Compound containing pyridinopyrrole structure and application of compound as ubiquitin specific protease 1 inhibitor

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to a compound containing a pyridinopyrrole structure and application of the compound as a ubiquitin specific protease 1 inhibitor. The compound containing the pyridinopyrrole structure is a compound as shown in a formula II, a salt thereof or a solvate thereof. The compound disclosed by the invention can be used as a ubiquitin specific protease 1 (USP1) inhibitor for treating USP1-mediated diseases, such as inflammation, tumors and the like, and has an excellent treatment effect. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to a compound containing a pyrido[3,2-b]pyrrole structure and its use as a ubiquitin-specific protease 1 inhibitor. Background Art

[0002] Ubiquitin is a small protein (76 amino acids) that is ligated to target proteins post-transcriptionally. The outcome of ubiquitination is determined by the number and linkage topology of ubiquitin molecules bound to the target protein. For example, proteins presenting polyubiquitin chains linked through lysine 48 are generally targets for the proteasome for degradation, while monoubiquitination or polyubiquitin chains linked through other lysines regulate non-proteolytic functions such as cell cycle regulation, DNA damage repair, transcription, and endocytosis. Ubiquitination is a reversible process, which is the process of removing ubiquitin from target proteins by deubiquitinating enzymes.

[0003] Ubiquitin-specific protease 1 (USP1) is a deubiquitinating enzyme that plays a role in DNA damage repair. USP1 interacts with UAF1 (USP1-associated factor 1) to form a complex required for deubiquitinating enzyme activity. The USP1 / UAF1 complex deubiquitinates monoubiquitinated proliferating cell nuclear antigen (PCNA) and monoubiquitinated Fanconi anemia complementation group D2 (FANCD2), and monoubiquitinated PCNA and monoubiquitinated FANCD2 are proteins that play important functions in the translesion synthesis (TLS) and Fanconi anemia (FA) pathways, respectively. The USP1 / UAF1 complex also deubiquitinates Fanconi anemia complementation group I (FANCI). These two pathways are essential for repairing DNA damage induced by DNA cross-linking agents such as cisplatin and mitomycin C (MMC).

[0004] Therefore, inhibitors of ubiquitin-specific protease 1 (USP1) are expected to be used for the treatment of various diseases such as cancer. Currently, there is a lack of safe and effective targeted deubiquitinases that can be used in clinical practice. Therefore, there is an urgent need in the art to develop new ubiquitin-specific protease 1 inhibitors. Summary of the Invention

[0005] Aiming at the problems of the prior art, the present invention provides a compound containing a pyrido[3,2-b]pyrrole structure and its use as a ubiquitin-specific protease 1 inhibitor.

[0006] The compound shown in Formula II, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof:

[0007]

[0008] Wherein,

[0009] X3 is selected from N or CR8; X4 is selected from N or CR9; X5 is selected from N or CR 10 ;

[0010] R1 is selected from hydrogen, hydroxy, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl;

[0011] R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, cyano, halogen, sulfonamide, -OR 31c , substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted azetidinyl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxy, nitro, carboxy, cyano, mercapto, carboxamide, sulfonamide, C1-C6 acyl, C1-C6 sulfonyl, -NR 32a R 32b , -OR 31c , C3-C8 cycloalkyl, pyrrolidine, tetrahydrofuryl, oxetanyl, azetidinyl, or two adjacent substituents are linked to form phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, furyl, thienyl, C3-C8 cycloalkyl, oxetanyl, azetidinyl;

[0012] R 31cSelected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted azetidinyl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxy, nitro, carboxyl, cyano, mercapto, carboxamido, sulfonamido, C1-C6 acyl, C1-C6 sulfonyl, -NR 32a R 32b , C3-C8 cycloalkyl, pyrrolidine, tetrahydrofuryl, oxetanyl, azetidinyl, or two adjacent substituents are linked to form phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, furyl, thienyl, C3-C8 cycloalkyl, oxetanyl, azetidinyl;

[0013] R 31a and R 31b each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl;

[0014] R 32a and R 32b each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl;

[0015] R4 and R5 each independently selected from hydrogen, hydroxy, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0016] R6, R7, R8, R9, R 10 each independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, hydroxy, nitro, amino, carboxyl, cyano, mercapto, carboxamido, sulfonamido, C1-C6 acyl, C1-C6 sulfonyl, C3-C8 cycloalkyl, pyrrolidine, tetrahydrofuryl, oxetanyl, azetidinyl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxy, nitro, carboxyl, cyano, amino, mercapto, carboxamido, sulfonamido, C1-C6 acyl, C1-C6 sulfonyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, furyl, thienyl, C3-C8 cycloalkyl, oxetanyl, azetidinyl, tetrahydrofuryl.

[0017] Preferably, R6, R7, R8, R9, R 10 are each independently selected from hydrogen, methoxy, deuterated methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, 2-fluoroethoxy, 2-methoxyethoxy, cyclopropoxy, cyclobutoxy, benzyloxy, methyl, ethyl, isopropyl, 2-fluoroisopropyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylamino, cyano, halogen, methylsulfonyl, ethylsulfonyl, trifluoromethyl.

[0018] Preferably, R1 is selected from hydrogen, C1-C2 alkyl, C2-C3 alkenyl, cyclopropyl;

[0019] and / or, R4, R5 are selected from hydrogen.

[0020] Preferably, R3 is selected from a substituted or unsubstituted pyrrolyl, a substituted or unsubstituted imidazolyl, a substituted or unsubstituted pyrazolyl, a substituted or unsubstituted triazolyl, a substituted or unsubstituted tetrazolyl, wherein the substituent is selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, triazolyl, cyano, amino, C1-C4 alkylamino, C1-C4 alkylsulfonyl, oxetanyl, C1-C4 alkylazetidinyl.

[0021] Preferably, the compound has the structure shown in Formula IV:

[0022]

[0023] wherein,

[0024] R1 is selected from hydrogen or methyl;

[0025] R1' is selected from hydrogen or cyclopropyl;

[0026] R3” is selected from a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C4 alkenyl, wherein the substituent is selected from cyclopropyl.

[0027] Preferably, the structural formula of the compound is selected from:

[0028]

[0029]

[0030] The present invention also provides the use of the above compound, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof in the preparation of a USP1 inhibitor.

[0031] The present invention also provides the use of the above compound, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof in the preparation of a medicament for preventing and / or treating USP1-mediated diseases.

[0032] Preferably, the disease is cancer;

[0033] Preferably, the cancer is breast cancer;

[0034] More preferably, the breast cancer is triple-negative breast cancer.

[0035] The present invention also provides a medicament which is prepared from the above compound, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof as an active ingredient, plus a pharmaceutically acceptable excipient or adjuvant.

[0036] The present invention also provides a pharmaceutical composition, the active ingredient of which comprises the above compound, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof.

[0037] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0038] Definition of terms used in the present invention: Unless otherwise specified, the initial definitions provided for groups or terms herein apply to such groups or terms throughout the specification; for terms not specifically defined herein, meanings that can be given to them by those skilled in the art should be provided according to the disclosure and context.

[0039] "Substituted" means that a hydrogen atom in a molecule is replaced by other different atoms or molecules.

[0040] The minimum and maximum carbon atom contents in a hydrocarbon group are indicated by a prefix. For example, the prefix C a ~C b alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C1-C6 alkyl" means an alkyl group containing 1 to 6 carbon atoms; "C1-C6 alkoxy" means an alkoxy group containing 1 to 6 carbon atoms.

[0041] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of carbon atoms. For example, C1-C8 alkyl refers to an alkyl group having 1 to 8 carbon atoms, that is, an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. The alkyl group can be straight-chain or branched-chain. Representative branched-chain alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, etc.

[0042] "Alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. All alkenyl groups can be straight-chain or branched-chain.

[0043] "Alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. All alkynyl groups can be straight-chain or branched-chain.

[0044] The structure of "alkoxy" is The structure of "alkylthio" is a1 is an integer from 0 to 5.

[0045] "Halogen" is fluorine, chlorine, bromine, or iodine.

[0046] The structure of "sulfonamido" is The structure of carboxamido is The structure of sulfonyl is The structure of carbonyl is wherein R is a C1-C6 alkyl.

[0047] "Cycloalkyl" refers to a saturated or unsaturated all-carbon monocyclic or polycyclic (including fused rings, spiro rings, or bridged rings) that does not have a conjugated π-electron system, such as including but not limited to: C3-C8 cycloalkyl means that the cycloalkyl forms a closed structure with 3-8 carbon atoms.

[0048] "Heterocycloalkyl" means that at least one carbon atom on the ring of the cycloalkyl is replaced by a heteroatom, and the heteroatom is O, N, or S, such as including but not limited to:

[0049] 3-8 membered heterocycloalkyl means that the heterocycloalkyl forms a closed structure with 3-8 atoms.

[0050] "Aryl" refers to an all-carbon monocyclic or polycyclic (including fused rings, spiro rings, or bridged rings) having a conjugated π-electron system, such as including but not limited to: phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, and indenyl. The aromatic ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N, or S, and the point of attachment to the parent must be on a carbon atom of the ring having a conjugated π-electron system, such as including but not limited to C6-C14 aryl means that the aryl forms a closed structure with 6-12 carbon atoms.

[0051] "Heteroaryl" means an aryl in which at least one carbon atom on the ring of the conjugated π-electron system is replaced by a heteroatom, and the heteroatom is O, N or S, such as including but not limited to:

[0052]

[0053] 5-14 membered heteroaryl means that the heteroaryl forms a closed structure with 5-14 atoms.

[0054] R a and R b "Linked to form a ring" means that at least one atom in R a and R b are respectively connected by a chemical bond, so that R a , R b and their molecular backbone structures together form a cyclic structure.

[0055] The present invention provides a class of compounds containing a pyrido[3,2-b]pyrrole structure. The compounds of the present invention can be used as ubiquitin-specific protease 1 (USP1) inhibitors to treat USP1-mediated diseases such as cancer, and have excellent therapeutic effects.

[0056] Obviously, based on the above content of the present invention, according to the common general technical knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can be made.

[0057] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention. Specific Embodiments

[0058] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.

[0059] Example 1. Synthesis of the Compounds of the Present Invention

[0060] I. Synthesis of Intermediates

[0061] 1. Synthesis of Intermediate 1,4-Cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

[0062]

[0063] Synthesis of 4-Cyclopropyl-6-methoxypyrimidine

[0064] In a dry 100 mL three-necked round-bottom flask, Pd(dppf)Cl2 (405 mg, 0.5 mmol), 4-chloro-6-methoxypyrimidine (1.45 g, 10 mmol), cyclopropylboronic acid (1.03 g, 12 mmol), and potassium carbonate (2.76 g, 20 mmol) were successively added. After evacuating and replacing with nitrogen three times using a vacuum pump, a mixed solution of toluene and water (7:3) (50 mL) was added under N2 protection. The reaction solution was stirred at 80 °C for 48 h. After the reaction was completed, it was filtered through diatomaceous earth. The filtrate was concentrated and then separated and purified by silica gel column chromatography (PE / EtOAc = 50:1) to obtain 4-cyclopropyl-6-methoxypyrimidine with a yield of 90%. 1 H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 6.56 (s, 1H), 3.94 (s, 3H), 1.97 - 1.81 (m, 1H), 1.12 - 1.07 (m, 2H), 1.14 - 0.99 (m, 2H).

[0065] Synthesis of 5-bromo-4-cyclopropyl-6-methoxypyrimidine

[0066] 4-Cyclopropyl-6-methoxypyrimidine (1.6 g, 10.7 mmol) was dissolved in ethanol (50 mL), and Br2 (1.87 g, 11.7 mmol) was slowly added dropwise under an ice bath. After the addition was complete, the temperature was slowly raised to room temperature and stirred for 16 h. After monitoring the reaction by TLC and completion, the reaction solution was concentrated and separated and purified by silica gel column chromatography (PE / EtOAc = 20:1) to obtain 5-bromo-4-cyclopropyl-6-methoxypyrimidine with a yield of 98%. 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (s, 1H), 4.04 (s, 3H), 2.56 - 2.49 (m, 1H), 1.19 - 1.16 (m, 1H), 1.11 - 1.07 (m, 1H).

[0067] Synthesis of 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

[0068] In a dry 50 mL three-necked round-bottom flask, Pd(dppf)Cl2 (218 mg, 0.3 mmol), 5-bromo-4-cyclopropyl-6-methoxypyrimidine (687 mg, 3 mmol), bis(pinacolato)diboron (1.52 g, 6 mmol), and potassium acetate (883 mg, 9 mmol) were added in sequence. After evacuating and replacing with nitrogen three times using a vacuum pump, ultra-dry dioxane (20 mL) was added under N2 protection, and the reaction solution was stirred at 80 °C for 18 h. After the reaction was completed, it was filtered through diatomaceous earth, and the filtrate was concentrated and then separated and purified by silica gel column chromatography (PE / EtOAc = 50:1) to obtain the intermediate 1,4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine with a yield of 80%. 1 H NMR (400 MHz, Chloroform-d) δ 8.48 (s, 1H), 3.85 (s, 3H), 2.02 (m, 1H), 1.33 - 1.28 (s, 12H), 1.10 (m, 2H), 0.95 - 0.85 (m, 2H).

[0069] 2. Synthesis of Intermediate 2, 2-(4-(Chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

[0070]

[0071] Synthesis of Methyl 4-(4-(Trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0072] To a mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one (3.1 g, 11.49 mmol) and water (6 mL), NAOAC (951.8 mg, 11.6 mmol) was added, and the reaction solution was heated at 100 °C for 1 h. After cooling to room temperature, methyl 4-formylbenzoate (1.7 g, 10.34 mmol) was dissolved in MeOH (47 mL) and NH3·H2O (11 mL), and slowly added dropwise to the reaction solution. After the addition was complete, the reaction system was heated to 100 °C and stirred for 2 h. After monitoring the reaction by TLC and completion, water (50 mL) was added to quench the reaction, and a large amount of pale yellow solid precipitated. It was filtered by suction, and the filter cake was washed twice with DCM (10 mL) and dried under vacuum to obtain the product methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate with a yield of 83%. H NMR (400 MHz, DMSO-d6) δ 13.45 (s, 1H), 8.16 - 8.11 (m, 2H), 8.10 - 8.04 (m, 2H), 8.01 (dt, J = 2.6, 1.3 Hz, 1H), 3.89 (s, 3H).

[0073] Synthesis of Methyl 4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0074] Dissolve methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1.9 g, 7.03 mmol) in ultradry DMF (30 mL), add NaH (338 mg, 8.44 mmol) under ice bath, and stir for 5 min. Raise the reaction system to room temperature, add CH3I (0.53 mL, 8.44 mmol), and continue the reaction at room temperature for 3 h. After monitoring the reaction by TLC until completion, add 30 mL of water, extract three times with 10 mL of ethyl acetate, combine the organic phases, wash three times with 10 mL of saturated brine, dry the organic phase over anhydrous sodium sulfate and concentrate, and separate and purify by silica gel column chromatography (PE / EtOAc = 5:1) to obtain methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate with a yield of 92%. 1 1H NMR (400 MHz, Chloroform-d) δ 8.14 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.35 (s, 0H), 3.95 (s, 2H), 3.81 (s, 2H).

[0075] Synthesis of (4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol

[0076] Dissolve methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (300 mg, 1.06 mmol) in ultradry tetrahydrofuran (30 mL), add LiAlH4 (81 mg, 2.12 mmol) portionwise under ice bath, and react at room temperature for 2 h. After monitoring the reaction by TLC until completion, slowly add ice water to quench under ice bath, and then add 0.08 mL of 15% NaOH solution. Filter the reaction solution through diatomaceous earth, extract the filtrate with 15 mL of dichloromethane / methanol solution (10:1), dry the organic phase over anhydrous sodium sulfate and concentrate to obtain the crude product (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol with a yield of 81%.

[0077] Synthesis of 2-(4-(Chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

[0078] (4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (512 mg, 2 mmol) was dissolved in 1,2-dichloroethane (50 mL), and SOCl2 (581 μL, 8 mmol) was slowly added dropwise under an ice bath. After the addition was complete, the reaction system was heated to 50 °C and stirred for 4 h. After monitoring the reaction by TLC until completion, the reaction solution was cooled to room temperature, and water was slowly added dropwise to quench the reaction. The mixture was extracted three times with 15 mL of dichloromethane, and the organic phases were combined, washed three times with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (DCM = 100%) to obtain the intermediate 2,2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole, with a yield of 88%. 1 1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 7.30 (s, 1H), 4.63 (s, 2H), 3.77 (s, 3H).

[0079] 3. Synthesis of intermediate 3, 2-(4-(chloromethyl)phenyl)-1-methyl-d3-4-(trifluoromethyl)-1H-imidazole

[0080] Synthesis of methyl 4-(1-methyl-d3-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0081] The synthetic route was the same as that of intermediate 2, except that specific reaction raw materials were selected according to the different substituents of the product. 1 1H NMR (400 MHz, Chloroform-d) δ 8.17 - 8.13 (m, 2H), 7.77 - 7.73 (m, 2H), 7.35 (q, J = 1.3 Hz, 1H), 3.96 (s, 3H).

[0082] (4-(1-Methyl-d3-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol synthesis

[0083] The synthetic route was the same as that of intermediate 2, except that specific reaction raw materials were selected according to the different substituents of the product. 1 1H NMR (400 MHz, Chloroform-d) δ 8.17 - 8.13 (m, 2H), 7.77 - 7.73 (m, 2H), 7.35 (q, J = 1.3 Hz, 1H), 4.67 (s, 2H).

[0084] Synthesis of 2-(4-(chloromethyl)phenyl)-1-methyl-d3-4-(trifluoromethyl)-1H-imidazole

[0085] The synthesis route is the same as that of Intermediate 2, except that specific reaction raw materials are selected according to the different substituents of the product. 1 HNMR(400MHz,Chloroform-d)δ7.63(d,J=7.8Hz,2H),7.49(d,J=7.8Hz,2H),4.63(s,2H).

[0086] 4. Synthesis of Intermediate 4, 2-(4-(chloromethyl)phenyl)-1-ethyl-4-(trifluoromethyl)-1H-imidazole

[0087] The synthesis route is the same as that of Intermediate 2, except that specific reaction raw materials are selected according to the different substituents of the product. 1 HNMR(400MHz,Chloroform-d)δ7.63(d,J=7.8Hz,2H),7.49(d,J=7.8Hz,2H),4.63(s,2H),4.05(q,J=7.3Hz,2H),1.43(t,J=7.3Hz,3H).

[0088] 5. Synthesis of Intermediate 5, 2-(4-(chloromethyl)phenyl)-1-propyl-4-(trifluoromethyl)-1H-imidazole

[0089] The synthesis route is the same as that of Intermediate 2, except that specific reaction raw materials are selected according to the different substituents of the product (3-bromopropane can be used to replace methyl iodide). 1 H NMR(400MHz,Chloroform-d)δ7.58(d,J=7.7Hz,2H),7.50(d,J=7.6Hz,2H),7.36(s,1H),4.64(s,2H),3.98(t,J=7.4Hz,2H),1.80(h,J=7.4Hz,2H),0.91(t,J=7.3Hz,3H).

[0090] 6. Synthesis of Intermediate 6, 2-(4-(chloromethyl)phenyl)-1-sec-butyl-4-(trifluoromethyl)-1H-imidazole

[0091] The synthesis route is the same as that of Intermediate 2, except that specific reaction raw materials are selected according to the different substituents of the product (2-bromobutane can be used to replace methyl iodide). 1 H NMR(400MHz,Chloroform-d)δ7.63(d,J=7.8Hz,2H),7.49(d,J=7.8Hz,2H),4.63(s,2H),4.27(h,J=6.9Hz,1H),1.76(p,J=7.3Hz,2H),1.49(d,J=6.7Hz,3H),0.75(t,J=7.4Hz,3H).

[0092] 7. Synthesis of Intermediate 7, 2-(4-(Chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole

[0093] The synthesis route is the same as that of Intermediate 2, except that specific reaction raw materials are selected according to the different substituents of the product (simply replace methyl iodide with 2-iodopropane). 1 H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 4.63 (s, 2H), 4.57 (h, J = 6.7 Hz, 1H), 1.48 (d, J = 6.7 Hz, 6H).

[0094] 8. Synthesis of Intermediate 8, 2-(4-(Chloromethyl)phenyl)-1-allyl-4-(trifluoromethyl)-1H-imidazole

[0095] The synthesis route is the same as that of Intermediate 2, except that specific reaction raw materials are selected according to the different substituents of the product (simply replace methyl iodide with 2-iodopropane). 1 H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 6.00 (ddt, J = 16.7, 10.3, 5.2 Hz, 1H), 5.39 (dt, J = 10.3, 1.6 Hz, 1H), 5.19 (dd, J = 17.1, 1.8 Hz, 1H), 4.65 (dt, J = 5.1, 1.7 Hz, 2H), 4.63 (s, 2H).

[0096] 9. Synthesis of Intermediate 9, 2-(4-(Chloromethyl)phenyl)-1-cyclopropylmethyl-4-(trifluoromethyl)-1H-imidazole

[0097] The synthesis route is the same as that of Intermediate 2, except that specific reaction raw materials are selected according to the different substituents of the product (simply replace methyl iodide with 2-iodopropane). 1 H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 4.63 (s, 2H), 3.89 (d, J = 7.0 Hz, 2H), 1.21 - 1.11 (m, 1H), 0.76 - 0.67 (m, 2H), 0.34 - 0.30 (m, 2H).

[0098] 10. Synthesis of Intermediate 10, 2-(4-(Chloromethyl)phenyl)-1-butyl-4-(trifluoromethyl)-1H-imidazole

[0099] The synthetic route is the same as that of Intermediate 2, except that specific reaction raw materials are selected according to the different substituents of the product (substituting 1-bromobutane for methyl iodide is sufficient). 1 H NMR(400MHz,Chloroform-d)δ7.63(d,J=7.8Hz,2H),7.49(d,J=7.8Hz,2H),4.63(s,2H),4.06(t,J=6.2Hz,2H),1.78(p,J=6.5Hz,2H),1.44-1.30(m,2H),0.94(t,J=7.6Hz,3H).

[0100] 11. Synthesis of Intermediate 11, 2-(4-(chloromethyl)phenyl)-1-(3-butenyl)-4-(trifluoromethyl)-1H-imidazole

[0101] The synthetic route is the same as that of Intermediate 2, except that specific reaction raw materials are selected according to the different substituents of the product (substituting 4-bromo-1-butene for methyl iodide is sufficient). 1 H NMR(400MHz,Chloroform-d)δ7.61-7.56(m,2H),7.53-7.48(m,2H),7.38-7.34(m,1H),5.67(ddt,J=17.1,10.3,6.8Hz,1H),5.13-5.03(m,2H),4.64(s,2H),4.09(t,J=7.3Hz,2H),2.54-2.46(m,2H).

[0102] 12. Synthesis of Intermediate 12, 2-(3-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

[0103] The synthetic route of Intermediate 12 is similar to that of Intermediate 2, except that methyl 4-formylbenzoate is replaced with methyl 3-formylbenzoate. 1 H NMR(400MHz,Chloroform-d)δ8.29(t,J=1.8Hz,1H),8.14(dt,J=7.9,1.5Hz,1H),7.89(dt,J=7.8,1.5Hz,1H),7.58(t,J=7.8Hz,1H),7.35(q,J=1.2Hz,1H),4.63(s,2H),3.81(s,3H).

[0104] 13. Synthesis of Intermediate 13, 2-(4-(chloromethyl)-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

[0105] The synthetic route of Intermediate 13 is similar to that of Intermediate 2, except that methyl 4-formylbenzoate is replaced with methyl 4-formyl-3-fluorobenzoate as the starting material. 1 H NMR(400MHz,DMSO-d6)δ8.03(d,J=1.3Hz,1H),7.63(t,J=7.7Hz,1H),7.53(dd,J=11.0,1.6Hz,1H),7.46(dd,J=7.9,1.6Hz,1H),4.87(s,2H),3.63(d,J=1.6Hz,3H).

[0107] 14. Synthesis of Intermediate 14, 2-(4-(Chloromethyl)-3-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

[0108] The synthetic route of Intermediate 14 is similar to that of Intermediate 2, except that methyl 4-formylbenzoate is replaced with methyl 4-formyl-2-fluorobenzoate as the starting material. 1 H NMR(400MHz,DMSO-d6)δ8.00(t,J=1.3Hz,1H),7.70(t,J=7.8Hz,1H),7.67-7.59(m,2H),4.87(s,2H),3.84(s,3H).

[0110] 15. Synthesis of Intermediate 15, 2-(Chloromethyl)-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine

[0111] The synthetic route of Intermediate 15 is similar to that of Intermediate 2, except that methyl 4-formylbenzoate is replaced with methyl 5-formylpyridine-2-carboxylate as the starting material. 1 H NMR(400MHz,DMSO-d6)δ9.09(dd,J=2.2,0.8Hz,1H),8.38(dd,J=8.2,2.3Hz,1H),8.19(dd,J=8.1,0.8Hz,1H),8.09(d,J=1.3Hz,1H),4.93(s,2H),3.89(s,3H).

[0112] 16. Synthesis of Intermediate 16, 5-(Chloromethyl)-2-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine

[0113] The synthetic route of Intermediate 16 is similar to that of Intermediate 2, except that methyl 4-formylbenzoate is replaced with methyl 6-formylnicotinate as the starting material. 11H NMR (400 MHz, DMSO-d6) δ 9.14 (dd, J = 2.2, 0.8 Hz, 1H), 8.40 (dd, J = 8.4, 2.2 Hz, 1H), 8.25 (dd, J = 8.4, 0.8 Hz, 1H), 8.09 (d, J = 1.3 Hz, 1H), 4.99 (s, 3H), 3.92 (s, 3H).

[0114] 17. Synthesis of Intermediate 17, 1-(4-(Chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole

[0115]

[0116] Synthesis of Methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate

[0117] Under an ice bath, methyl 4-hydrazinobenzoate hydrochloride (5 g, 24.6 mmol) and 1,1,1-trifluoropentane-2,4-dione (3 mL, 24.6 mmol) were dissolved in hexafluoroisopropanol (25 mL), and triethylamine (2.73 mL, 49.2 mmol) was slowly added dropwise. After the addition was complete, the reaction system was warmed to room temperature and stirred for 4 h. After monitoring the reaction by TLC until completion, the reaction was quenched by adding water. The mixture was extracted three times with 15 mL of dichloromethane, and the combined organic phases were washed three times with 10 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography (PE / EtOAc = 5:1) to obtain methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate with a yield of 60%. 1 1H NMR (400 MHz, Chloroform-d) δ 8.22 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz 2H), 6.50 (s, 1H), 3.96 (s, 3H), 2.41 (s, 3H).

[0118] Synthesis of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol

[0119] Methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (1.26 g, 4.44 mmol) was dissolved in ultradry tetrahydrofuran (60 mL). LiAlH4 (202 mg, 5.328 mmol) was added portionwise under an ice bath, and the reaction mixture was warmed to room temperature and stirred for 2 h. After the reaction was monitored by TLC and completed, ice water was slowly added dropwise to quench the reaction under an ice bath, and then 0.08 mL of 15% NaOH solution was added. The reaction mixture was filtered through diatomaceous earth, and the filtrate was extracted with 15 mL of a dichloromethane / methanol solution (10:1). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol, with a yield of 80%.

[0120] Synthesis of 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole

[0121] (4-(5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (512 mg, 2 mmol) was dissolved in 1,2-dichloroethane (50 mL). SOCl2 (581 μL, 8 mmol) was slowly added dropwise under an ice bath. After the addition was complete, the reaction mixture was warmed to 50 °C and stirred for 4 h. After the reaction was monitored by TLC and completed, the reaction mixture was cooled to room temperature, and water was slowly added dropwise to quench the reaction. The mixture was extracted three times with 15 mL of dichloromethane, and the combined organic phases were washed three times with 10 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated, and then separated and purified by silica gel column chromatography (DCM = 100%) to obtain Intermediate 17, 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole, with a yield of 70%. 1 1H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 8.0 Hz 2H), 7.44 (d, J = 8.0 Hz 2H), 6.46 (s, 1H), 4.63 (s, 2H), 2.35 (s, 3H).

[0122] 18. Synthesis of Intermediate 18, 6-bromo-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine

[0123]

[0124] Synthesis of 6-chloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine

[0125] Under an ice bath, 6-chloro-1H-pyrrolo[3,2-c]pyridine (5.0 g, 32.9 mmol) was dissolved in acetonitrile (60 mL), and then triethylamine (7.8 g, 82.3 mmol) and DMAP (2.4 g, 19.8 mmol) were added. Subsequently, p-toluenesulfonyl chloride (7.5 g, 39.5 mmol) was added in batches. After monitoring the reaction by TLC until completion, the reaction solution was added to water (200 mL). A large amount of solid precipitated. After filtration and drying of the filter cake, 8.9 g of the crude product 6-chloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine was obtained, with a yield of 88%. 1 H NMR (400 MHz, Chloroform-d) δ 8.62 (d, J = 0.9 Hz, 1H), 7.92 (t, J = 0.9 Hz, 1H), 7.83 - 7.77 (m, 2H), 7.57 (d, J = 3.7 Hz, 1H), 7.35 - 7.27 (m, 2H), 6.71 (dd, J = 3.7, 0.9 Hz, 1H), 2.39 (s, 3H).

[0126] Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine

[0127] Into a dry 500 mL three-necked round-bottom flask, XphosPdG2 (2.3 g, 2.9 mmol), Xantphos (1.6 g, 2.9 mmol), 6-chloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine (8.9 g, 29.1 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (7.3 g, 39.8 mmol), and potassium carbonate (13.7 g, 99.5 mmol) were added in sequence. After evacuating and replacing nitrogen three times with a vacuum pump, a mixed solution of dioxane and water (7:3) (150 mL) was added under N2 protection. The reaction solution was stirred at 80 °C for 3 h. After the reaction was completed, the reaction solution was poured into water (300 mL). A large amount of solid precipitated. After filtration and drying of the filter cake, 13.2 g of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine was obtained, with a yield of 79%. 1HNMR(400MHz,Chloroform-d)δ8.98(d,J=1.0Hz,1H),8.65(s,1H),8.02(d,J=0.9Hz,1H),7.86-7.80(m,2H),7.64(d,J=3.7Hz,1H),7.28(d,J=8.5Hz,2H),6.78(dd,J=3.7,0.8Hz,1H),3.92(s,3H),2.39(s,3H),1.75-1.71(m,1H),1.24-1.19(m,2H),0.87(ddd,J=8.0,4.0,2.5Hz,2H).

[0128] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine

[0129] Dissolve 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine (13 g, 30.9 mmol) in methanol (80 mL), then add sodium hydroxide (3.1 g, 77.3 mmol) and water (20 mL), react at room temperature for 2 h. After monitoring the reaction by TLC until it is completed, add the reaction solution to water (200 mL). A large amount of solid precipitates. Filter, and after drying the filter cake, 6.4 g of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine is obtained, with a yield of 78%. 1 HNMR(400MHz,Chloroform-d)δ9.34(s,1H),9.07(d,J=0.9Hz,1H),8.61(s,1H),7.38(d,J=1.0Hz,1H),7.27(d,J=3.5Hz,1H),6.69(dt,J=2.8,1.2Hz,1H),3.87(s,3H),1.83-1.80(m,1H),1.20-1.12(m,2H),0.89-0.81(m,3H).

[0130] Synthesis of 6-Bromo-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine

[0131] Dissolve 6-bromo-1H-pyrrolo[3,2-c]pyridine (1.97 g, 10 mmol) in N,N-dimethylformamide (DMF) (20 mL). Add NaH (440 mg, 11 mmol) under an ice bath and stir for 5 minutes. Then add 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (2.75 g, 10 mmol), and continue the reaction at room temperature for 1 h. After monitoring the reaction by TLC until completion, add 100 mL of water, stir for half an hour, and a large amount of solid will precipitate. Filter, and slurry the filter cake with ether / petroleum ether (v:v = 1:1, 20 mL). After suction filtration and drying, 6-bromo-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine is obtained with a yield of 81%. 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 0.8 Hz, 1H), 7.92 (dt, J = 6.7, 1.2 Hz, 2H), 7.75 - 7.67 (m, 3H), 7.40 - 7.33 (m, 2H), 6.72 (dd, J = 3.3, 0.9 Hz, 1H), 5.57 (s, 2H), 3.76 (s, 3H).

[0132] 19. Synthesis of 4,6-dichloro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Intermediate 19)

[0133] Dissolve 4,6-dichloro-1H-pyrrolo[3,2-C]pyridine (2.0 g, 10.7 mmol) in N,N-dimethylformamide (DMF) (20 mL). Add NaH (0.28 g, 11.8 mmol) under an ice bath and stir for 5 minutes. Then add Intermediate 2 (2.9 m, 10.7 mmol), and continue the reaction at room temperature for 1 h. After monitoring the reaction by TLC until completion, add 100 mL of water, extract with ethyl acetate (50 ml * 3). After concentrating the organic phase, mix with silica gel and separate and purify by silica gel column chromatography (PE / EtOAc = 1:1) to obtain Intermediate 12 with a yield of 87%. 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 1.4 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.82 (d, J = 3.4 Hz, 1H), 7.74 - 7.68 (m, 2H), 7.38 (d, J = 8.2 Hz, 2H), 6.74 - 6.66 (m, 1H), 3.76 (s, 3H).

[0134] Synthesis of 6-Chloro-4-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Intermediate 20)

[0135]

[0136] Intermediate 19 (200 mg, 0.47 mmol), methylboronic acid (37 mg, 0.61 mmol), DppfPdCl2 (34 mg, 0.047 mmol) and potassium carbonate (162 mg, 1.2 mmol) were added to a 50 mL three-necked flask. Subsequently, dioxane / water (v / v = 7:4, 22 mL) was added. After displacing N2 three times, the mixture was reacted at 90 °C for 5 h. After the reaction was completed, the reaction solution was concentrated and then mixed with silica gel, and separated and purified by silica gel column chromatography (PE / EtOAc = 1:1) to obtain Intermediate 20 with a yield of 65%. 1 H NMR (400 MHz, Chloroform-d) δ 7.58 (dd, J = 8.1, 1.9 Hz, 2H), 7.32 - 7.27 (m, 1H), 7.16 (dd, J = 8.4, 1.8 Hz, 2H), 7.12 (d, J = 3.3 Hz, 1H), 7.04 (s, 1H), 6.62 (dd, J = 3.0, 1.7 Hz, 1H), 5.31 (d, J = 7.7 Hz, 2H), 3.73 (d, J = 1.7 Hz, 3H), 2.73 (d, J = 1.6 Hz, 3H).

[0137] Synthesis of 6-Chloro-4-ethyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Intermediate 21)

[0138] The synthesis of Intermediate 21 is similar to that of Intermediate 20, except that ethylboronic acid is used instead of methylboronic acid, and the yield is 66%. 1 HNMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 1.4 Hz, 1H), 7.72 - 7.67 (m, 2H), 7.64 (d, J = 3.3 Hz, 1H), 7.57 (d, J = 1.0 Hz, 1H), 7.37 - 7.32 (m, 2H), 6.76 (dd, J = 3.3, 1.0 Hz, 1H), 5.53 (s, 2H), 3.75 (s, 3H), 2.97 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H).

[0139] Synthesis of 6-chloro-4-vinyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Intermediate 22)

[0140] The synthesis of Intermediate 22 is similar to that of Intermediate 20, just replace methylboronic acid with vinylboronic acid, and the yield is 76%. 1 HNMR(400MHz,DMSO-d6)δ7.92(d,J=1.4Hz,1H),7.74-7.65(m,4H),7.37-7.33(m,2H),7.20(dd,J=17.2,10.7Hz,1H),6.95(dd,J=3.4,0.9Hz,1H),6.39(dd,J=17.2,2.0Hz,1H),5.62(dd,J=10.8,2.0Hz,1H),5.56(s,2H),3.75(s,3H).

[0141] Synthesis of 6-chloro-4-cyclopropyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Intermediate 24)

[0142] The synthesis of Intermediate 24 is similar to that of Intermediate 20, just replace methylboronic acid with cyclopropylboronic acid, and the yield is 70%. 1 HNMR(400MHz,DMSO-d6)δ7.92(d,J=1.4Hz,1H),7.72-7.67(m,2H),7.64(d,J=3.3Hz,1H),7.46(d,J=0.9Hz,1H),7.35-7.30(m,2H),6.90(dd,J=3.3,0.9Hz,1H),5.52(s,2H),3.75(s,3H),2.50-2.46(m,1H),1.08-1.01(m,4H).

[0143] Synthesis of 6-chloro-4-isopropenyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Intermediate 25)

[0144] The synthesis of Intermediate 25 is similar to that of Intermediate 20, just replace methylboronic acid with isopropenylboronic acid, and the yield is 79%. 1HNMR(400MHz, DMSO-d6) δ 7.92 (d, J = 1.4 Hz, 1H), 7.75 - 7.67 (m, 4H), 7.36 (d, J = 8.0 Hz, 2H), 6.83 (dd, J = 3.4, 0.9 Hz, 1H), 5.80 - 5.70 (m, 1H), 5.57 (d, J = 4.4 Hz, 3H), 3.75 (s, 3H), 2.22 (d, J = 1.1 Hz, 3H).

[0145] 25. Synthesis of 6-chloro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-cyano-1H-pyrrolo[3,2-c]pyridine (Intermediate 26)

[0146]

[0147] The synthesis of Intermediate 26 is the same as that of Intermediate 19, just replace 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine with 6-chloro-3-cyano-1H-pyrrolo[3,2-C]pyridine. 1 H NMR(400MHz, Chloroform-d) δ 9.00 (d, J = 0.7 Hz, 1H), 7.93 (s, 1H), 7.88 - 7.80 (m, 2H), 7.54 (d, J = 14.8 Hz, 2H), 7.22 (dt, J = 8.5, 1.0 Hz, 2H), 5.40 (t, J = 1.0 Hz, 2H), 3.84 (s, 3H).

[0148] 26. Synthesis of Intermediate 27, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-cyclopropyl-1H-pyrrolo[3,2-c]pyridine

[0149]

[0150] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-bromo-1-tosyl-1H-pyrrolo[3,2-c]pyridine

[0151] Dissolve 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine (1.0 g, 2.38 mmol) in dichloromethane (20 mL), and then slowly add bromine (0.42 g, 2.6 mmol). After the reaction is completed, slowly add a saturated solution of sodium thiosulfate. After the organic phase is evaporated to dryness, it is mixed with silica gel of 60 - 100 mesh and then purified by column chromatography to obtain the target compound. 11H NMR (400 MHz, Chloroform-d) δ 8.98 (d, J = 1.0 Hz, 1H), 8.65 (s, 1H), 8.02 (d, J = 0.9 Hz, 1H), 7.86 (s, 1H), 7.64 (d, J = 3.7 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 6.78 (dd, J = 3.7, 0.8 Hz, 1H), 3.92 (s, 3H), 2.39 (s, 3H), 1.75 - 1.71 (m, 1H), 1.24 - 1.19 (m, 2H), 0.87 (ddd, J = 8.0, 4.0, 2.5 Hz, 2H).

[0152] 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-3-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-c]pyridine

[0153] The synthesis method is similar to that of Intermediate 20. The target compound can be obtained by replacing methylboronic acid with cyclopropylboronic acid. 1 1H NMR (400 MHz, Chloroform-d) δ 9.25 (d, J = 0.7 Hz, 1H), 8.47 (s, 1H), 8.29 (d, J = 0.6 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.32 (dq, J = 8.5, 0.8 Hz, 2H), 7.16 (d, J = 0.6 Hz, 1H), 3.96 (s, 2H), 2.85 (p, J = 5.8 Hz, 1H), 2.47 (q, J = 5.8 Hz, 1H), 2.38 (t, J = 0.7 Hz, 3H), 1.51 (d, J = 5.8 Hz, 4H), 1.04 - 0.85 (m, 4H).

[0154] 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-3-cyclopropyl-1H-pyrrolo[3,2-c]pyridine

[0155] Dissolve 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-c]pyridine (0.3 g, 0.65 mmol) in dichloromethane / methanol (v:v = 20:5, 25 mL), then add sodium hydroxide (65 mg, 1.6 mmol), and react at room temperature for 2 h. After the reaction is completed, add 25 mL of water. After liquid separation and drying, the organic phase is evaporated to dryness without purification to obtain the target compound.

[0156] 27. Synthesis of Intermediate 28, 6-chloro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-1H-pyrrolo[3,2-c]pyridine

[0157]

[0158] 6-Chloro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-iodo-1H-pyrrolo[3,2-c]pyridine

[0159] The synthesis of the target compound was the same as that of Compound 5, except that 6-chloro-1H-pyrrolo[3,2-c]pyridine was used instead of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine, and the yield was 85%. 1 HNMR(400MHz,Chloroform-d)δ8.62(d,J=0.9Hz,1H),7.62-7.57(m,2H),7.30(q,J=1.2Hz,1H),7.17(d,J=1.0Hz,1H),7.11(d,J=8.1Hz,2H),6.98(d,J=0.9Hz,1H),5.41(s,2H),3.75(s,3H).

[0160] 6-Chloro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-1H-pyrrolo[3,2-c]pyridine

[0161] The synthesis of Intermediate 28 was the same as that of Intermediate 20, and the yield was 65%. 1 H NMR(400MHz,Chloroform-d)δ8.62(d,J=0.9Hz,1H),7.62-7.57(m,2H),7.30(q,J=1.2Hz,1H),7.17(d,J=1.0Hz,1H),7.11(d,J=8.1Hz,2H),6.98(d,J=0.9Hz,1H),5.41(s,2H),3.75(s,3H),3.67(s,3H).

[0162] 28. 6-Chloro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-cyclopropyl-1H-pyrrolo[3,2-c]pyridine (Intermediate 29)

[0163] The synthesis of Intermediate 29 was the same as that of Intermediate 20, except that cyclopropylboronic acid was used instead of methylboronic acid, and the yield was 65%. 1HNMR(400MHz, Chloroform-d) δ 9.08 - 9.03 (m, 1H), 8.46 (s, 1H), 7.85 - 7.77 (m, 3H), 7.72 (s, 1H), 7.32 (dt, J = 8.4, 0.9 Hz, 2H), 6.24 (dd, J = 1.4, 0.6 Hz, 1H), 5.62 (t, J = 1.0 Hz, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 2.83 (p, J = 5.8 Hz, 1H), 2.32 (p, J = 5.8 Hz, 1H), 1.37 (td, J = 10.1, 5.9 Hz, 2H), 1.00 - 0.83 (m, 4H), 0.79 (td, J = 10.1, 5.8 Hz, 2H).

[0164] 29. 6-Chloro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-isopropenyl-1H-pyrrolo[3,2-c]pyridine (Intermediate 30)

[0165] The synthesis of Intermediate 30 is the same as that of Intermediate 20, except that isopropenylboronic acid is used instead of methylboronic acid, and the yield is 75%. 1 HNMR(400MHz, Chloroform-d) δ 9.06 (d, J = 1.4 Hz, 1H), 8.47 (s, 1H), 7.85 - 7.77 (m, 3H), 7.71 (s, 1H), 7.34 (dt, J = 8.3, 1.1 Hz, 2H), 7.01 - 6.96 (m, 1H), 5.75 (t, J = 1.0 Hz, 2H), 5.12 (dq, J = 2.1, 1.0 Hz, 1H), 5.02 (dq, J = 2.1, 1.0 Hz, 1H), 3.97 (s, 3H), 3.84 (s, 3H), 2.83 (p, J = 5.8 Hz, 1H), 2.06 (t, J = 0.9 Hz, 3H), 0.99 - 0.76 (m, 5H).

[0166] II. Synthesis of Compounds

[0167] Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 1)

[0168]

[0169] In a dry 25 mL three-necked round-bottom flask, XphosPdG2 (36 mg, 0.046 mmol), Xantphos (26 mg, 0.046 mmol), 6-bromo-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (200 mg, 0.46 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (110 mg, 0.60 mmol), and potassium carbonate (158 mg, 1.1 mmol) were added successively. After evacuating and replacing with nitrogen three times using a vacuum pump, a mixed solution of dioxane and water (7:3) (10 mL) was added under N2 protection. The reaction mixture was stirred at 80 °C for 3 h. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated and then separated and purified by silica gel column chromatography (PE / EtOAc = 1:1) to obtain 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine with a yield of 80%. 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.63 (s, 1H), 7.95 - 7.89 (m, 1H), 7.75 - 7.64 (m, 4H), 7.41 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 3.2 Hz, 1H), 5.57 (s, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 1.76 (tt, J = 8.2, 4.7 Hz, 1H), 1.01 (dq, J = 5.9, 3.5 Hz, 2H), 0.80 (dq, J = 6.9, 3.4 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 169.45, 166.61, 156.74, 148.20, 144.12, 143.84, 140.36, 137.91, 132.19, 131.80, 131.42, 131.03, 129.81, 129.77, 129.44, 129.11, 127.27, 124.78, 122.99, 122.07, 122.03, 121.99, 121.96, 120.35, 120.34, 107.03, 101.98, 54.07, 49.70, 34.81, 13.88, 10.94.

[0170] Synthesis of 6-(2-cyclopropylpyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 2)

[0171]

[0172] The synthesis of Compound 2 is the same as that of Compound 1. Just replace (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid with 2-cyclopropyl-4-pyrimidineboronic acid pinacol ester, and the yield is 88%. 1 H NMR(400MHz,DMSO-d6)δ9.32(s,2H),8.97(d,J=0.9Hz,1H),8.37(s,1H),7.90(d,J=1.4Hz,1H),7.73-7.67(m,3H),7.44(d,J=8.2Hz,2H),6.74(d,J=3.1Hz,1H),5.63(s,2H),3.73(s,3H),2.26(tt,J=7.6,5.2Hz,1H),1.07(dd,J=7.1,4.7Hz,4H).

[0173] Synthesis of 3,5-dimethyl-4-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)isoxazole (Compound 3)

[0174]

[0175] The synthesis of Compound 3 is the same as that of Compound 1, except that specific reaction raw materials are selected according to the different substituents of the product, and the yield is 88%. 1 H NMR(400MHz,DMSO-d6)δ8.92(d,J=1.0Hz,1H),7.92(d,J=1.4Hz,1H),7.74-7.67(m,3H),7.65(s,1H),7.47-7.40(m,2H),6.71(d,J=3.1Hz,1H),5.60(s,2H),3.74(s,3H),2.34(s,3H).

[0176] Synthesis of 6-(6-fluoro-4-methylpyridin-3-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 4)

[0177]

[0178] The synthesis of Compound 4 is the same as that of Compound 1, except that specific reaction raw materials are selected according to the different substituents of the product, and the yield is 88%. 11H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 1.0 Hz, 1H), 8.24 (s, 1H), 7.91 (d, J = 1.4 Hz, 1H), 7.84 (d, J = 1.1 Hz, 1H), 7.73 (d, J = 3.3 Hz, 1H), 7.72 - 7.66 (m, 2H), 7.45 - 7.40 (m, 2H), 7.15 (d, J = 1.6 Hz, 1H), 6.74 (dd, J = 3.2, 0.8 Hz, 1H), 5.61 (s, 2H), 3.74 (s, 3H), 2.40 (s, 3H).

[0179] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 5)

[0180]

[0181] Dissolve intermediate 11 (150 mg, 0.563 mmol) in N,N-dimethylformamide (DMF) (10 mL). Add NaH (30 mg, 0.73 mmol) under ice bath and stir for 5 minutes. Add intermediate 4 (180 mg, 0.62 mmol) and continue the reaction at room temperature for 1 h. After monitoring the reaction by TLC until completion, add 50 mL of water and extract with ethyl acetate (20 ml × 3). After concentrating the organic phase, mix with silica gel and separate and purify by silica gel column chromatography (PE / EtOAc = 1:1) to obtain Compound 5 with a yield of 87%. 1 1H NMR (400 MHz, Chloroform-d) δ 9.07 (d, J = 1.0 Hz, 1H), 8.61 (s, 1H), 7.59 - 7.52 (m, 2H), 7.35 (dt, J = 7.0, 1.1 Hz, 2H), 7.28 - 7.21 (m, 3H), 6.73 (dd, J = 3.2, 0.9 Hz, 1H), 5.40 (s, 2H), 4.03 (q, J = 7.3 Hz, 2H), 3.87 (s, 3H), 1.78 (tt, J = 8.0, 4.7 Hz, 1H), 1.42 (t, J = 7.3 Hz, 3H), 1.15 (dt, J = 6.4, 3.3 Hz, 2H), 0.85 - 0.78 (m, 2H).

[0182] Synthesis of 1-(4-(1-Ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-isopropylphenyl)-1H-pyrrolo[3,2-c]pyridine (Compound 6)

[0183]

[0184] The synthesis of Compound 6 is the same as that of Compound 1, except that specific reaction raw materials are selected according to the different substituents of the product, and the yield is 82%. 1 H NMR (400 MHz, Chloroform-d) δ 9.00 (d, J = 1.0 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.41 - 7.32 (m, 3H), 7.30 (dd, J = 7.6, 1.5 Hz, 1H), 7.24 - 7.18 (m, 5H), 6.71 (d, J = 3.3 Hz, 1H), 5.38 (s, 2H), 4.01 (q, J = 7.3 Hz, 2H), 3.15 (h, J = 6.9 Hz, 1H), 1.39 (t, J = 7.3 Hz, 3H), 1.12 (d, J = 6.8 Hz, 6H).

[0185] Synthesis of 6-(2-Methoxy-4-methylpyridin-3-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 7)

[0186]

[0187] The synthesis of Compound 7 is the same as that of Compound 1, except that specific reaction raw materials are selected according to the different substituents of the product, and the yield is 72%. 1 H NMR (400 MHz, Chloroform-d) δ 8.96 (d, J = 1.0 Hz, 1H), 7.97 (d, J = 5.2 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.22 (d, J = 1.3 Hz, 1H), 7.19 - 7.11 (m, 4H), 6.75 (d, J = 5.2 Hz, 1H), 6.64 (dd, J = 3.2, 0.9 Hz, 1H), 5.31 (s, 2H), 3.75 (s, 3H), 3.65 (s, 3H), 2.01 (s, 3H).

[0188] Synthesis of 6-(2-Methoxy-6-(trifluoromethyl)phenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 8)

[0189]

[0190] The synthesis of Compound 8 is the same as that of Compound 1, except that specific reaction raw materials are selected according to the different substituents of the product, and the yield is 80%. 11H NMR (400 MHz, Chloroform-d) δ 8.97 - 8.91 (m, 1H), 7.52 - 7.47 (m, 2H), 7.38 (t, J = 8.2 Hz, 1H), 7.27 - 7.20 (m, 2H), 7.15 - 7.10 (m, 4H), 7.08 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 3.2 Hz, 1H), 5.30 (s, 2H), 3.64 (d, J = 6.9 Hz, 6H).

[0191] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 9)

[0192]

[0193] The synthesis of Compound 9 is the same as that of Compound 5, with the difference being the selection of specific reaction raw materials according to the different substituents of the product, and the yield is 86%. 1 1H NMR (400 MHz, Chloroform-d) δ 9.00 (d, J = 1.0 Hz, 1H), 8.54 (s, 1H), 7.53 (dd, J = 8.4, 1.9 Hz, 2H), 7.25 (dt, J = 13.8, 1.2 Hz, 2H), 7.19 - 7.14 (m, 3H), 6.66 (dd, J = 3.3, 0.9 Hz, 1H), 5.33 (s, 2H), 3.80 (s, 3H), 1.73 - 1.69 (m, 1H), 1.09 (dt, J = 6.5, 3.8 Hz, 2H), 0.77 - 0.71 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 169.42, 166.59, 156.71, 148.18, 144.09, 143.81, 140.33, 137.89, 132.16, 131.77, 131.38, 131.00, 129.81, 129.39, 129.09, 127.25, 124.77, 122.99, 121.99, 121.95, 120.35, 107.02, 101.95, 54.05, 49.69, 13.87, 10.93.

[0194] Synthesis of 1-(4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (Compound 10)

[0195]

[0196] The synthesis of Compound 10 is the same as that of Compound 1, except that specific reaction raw materials are selected according to the different substituents of the product, and the yield is 86%. 1 H NMR(400MHz,Chloroform-d)δ8.96(d,J=1.0Hz,1H),8.20(dd,J=8.0,1.3Hz,1H),7.66(td,J=7.5,1.4Hz,1H),7.62-7.55(m,3H),7.51-7.45(m,2H),7.29(q,J=1.2Hz,1H),7.26-7.21(m,3H),6.72(dd,J=3.2,0.9Hz,1H),5.40(s,2H),3.72(s,3H),3.22(s,3H). 13 C NMR(101MHz,CDCl3)δ148.90,148.32,142.65,142.21,140.25,139.29,137.79,133.24,132.48,130.16,129.55,129.49,129.11,128.33,127.26,124.97,121.91,106.27,101.99,65.86,49.80,45.55,34.88.

[0197] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-propyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 11)

[0198]

[0199] The synthesis of Compound 11 is the same as that of Compound 5, except that specific reaction raw materials are selected according to the different substituents of the product, and the yield is 86%. 1 H NMR(400MHz,Chloroform-d)δ9.07(d,J=1.0Hz,1H),8.61(s,1H),7.57-7.52(m,2H),7.34(dt,J=4.4,1.1Hz,2H),7.26-7.20(m,3H),6.73(dd,J=3.3,0.9Hz,1H),5.40(s,2H),3.96-3.91(m,2H),3.87(s,3H),1.80-1.71(m,5H),1.18-1.14(m,2H),0.87(t,J=7.4Hz,3H),0.83-0.78(m,2H). 1313C NMR (101 MHz, CDCl3) δ 169.43, 166.59, 156.75, 148.06, 144.21, 143.87, 140.37, 137.83, 129.68, 129.65, 129.55, 127.25, 124.72, 120.32, 120.08, 106.93, 102.00, 54.07, 49.69, 48.84, 24.20, 13.87, 10.96, 10.92, 1.01.

[0200] Synthesis of 6-(2-Isopropylphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 12)

[0201]

[0202] The synthesis of Compound 12 is the same as that of Compound 1, except that specific reaction raw materials are selected according to the different substituents of the product, and the yield is 86%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.74 - 7.63 (m, 3H), 7.58 (s, 1H), 7.44 - 7.30 (m, 4H), 7.23 (dtd, J = 14.5, 7.6, 1.6 Hz, 2H), 6.70 (d, J = 3.2 Hz, 1H), 5.58 (s, 2H), 3.73 (s, 3H), 3.15 (h, J = 6.9 Hz, 1H), 1.06 (d, J = 6.9 Hz, 6H).

[0203] Synthesis of 1-(4-(1-(sec-Butyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine (Compound 13)

[0204]

[0205] The synthesis of Compound 13 is the same as that of Compound 5, except that specific reaction raw materials are selected according to the different substituents of the product, and the yield is 85%. 11H NMR (400 MHz, Chloroform-d) δ 9.07 (d, J = 1.0 Hz, 1H), 8.61 (s, 1H), 7.52 - 7.47 (m, 2H), 7.37 (p, J = 1.2 Hz, 2H), 7.27 - 7.22 (m, 3H), 6.73 (dd, J = 3.2, 0.9 Hz, 1H), 5.40 (s, 2H), 4.21 (h, J = 7.0 Hz, 1H), 3.88 (s, 3H), 1.79 (ddd, J = 7.9, 4.5, 3.3 Hz, 1H), 1.73 (t, J = 7.4 Hz, 2H), 1.44 (d, J = 6.7 Hz, 3H), 1.18 - 1.14 (m, 2H), 0.84 - 0.79 (m, 2H), 0.72 (t, J = 7.4 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 169.45, 166.61, 156.77, 148.29, 144.19, 143.87, 140.38, 137.88, 132.90, 132.52, 132.14, 131.75, 129.99, 129.74, 127.28, 125.72, 124.75, 123.07, 120.41, 120.35, 116.24, 116.20, 106.97, 102.01, 54.52, 54.08, 49.70, 30.97, 22.07, 13.90, 10.94, 10.58.

[0206] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 14)

[0207]

[0208] The synthesis of Compound 14 was the same as that of Compound 5, except that specific reaction raw materials were selected according to the different substituents of the product, and the yield was 80%. 11H NMR (400 MHz, Chloroform-d) δ 9.08 (s, 1H), 8.61 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.43 - 7.40 (m, 1H), 7.36 (s, 1H), 7.28 - 7.22 (m, 3H), 6.73 (d, J = 3.2 Hz, 1H), 5.41 (s, 2H), 4.50 (hept, J = 6.7 Hz, 1H), 3.88 (s, 3H), 1.78 (tt, J = 8.3, 4.6 Hz, 1H), 1.44 (d, J = 6.7 Hz, 6H), 1.16 (dq, J = 6.4, 3.9 Hz, 2H), 0.81 (dq, J = 7.0, 3.8 Hz, 2H). 13 13C NMR (101 MHz, CDCl3) δ 169.44, 166.61, 156.78, 147.50, 144.18, 143.88, 140.37, 137.93, 132.44, 132.06, 129.84, 129.75, 129.68, 127.31, 124.76, 123.05, 120.32, 116.31, 116.27, 107.00, 102.02, 54.09, 49.74, 48.70, 23.95, 13.90, 10.94.

[0210] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-(cyclopropylmethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 15)

[0211]

[0212] The synthesis of Compound 15 was consistent with that of Compound 5, except that specific reaction raw materials were selected according to the different substituents of the product, and the yield was 88%. 11H NMR (400 MHz, Chloroform-d) δ 9.07 (d, J = 1.0 Hz, 1H), 8.61 (s, 1H), 7.59 - 7.51 (m, 3H), 7.35 (d, J = 1.0 Hz, 1H), 7.27 - 7.22 (m, 3H), 6.73 (dd, J = 3.3, 0.9 Hz, 1H), 5.40 (s, 2H), 3.87 (s, 3H), 3.82 (d, J = 7.0 Hz, 2H), 1.78 (tt, J = 8.4, 4.7 Hz, 1H), 1.16 (dd, J = 4.6, 2.7 Hz, 2H), 1.14 - 1.08 (m, 1H), 0.81 (dq, J = 6.9, 3.8 Hz, 2H), 0.72 - 0.65 (m, 2H), 0.29 (q, J = 5.3 Hz, 2H). 13 13C NMR (101 MHz, CDCl3) δ 169.45, 166.61, 156.77, 147.87, 144.16, 143.86, 140.38, 137.86, 132.32, 131.93, 131.55, 131.16, 129.75, 129.50, 127.25, 124.76, 123.07, 120.42, 120.31, 119.88, 119.84, 106.99, 102.02, 54.09, 52.03, 49.72, 13.89, 11.42, 10.96, 4.26.

[0213] Synthesis of 1-(4-(1-Allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine (Compound 16)

[0214]

[0215] The synthesis of Compound 16 is the same as that of Compound 5, with the difference that specific reaction raw materials are selected according to the different substituents of the product, and Intermediate 8 is used instead of Intermediate 2, and the yield is 82%. 11H NMR (400 MHz, Chloroform-d) δ 9.06 (d, J = 1.2 Hz, 1H), 8.60 (s, 1H), 7.62 - 7.53 (m, 2H), 7.35 - 7.32 (m, 2H), 7.26 - 7.21 (m, 3H), 6.72 (d, J = 3.2 Hz, 1H), 5.95 (ddt, J = 16.9, 10.3, 5.1 Hz, 1H), 5.40 (s, 2H), 5.34 (dd, J = 10.4, 1.7 Hz, 1H), 5.13 (dt, J = 17.1, 1.8 Hz, 1H), 4.59 (dd, J = 5.1, 1.8 Hz, 2H), 3.87 (s, 3H), 1.78 (tt, J = 8.3, 4.7 Hz, 1H), 1.15 (dt, J = 6.2, 3.3 Hz, 2H), 0.84 - 0.77 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 169.43, 166.59, 156.74, 148.16, 144.14, 143.85, 140.34, 138.04, 132.18, 129.77, 129.47, 129.15, 129.02, 127.27, 124.76, 120.75, 120.71, 120.67, 120.63, 120.33, 118.98, 107.00, 101.98, 54.07, 49.72, 49.53, 13.88, 10.95.

[0216] Synthesis of 1-(4-(1-(3-butenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine (Compound 17)

[0217]

[0218] The synthesis of Compound 17 was the same as that of Compound 5, except that specific reaction raw materials were selected according to the different substituents of the product, and the yield was 82%. 11H NMR (400 MHz, Chloroform-d) δ 9.07 (d, J = 1.1 Hz, 1H), 8.61 (s, 1H), 7.57 - 7.52 (m, 2H), 7.35 (d, J = 1.2 Hz, 2H), 7.27 - 7.21 (m, 3H), 6.73 (dd, J = 3.2, 0.9 Hz, 1H), 5.63 (ddt, J = 17.1, 10.3, 6.8 Hz, 1H), 5.40 (s, 2H), 5.10 - 5.00 (m, 2H), 4.05 (t, J = 7.3 Hz, 2H), 3.87 (s, 3H), 2.51 - 2.43 (m, 2H), 1.79 (ddd, J = 8.1, 6.4, 4.0 Hz, 1H), 1.16 (dt, J = 6.4, 3.3 Hz, 2H), 0.85 - 0.77 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 169.45, 166.60, 156.75, 148.10, 144.20, 143.87, 140.38, 137.95, 132.81, 132.61, 132.01, 131.62, 131.23, 129.73, 129.70, 129.58, 129.45, 129.17, 127.30, 127.23, 126.87, 124.75, 122.98, 120.34, 120.22, 120.18, 120.14, 120.10, 118.83, 106.96, 102.02, 54.08, 49.69, 46.60, 34.90, 13.89, 10.96.

[0220] Synthesis of 1-(4-(1-butyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine (Compound 18)

[0221]

[0222] The synthesis of Compound 18 was the same as that of Compound 5, except that specific reaction raw materials were selected according to the different substituents of the product, and the yield was 85%. 11H NMR (400 MHz, Chloroform-d) δ 9.07 (d, J = 1.0 Hz, 1H), 8.61 (s, 1H), 7.57 - 7.53 (m, 2H), 7.35 (dt, J = 4.0, 1.1 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 3.3 Hz, 1H), 6.73 (dd, J = 3.3, 0.9 Hz, 1H), 5.40 (s, 2H), 3.97 (t, J = 7.5 Hz, 2H), 3.88 (s, 3H), 1.79 (ddd, J = 8.5, 6.6, 4.2 Hz, 1H), 1.75 - 1.68 (m, 2H), 1.26 (dt, J = 14.4, 7.2 Hz, 2H), 1.18 - 1.14 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H), 0.84 - 0.79 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 169.45, 166.61, 156.76, 148.06, 144.21, 143.88, 140.39, 137.85, 132.44, 132.05, 131.66, 131.28, 129.71, 129.66, 129.55, 127.27, 124.74, 123.02, 120.35, 120.13, 120.10, 120.06, 120.02, 106.96, 102.01, 54.09, 49.70, 47.04, 32.94, 19.67, 13.89, 13.46, 10.95.

[0224] Synthesis of 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-(trifluoromethyl)phenyl)-1H-pyrrolo[3,2-c]pyridine (Compound 19)

[0225]

[0226] The synthesis of Compound 19 is the same as that of Compound 1, except that specific reaction raw materials are selected according to the different substituents of the product, and the yield is 80%. 1 1H NMR (400 MHz, Chloroform-d) δ 9.00 (s, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.58 (dd, J = 8.1, 2.1 Hz, 4H), 7.50 - 7.45 (m, 1H), 7.30 (d, J = 5.6 Hz, 2H), 7.25 (s, 1H), 7.20 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 3.2 Hz, 1H), 5.38 (s, 2H), 3.71 (s, 3H). 1313C NMR (101 MHz, CDCl3) δ 149.01, 148.36, 143.20, 141.14, 139.96, 137.87, 132.27, 131.84, 131.42, 129.99, 129.52, 129.03, 128.38, 128.09, 127.74, 127.07, 126.21, 126.16, 126.11, 126.06, 125.63, 124.76, 122.99, 121.93, 121.90, 121.86, 121.82, 120.33, 105.37, 105.34, 101.80, 49.89, 34.74.

[0227] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(3-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 20)

[0228]

[0229] The synthesis of Compound 20 is the same as that of Compound 5, except that Intermediate 12 is used instead of Intermediate 2, and the yield is 89%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 1.1 Hz, 1H), 8.62 (s, 1H), 7.93 (t, J = 1.3 Hz, 1H), 7.76 (d, J = 3.1 Hz, 2H), 7.67 (d, J = 1.7 Hz, 1H), 7.63 (dt, J = 7.4, 1.5 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.43 (dt, J = 7.7, 1.5 Hz, 1H), 6.71 (dd, J = 3.2, 0.8 Hz, 1H), 5.56 (s, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 1.72 (tt, J = 8.3, 4.7 Hz, 1H), 0.98 (dq, J = 5.9, 3.5 Hz, 2H), 0.77 (dt, J = 8.2, 3.3 Hz, 2H). 13 13C NMR (101 MHz, DMSO) δ 168.97, 166.53, 156.94, 148.17, 143.43, 143.37, 140.02, 138.72, 131.42, 129.96, 129.46, 128.92, 128.19, 124.83, 124.39, 120.66, 108.08, 101.35, 65.39, 54.08, 35.19, 15.64, 10.93.

[0230] Synthesis of 1-(3-Fluoro-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine (Compound 21)

[0231]

[0232] The synthesis of Compound 21 was the same as that of Compound 5, except that Intermediate 13 was used instead of Intermediate 2, with a yield of 88%. 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 1.0 Hz, 1H), 8.63 (s, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.73 (s, 1H), 7.66 (d, J = 3.3 Hz, 1H), 7.62 (dd, J = 11.0, 1.7 Hz, 1H), 7.54 (dd, J = 8.0, 1.7 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 6.73 (dd, J = 3.2, 0.8 Hz, 1H), 5.62 (s, 2H), 3.79 (d, J = 7.1 Hz, 6H), 1.78 (tt, J = 8.3, 4.7 Hz, 1H), 1.02 (dq, J = 5.8, 3.5 Hz, 2H), 0.82 (dt, J = 8.2, 3.3 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 168.99, 166.55, 161.48, 159.03, 156.96, 146.87, 146.85, 143.51, 143.46, 140.15, 131.45, 131.40, 131.36, 130.63, 130.58, 129.73, 129.35, 126.03, 125.88, 125.25, 125.22, 124.80, 124.76, 124.71, 123.84, 121.19, 120.63, 116.12, 115.89, 107.97, 101.54, 54.20, 43.52, 43.49, 35.34, 14.10, 11.00.

[0233] Synthesis of 1-(2-Fluoro-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine (Compound 22)

[0234]

[0235] The synthesis of Compound 22 was the same as that of Compound 5, except that Intermediate 14 was used instead of Intermediate 2, with a yield of 83%. 11H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.64 (s, 1H), 8.00 (d, J = 1.4 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.38 (dd, J = 11.0, 1.5 Hz, 1H), 7.25 (dd, J = 8.0, 1.5 Hz, 1H), 6.74 (d, J = 3.2 Hz, 1H), 5.59 (s, 2H), 3.80 (s, 3H), 3.57 (d, J = 1.5 Hz, 3H), 1.77 (tt, J = 8.3, 4.7 Hz, 1H), 1.02 (dq, J = 5.9, 3.5 Hz, 2H), 0.82 (dt, J = 8.2, 3.3 Hz, 2H). 13 13C NMR (101 MHz, DMSO) δ 168.99, 166.55, 161.10, 158.63, 156.96, 143.59, 143.52, 143.49, 143.05, 142.97, 140.10, 132.97, 132.95, 131.43, 130.24, 129.86, 124.83, 124.27, 124.24, 124.01, 123.97, 120.64, 116.91, 116.76, 115.62, 115.40, 108.08, 101.57, 54.18, 48.63, 34.32, 34.28, 14.09, 10.97.

[0237] Synthesis of 1 - ((5 - (1 - methyl - 4 - (trifluoromethyl)-1H - imidazol - 2 - yl)benzyl)-6-(4 - cyclopropyl - 6 - methoxypyrimidin - 5 - yl)-1H - pyrrolo[3,2 - c]pyridine (Compound 23)

[0238]

[0239] The synthesis of Compound 23 is the same as that of Compound 5, using Intermediate 15 instead of Intermediate 2, with a yield of 80%. 11H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 1.0 Hz, 1H), 8.89 - 8.84 (m, 1H), 8.62 (s, 1H), 8.14 (dd, J = 8.2, 2.3 Hz, 1H), 8.00 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 3.3 Hz, 1H), 7.66 (d, J = 1.0 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 6.73 (dd, J = 3.3, 0.9 Hz, 1H), 5.67 (s, 2H), 3.78 (d, J = 0.9 Hz, 6H), 1.75 (tt, J = 8.3, 4.7 Hz, 1H), 1.00 (dq, J = 5.8, 3.4 Hz, 2H), 0.83 - 0.77 (m, 2H).

[0240] Synthesis of 1 - ((6 - (1 - methyl - 4 - (trifluoromethyl)-1H - imidazol - 2 - yl)benzyl)-6-(4 - cyclopropyl - 6 - methoxypyrimidin - 5 - yl)-1H - pyrrolo[3,2 - c]pyridine (Compound 24)

[0241]

[0242] The synthesis of Compound 24 was the same as that of Compound 5, except that Intermediate 18 was used instead of Intermediate 2, and the yield was 75%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 1.0 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.63 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 1.3 Hz, 1H), 7.84 (dd, J = 8.3, 2.3 Hz, 1H), 7.81 (d, J = 1.0 Hz, 1H), 7.78 (d, J = 3.2 Hz, 1H), 6.73 (dd, J = 3.2, 0.8 Hz, 1H), 5.60 (s, 2H), 4.05 (s, 3H), 3.80 (s, 3H), 1.76 (tt, J = 8.4, 4.7 Hz, 1H), 1.01 (dq, J = 5.8, 3.4 Hz, 2H), 0.86 - 0.76 (m, 2H). 13C NMR (101 MHz, DMSO) δ 168.98, 166.55, 156.96, 148.94, 148.33, 145.44, 143.51, 143.48, 139.97, 136.98, 133.56, 131.28, 129.51, 129.13, 125.98, 125.94, 124.87, 123.11, 120.63, 108.08, 101.63, 54.20, 46.73, 36.99, 14.10, 10.98.

[0243] Synthesis of 1-(4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-methylphenyl)-1H-pyrrolo[3,2-c]pyridine (Compound 25)

[0244]

[0245] The synthesis of Compound 25 was the same as that of Compound 1, except that 2-methylphenylboronic acid was used instead of (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid, and the yield was 88%. 1 H NMR (400 MHz, Chloroform-d) δ 9.02 (d, J = 1.0 Hz, 1H), 7.61 - 7.57 (m, 2H), 7.39 (dt, J = 5.7, 1.8 Hz, 1H), 7.29 (q, J = 1.2 Hz, 1H), 7.26 (d, J = 1.4 Hz, 4H), 7.21 (dd, J = 5.8, 2.5 Hz, 3H), 6.72 (dd, J = 3.3, 0.9 Hz, 1H), 5.39 (s, 2H), 3.72 (s, 3H), 2.31 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 151.65, 148.27, 143.09, 141.39, 140.52, 138.02, 135.95, 131.91, 131.52, 130.61, 129.99, 129.60, 129.51, 129.06, 127.74, 127.07, 125.74, 124.16, 122.97, 121.97, 121.93, 121.89, 105.08, 101.80, 49.75, 34.85, 20.42.

[0246] Synthesis of 1-(4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-difluoromethoxyphenyl)-1H-pyrrolo[3,2-c]pyridine (Compound 26)

[0247]

[0248] The synthesis of Compound 26 was the same as that of Compound 1, except that 2-(difluoromethoxy)phenylboronic acid was used instead of (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid, and the yield was 68%. 1 H NMR(400MHz,Chloroform-d)δ9.03(d,J=1.1Hz,1H),7.93-7.84(m,1H),7.68(d,J=1.1Hz,1H),7.60-

[0249] 7.55(m,2H),7.37-7.32(m,2H),7.27(d,J=1.3Hz,1H),7.26-7.22(m,3H),7.21-7.17(m,1H),6.70(dd,J=3.3,1.0Hz,1H),5.39(s,2H),3.70(s,3H). 13 CNMR(101MHz,CDCl3)δ148.63,148.60,148.35,145.86,143.65,140.27,138.00,133.70,133.37,132.09,131.80,131.42,130.05,129.50,129.15,129.03,128.12,127.15,126.15,124.77,123.00,121.96,121.92,121.88,121.84,120.46,120.35,119.47,116.90,114.34,106.20,101.75,49.75,34.77.

[0250] Synthesis of 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2,5-dimethoxyphenyl)-1H-pyrrolo[3,2-c]pyridine (Compound 27)

[0251]

[0252] The synthesis of Compound 27 was the same as that of Compound 1, except that 2,5-dimethoxyphenylboronic acid was used instead of (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid, and the yield was 78%. 11H NMR (400 MHz, Chloroform-d) δ 9.02 (d, J = 1.1 Hz, 1H), 7.80 (t, J = 1.0 Hz, 1H), 7.58 - 7.54 (m, 2H), 7.45 (d, J = 3.1 Hz, 1H), 7.28 - 7.20 (m, 3H), 7.17 (d, J = 3.2 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 6.86 (dd, J = 8.9, 3.1 Hz, 1H), 6.66 (dd, J = 3.2, 0.9 Hz, 1H), 5.37 (s, 2H), 3.82 (s, 3H), 3.71 (s, 3H), 3.68 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 154.01, 151.08, 148.29, 147.13, 143.31, 140.39, 138.27, 132.15, 131.77, 131.38, 131.02, 131.00, 129.62, 129.39, 128.94, 127.24, 124.49, 123.01, 122.01, 121.97, 121.93, 121.89, 120.36, 116.27, 114.67, 113.46, 106.11, 101.69, 56.63, 55.86, 49.61, 34.82.

[0253] Synthesis of 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-cyclopropylphenyl)-1H-pyrrolo[3,2-c]pyridine (Compound 28)

[0254]

[0255] The synthesis of Compound 28 is the same as that of Compound 1, except that 2-cyclopropylphenylboronic acid is used instead of (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid, and the yield is 82%. 11H NMR (400 MHz, Chloroform-d) δ 9.03 (d, J = 1.1 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.45 - 7.41 (m, 2H), 7.29 (q, J = 1.2 Hz, 1H), 7.27 (d, J = 1.7 Hz, 1H), 7.24 - 7.19 (m, 4H), 6.95 (dd, J = 7.6, 1.4 Hz, 1H), 6.72 (dd, J = 3.3, 0.9 Hz, 1H), 5.39 (s, 2H), 3.72 (s, 3H), 3.46 (s, 3H), 2.01 (ddd, J = 8.4, 6.0, 3.0 Hz, 1H), 0.71 - 0.65 (m, 2H), 0.65 - 0.60 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 151.42, 148.25, 143.25, 142.10, 141.02, 140.37, 138.15, 132.13, 131.89, 131.50, 131.21, 130.01, 129.57, 129.47, 129.02, 127.89, 127.01, 125.30, 124.24, 124.17, 122.96, 121.94, 121.91, 105.67, 101.74, 49.72, 34.83, 13.48, 9.42.

[0256] Synthesis of 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine (Compound 29)

[0257]

[0258] The synthesis of Compound 29 is the same as that of Compound 1, except that 2-methoxyphenylboronic acid is used instead of (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid, and the yield is 85%. 11H NMR (400 MHz, Chloroform-d) δ 9.02 (d, J = 1.0 Hz, 1H), 7.80 (dd, J = 7.6, 1.8 Hz, 1H), 7.75 (t, J = 1.0 Hz, 1H), 7.58 - 7.54 (m, 2H), 7.32 (ddd, J = 8.2, 7.4, 1.8 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 7.25 - 7.21 (m, 2H), 7.16 (d, J = 3.3 Hz, 1H), 7.07 (td, J = 7.5, 1.1 Hz, 1H), 6.98 (dd, J = 8.3, 1.0 Hz, 1H), 6.66 (dd, J = 3.2, 1.0 Hz, 1H), 5.37 (s, 2H), 3.78 (s, 3H), 3.68 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 156.71, 148.31, 147.47, 143.32, 140.40, 138.30, 131.52, 130.18, 129.50, 129.40, 129.02, 128.94, 127.23, 124.39, 121.95, 121.91, 121.03, 111.52, 106.05, 101.70, 49.60, 34.83, 24.84.

[0259] Synthesis of 1-(4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine (Compound 30)

[0260]

[0261] The synthesis of Compound 30 is the same as that of Compound 1, except that 2-(trifluoromethyl)pyridine-3-boronic acid is used instead of (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid, and the yield is 65%. 1 1H NMR (400 MHz, Chloroform-d) δ 9.03 (d, J = 1.0 Hz, 1H), 8.71 (dd, J = 4.7, 1.6 Hz, 1H), 8.00 (dd, J = 7.8, 1.6 Hz, 1H), 7.61 - 7.54 (m, 3H), 7.33 (s, 1H), 7.30 (t, J = 2.4 Hz, 2H), 7.23 - 7.19 (m, 2H), 6.75 (dd, J = 3.2, 0.9 Hz, 1H), 5.41 (s, 2H), 3.72 (s, 3H). 13CNMR(101MHz,CDCl3)δ148.30,148.11,146.31,145.31,144.98,144.65,144.33,143.74,140.75,139.82,137.62,137.28,132.25,131.86,131.48,131.09,130.48,129.59,129.18,127.06,126.09,125.89,125.15,123.35,122.97,121.92,121.88,120.61,120.32,105.66,105.63,105.61,101.86,50.05,34.73.

[0262] Synthesis of 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(4,6-dimethoxypyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine (Compound 31)

[0263]

[0264] The synthesis of Compound 31 is the same as that of Compound 1, except that (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid is replaced by 4,6-dimethoxypyrimidine-5-boronic acid, and the yield is 68%. 1 H NMR(400MHz,DMSO-d6)δ8.87(d,J=1.0Hz,1H),8.55(s,1H),7.92(d,J=1.4Hz,1H),7.72-7.67(m,3H),7.63(d,J=1.1Hz,1H),7.42-7.38(m,2H),6.71(dd,J=3.3,0.9Hz,1H),5.54(s,2H),3.82(s,6H),3.75(s,3H).

[0265] Synthesis of 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-methylpyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine (Compound 32)

[0266]

[0267] The synthesis of Compound 32 is the same as that of Compound 1, except that (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid is replaced by 2-methylpyridine-3-boronic acid, and the yield is 62%. 11H NMR (400 MHz, Chloroform-d) δ 9.04 (d, J = 1.0 Hz, 1H), 8.51 (dd, J = 4.8, 1.8 Hz, 1H), 7.73 (dd, J = 7.7, 1.8 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.30 (t, J = 1.3 Hz, 1H), 7.27 - 7.18 (m, 5H), 6.74 (dd, J = 3.2, 0.9 Hz, 1H), 5.42 (s, 2H), 3.73 (s, 3H), 2.54 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 156.22, 149.66, 148.19, 148.17, 143.63, 140.33, 137.83, 137.58, 136.82, 132.33, 131.94, 131.55, 131.17, 129.96, 129.56, 129.18, 127.06, 124.57, 122.95, 121.95, 121.92, 120.99, 105.25, 101.88, 49.84, 34.85, 24.86, 23.47.

[0268] Synthesis of 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-isopropoxypyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine (Compound 33)

[0269]

[0270] The synthesis of Compound 33 is the same as that of Compound 1, except that 2-isopropoxypyridine-3-boronic acid is used instead of (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid, and the yield is 82%. 1 1H NMR (400 MHz, Chloroform-d) δ 9.02 (d, J = 1.0 Hz, 1H), 8.41 (dd, J = 7.5, 2.0 Hz, 1H), 8.15 - 8.11 (m, 2H), 7.61 - 7.58 (m, 2H), 7.29 (q, J = 1.3 Hz, 1H), 7.25 - 7.22 (m, 2H), 7.21 (d, J = 3.2 Hz, 1H), 6.99 (dd, J = 7.5, 4.9 Hz, 1H), 6.69 (dd, J = 3.3, 0.9 Hz, 1H), 5.48 - 5.39 (m, 3H), 3.71 (s, 3H), 1.30 (d, J = 6.2 Hz, 6H). 1313C NMR (101 MHz, CDCl3) δ 160.03, 148.26, 145.79, 145.42, 143.41, 140.34, 139.53, 138.26, 131.90, 131.52, 129.79, 129.49, 129.03, 126.93, 124.58, 123.75, 122.96, 121.91, 121.87, 120.30, 116.98, 105.85, 101.75, 68.14, 49.54, 34.83, 22.28.

[0272] Synthesis of 1-(4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-fluoro-6-cyanophenyl)-1H-pyrrolo[3,2-c]pyridine (Compound 34)

[0273]

[0274] The synthesis of Compound 34 was the same as that of Compound 1, except that 2-fluoro-6-cyanophenylboronic acid was used instead of (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid, and the yield was 52%. 1 1H NMR (400 MHz, Chloroform-d) δ 9.11 (d, J = 1.0 Hz, 1H), 7.62 - 7.58 (m, 3H), 7.50 (dt, J = 1.9, 1.0 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.29 (dd, J = 3.1, 2.2 Hz, 2H), 7.26 - 7.22 (m, 2H), 6.75 (dd, J = 3.2, 0.9 Hz, 1H), 5.44 (s, 2H), 3.72 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 158.61, 148.29, 144.00, 141.48, 139.91, 137.65, 132.93, 130.60, 129.83, 129.80, 129.71, 129.60, 129.15, 127.14, 125.64, 121.93, 120.81, 120.58, 117.64, 114.81, 106.94, 102.17, 49.94, 34.87.

[0276] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 35)

[0277]

[0278] The synthesis of Compound 35 is the same as that of Compound 1, except that Intermediate 18 is replaced by Intermediate 20, and the yield is 82%. 1 HNMR(400MHz,Chloroform-d)δ8.59(s,1H),7.64-7.56(m,2H),7.32-7.29(m,1H),7.24(d,J=8.0Hz,2H),7.18(d,J=3.3Hz,2H),6.70(dd,J=3.2,1.0Hz,1H),5.38(s,2H),3.86(s,3H),3.73(s,3H),2.83(s,3H),1.76(tt,J=8.2,4.7Hz,1H),1.14(tt,J=6.4,2.6Hz,2H),0.79(dt,J=8.2,3.4Hz,2H). 13 CNMR(101MHz,CDCl3)δ169.50,166.63,156.62,152.35,148.23,143.74,140.16,138.06,132.19,131.80,131.42,131.03,129.41,129.02,128.73,127.26,127.24,123.61,122.02,121.98,121.95,121.91,120.60,104.99,101.81,54.00,49.82,34.80,21.93,13.89,10.84.

[0279] Synthesis of 6-(2-Isopropylphenyl)-4-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 36)

[0280]

[0281] The synthesis of Compound 36 is the same as that of Compound 1, except that Intermediate 18 is replaced by Intermediate 20, and 2-isopropylphenylboronic acid is replaced by 4-cyclopropyl-6-methoxypyrimidine-5-boronic acid, and the yield is 87%. 1 H NMR(400MHz,Chloroform-d)δ7.59-7.54(m,2H),7.38-7.27(m,4H),7.22-7.18(m,3H),7.16(d,J=3.3Hz,1H),7.07(s,1H),6.72-6.66(m,1H),5.34(s,2H),3.69(s,3H),3.13(hept,J=6.8Hz,1H),2.82(s,3H),1.12(d,J=6.8Hz,6H).13 CNMR (101 MHz, CDCl3) δ 151.70, 151.44, 148.32, 146.79, 141.21, 140.21, 138.23, 132.21, 131.82, 131.44, 131.05, 130.01, 129.43, 128.95, 128.44, 127.96, 127.06, 125.56, 125.33, 122.91, 121.95, 121.91, 103.14, 101.53, 49.85, 34.81, 29.31, 24.15, 21.99.

[0282] Synthesis of 6-(2-Isopropylphenyl)-4-ethyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 37)

[0283]

[0284] The synthesis of Compound 37 is the same as that of Compound 1, except that Intermediate 21 is used instead of Intermediate 18, and the yield is 76%. 1 HNMR (400 MHz, Chloroform-d) δ 7.54 - 7.49 (m, 2H), 7.40 - 7.28 (m, 4H), 7.22 - 7.17 (m, 4H), 7.09 (s, 1H), 6.71 (dd, J = 3.2, 0.9 Hz, 1H), 5.36 (s, 2H), 3.94 - 3.88 (m, 2H), 3.11 (h, J = 6.9 Hz, 1H), 2.85 (s, 3H), 1.80 - 1.69 (m, 2H), 1.13 (d, J = 6.9 Hz, 6H), 0.88 - 0.84 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 151.34, 148.20, 146.81, 140.26, 138.06, 132.37, 131.98, 131.60, 131.21, 130.04, 129.66, 129.43, 128.71, 128.13, 127.07, 125.59, 125.36, 123.06, 122.94, 120.41, 120.24, 120.10, 120.06, 120.02, 103.29, 101.68, 49.90, 48.85, 29.37, 24.21, 24.15, 21.74, 10.97.

[0285] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-methyl-1-(4-(1-propyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 38)

[0286]

[0287] The synthesis of Compound 38 is the same as that of Compound 1, except that Intermediate 4 is used instead of Intermediate 2, and the yield is 76%. 1 H NMR(400MHz,Chloroform-d)δ8.60(s,1H),7.56-7.52(m,2H),7.34(q,J=1.3Hz,1H),7.26-7.22(m,2H),7.18(d,J=3.4Hz,2H),6.71(dd,J=3.3,0.9Hz,1H),5.38(s,2H),3.96-3.91(m,2H),3.87(s,3H),2.84(s,3H),1.81-1.72(m,3H),1.17-1.12(m,2H),0.88(t,J=7.4Hz,3H),0.82-0.77(m,2H). 13 C NMR(101MHz,CDCl3)δ169.53,166.65,156.68,152.37,148.13,143.79,140.21,138.00,132.42,132.03,131.65,131.26,129.65,129.50,128.71,127.25,125.68,123.60,123.02,120.54,120.37,120.13,120.10,120.06,120.02,104.96,101.87,54.03,49.83,48.85,24.23,21.93,13.91,10.99,10.86.

[0288] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-ethyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 39)

[0289]

[0290] The synthesis of Compound 39 is the same as that of Compound 1, except that Intermediate 22 is used instead of Intermediate 18, and the yield is 73%. 1HNMR(400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.69 - 7.67 (m, 2H), 7.55 (d, J = 0.9 Hz, 1H), 7.43 - 7.40 (m, 2H), 6.75 (dd, J = 3.3, 0.9 Hz, 1H), 5.53 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.02 (q, J = 7.6 Hz, 2H), 1.81 (td, J = 8.1, 4.2 Hz, 1H), 1.30 (t, J = 7.5 Hz, 3H), 1.00 (dq, J = 4.8, 3.3 Hz, 2H), 0.80 (dq, J = 8.1, 3.4 Hz, 2H). 13 C NMR(101 MHz, DMSO) δ 169.07, 166.46, 156.74, 156.11, 148.19, 142.81, 140.15, 139.36, 130.42, 129.25, 129.00, 128.09, 124.34, 124.30, 124.26, 122.71, 121.31, 120.84, 106.28, 100.89, 54.18, 49.21, 35.27, 28.53, 14.14, 13.85, 10.87.

[0291] Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-vinyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 40)

[0292]

[0293] The synthesis of Compound 40 is the same as that of Compound 1, except that Intermediate 23 is used instead of Intermediate 18, and the yield is 77%. 1HNMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.77 (d, J = 3.3 Hz, 1H), 7.71 - 7.68 (m, 2H), 7.64 (d, J = 0.9 Hz, 1H), 7.42 - 7.39 (m, 2H), 7.25 (dd, J = 17.4, 10.9 Hz, 1H), 6.36 (dd, J = 17.4, 2.1 Hz, 1H), 5.59 - 5.54 (m, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 1.80 (td, J = 8.0, 4.2 Hz, 1H), 1.01 (dq, J = 5.9, 3.5 Hz, 2H), 0.83 - 0.78 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 169.04, 166.53, 156.90, 148.17, 147.86, 143.27, 141.17, 139.26, 135.26, 131.68, 129.60, 129.25, 129.23, 129.02, 128.03, 124.34, 124.30, 123.95, 122.71, 121.30, 120.71, 119.41, 107.45, 100.76, 54.22, 49.22, 35.27, 14.12, 10.91.

[0294] Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-cyclopropyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 41)

[0295]

[0296] The synthesis of Compound 41 is the same as that of Compound 1, except that Intermediate 24 is used instead of Intermediate 18, and the yield is 63%. 1 HNMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.72 - 7.66 (m, 3H), 7.47 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 3.2 Hz, 1H), 5.53 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 2.57 - 2.51 (m, 1H), 1.80 (tt, J = 8.3, 4.7 Hz, 1H), 1.09 - 0.97 (m, 6H), 0.81 (dt, J = 8.4, 3.3 Hz, 2H). 1313C NMR (101 MHz, DMSO) δ 169.07, 166.38, 156.66, 155.53, 148.20, 142.87, 139.75, 139.39, 130.42, 129.62, 129.24, 128.98, 128.01, 124.32, 124.28, 123.96, 123.21, 121.31, 120.85, 105.63, 100.77, 54.16, 49.22, 35.26, 14.36, 14.17, 10.80, 10.18.

[0297] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-isopropenyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 42)

[0298]

[0299] The synthesis of Compound 42 is the same as that of Compound 1, except that Intermediate 25 is used instead of Intermediate 18, and the yield is 63%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.69 - 7.67 (m, 2H), 7.44 - 7.41 (m, 2H), 6.84 (dd, J = 3.3, 0.9 Hz, 1H), 5.79 - 5.77 (m, 1H), 5.57 (s, 2H), 5.55 (t, J = 1.7 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 2.23 (t, J = 1.0 Hz, 3H), 1.88 (td, J = 8.1, 4.2 Hz, 1H), 1.02 (dq, J = 5.9, 3.4 Hz, 2H), 0.84 - 0.79 (m, 2H). 13 13C NMR (101 MHz, DMSO) δ 169.66, 166.99, 157.31, 152.70, 148.68, 144.88, 142.76, 141.63, 139.76, 131.96, 129.76, 129.54, 128.59, 124.84, 124.80, 121.88, 121.09, 118.08, 107.98, 102.77, 54.73, 49.71, 35.77, 22.64, 14.67, 11.36.

[0300] Synthesis of 6-(2-Isopropylphenyl)-3-cyano-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 43)

[0301]

[0302] The synthesis of Compound 43 was the same as that of Compound 1, substituting Intermediate 26 for Intermediate 18 and 2-isopropylphenylboronic acid for 4-cyclopropyl-6-methoxypyrimidine-5-boronic acid, with a yield of 87%. 1 H NMR(400MHz,DMSO-d6)δ9.03(d,J=1.0Hz,1H),8.71(s,1H),7.93(d,J=1.3Hz,1H),7.82(d,J=1.1Hz,1H),7.73-7.69(m,2H),7.50-7.46(m,2H),7.45-7.37(m,2H),7.28-7.23(m,2H),5.69(s,2H),3.75(s,3H),3.05(p,J=6.9Hz,1H),1.06(d,J=6.9Hz,6H). 13 C NMR(101MHz,DMSO)δ153.64,148.04,146.80,141.45,140.41,140.32,139.96,137.84,130.41,129.41,129.39,128.73,128.21,125.93,125.78,124.41,124.37,122.78,115.27,107.41,84.35,49.83,35.29,29.14,24.31.

[0303] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-3-cyano-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 44)

[0304]

[0305] The synthesis of Compound 44 was the same as that of Compound 1, substituting Intermediate 26 for Intermediate 18, with a yield of 66%. 11H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 1.0 Hz, 1H), 8.75 (s, 1H), 8.66 (s, 1H), 7.98 (d, J = 1.1 Hz, 1H), 7.94 (d, J = 1.3 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.53 - 7.49 (m, 2H), 5.66 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 1.70 (tt, J = 8.3, 4.6 Hz, 1H), 1.02 (dq, J = 5.9, 3.5 Hz, 2H), 0.84 - 0.79 (m, 2H). 13 13C NMR (101 MHz, DMSO) δ 169.06, 166.47, 157.34, 148.04, 145.96, 142.18, 140.19, 140.14, 137.75, 129.63, 129.47, 129.40, 129.26, 128.40, 124.42, 124.38, 123.93, 123.38, 121.28, 119.85, 115.15, 109.54, 84.53, 65.38, 54.31, 49.91, 35.29, 14.12, 11.11.

[0306] Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-cyano-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 45)

[0307]

[0308] The synthesis of Compound 45 is the same as that of Compound 5, using Intermediate 27 to replace 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine, with a yield of 86%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.63 (s, 1H), 7.98 - 7.87 (m, 1H), 7.75 - 7.61 (m, 3H), 7.48 - 7.32 (m, 3H), 5.46 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 2.07 (tq, J = 10.6, 5.4 Hz, 1H), 1.76 (tt, J = 8.3, 4.7 Hz, 1H), 1.01 (p, J = 3.6 Hz, 2H), 0.94 (dt, J = 8.5, 3.1 Hz, 2H), 0.81 (dq, J = 10.3, 3.4 Hz, 2H), 0.73 (dt, J = 5.1, 2.9 Hz, 2H). 13CNMR (101 MHz, DMSO) δ 168.95, 166.55, 156.93, 148.19, 143.61, 141.99, 140.43, 139.32, 129.61, 129.24, 128.99, 128.04, 126.98, 124.44, 124.32, 124.28, 123.96, 121.31, 120.70, 118.38, 107.97, 54.18, 48.93, 35.27, 14.11, 10.97, 7.31, 6.55.

[0309] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 46)

[0310]

[0311] The synthesis of Compound 46 is the same as that of Compound 1, except that intermediate 28 is used to replace 6-bromo-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine, and the yield is 68%. 1 HNMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 0.9 Hz, 1H), 8.60 (s, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.69 - 7.65 (m, 2H), 7.61 (d, J = 1.0 Hz, 1H), 7.19 - 7.15 (m, 2H), 6.52 (t, J = 1.1 Hz, 1H), 5.56 (s, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 2.44 (d, J = 1.1 Hz, 3H), 1.76 (td, J = 8.0, 4.2 Hz, 1H), 0.99 (dq, J = 4.7, 3.3 Hz, 2H), 0.82 - 0.77 (m, 2H).

[0312] Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-2-cyclopropyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 47)

[0313]

[0314] The synthesis of Compound 47 is the same as that of Compound 1, except that intermediate 29 is used to replace 6-bromo-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine, and the yield is 72%.1 HNMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 0.9 Hz, 1H), 8.61 (s, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.70 - 7.67 (m, 2H), 7.60 (d, J = 1.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 2H), 6.39 (s, 1H), 5.68 (s, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 2.01 (ddd, J = 13.4, 8.4, 5.1 Hz, 1H), 1.77 (tt, J = 8.3, 4.7 Hz, 1H), 0.98 (ddt, J = 8.6, 6.2, 3.2 Hz, 4H), 0.79 (dq, J = 9.8, 3.4 Hz, 2H), 0.76 - 0.71 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 168.94, 166.54, 156.86, 148.21, 146.09, 143.00, 142.26, 141.38, 139.52, 129.60, 129.27, 129.22, 128.74, 127.31, 124.30, 124.26, 123.99, 123.96, 121.31, 120.75, 107.54, 96.76, 54.18, 46.31, 35.27, 14.09, 10.95, 7.82, 7.75.

[0315] Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-isopropenyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine (Compound 48)

[0316]

[0317] The synthesis of Compound 48 is the same as that of Compound 1, except that intermediate 30 is used instead of 6-bromo-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-c]pyridine, and the yield is 66%. 1HNMR(400MHz, DMSO-d6) δ 8.93 (d, J = 1.0 Hz, 1H), 8.60 (s, 1H), 7.91 (d, J = 1.4 Hz, 1H), 7.67 - 7.64 (m, 2H), 7.56 (d, J = 1.0 Hz, 1H), 7.14 - 7.09 (m, 2H), 6.81 (d, J = 0.9 Hz, 1H), 5.63 (s, 2H), 5.42 (q, J = 1.7 Hz, 1H), 5.20 (d, J = 1.5 Hz, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 2.14 (d, J = 1.2 Hz, 3H), 1.74 (tt, J = 8.3, 4.7 Hz, 1H), 0.97 (dq, J = 5.9, 3.5 Hz, 2H), 0.80 - 0.75 (m, 2H).

[0318] The beneficial effects of the present invention are demonstrated by the following specific test examples.

[0319] Test Example 1: In vitro activity detection experiment of USP1 inhibitor enzyme and in vitro anti-tumor cell proliferation activity experiment

[0320] The compound to be tested was dissolved in DMSO to 10 mM. Using an ECHO instrument, the compound and pure DMSO were pipetted into each well of a 384-well plate. The total volume of the compound and DMSO was 50 nL, and the instrument obtained gradient-diluted sample concentrations through different ratios. The enzyme was diluted with freshly prepared reaction solution (20 mM Tris-HCl (pH 8.0), 2 mM CaCl2, 2 mM β-mercaptoethanol, 0.05% CHAPS, ddH2O). 5 μL of the diluted enzyme reaction solution was added to each well, and the enzyme and compound were mixed by centrifugation and shaking, and then placed on ice after centrifugation. The reaction solution dilution kit reporting system and substrate were diluted with the reaction solution, and 5 μL of the diluted liquid was added to each well and mixed by centrifugation. Incubate at room temperature for 1 h. The fluorescence signal was measured using an Envision microplate reader (PerkinElmer, excitation wavelength 485 nm, emission wavelength 530 nm) for each well. The inhibitory activity IC 50 value of the compound on enzyme activity was calculated using the four-parameter Logistic Model method. In the following formula, x represents the logarithmic form of the compound concentration; F(x) represents the effect value (the inhibition rate of enzyme activity under this concentration condition): F(x) = (A + ((B - A) / (1 + ((C / x) ^ D)))). A, B, C, and D are four parameters. Use Xlfit to further calculate the IC 50 value as the compound concentration required for 50% inhibition in the best-fit curve.

[0321] The obtained compounds were screened for in vitro anti-tumor cell proliferation activity using MDA-MB-436 cells (BACR1 mut / HRD+, p53 mutant). The cultured MDA-MB-436 cells were digested with trypsin, collected by centrifugation, resuspended by adjusting the concentration with culture medium (DMEM + 10% FBS), and the cells were seeded on 96-well plates (1000 cells / 50 μl / well) and cultured overnight in a 37 °C, 5% CO2 cell incubator. 50 μL of culture medium containing the compound or DMSO was added to each well and cultured in the cell incubator for 7 days. The medium was changed on the 4th day (discard the old medium and re-add 50 μL of culture medium containing the compound or DMSO). After 7 days, 100 μl 2.0 detection solution was added to each well, mixed by shaking for 2 min, and then placed in the dark at room temperature for 10 minutes. The fluorescence signal in each well was measured using a microplate reader (BioTek, Gen5 CHS3.11, excitation wavelength 485 nm, emission wavelength 528 nm). The chemiluminescence value [RLU]cpd at day 7 was obtained for the compound-treated group, the chemiluminescence value [RLU]cell at day 7 was obtained for the DMSO-alone group without adding the compound, and the chemiluminescence value [RLU]background of the cell-free and compound-free blank culture medium in parallel. The inhibition rate of the compound on proliferation Inhibition rat (%) = [1 - ([RLU]cpd - [RLU]background) / ([RLU]cell - [RLU]background)] * 100%, and the inhibition activity GI 50 value of the compound on proliferation was calculated using the four-parameter Logistic Model method. In the following formula, x represents the logarithmic form of the compound concentration; F(x) represents the effect value (the inhibition rate of proliferation under this concentration condition): F(x) = (A + ((B - A) / (1 +

[0322] ((C / x)^D)))). A, B, C, and D are four parameters. The GI 50 value was further calculated using Xlfit as the compound concentration required for 50% proliferation inhibition in the best-fit curve.

[0323] Table 1. Results of in vitro enzyme activity detection experiment and in vitro anti-tumor cell proliferation activity experiment of the USP1 inhibitor compounds of the present invention

[0324]

[0325]

[0326] The above experimental results indicate that the compounds of the present invention have good inhibitory activity against USP1 / UAF1 and have good inhibitory effects on the proliferation of tumor cells. Among them, in particular, compounds 11, 15, 17, 18, 35, 36, 47, etc. have significantly better effects.

[0327] As can be seen from the above embodiments, the present invention provides a series of compounds containing a pyrido[3,2-b]pyrrole structure. The compounds of the present invention can be used as ubiquitin-specific protease 1 (USP1) inhibitors to treat USP1-mediated diseases such as cancer, and have excellent therapeutic effects.

Claims

1. A compound of formula II, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof: Wherein, X3 is selected from N or CR8; X4 is selected from N or CR9; X5 is selected from N or CR 10 ; R1 is selected from hydrogen, hydroxy, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl; R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, cyano, halogen, sulfonamido, -OR 31c , substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted azetidinyl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxy, nitro, carboxy, cyano, mercapto, carboxamido, sulfonamido, C1-C6 acyl, C1-C6 sulfonyl, -NR 32a R 32b , -OR 31c , C3-C8 cycloalkyl, pyrrolidine, tetrahydrofuryl, oxetanyl, azetidinyl, or two adjacent substituents are connected to form phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, furyl, thienyl, C3-C8 cycloalkyl, oxetanyl, azetidinyl; R 31c selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted azetidinyl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxy, nitro, carboxyl, cyano, mercapto, carboxamido, sulfonamido, C1-C6 acyl, C1-C6 sulfonyl, -NR 32a R 32b , C3-C8 cycloalkyl, pyrrolidine, tetrahydrofuryl, oxetanyl, azetidinyl, or two adjacent substituents are connected to form phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, furyl, thienyl, C3-C8 cycloalkyl, oxetanyl, azetidinyl; R 31a and R 31b each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl; R 32a and R 32b each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl; R4 and R5 are each independently selected from hydrogen, hydroxy, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; R6, R7, R8, R9, R 10 each independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, hydroxy, nitro, amino, carboxy, cyano, mercapto, carboxamido, sulfonamido, C1-C6 acyl, C1-C6 sulfonyl, C3-C8 cycloalkyl, pyrrolidine, tetrahydrofuranyl, oxetanyl, azetidinyl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxy, nitro, carboxy, cyano, amino, mercapto, carboxamido, sulfonamido, C1-C6 acyl, C1-C6 sulfonyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, furyl, thienyl, C3-C8 cycloalkyl, oxetanyl, azetidinyl, tetrahydrofuranyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof, characterized in that: R6, R7, R8, R9, R 10 each independently selected from hydrogen, methoxy, deuterated methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, 2-fluoroethoxy, 2-methoxyethoxy, cyclopropoxy, cyclobutoxy, benzyloxy, methyl, ethyl, isopropyl, 2-fluoroisopropyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylamino, cyano, halogen, methylsulfonyl, ethylsulfonyl, trifluoromethyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof, characterized in that: R1 is selected from hydrogen, C1-C2 alkyl, C2-C3 alkenyl, cyclopropyl; And / or, R4 and R5 are selected from hydrogen.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof, characterized in that: R3 is selected from a substituted or unsubstituted pyrrolyl, a substituted or unsubstituted imidazolyl, a substituted or unsubstituted pyrazolyl, a substituted or unsubstituted triazolyl, a substituted or unsubstituted tetrazolyl, wherein the substituent is selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, triazolyl, cyano, amino, C1-C4 alkylamino, C1-C4 alkylsulfonyl, oxetanyl, C1-C4 alkylazetidinyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof, characterized in that: The compound has the structure shown in formula IV: Wherein, R1 is selected from hydrogen or methyl; R1' is selected from hydrogen or cyclopropyl; R3” is selected from a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C4 alkenyl, wherein the substituent is selected from cyclopropyl.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof, characterized in that: The structural formula of the compound is selected from:

7. Use of the compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof in the preparation of a USP1 inhibitor.

8. Use of the compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof in the preparation of a medicament for preventing and / or treating a USP1-mediated disease.

9. The use according to claim 8, characterized in that: The disease is cancer; Preferably, the cancer is breast cancer; More preferably, the breast cancer is triple-negative breast cancer.

10. A drug, characterized in that: It is prepared from the compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or a solvate thereof as an active ingredient, plus a pharmaceutically acceptable excipient or auxiliary ingredient.

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