonylpiperazine-1-carboxylate (25-1)

[0292] Compound 24-2 (5.0 g, 17.40 mmol) was dissolved in dichloromethane (100 mL), and cyclopropylcarbonyl chloride (1.98 g, 19.1 mmol) and triethylamine (3.4 g, 34.8 mmol) were slowly added, and the reaction was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was extracted with water (100 mL), and the aqueous phase was extracted with dichloromethane (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography (V 正己烷： V 乙酸乙酯 =3:1-1:1) was purified to give compound 25-1 (2.0 g, yellow oil).

[0293] Step 3: Synthesis of 4-[(2S)-1-[(tert-butoxy)carbonyl]-4-cyclopropanecarbonylpiperazin-2-yl]benzoic acid (25-2)

[0294] Compound 25-1 (2.0 g, 5.3 mmol) was dissolved in isopropanol (20 mL), water (30 mL) and tetrahydrofuran (20 mL), and Ba(OH)2·H2O (3.06 g, 16.2 mmol) was slowly added, and the reaction was stirred at 100 degrees for 12 hours. After the reaction, the reaction solution was adjusted to pH = 2-3 with 1N hydrochloric acid aqueous solution, extracted with ethyl acetate (50 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried, and the crude product was purified by column chromatography (V 正己烷： V 乙酸乙酯 =3:1-1:1) was purified to give compound 25-2 (1.5 g, yellow oil).

[0295] Step 4: Synthesis of ((2S)-4-cyclopropanecarbonyl-2-[4-(methoxycarbonyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (25-3)

[0296] Compound 25-2 (1.5 g, 4.0 mmol) was dissolved in DMF (15 mL), potassium carbonate (1.1 g, 8 mmol) and iodomethane (0.79 g, 5.56 mmol) were slowly added, and the reaction was stirred at room temperature for 12 h. After the reaction was completed, water (150 mL) was added, and ethyl acetate (50 mL × 3) was extracted, and the organic phases were combined, washed with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (V 正己烷： V 乙酸乙酯 =3:1-1:1) was purified to give compound 25-3 (1.0 g, yellow oil).

[0297] Step 5: Synthesis of methyl 4-[(2S)-4-cyclopropanecarbonylpiperazin-2-yl]benzoate (25-4)

[0298] Compound 25-3 (1.0 g, 2.8 mmol) was dissolved in dichloromethane (10 mL), and a methanol solution of hydrochloric acid (2 mL, 4 N) was slowly added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, water (50 mL) was added, and the solution was adjusted to pH 9-11 with a sodium hydroxide solution (1 N), and extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with water (50 mL × 3), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (V 正己烷： V 乙酸乙酯 =3:1-0:1) to obtain compound 25-4 (0.2 g, yellow oil). Step 6: Synthesis of tert-butyl 4-({(2S)-4-cyclopropanecarbonyl-2-[4-(methoxycarbonyl)phenyl]piperazin-1-yl}methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (25-5)

[0299] Compound 9-12 (408 mg, 1.3 mmol) and compound 25-4 (190 mg, 0.66 mmol) were dissolved in DMF (10 mL), followed by the addition of Cs2CO3 (645 mg, 1.98 mmol) and potassium iodide (111 mg, 1.98 mmol), and the reaction was stirred at room temperature for 16 h. After the reaction was completed, water (50 mL) was added, and ethyl acetate (30 mL x 2) was extracted, and the organic phases were combined, and the organic phases were washed with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (V 正己烷： V 乙酸乙酯 =3:1-1:1) was purified to give compound 25-5 (100 mg, white solid).

[0300] Step 7: Synthesis of 4-{(2S)-4-cyclopropanecarbonyl-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperazin-2-yl}benzoic acid (25)

[0301] Compound 25-5 (90 mg, 0.159 mmol) was dissolved in a mixed solution of methanol and water (2 mL, V 甲醇 :V 水 =5:1), lithium hydroxide (37.6 mg, 1.57 mmol) was added, and the reaction was stirred at 70°C for 16 h. After the reaction, the reaction solution was adjusted to a neutral pH with 1M hydrochloric acid, methanol was removed, water (10 mL) was added, and ethyl acetate (30 mL x 2) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying, and the crude product was purified by medium pressure chromatography to obtain compound 25 (60 mg, transparent oil), with a yield of 84%, [M+H] + :448.22.

[0302] 1 H NMR (400MHz, Methanol-d4) δ8.26 (d, J=8.0Hz, 2H), 7.83 (d, J=8.0Hz, 2H), 7.35 (d, J=4.0Hz, 1H), 6.82 (s, 1H), 6.37 (d, J=4.0Hz, 1H), 4.42-4.39 (m, 2H), 4.32-4 .28(m, 1H), 3.83(s, 3H), 3.55(d, J=12.0Hz, 1H), 3.36(s, 2H), 2.81(m, 1H), 2.53 (s, 3H), 1.97 (m, 2H), 1.31 (s, 1H), 0.75 (d, J=8.0Hz, 2H), 0.49 (d, J=8.0Hz, 2H).

[0303] Embodiment 21

[0304] Synthesis of 4-[(2S,4S)-4-ethoxy-1-[(5-methylsulfonylamino-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (Compound 29)

[0305]

[0306] Step 1: Synthesis of tert-butyl 4-formyl-5-methylsulfonylamino-7-methyl-1H-indole-1-carboxylate (29-2)

[0307] Compound 29-1 (1.0 g, 2.96 mmol), cesium carbonate (1.9 g, 5.91 mmol), methanesulfonamide (0.42 g, 4.44 mmol), cuprous iodide (55 mg, 0.29 mmol) and ethylene glycol (1 mL) were added to DMF (10 mL) and stirred overnight at 110 ° C under nitrogen protection. Water (60 mL) was added and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water (30 mL × 3) and saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =5:1-1:1) was purified to give compound 29-2 (360.00 mg, white solid).

[0308] Step 2: Synthesis of tert-butyl 4-{[(2S,4S)-4-ethoxy-2-[4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methanesulfonylamino-7-methyl-1H-indole-1-carboxylate (29-3)

[0309] Compound 29-2 (225.5 mg, 0.64 mmol), compound 26-3 (167.9 mg, 0.64 mmol) and anhydrous magnesium sulfate (150 mg) were added to dichloromethane (5.0 mL), and the mixture was reacted at room temperature for 12 h. Sodium borohydride (48.64 mg, 1.28 mmol) was added, and the mixture was stirred for 0.5 h. A few drops of methanol were added, and the mixture was reacted at room temperature for 2 hours. The solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =3:1-1:1) to give compound 29-3 (172.00 mg, yellow oil).

[0310] Step 3: Synthesis of 4-[(2S,4S)-4-ethoxy-1-[(5-methylsulfonylamino-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (29)

[0311] Compound 29-3 (172.00 mg, 0.28 mmol) was dissolved in methanol (9.0 mL), THF (4.5 mL) and H2O (3.0 mL), LiOH (42.5 mg, 1.12 mmol) was added, and the mixture was stirred at 70°C overnight. The solvent was concentrated, and the crude product was purified by high pressure preparative chromatography (ACN:H2O=50:1-0:1, TFA0.5%) to obtain compound 29 (50.00 mg, white solid). [M+H] + :486.20.

[0312] 1 H NMR (400MHz, Methanol-d4) δ8.16 (d, J=7.9Hz, 2H), 7.63 (d, J=7.8Hz, 2H), 7.32 (d, J=3.2 Hz, 1H), 6.78 (s, 1H), 6.35 (s, 1H), 4.78-4.62 (m, 1H), 4.65 (s, 1H), 4.37 (d, J=12.6Hz, 1H) , 4.18 (d, J=12.7Hz, 1H), 4.11-40.6 (m, 3H), 3.84-3.71 (m, 1H), 3.61-3.60 (q, J=7.0Hz, 3H ), 3.58-3.42 (m, 1H), 2.78 (s, 2H), 2.53 (s, 3H), 2.04-2.01 (m, 1H), 1.31 (t, J=8.0Hz, 3H).

[0313] Embodiment 22

[0314] Synthesis of 4-{1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-4-[(methylsulfamoyl)methyl]piperidin-2-yl}benzoic acid (Compound 31)

[0315]

[0316] Step 1: Synthesis of 2-(4-cyanophenyl)-4-methylenepiperidine-1-carboxylic acid benzyl ester (31-2)

[0317] At zero degrees, under nitrogen protection, add compound Ph3PMeI (9.0 g, 22.35 mmol) and sodium hydrogen (1.2 g, 29.8 mmol, 60%) to DMSO (150 mL), stir at room temperature for 0.5 hours, add compound 31-1 (5.0 g, 14.9 mmol), stir at 70°C for 2 hours, cool to room temperature, add water (200 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with water (50 mL×3), saturated brine (50 mL) in turn, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify the crude product by column chromatography (V正己烷 :V 乙酸乙酯 =3:1-1:1) to give compound 31-2 (4.0 g, yellow oil).

[0318] Step 2: Synthesis of benzyl 2-(4-cyanophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (31-3)

[0319] At zero degrees, under nitrogen protection, 9-BBN (48 mL, 24.0 mmol, 0.5 N) was slowly added dropwise to a tetrahydrofuran solution (100 mL) of compound 31-2 (4.0 g, 12.0 mmol). Stir at room temperature for 5 hours, and then add sodium hydroxide aqueous solution (12 mL, 36.0 mmol, 3 N) and hydrogen peroxide (60 mL, 30%). Stir at 70 ° C for 2 hours, spin off the solvent, cool to room temperature, add water (100 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with water (50 mL × 3), saturated brine (50 mLX1), dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify the crude product by column chromatography (V 正己烷 :V 乙酸乙酯 =3:1-1:1) to give compound 31-3 (3.0 g, yellow oil).

[0320] Step 3: Synthesis of benzyl 4-(bromomethyl)-2-(4-cyanophenyl)piperidine-1-carboxylate (31-4)

[0321] Under nitrogen protection, compound 31-3 (3.0 g, 8.56 mmol), carbon tetrabromide (2.8 g, 8.56 mmol) and triphenylphosphine (2.2 g, 8.56 mmol) were added to dichloromethane (150 mL). The mixture was stirred at room temperature for 12 hours, water (200 mL) was added, and dichloromethane (50 mL×3) was used for extraction. The organic phases were combined, washed with water (50 mL×3) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =3:1-1:1) to give compound 31-4 (2.6 g, yellow oil).

[0322] Step 4: Synthesis of benzyl 2-(4-cyanophenyl)-4-(sulfonylmethyl)piperidine-1-carboxylate (31-5)

[0323] Under nitrogen protection, compound 31-4 (2.6 g, 6.3 mmol) and thiourea (1.4 g, 18.9 mmol) were added to ethanol (150 mL). The mixture was stirred under reflux for 12 hours, concentrated to remove the solvent, and sodium hydroxide aqueous solution (11.34 mL, 22.68 mmol, 2N) was added. Under nitrogen protection, the mixture was refluxed for 2 hours, cooled to room temperature, and water (100 mL) was added. The mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with water (50 mL×3) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =3:1-1:1) to give compound 31-5 (1.5 g, yellow oil).

[0324] Step 5: Synthesis of benzyl 4-[(chlorosulfonyl)methyl]-2-(4-cyanophenyl)piperidine-1-carboxylate (31-6)

[0325] Under an ice-water bath, compound 31-5 (1.5 g, 4.1 mmol) was added to glacial acetic acid (10 mL) and water (3 mL), and then dichlorohydantoin (1.2 g, 6.1 mmol) was slowly added. The mixture was stirred for 2 hours under an ice-water bath, and water (100 mL) was added. The mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined, washed with water (50 mL) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =3:1-1:1) to give compound 31-6 (0.9 g, yellow solid).

[0326] Step 6: Synthesis of benzyl 2-(4-cyanophenyl)-4-[(methylsulfamoyl)methyl]piperidine-1-carboxylate (31-7)

[0327] Compound 31-6 (0.9 g, 2.1 mmol) and methylamine methanol solution (4 mL, 30%) were added to dichloromethane (10 mL), stirred for 12 hours, and the solvent was concentrated under reduced pressure. The crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =3:1-0:1) to give compound 31-7 (0.5 g, yellow solid).

[0328] Step 7: Synthesis of methyl 4-{4-[(methylsulfamoyl)methyl]piperidin-2-yl}benzoate (31-8)

[0329] Compound 31-7 (0.5 g, 1.17 mmol) was dissolved in methanol (2 mL), and then a mixed solution (5 mL) of concentrated sulfuric acid: water = 1:1 was added thereto, and the reaction was stirred at 80°C for 16 h, and condensed and refluxed. After the reaction was completed, the reaction solution was adjusted to pH 7-8.5 with 2N sodium hydroxide aqueous solution, extracted with dichloromethane (10 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate with saturated brine (8 mL), filtered, and spin-dried to obtain compound 31-8 (0.22 g crude product, brown solid).

[0330] Step 8: Synthesis of tert-butyl 5-methoxy-4-({2-[4-(methoxycarbonyl)phenyl]-4-methylpiperidin-1-yl}methyl)-7-methyl-1H-indole-1-carboxylate (31-9)

[0331] Compound 31-8 (218 mg, 0.64 mmol), compound 6-7 (167.9 mg, 0.64 mmol) and anhydrous magnesium sulfate (150 mg) were added to dichloromethane (5.0 mL), and the mixture was reacted at room temperature for 12 h. Sodium borohydride (48.64 mg, 1.28 mmol) was added, and the mixture was stirred for 0.5 h. A few drops of methanol were added, and the mixture was reacted at room temperature for 2 hours. The solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography (V 正己烷 :V 乙酸乙酯 =3:1-1:1) to give compound 31-9 (170.00 mg, yellow oil).

[0332] Step 9: Synthesis of 4-{1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-4-[(methylsulfamoyl)methyl]piperidin-2-yl}benzoic acid (31)

[0333] Compound 31-9 (170.00 mg, 0.33 mmol) was dissolved in methanol (9.0 mL), THF (4.5 mL) and H2O (3.0 mL), LiOH (42.5 mg, 1.12 mmol) was added, and the mixture was stirred at 70°C overnight. The solvent was concentrated, and the crude product was purified by high pressure preparative chromatography (ACN:H2O=50:1-0:1, TFA0.5%) to obtain compound 31 (80.00 mg, white solid). [M+H] + :486.20.

[0334] 1H NMR (400MHz, DMSO) δ12.63 (s, 1H), 10.55 (s, 1H), 7.93 (d, J=8.0Hz, 2H), 7.62 (d, J=8.0Hz, 2H), 7. 26 (t, J=4.0Hz, 1H), 6.64 (s, 1H), 6.41 (t, J=4.0Hz, 1H), 3.95-3.91 (m, 1H), 3.78-3.72 (m, 4H), 3.5 6 (d, J=12.0Hz, 1H), 3.29-3.26 (m, 1H), 3.16 (q, J=16.0Hz, 1H), 2.68-2.63 (m, 2H), 2.45 (s, 3H), 2 .35-2.26 (m, 1H), 2.23-2.07 (m, 2H), 1.77-1.73 (m, 1H), 1.48-1.36 (m, 2H), 1.18 (t, J=8.0Hz, 3H).

[0335] Assessment of pharmacological activity

[0336] Binding test of the compound of the present invention to Factor B protein (SPR method)

[0337] The affinity between the compound of the present invention and FactorB protein was detected by SPR method

[0338] Materials and instruments

[0339] instrument:

[0340] instrument brand model Biacore8K GE Healthcare 29129951

[0341] Experimental Materials:

[0342] Test methods

[0343] Reagents / consumables brand Part Number batch number Validity Storage conditions 96-wellPlate greinerbio-one 650101 E210733E N / A Room temperature CM5 chip Cytiva 29149603 10326760 2023-10 2-8℃ AmineCouplingKit Cytiva BR100050 33477 2023-04 2-8℃ 10mM sodium acetate pH 4.0 Cytiva BR100349 32657 2023-08 2-8℃ P20 Cytiva BR100054 8250595 2024-01 2-8℃ PBS Cytiva BR100672 33120 2023-06 2-8℃ DMSO Sigma D4540 SHBP4381 2024-03 Room temperature Factor B SinoBiological 17064-H08H -80℃

[0344] This experiment uses the amino coupling method, that is, the Factor B protein is directly fixed on the CM5 chip using Biacore 8K, and then the compound is used as the analyte. The analyte is diluted to the required concentration with running buffer (10mM PBS, pH7.4, 137mM NaCl, 2.7mM KCl, 0.05% P20, 5% DMSO) and multi-cycle kinetic detection is performed. Each cycle is injected for 180 seconds, dissociated for 180 seconds, and then the next cycle is performed to obtain the affinity kinetic analysis data of the test sample and the Factor B protein. The final data was analyzed by Kinetics fitting according to the 1:1 model using Biacore Insight Evaluation Software (V 2.0.15.12933). Prepare running buffer: 10mM PBS, pH7.4, 137mM NaCl, 2.7mM KCl, 0.05% P20, 5% DMSO. CM5 chip activation: Use 400mM EDC and 100mM NHS in the Amine Coupling Kit to activate for 420 seconds at a flow rate of 10μL / min. Target protein coupling: Dilute Factor B protein to 30μg / mL with 10mM sodium acetate (pH 4.0) and couple for 500 seconds at a flow rate of 10μL / min. CM5 chip blocking: Use 1M ethanolamine in the Amine Coupling Kit to block for 420 seconds at a flow rate of 10μL / min. Analyte concentration: Use running buffer to dilute the test compound to the required concentration. Sample injection analysis: Each concentration of the analyte working solution is one cycle, and the flow rate is 30μL / min for 180 seconds and the dissociation is 180 seconds. All results were kinetics fitted and analyzed according to the 1:1 model. At a concentration of 500uM, the experimental results are shown in Table 1 below, where the control groups are set up as follows: control group 1 has the following structural formula, and the preparation method refers to patent CN105579444A; control group 2 has the following structural formula, and the preparation method refers to patent CN114057758A; control group 3 has the following structural formula, and the preparation method refers to patent WO2022256586A2.

[0345]

[0346] Table 1 Optical surface plasmon resonance (SPR) binding force detection results

[0347] Compound No. Rmax(RU) Control group 1 89.8 Control group 2 83.6 Control group 3 90.7 Compound 3 195.6 Compound 4 163.4 Compound 6 95.8 Compound 7 90.1 Compound 8 100.2 Compound 10 94.2 Compound 11 88.6 Compound 12 84.1 Compound 13 111.3 Compound 14 105.7 Compound 15 99.2 Compound 16 110.1 Compound 17 92.3 Compound 18 96.4 Compound 20 95.6 Compound 21 111.2 Compound 22 102.5 Compound 23 91.6 Compound 24 100.2 Compound 25 104.3 Compound 29 96.7 Compound 31 89.9

[0348] It can be concluded from Table 1 that at a concentration of 500uM, compared with the compound in the control group, the compound of the present invention has a higher Rmax (RU), has a more significant binding ability with the target protein, and is significantly better than the compound in the control group, indicating that the compound of the present invention has a better binding ability with the target protein.

[0349] Inhibition of activation of Wieslab complement alternative pathway by the compounds of the present invention (enzyme activity assay)

[0350] The purpose of this experiment is to determine the inhibitory activity of the compounds of the present invention against the complement alternative pathway in human serum using the Wieslab complement system alternative pathway kit.

[0351] Dilute the serum with diluent (1:23). Add the compound to the diluted serum, 8 concentration gradients, up to 10mM, 5-fold gradient dilution. Incubate at room temperature for 15 minutes. Add the compound and serum mixture to the 96-well plate provided by the kit (100uL / well) and activate at 37 degrees for 1 hour. Wash three times with washing buffer. Add the detection antibody (100uL) provided by the kit and incubate at room temperature for 30 minutes. Wash three times with washing buffer. Add the substrate (100uL) and incubate at room temperature for 30 minutes. Initially detect the absorbance at 405nM using an enzyme reader. The experimental results are shown in Table 2 below.

[0352] Table 2 Results of inhibitory activity on the complement alternative pathway in human serum

[0353] Compound No. <![CDATA[APMACIC 50 (nM)]]> Control group 1 45.3 Control group 2 41.2 Control group 3 39.8 Compound 3 17.1 Compound 4 22.7 Compound 6 37.2 Compound 12 38.6

[0354] The compounds of the examples of the present invention have obvious inhibitory activity on the complement alternative pathway in human serum.

Claims

1. A compound represented by formula (I), or its tautomer, and a pharmaceutically acceptable salt thereof, in, is a single bond or a double bond; Y is selected from CR a R b ; R a , R b Each is independently selected from hydrogen or absent; or R a , R b Together with the carbon atom to which it is attached, it forms a double bond; R1 is selected from -COOH, -CN, R2 and R3 are each independently selected from H, deuterium, halogen, -C 1-6 alkyl; Or R2 and R3 together form an imino group; Or R2, R3 together with the carbon atom to which they are attached form a 3 to 8-membered cycloalkyl group; R4 is selected from -C 1-6 Alkyl or H; L is selected from a bond, O, NH; R5 is selected from -C(=O)NR c R d 、-S(O) t -C 1-6 Alkyl, -S(O) t -3 to 8 membered cycloalkyl, C 1-6 Alkyl, 3 to 8 membered cycloalkyl, wherein the alkyl is optionally further substituted by one or more substituents selected from halogen, deuterium, and alkoxy; R c , R d Each independently selected from hydrogen or C 1-6 alkyl; W is selected from NR e , CR f R g ; R e Selected from -C(=O)NH-3 to 8-membered cycloalkyl or -C(=O)-3 to 8-membered cycloalkyl; R f , R g Each is independently selected from hydrogen, deuterium, 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl, -C 1-6 Alkyl, -TS(O) t -X, -NHC(=O)-C 1-6 Alkyl-NR c R d , -SC(=O)-3 to 8-membered cycloalkyl, -O-3 to 8-membered heterocyclic group, -OC 1-6 Alkyl, guanidinyl; wherein the alkyl, cycloalkyl and heterocyclic groups may be optionally further substituted by one or more substituents selected from halogen, deuterium, alkyl, alkoxy and -OH; T is selected from a bond, O, -NH-, -N(CH3)-, C 1-6 alkyl; X is selected from C 1-6 Alkyl, 3 to 8 membered cycloalkyl or NR c R d ; wherein the alkyl group may be further substituted by one or more halogens, deuterium, or 3 to 8 membered cycloalkyl groups; or R f , R g Together with the carbon atom to which it is attached, it forms a 3- to 8-membered heterocyclic group, which may be further selected from C 1-6 Alkyl, -S(O) t -C 1-3 Alkyl, -S(O) t -C 3-6 Cycloalkyl, -S(O) t -NH-C 1-3 Alkyl, -C(=O)-C 1-3 One or more substituents in the alkyl group are substituted; t is selected from 0, 1, 2; Wherein, the compound of general formula (I) is not selected from the following compounds 2. The compound according to claim 1, or its tautomer, characterized in that: The compound has a structure shown in the following formula (II): R h Selected from C 1-6 Alkyl, -S(O) t -C 1-3 Alkyl, -S(O) t -C 3-6 Cycloalkyl, -S(O) t -NH-C 1-3 Alkyl, -C(=O)-C 1-3 alkyl.

3. The compound according to claim 1, or its tautomer, characterized in that: The compound has a structure shown in the following formula (III): T is selected from a bond, O, -NH-, -N(-CH3)-, C 1-6 alkyl; X is selected from C 1-6 Alkyl, 3 to 8 membered cycloalkyl or NR c R d ; The alkyl group may be further substituted by one or more halogens, deuterium, or 3 to 8-membered cycloalkyl groups; R c Selected from H; R d Selected from C 1-6 alkyl.

4. The compound according to claim 3, or its tautomer, characterized in that: T is selected from a bond, -NH-; X is selected from C 1-6 Alkyl, 3 to 8 membered cycloalkyl; the alkyl may be further substituted by one or more halogen, deuterium, 3 to 8 membered cycloalkyl.

5. The compound according to claim 1, or its tautomer, characterized in that: The compound has a structure shown in the following formula (IV): R2 and R3 are each independently selected from deuterium, fluorine, -C 1-6 alkyl.

6. The compound according to claim 1, or its tautomer, characterized in that: The compound has a structure shown in the following formula (V): R i is selected from 3 to 8 membered cycloalkyl or -NH-3 to 8 membered cycloalkyl.

7. The compound according to claim 1, or its tautomer, and its pharmaceutically acceptable salt, characterized in that: The compound has a structure shown in the following formula (VI): L is selected from a bond, NH; R5 is selected from -S(O) t -C 1-6 Alkyl, -(C=O)NR c R d 、-OC 1-6 Alkyl, wherein the -OC 1-6 The alkyl group in the alkyl group is further substituted by one or more substituents selected from F, deuterium, and alkoxy.

8. The compound according to claim 1, or its tautomer, characterized in that: The compound is selected from any one of the following structures:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or its tautomer, and a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients.

10. Use of the compound according to any one of claims 1 to 8, or its tautomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating and / or preventing a disease or disorder mediated by activation of the complement alternative pathway.

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