Non-selective cation channel TRPA1 antagonist and use thereof

Abstract

A non-selective cation channel TRPA1 antagonist and the use thereof. The non-selective cation channel TRPA1 antagonist is a compound as shown in formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and can be used for treating and / or preventing various diseases or conditions related to TRPA1.

Description

A non-selective cation channel TRPA1 antagonist and its use

[0001] This application claims priority to Chinese Patent Application No. 2024101770695 filed on February 8, 2024, and Chinese Patent Application No. 2024107391404 filed on June 7, 2024. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present application relates to, but is not limited to, the field of medical technology, and specifically to a non-selective cation channel TRPA1 antagonist and uses thereof. Background Art

[0003] TRPA1 (transient receptor potential cation channel subfamily member 1) is a voltage-gated ion channel protein found on the plasma membrane of mammalian cells. Similar in structure to other TRP family proteins, it possesses six transmembrane segments (S), with the S5 and S6 transmembrane domains forming an embedded pore region through which various cations, including Ca2+, pass. Structurally, TRPA1 is characterized by a large intracellular domain formed by ankyrin repeats at its N-terminus.

[0004] TRPA1 was first discovered in a human lung fibroblast cell line. Subsequent studies have shown that TRPA1 is widely present in subpopulations of primary sensory neurons in the dorsal root ganglion (DRG), vagus nerve (VG) and trigeminal ganglion (TG), mainly in unsheathed C nerve fibers and sheathed Aσ nerve fibers, and is found to be co-expressed with nociceptive channels such as P2X3, Nav1.8, and TRPV1. In addition, TRPA1 is also expressed in the small intestine, colon, pancreas, skeletal muscle, heart, brain, and T and B lymphocytes. In mammals, TRPA1 can be activated by reactive, electrophilic stimuli (e.g., allyl isothiocyanate, reactive oxygen species) and non-reactive substances such as nicotine and menthol, acting as a sensor for environmental and endogenous stimuli, causing changes such as pain, cold, and itching.

[0005] Mutations in the TRPA1 gene function have been shown to be the cause of familial episodic pain syndrome. In addition, antagonism of TRPA1 has shown significant effects in pain relief in different pain models (Wei H, Koivisto A et al. Pain. 2011 Mar; 152(3): 582–91.). TRPA1 also plays a key role in the treatment of cough associated with asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and post-viral cough (Grace MS, Belvisi MG. Pulm Pharmacol Ther. 2011 Jun; 24(3): 286–8). Studies have shown that knocking out TRPA1 can reduce lung inflammation in asthma models (Caceres AI, et. Proc Natl Acad Sci US A. 2009 Jun 2; 106(22): 9099–104.). Knocking out TRPA1 can alleviate the corresponding symptoms in atopic dermatitis, contact dermatitis, and psoriasis-related pruritus. Drugs that antagonize TRPA1 or knockout TRPA1 can prevent myelin damage under hypoxic-ischemic conditions (Hamilton NB, et al. Nature. 2016 Jan 28; 529(7587): 523–7.). Reduced anxiety behavior was observed in TRPA1 knockout mice, and memory was improved in aged mice, indicating that TRPA1 is a potential target for the treatment of anxiety and dementia. The use of TRPA1 antagonists can alleviate the symptoms of overactive bladder and bladder inflammation (Chen Z, et al. BMC Urol. 2016 Jun 17; 16(1): 33.). TRPA1 transcription levels are upregulated in colon tissues of patients with Crohn's disease and ulcerative colitis. Expression in CD4+ T cells and the effectiveness of antagonizing TRPA1 in animal colitis models further demonstrate its important role in these inflammatory diseases. Finally, inhibition of TRPA1 can alleviate myocardial ischemia-reperfusion injury and improve cardiac repair after myocardial infarction by promoting angiogenesis (Conklin DJ, et. Am J Physiol-Heart Circ Physiol. 2019 Apr; 316(4): H889–99.), indicating the potential therapeutic role of TRPA1 in heart diseases.

[0006] In view of the above-mentioned physiological effects of TRPA1, TRPA1 antagonists with different chemical structures have recently been disclosed for the treatment and / or prevention of TRPA1-related diseases and / or conditions, including WO2015155306A1, WO2017060488A1, WO2021074198A1, WO2022002780A1, WO2022002782A1, WO2022079091A1, WO2022219013A1, WO2022219015A1, WO2023150592A2 and WO2023215775A1; in addition, many companies are actively developing compounds that can antagonize TRPA1, such as GRC-17536 and LY-3526318 in clinical phase II, and CB-189625 and GDC6599 in clinical phase I. However, no drug targeting TRPA1 has been successfully marketed yet. Therefore, there is an urgent need for new TRPA1 antagonists or inhibitors suitable for treating the above-mentioned diseases. Summary of the Invention

[0007] The present invention provides a novel compound as a non-selective cation channel TRPA1 antagonist. The compound of the present invention has better inhibitory activity against TRPA1, and has more excellent pharmacodynamic and / or pharmacokinetic properties, good safety, and can be used to treat and / or prevent diseases related to TRPA1.

[0008] To this end, the present invention adopts the following technical solutions:

[0009] In one aspect, the present invention provides a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

[0010] in,

[0011] Ring A is selected from:

[0012] X1, X2, X3 and X4 are N or CR 5 , and the number of N in X1, X2, X3 and X4 is 0, 1 or 2; Ring B is selected from 5-membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 3 R a1 substituted; wherein the heteroaryl group contains 1 to 4 heteroatoms selected from N, O and S;

[0013] Ring C is selected from C 6-14 aryl, 5- to 14-membered heteroaryl, 5- to 14-membered heterocyclyl, wherein the heteroaryl and heterocyclyl each contain 1 to 4 heteroatoms selected from N, O and S;

[0014] R is independently selected from H, halogen, cyano, -SF5, C 1-6 Alkyl, C3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 5- to 7-membered heterocyclic group, -C(O)NR b R c 、-NR b R c 、-P(O)R b R c 、-S(O)2NR b R c 、-NR d C(O)R e 、-C(O)R e 、-C(O)OR e 、-S(NH)(O)R e , wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1- 3-alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 5 to 7 membered heterocyclic group optionally substituted by 1 to 3 R a2 substituted; wherein the 5- to 7-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S;

[0015] R 1 、R 2 、R 3 and R 4 Each independently selected from H, D, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 R a3 replace;

[0016] X is selected from N and CR 10 ;

[0017] R 5 Each independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C3-6 Cycloalkyl, -C 1-3 Alkylene-C 3- 6-cycloalkyl, -C(O)NR b R c 、-NR b R c 、C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted with 1 to 3 R a4 replace;

[0018] R 6 Each independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3- 6-cycloalkyl, -C(O)NR b R c 、-NR b R c 、C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted with 1 to 3 R a5 replace;

[0019] R 7 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 R a6 replace;

[0020] R 8 Selected from H, halogen, cyano, C 1-6 Alkyl, C3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C(O)NR b R c 、-NR b R c 、-OC 1-6 Alkyl, -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 The alkyl group is optionally substituted with 1 to 3 R a7 replace;

[0021] R 9 Selected from H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)NR b R c 、-NR b R c 、-NR d C(O)R e 、-C(O)R e 、-C(O)OR e , wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted with 1 to 3 R a8 replace;

[0022] R 10 Selected from H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C(O)NR b R c 、-NR b R c、-OC 1-6 Alkyl, -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 The alkyl group is optionally substituted with 1 to 3 R a9 replace;

[0023] p is an integer selected from 0, 1, 2, 3, 4 and 5;

[0024] m is an integer selected from 0, 1 and 2;

[0025] R b and R c Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, or R b and R c and the atoms to which they are attached together form a 5- to 7-membered heterocycloalkyl group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, 5 to 7 membered heterocycloalkyl optionally substituted by 1 to 3 R a10 replace;

[0026] R d and R e Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3- 6-cycloalkyl, -C 1-3 Alkylene-C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 R a11 replace;

[0027] R a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R a11Each independently selected from halogen, cyano, hydroxy, amino, C 1-3 Haloalkyl or C 1-3 alkyl;

[0028] * The configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration;

[0029] It is provided that when ring A is selected from When ring B is not

[0030] And when ring A is When the number of N in X1, X2, X3 and X4 is 0, the ring B is not In one embodiment, ring A is selected from

[0031] n is an integer selected from 0, 1, 2 and 3;

[0032] It is provided that when ring A is selected from When ring B is not

[0033] In one embodiment, Ring A is Preferably, ring A is

[0034] In one embodiment, Ring A is Preferably, ring A is

[0035] In one embodiment, Ring A is In one embodiment, Ring A is

[0036] In one embodiment, Ring B is selected from one of the following structures:

[0037] In one embodiment, Ring B is selected from one of the following structures:

[0038] In one embodiment, Ring B is Preferably In another embodiment, Ring B is Preferably In another embodiment, Ring B is Preferably In another embodiment, Ring B is Preferably In another embodiment, Ring B is Preferably In another embodiment, Ring B is Preferably

[0039] In one embodiment, ring B can also be independently selected from other five-membered heteroaryl groups.

[0040] In one embodiment, ring C is C 6-14 aryl or 5- to 14-membered heteroaryl; wherein the 5- to 14-membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S.

[0041] In one embodiment, Ring C is selected from one of the following structures:

[0042] In one embodiment, Ring C is In another embodiment, Ring C is In another embodiment, Ring C is In another embodiment, Ring C is In another embodiment, Ring C is In another embodiment, Ring C is

[0043] In one embodiment, Ring C is selected from one of the following structures:

[0044] In one embodiment, Ring C is In one embodiment, Ring C is

[0045] In one embodiment, ring C can also be independently selected from other C 6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl.

[0046] In one embodiment, the fragment Can

[0047] In one embodiment, the fragment for

[0048] In one embodiment, the fragment Can

[0049] In one embodiment, each R is independently H. In another embodiment, each R is independently halogen. In another embodiment, each R is independently cyano. In another embodiment, each R is independently -SF5. In another embodiment, each R is independently C 1-6 In another embodiment, each R is independently C 3-6 In another embodiment, each R is independently -C 1-3 Alkylene-C 3-6 Cycloalkyl.

[0050] In another embodiment, each R is independently -OC 1-6 In another embodiment, each R is independently -SC 1- In another embodiment, each R is independently C 2-6 In another embodiment, each R is independently C 2- 6 alkynyl.

[0051] In another embodiment, each R is independently a 5- to 7-membered heterocyclyl. In another embodiment, each R is independently -C(O)NR b R c In another embodiment, each R is independently -NR b R c In another embodiment, each R is independently -P(O)R b R c In another embodiment, each R is independently -S(O)2NR b R c In another embodiment, each R is independently -C(O)R e In another embodiment, each R is independently -C(O)OR e In another embodiment, each R is independently -S(NH)(O)R e In another embodiment, the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 5 to 7 membered heterocyclic group optionally substituted by 1 to 3 R a2 In another embodiment, the 5- to 7-membered heterocyclyl contains 1 to 3 heteroatoms selected from N, O, and S.

[0052] In another embodiment, each R is independently H, halogen, cyano, -SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 5- to 7-membered heterocyclic group, -C(O)NR b R c 、-NR b R c 、-P(O)R b R c 、-S(O)2NR b R c 、-NR d C(O)R e 、-C(O)R e 、-C(O)OR e or -S(NH)(O)R e .

[0053] In another embodiment, each R is independently H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 R a2 replace.

[0054] In one embodiment, R a2 are independently halogen.

[0055] In one embodiment, R 1 、R 2 、R 3 and R 4 are each independently H. In another embodiment, R 1 、R 2 、R 3 and R 4 In another embodiment, at least one of R 1 、R 2 、R 3 and R 4 At least one of them is C 1-3 In another embodiment, R 1 、R 2 、R 3 and R 4 At least one of them is a halogen.

[0056] In one embodiment, R1 、R 2 、R 3 and R 4 Each independently represents H, D, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl.

[0057] In one embodiment, R 1 、R 2 、R 3 and R 4 are each independently H, D, halogen or C 1-6 alkyl.

[0058] In one embodiment, X is N. In another embodiment, X is CH.

[0059] In one embodiment, X is N or CH.

[0060] In one embodiment, R 5 are each independently H. In another embodiment, R 5 In another embodiment, R 5 In another embodiment, R 5 In another embodiment, R 5 Each independently is C 1-6 In another embodiment, R 5 Each independently -OC 1-6 In another embodiment, R 5 Each independently is C 3-6 In another embodiment, R 5 Each independently is -C 1-3 Alkylene-C 3-6 In another embodiment, R 5 Each is independently -C(O)NR b R c In another embodiment, R 5 Each independently is -NR b R c In another embodiment, R 5 Each independently is C 2-6 In another embodiment, R 5 Each independently is C 2-6 In another embodiment, the C 1-6 Alkyl, -OC 1-6 Alkyl, C3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2- 6 alkynyl is optionally substituted with 1 to 3 R a4 replace.

[0061] In one embodiment, R 5 are independently H, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C(O)NR b R c 、-NR b R c 、C 2-6 Alkenyl or C 2-6 Alkynyl.

[0062] In one embodiment, R 5 is H, halogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens.

[0063] In one embodiment, R 5 are each independently H, halogen or C 1-6 alkyl.

[0064] In one embodiment, R 5 are independently H, halogen, C 1-6 Alkyl or cyano.

[0065] In one embodiment, R 6 are each independently H. In another embodiment, R 6 In another embodiment, R 6 In another embodiment, R 6 In another embodiment, R 6 Each independently is C 1-6 In another embodiment, R 6 Each independently -OC 1-6 In another embodiment, R 6 Each independently is C 3-6 In another embodiment, R 6 Each independently is -C 1-3 Alkylene-C 3-6In another embodiment, R 6 Each is independently -C(O)NR b R c In another embodiment, R 6 Each independently is -NR b R c In another embodiment, R 6 Each independently is C 2-6 In another embodiment, R 6 Each independently is C 2-6 In another embodiment, the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2- 6 alkynyl is optionally substituted with 1 to 3 R a5 replace.

[0066] In one embodiment, R 6 are independently H, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C(O)NR b R c 、-NR b R c 、C 2-6 Alkenyl or C 2-6 Alkynyl.

[0067] In one embodiment, R 6 Each independently is H, C 1-6 Alkyl or -NR b R c .

[0068] In one embodiment, R 7 is H. In another embodiment, R 7 C 1-6 In another embodiment, R 7 C 3-6 In another embodiment, R 7 -C 1-3 Alkylene-C 3-6 In another embodiment, the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C1-3 Alkylene-C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 R a6 replace.

[0069] In one embodiment, R 7 H, C 1-6 Alkyl, C 3-6 Cycloalkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl.

[0070] In one embodiment, R 7 H, C 1-6 Alkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl.

[0071] In one embodiment, R 8 is H. In another embodiment, R 8 In another embodiment, R 8 In another embodiment, R 8 C 1-6 In another embodiment, R 8 C 3-6 In another embodiment, R 8 -C 1-3 Alkylene-C 3-6 In another embodiment, R 8 -C(O)NR b R c In another embodiment, R 8 -NR b R c In another embodiment, R 8 For-OC 1-6 In another embodiment, R 8 For-SC 1-6 In another embodiment, the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 The alkyl group is optionally substituted with 1 to 3 R a7 replace.

[0072] In one embodiment, R 8 H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3Alkylene-C 3-6 Cycloalkyl, -C(O)NR b R c 、-NR b R c 、-OC 1-6 Alkyl or -SC 1-6 alkyl.

[0073] In one embodiment, R 8 is H, halogen or C 1-6 alkyl.

[0074] In one embodiment, R 9 is H. In another embodiment, R 9 In another embodiment, R 9 In another embodiment, R 9 C 1-6 In another embodiment, R 9 C 3-6 In another embodiment, R 9 -C 1-3 Alkylene-C 3-6 In another embodiment, R 9 For-OC 1-6 In another embodiment, R 9 For-SC 1-6 In another embodiment, R 9 C 2-6 In another embodiment, R 9 C 2-6 In another embodiment, R 9 -C(O)NR b R c In another embodiment, R 9 -NR b R c In another embodiment, R 9 -NR d C(O)R e In another embodiment, R 9 -C(O)R e In another embodiment, R 9 -C(O)OR e In another embodiment, the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6Alkyl, -SC 1-6 Alkyl, C 2- 6 alkenyl, C 2-6 Alkynyl is optionally substituted with 1 to 3 R a8 replace.

[0075] In one embodiment, R 9 H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)NR b R c 、-NR b R c 、-NR d C(O)R e 、-C(O)R e or-C(O)OR e .

[0076] In one embodiment, R 9 is H, halogen or C 1-6 alkyl.

[0077] In one embodiment, R 10 is H. In another embodiment, R 10 In another embodiment, R 10 In another embodiment, R 10 C 1-6 In another embodiment, R 10 C 3-6 In another embodiment, R 10 -C 1-3 Alkylene-C 3-6 In another embodiment, R 10 -C(O)NR b R c In another embodiment, R 10 -NR b R c In another embodiment, R 10 For-OC 1-6 In another embodiment, R 10 For-SC 1-6 In another embodiment, the C 1-6 Alkyl, C 3-6Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 The alkyl group is optionally substituted with 1 to 3 R a9 replace.

[0078] In one embodiment, R 10 H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C(O)NR b R c 、-NR b R c 、-OC 1-6 Alkyl or -SC 1-6 alkyl.

[0079] In one embodiment, R 10 is H, halogen or C 1-6 alkyl.

[0080] In one embodiment, p is 0. In another embodiment, p is 1. In another embodiment, p is 2. In another embodiment, p is 3. In another embodiment, p is 4. In another embodiment, p is 5.

[0081] In another embodiment, p is 1 or 2.

[0082] In one embodiment, m is 0. In another embodiment, m is 1. In another embodiment, m is 2.

[0083] In one embodiment, m is 0 or 1.

[0084] In one embodiment, n is 0. In another embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3.

[0085] In one embodiment, n is 0 or 1.

[0086] In one embodiment, R b and R c are each independently H. In another embodiment, R b and R c Each independently is C 1-3 In another embodiment, R b and R c Each independently is -C 1-3 Alkylene-C3-6 In another embodiment, R b and R c and the atoms to which they are attached together form a 5- to 7-membered heterocycloalkyl. b and R c Any one of them is H, and the other is selected from C 1-3 Alkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl.

[0087] In one embodiment, R b and R c Each independently is H, C 1-6 Alkyl, C 3-6 Cycloalkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl; preferably, R b and R c Each independently is H or C 1-6 alkyl.

[0088] In one embodiment, R d and R e are each independently H. In another embodiment, R d and R e Each independently is C 1-3 In another embodiment, R d and R e Each independently is -C 1-3 Alkylene-C 3-6 In another embodiment, R d and R e Any one of them is H, and the other is selected from C 1-3 Alkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl.

[0089] In one embodiment, R d and R e Each independently is H, C 1-6 Alkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl, preferably H or C 1-6 alkyl.

[0090] In one embodiment, R a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、Ra8 、R a9 、R a10 and R a11 In another embodiment, R a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R a11 In another embodiment, R a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R a11 In another embodiment, R a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R a11 In another embodiment, R a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R a11 C 1-3 In another embodiment, R a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R a11 C 1-3 Halogenated alkyl.

[0091] In one embodiment, R a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R a11 Halogen or C 1-3 alkyl.

[0092] In one embodiment, the configuration of the carbon atom at the * position is R. In another embodiment, the configuration of the carbon atom at the * position is S; preferably, the configuration of the carbon atom at the * position is R.

[0093] In one embodiment, the 5-membered heteroaryl group may be one of the following structures:

[0094] Preferably, the 5-membered heteroaryl group is

[0095] In one embodiment, the C 6-14 Aryl can be C 6-10 Aryl, such as phenyl or naphthyl, is preferably phenyl.

[0096] In one embodiment, the 5- to 14-membered heteroaryl group may be a 5- to 10-membered heteroaryl group.

[0097] In one embodiment, the 5- to 14-membered heteroaryl group may independently be a monocyclic or polycyclic ring; the polycyclic ring may be a paracyclic ring; the polycyclic ring may be a bicyclic or tricyclic ring; preferably, the 5- to 14-membered heteroaryl group may be a 5- to 6-membered monocyclic heteroaryl group or a 9- to 10-membered bicyclic heteroaryl group.

[0098] In one embodiment, the 5- to 14-membered heteroaryl group may be one of the following structures:

[0099] In one embodiment, the 5- to 14-membered heterocyclic group may be a 5- to 10-membered heterocyclic group.

[0100] In one embodiment, in the 5- to 14-membered heterocyclic group, the heterocyclic group can independently be a heterocycloalkyl group or a heterocycloalkenyl group;

[0101] When the heterocyclic group is a heterocycloalkyl group, the heterocycloalkyl group does not contain an unsaturated bond;

[0102] When the heterocyclic group is a heterocycloalkenyl group, the heterocycloalkenyl group contains 1, 2, 3 or 4 unsaturated bonds, and the heterocycloalkenyl group is not aromatic.

[0103] In one embodiment, the 5- to 14-membered heterocyclic group may independently be a monocyclic or polycyclic ring; the polycyclic ring may be a paracyclic ring; the polycyclic ring may be a bicyclic or tricyclic ring; preferably, the 5- to 14-membered heterocyclic group may be a 5- to 6-membered monocyclic heterocyclic group or a 9- to 10-membered bicyclic heterocyclic group.

[0104] In one embodiment, the halogen may independently be fluorine, chlorine, bromine or iodine.

[0105] In one embodiment, the C 1-6 The alkyl group can independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0106] In one embodiment, the C 3-6 Cycloalkyl groups independently can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0107] In one embodiment, the C 1-3 The alkylene groups independently can be methylene, ethylene, n-propylene or isopropylene.

[0108] In one embodiment, the -OC 1-6 The alkyl group can independently be -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-isobutyl or -O-tert-butyl.

[0109] In one embodiment, the -SC 1-6 The alkyl group can independently be -S-methyl, -S-ethyl, -S-n-propyl, -S-isopropyl, -S-n-butyl, -S-isobutyl or -S-tert-butyl.

[0110] In one embodiment, the C 2-6 Alkenyl groups independently may be C 2-4 Alkenyl, such as ethenyl, propenyl or butenyl.

[0111] In one embodiment, the C 2-6 Alkynyl groups independently may be C 2-4 Alkynyl, for example ethynyl, propynyl or butynyl.

[0112] In one embodiment, in the 5- to 7-membered heterocyclic group, the heterocyclic group can independently be a heterocycloalkyl group or a heterocycloalkenyl group;

[0113] When the heterocyclic group is a heterocycloalkyl group, the heterocycloalkyl group does not contain an unsaturated bond;

[0114] When the heterocyclic group is a heterocycloalkenyl group, the heterocycloalkenyl group contains one or two unsaturated bonds and is not aromatic.

[0115] In one embodiment, the C 1-3 Haloalkyl can independently be -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3.

[0116] In one embodiment, the C 1-3 Alkyl groups independently can be methyl, ethyl, n-propyl or isopropyl.

[0117] In one embodiment, Ring A is selected from:

[0118] Ring B is

[0119] n is an integer selected from 0, 1, 2 and 3.

[0120] In one embodiment, Ring A is selected from:

[0121] Ring B is

[0122] n is an integer selected from 0, 1, 2 and 3.

[0123] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the general formula (I) has the structural characteristics of the general formula (II-1):

[0124] Among them, R, p, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 , Ring B, * and Ring C are as defined above.

[0125] In one embodiment, the present invention provides a compound represented by the above general formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (II-2):

[0126] Among them, R, p, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R7 , * and Ring C are as defined above.

[0127] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has the structural characteristics of formula (II-3):

[0128] Wherein, in the general formula (II-3), R is a halogen;

[0129] P is 0, 1, or 2;

[0130] X is N or CH, preferably N;

[0131] R 5 is H, halogen or C 1-6 alkyl;

[0132] R 6 H, C 1-6 Alkyl or -NH2;

[0133] R 7 H, C 1-6 Alkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl;

[0134] The configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.

[0135] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (II-4):

[0136] in,

[0137] R is a halogen;

[0138] P is 0, 1, or 2;

[0139] X is N or CH, preferably N;

[0140] R 5 is H, halogen or C 1-6 alkyl;

[0141] R 6 H, C 1-6 Alkyl or -NH2;

[0142] R 7 H, C 1-6 Alkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl;

[0143] The configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.

[0144] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has the structural characteristics of formula (III-1):

[0145] Among them, R, p, X, m, R in the general formula (III-1) 1 、R 2 、R 3 、R 4 、R 5 、R 6 , Ring B, * and Ring C are as defined above.

[0146] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (III-2):

[0147] Among them, R, p, X, m, R in the general formula (III-2) 1 、R 2 、R 3 、R 4 、R 5 、R 6 , * and Ring C are as defined above.

[0148] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has the structural characteristics of formula (III-3):

[0149] Among them, in the general formula (III-3),

[0150] R is halogen;

[0151] P is 0, 1, or 2;

[0152] m is 0 or 1;

[0153] R 5 is H, halogen or C 1-6 alkyl;

[0154] R 6 H, C 1-6 Alkyl or -NH2;

[0155] * The configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration;

[0156] Preferably, the structural fragment for

[0157] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (IV-1):

[0158] Among them, R, p, X, n, R in the general formula (IV-1) 1 、R 2 、R 3 、R 4 、R 5 、R 6 , Ring B, * and Ring C are as defined above.

[0159] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (IV-2):

[0160] Among them, R, p, X, n, R in the general formula (IV-2) 1 、R 2 、R 3 、R 4 、R 5 、R 6 , * and Ring C are as defined above.

[0161] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (IV-3):

[0162] Wherein, in the general formula (IV-3), R is a halogen;

[0163] P is 0, 1, or 2;

[0164] n is 0 or 1;

[0165] R 5 is H, halogen or C 1-6 alkyl;

[0166] R 6 H, C 1-6 Alkyl or -NH2;

[0167] The configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.

[0168] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (IV-4):

[0169] Among them, in the general formula (IV-4),

[0170] R is halogen;

[0171] P is 0, 1, or 2;

[0172] n is 0 or 1;

[0173] R 5 is H, halogen or C 1-6 alkyl;

[0174] R 6 H, C 1-6 Alkyl or -NH2;

[0175] The configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.

[0176] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has the structural characteristics of formula (IV-5):

[0177] Among them, in the general formula (IV-5),

[0178] R is halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 R a2 replace;

[0179] R a2 are independently halogen;

[0180] P is 0, 1, or 2;

[0181] n is 0, 1, or 2;

[0182] R 5 H, halogen, C 1-6 Alkyl or cyano;

[0183] R 6 H, C 1-6 Alkyl or -NH2;

[0184] * The configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration;

[0185] Preferably, ring C is

[0186] Preferably, the structural fragment for

[0187] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (V-1):

[0188] Among them, R, p, X, R in the general formula (V-1) 1 、R 2 、R 3 、R 4 、R 6 、R 8 、R 9 , Ring B, * and Ring C are as defined above.

[0189] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has the structural characteristics of formula (V-2):

[0190] Among them, R, p, X, R in the general formula (V-2) 1 、R 2 、R 3 、R 4 、R 6 、R 8 、R 9 , * and Ring C are as defined above.

[0191] In one embodiment, the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has the structural characteristics of formula (V-3):

[0192] Among them, in the general formula (V-3),

[0193] R is a halogen;

[0194] P is 0, 1, or 2;

[0195] R 6 H, C 1-6 Alkyl or -NH2;

[0196] R 8is H, halogen or C 1-6 alkyl;

[0197] R 9 is H, halogen or C 1-6 alkyl;

[0198] The configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.

[0199] In one embodiment, the compound represented by formula (I) has the structural characteristics of formula (VI):

[0200] Among them, ring A is

[0201] Ring C, R, p, n, R 5 、R 6 and * are as defined above.

[0202] In one embodiment, the compound represented by formula (I) has the structural characteristics of formula (VI):

[0203] Among them, ring A is

[0204] Ring C is

[0205] R is halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0206] P is 0, 1, or 2;

[0207] n is 0, 1, or 2;

[0208] R 5 is H, halogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0209] R 6 H, C 1-6 Alkyl or -NH2;

[0210] The configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.

[0211] In one embodiment, the compound represented by formula (I) has the structural characteristics of formula (VI):

[0212] Among them, ring A is

[0213] Ring C is

[0214] R is halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0215] P is 0, 1, or 2;

[0216] n is 0, 1, or 2;

[0217] The configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.

[0218] In one embodiment, preferred compounds of the present invention include, but are not limited to, the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0219] In another aspect, the present invention also provides any intermediate described in the present invention.

[0220] In another aspect, the present invention further provides a method for preparing the compound of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof, the preparation method comprising the following steps:

[0221] (1) The compound of formula (I-1) and the compound of formula (I-2) undergo a substitution reaction under the action of an inorganic base to obtain a compound of formula (I-3);

[0222] (2) The compound of formula (I-3) is subjected to carbonyl reduction reaction to obtain the compound of formula (I-4), and then the compound of formula (I-4) is subjected to substitution reaction with the undeprotonated ring A to obtain the compound of formula (I);

[0223] In the above-mentioned preparation method, Y in formula (I-1) to (I-4) 1 、Y 2 represents a leaving group, such as bromine, chloride or sulfonate, and the other groups in formulae (I-1) to (I-4) and formula (I) are as defined above.

[0224] In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient. In a specific embodiment, the compound of the present invention is provided in the pharmaceutical composition in an effective amount. In a specific embodiment, the compound of the present invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of the present invention is provided in a prophylactic effective amount.

[0225] In another aspect, the present invention also provides use of the compound of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating diseases and / or disorders associated with TRPA1.

[0226] In one embodiment, the disease and / or disorder associated with TRPAl is pain, respiratory disease, fibrotic disease, urinary system disease, autoimmune disease, central nervous system (CNS) disease, inflammatory disease, gastrointestinal disease or cardiovascular disease.

[0227] In a specific embodiment, the pain is postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain, or inflammation-induced pain.

[0228] In a specific embodiment, the respiratory disease is asthma, cough, chronic obstructive pulmonary disease or sleep apnea.

[0229] In another aspect, the present invention also provides a use of a compound of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating a disease and / or disorder; the disease and / or disorder is pain, respiratory disease, fibrotic disease, urinary system disease, autoimmune disease, central nervous system (CNS) disease, inflammatory disease, gastrointestinal disease or cardiovascular disease.

[0230] In a specific embodiment, the pain is postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain, or inflammation-induced pain.

[0231] In a specific embodiment, the respiratory disease is asthma, cough, chronic obstructive pulmonary disease or sleep apnea.

[0232] Definition and Description

[0233] The following definitions are provided for the terms used to describe the present invention in the specification and claims of this application. For specific terms, if the meaning defined in this application is inconsistent with the meaning commonly understood by those skilled in the art, the meaning defined in this application shall prevail; if not defined in this application, the meaning commonly understood by those skilled in the art shall prevail. In this application, the names of compounds correspond to their structural formulas. When the compound names are inconsistent with the structural formula, the structural formula shall prevail, or the specific circumstances of the present invention combined with the knowledge of those skilled in the art shall be inferred.

[0234] As used herein, numerical ranges defined in substituents such as 6-14, 1-6, 1-3, 5 to 14, 5 to 7, etc. indicate integers within the range, such as 1-6 is 1, 2, 3, 4, 5, or 6, 1 to 3 is 1, 2, or 3, and 1 to 4 is 1, 2, 3, or 4.

[0235] "Halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0236] "Alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group.

[0237] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, "C 1-3 "Alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 3 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl, and n-hexyl. The alkyl group in this application is preferably C 1-3 alkyl.

[0238] “C 1-3 "Haloalkyl" refers to the above-mentioned "C 1-3 "Alkyl" is substituted by one or more halogen groups. Exemplary halogenated alkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CH F CH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, etc.

[0239] “C 3-6 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 6 ring carbon atoms and zero heteroatoms. In some embodiments, C 3- C5 cycloalkyl is preferred, and C3 cycloalkyl is more preferred. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0240] “C 2-6 "Alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms, said alkenyl group containing at least one carbon-carbon double bond. 2-6 Non-limiting examples of "alkenyl" include, but are not limited to, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, and the like.

[0241] “C 2-6 "Alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms, said alkynyl group containing at least one carbon-carbon triple bond. 2-6 Non-limiting examples of "alkynyl" include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

[0242] “C 6-14 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, C6 aryl is particularly preferred. Aryl also includes ring systems in which the above-mentioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, and at least one ring is aromatic.

[0243] "5 to 14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the heteroaryl ring. In some embodiments, 5 to 10 membered heteroaryl groups are preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5- to 6-membered heteroaryl groups are particularly preferred and are 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. For example, a "5-membered heteroaryl" is a 5-membered monocyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.

[0244] "5- to 14-membered heterocyclyl" refers to a 5- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, preferably nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, or 3. The heterocyclyl group can independently be a heterocycloalkyl or a heterocycloalkenyl group; when the heterocyclyl group is a heterocycloalkyl group, the heterocycloalkyl group contains no unsaturated bonds; when the heterocyclyl group is a heterocycloalkenyl group, the heterocycloalkenyl group contains 1, 2, 3, or 4 unsaturated bonds, and the heterocycloalkenyl group is not aromatic. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as long as valence permits. In some embodiments, 5- to 7-membered heterocyclyl groups are particularly preferred, which are 5- to 7-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably, 5- to 6-membered heterocyclyl groups are 5- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Exemplary heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, and the like.

[0245] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0246] "Pharmaceutically acceptable salts" refer to pharmaceutically acceptable organic or inorganic salts, as defined above, of the compounds of the present invention, which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts, which may be formed in the presence of acidic protons capable of reacting with inorganic or organic bases.

[0247] The term "optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, the term "optionally substituted with one or more substituents" means that the atom may or may not be substituted. When substituted, it means that any one or more hydrogen atoms on the specified atom are replaced by a substituent.

[0248] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0249] "Cyano" refers to -CN.

[0250] "Hydroxy" refers to -OH.

[0251] The term "therapeutically effective amount" refers to an amount administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

[0252] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient (API). These substances are generally classified into two categories: excipients and additives. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0253] The term "treat" refers to eliminating the cause or alleviating the symptoms of a disease.

[0254] The term "prevent" refers to reducing the risk of developing a disease.

[0255] The term "patient" refers to any animal, typically a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.

[0256] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0257] The reagents and raw materials used in the present invention are commercially available.

[0258] The positive progress of the present invention is that the compounds of the present invention have better inhibitory activity against TRPA1, or have more excellent pharmacodynamic and / or pharmacokinetic properties, are safe, and can be used to treat and / or prevent diseases related to TRPA1. DETAILED DESCRIPTION

[0259] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0260] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6The units are given. NMR measurements were performed using a Bruker Ultrashield 400 MHz nuclear magnetic resonance instrument. The solvents used for the measurements were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and deuterated water (D2O). The chemical shift δ values ​​(ppm) were reported using tetramethylsilane (TMS) as the internal standard.

[0261] LCMS was determined using Waters ACQUITY UPLC.

[0262] High performance liquid chromatography (HPLC) was measured by Waters preparative high performance liquid chromatograph using a YMC-Triart-C18 EXRS (20 mm×100 mm×5 μm) column.

[0263] The thin layer chromatography silica gel plate used was West Asia Reagent GF254 silica gel plate.

[0264] Column chromatography used 200-300 mesh silica gel from Qingdao Ocean Chemical Co., Ltd. as the carrier.

[0265] DCM represents dichloromethane; RT represents room temperature; EtOH represents ethanol; KOH represents potassium hydroxide; H2SO4 represents sulfuric acid; NH3H2O ​​represents aqueous ammonia; dioxane represents 1,4-dioxane; HC(OEt)3 represents triethyl orthoformate; Zn(CN)2 represents zinc cyanide; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium; dppf represents 1,1-bis(diphenylphosphino)ferrocene; Tetrabutylammonium tribromide represents tetrabutylammonium tribromide; DCE represents 1,2-dichloroethane; LiHMDS represents lithium bis(trimethylsilylamide); THF represents tetrahydrofuran; DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene; LDA represents lithium diisopropylamide; NMP represents N-methylpyrrolidone; LiAlH4 represents lithium aluminum hydride; DEAD represents diisopropyl azodicarboxylate; PPh3 represents triphenylphosphine; POCl3 represents phosphorus oxychloride; t-BuOK represents potassium tert-butoxide; NH4OAc represents ammonium acetate; Xphos-Pd-G3 represents methanesulfonate(2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium; and MeI represents iodomethane.

[0266] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. This application uses the following abbreviations: mM represents the concentration unit mmol / L; M represents the concentration unit mol / L; K2CO3 represents potassium carbonate; DMA represents N,N-dimethylacetamide; NaBH4 represents sodium borohydride; MeOH represents methanol; MeCN represents acetonitrile; TLC: thin layer chromatography; 1H NMR: hydrogen nuclear magnetic resonance spectroscopy; LC-MS: liquid chromatography-mass spectrometry; DMSO represents dimethyl sulfoxide; EDTA represents ethylenediaminetetraacetic acid; DMEM stands for Dulbecco's Modified Eagle Medium, which is a widely used basal culture medium; HEPES represents N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid. The compounds are named according to the conventional naming rules in the field, and commercially available reagents use the supplier's catalog name.

[0267] Synthesis of intermediate a1:

[0268] Synthesis of intermediate a1-3: To a clean, dry flask, 5-chloromethyltetrazole (a1-1) (2.00 g, 16.87 mmol), N,N-dimethylacetamide (34 mL), 2-bromo-4'-chloroacetophenone (a1-2) (4.33 g, 18.56 mmol), and anhydrous potassium carbonate (3.26 g, 23.62 mmol) were added sequentially. The reaction system was stirred at room temperature for 1 hour. TLC indicated that the starting materials had essentially reacted completely. The reaction solution was diluted with water (30 mL), then extracted with ethyl acetate (30 mL x 3). The resulting mixture was separated, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:5) to obtain 2.41 g of a yellow solid in a yield of 52.75%. LC-MS (ESI) m / z: 271.24 (M+H) + .

[0269] Synthesis of Intermediate a1: To a clean, dry flask, add Intermediate a1-3 (1.50 g, 5.53 mmol), replace the atmosphere with nitrogen three times, and add methanol (12 mL). In an ice-water bath, slowly add sodium borohydride (294.24 mg, 7.78 mmol). After stirring the reaction mixture at room temperature for 1 hour, TLC confirmed that the reaction was essentially complete. The solvent was removed by rotary evaporation under reduced pressure. Water (10 mL) and ethyl acetate (10 mL x 3) were added to the crude product, followed by extraction and separation. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:4) to obtain 1.32 g of a yellow solid in a yield of 87.42%. LC-MS (ESI) m / z: 273.14 (M+H). + ; 1 H NMR (400MHz, CDCl3) δ7.43–7.30(m,4H),5.34(dd,J=8.6,4.2Hz,1H),4.92–4.67(m,4H),2.86(s,1H).

[0270] Synthesis of intermediate a1-R:

[0271] Synthesis of intermediate a1-R: a1-3 (250 mg, 0.92 mmol) was placed in a clean, dry single-necked flask (25 mL), and the atmosphere was replaced with nitrogen three times. Acetonitrile (5 mL) was added, and under nitrogen, ruthenium (II) chloride (mesitylene) [(S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine] (CAS174813-81-1, 6.18 mg, 0.01 mmol) and formic acid-triethylamine (5:2) addition compound (0.5 mL) were added in sequence. The reaction was stirred at room temperature overnight. TLC detected that the raw materials were basically reacted. The solvent was evaporated under reduced pressure, and water (4 mL) was added to the reaction system to quench the reaction. The mixture was extracted with ethyl acetate (3 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure on a rotary evaporator to obtain a crude product, which was separated and purified by silica gel chromatography (EA: PE = 1: 5) to obtain 119 mg of a yellow solid with a yield of 47.22% and an ee value of 96% (hand-type column: Mobile phase: n-hexane / isopropanol = 90 / 10, flow rate 1 ml / min, peak retention time 11.201 min, column temperature 40°C). LC-MS (ESI) m / z: 273.26 (M+H) + ; 1 HNMR (400MHz, CDCl3) δ7.43–7.30(m,4H),5.34(dd,J=8.6,4.2Hz,1H),4.92–4.67(m,4H),2.86(s,1H).

[0272] Synthesis of intermediate a2:

[0273] Synthesis of Intermediate a2-2: To a clean, dry flask, 2-acetylbenzothiophene (a2-1) (2.00 g, 11.35 mmol), dichloromethane (7.5 mL), and methanol (7.5 mL) were added sequentially. A solution of tetrabutylammonium tribromide (6.02 g, 12.49 mmol) in dichloromethane (30 mL) was slowly added while stirring. The reaction mixture was stirred at room temperature for 12 hours. TLC indicated that the reaction was essentially complete. The solvent was removed by rotary evaporation under reduced pressure. Water (15 mL) and ethyl acetate (10 mL x 3) were added to the crude product, and the mixture was extracted and separated. The combined organic phases were washed sequentially with saturated sodium bicarbonate solution (25 mL), saturated sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was then evaporated under reduced pressure to remove the solvent. The crude product was washed with ethyl acetate and petroleum ether (volume ratio of 1:4), filtered, and the filter cake was collected and dried to obtain 2.74 g of a yellow solid with a yield of 94.65%. LC-MS (ESI) m / z: 255.10 (M+H) + .

[0274] Synthesis of intermediate a2-3: To a clean, dry flask were added 5-chloromethyltetrazole (a1-1) (424 mg, 3.58 mmol), N,N-dimethylacetamide (7 mL), intermediate a2-2 (1.01 g, 3.94 mmol), and anhydrous potassium carbonate (692 mg, 5.01 mmol). The reaction system was stirred at room temperature for 1 hour. TLC indicated that the starting materials had essentially reacted completely. The reaction solution was diluted with water (10 mL), then extracted with ethyl acetate (10 mL x 3). The resulting mixture was separated, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:4) to obtain 452 mg of a yellow solid in a yield of 43.13%. LC-MS (ESI) m / z: 293.23 (M+H) + .

[0275] Synthesis of Intermediate a2: To a clean, dry flask, add Intermediate a2-3 (200 mg, 0.68 mmol), replace the atmosphere with nitrogen three times, and add methanol (1.5 mL). In an ice-water bath, slowly add sodium borohydride (39 mg, 1.02 mmol). After stirring the reaction mixture at room temperature for 1 hour, TLC confirmed that the reaction was essentially complete. The solvent was removed by rotary evaporation under reduced pressure. Water (10 mL) and ethyl acetate (10 mL x 3) were added to the crude product, followed by extraction and separation. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:4) to obtain 147 mg of a white solid in a yield of 73.35%. LC-MS (ESI) m / z: 295.22 (M+H) + .

[0276] Synthesis of intermediate a3:

[0277] Synthesis of intermediate a3-2: To a clean, dry flask, 5-chloromethyltetrazole (a1-1) (356 mg, 3.00 mmol), N,N-dimethylacetamide (4 mL), 2-bromo-1-(4-chloro-3-fluorophenyl)ethanone (a3-1) (754 mg, 3.00 mmol), and anhydrous potassium carbonate (621 mg, 4.50 mmol) were added sequentially. The reaction system was stirred at room temperature for 1 hour. TLC indicated that the starting materials had essentially reacted completely. The reaction solution was diluted with water (10 mL), then extracted with ethyl acetate (10 mL x 3). The resulting mixture was separated, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, 1:5 volume ratio) to obtain 110 mg of an oily product in a yield of 12.69%.

[0278] Synthesis of Intermediate a3: To a clean, dry flask, add Intermediate a3-2 (110 mg, 0.38 mmol), replace the atmosphere with nitrogen three times, and add methanol (1 mL). In an ice-water bath, slowly add sodium borohydride (21 mg, 0.55 mmol). The reaction mixture was brought to room temperature and stirred for 1 hour. TLC confirmed that the reaction was essentially complete. The solvent was removed under reduced pressure on a rotary evaporator. Water (3 mL) and ethyl acetate (3 mL x 3) were added to the crude product, followed by extraction and separation. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio 1:4) to obtain 105 mg of a yellow solid in a 94.60% yield. LC-MS (ESI) m / z: 290.94 (M+H) + .

[0279] Synthesis of intermediate a4:

[0280] Synthesis of intermediate a4-2: 2-Amino-3-cyano-4-methylpyridine (a4-1) (1.00 g, 7.51 mmol) and 20% potassium hydroxide solution (14 mL) were added sequentially to a clean, dry flask. The reaction mixture was heated to reflux and stirred at reflux for 12 hours. TLC indicated that the reaction was essentially complete. The reaction mixture was cooled to room temperature and the pH was adjusted to approximately 3 by adding dilute hydrochloric acid (4 M). The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. Ethanol (15 mL) was added to the crude product and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to afford 1.09 g of a yellow solid, a yield of 95.36%. LC-MS (ESI) m / z: 153.18 (M+H) + .

[0281] Synthesis of Intermediate a4: To a clean, dry flask, intermediate a4-2 (500 mg, 3.29 mmol), ethanol (6 mL), and formamidine acetate (1.03 g, 9.87 mmol) were added sequentially. The reaction mixture was heated to reflux and stirred at reflux for 12 hours. TLC confirmed that the reaction was essentially complete. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with methanol (4 mL x 3) and dried to yield 336 mg of a yellow solid, a yield of 63.40%. LC-MS (ESI) m / z: 162.22 (M+H). + .

[0282] Synthesis of intermediate a5:

[0283] Synthesis of intermediate a5-3: To a clean, dry flask were added 5-chloromethyltetrazole (a1-1) (1.00 g, 8.44 mmol), N,N-dimethylacetamide (16 mL), 2-bromo-1-(3-chlorophenyl)ethanone (a5-2) (2.17 g, 9.28 mmol), and anhydrous potassium carbonate (1.63 g, 11.82 mmol). The reaction system was stirred at room temperature for 1 hour. TLC indicated that the starting materials had essentially reacted completely. The reaction solution was diluted with water (20 mL), then extracted with ethyl acetate (15 mL x 3). The resulting mixture was separated, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:5) to obtain 1.18 g of a yellow oil in a yield of 51.75%. LC-MS (ESI) m / z: 271.12 (M+H). + .

[0284] Synthesis of Intermediate a5: To a clean, dry flask, add Intermediate a5-3 (1.20 g, 4.44 mmol), replace the atmosphere with nitrogen three times, and add methanol (10 mL). In an ice-water bath, slowly add sodium borohydride (252 mg, 7.78 mmol). The reaction mixture was brought to room temperature and stirred for 1 hour. TLC confirmed that the reaction was essentially complete. The solvent was removed by rotary evaporation under reduced pressure. Water (10 mL) and ethyl acetate (10 mL x 3) were added to the crude product, followed by extraction and separation. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:1) to obtain 916 mg of a colorless oil in a 75.70% yield. LC-MS (ESI) m / z: 273.15 (M+H) + .

[0285] Synthesis of intermediate a6:

[0286] Synthesis of intermediate a6-2: To a clean, dry flask were added 5-chloromethyltetrazole (a1-1) (1.00 g, 8.44 mmol), N,N-dimethylacetamide (16 mL), 2-bromo-4'-fluoroacetophenone (a6-1) (2.17 g, 9.28 mmol), and anhydrous potassium carbonate (1.63 g, 11.82 mmol). The reaction system was stirred at room temperature for 1 hour. TLC indicated that the starting materials were essentially reacted. The reaction solution was diluted with water (40 mL), then extracted with ethyl acetate (15 mL x 3). The resulting mixture was separated, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:5) to obtain 1.32 g of a yellow solid in a yield of 61.68%. LC-MS (ESI) m / z: 255.17 (M+H). + .

[0287] Synthesis of Intermediate a6: To a clean, dry flask, add Intermediate a6-2 (1.30 g, 5.12 mmol), replace the atmosphere with nitrogen three times, and add methanol (20 mL). In an ice-water bath, slowly add sodium borohydride (290 mg, 7.68 mmol). The reaction mixture was brought to room temperature and stirred for 1 hour. TLC indicated that the reaction was essentially complete. The solvent was removed by rotary evaporation under reduced pressure. Water (10 mL) and ethyl acetate (10 mL x 3) were added to the crude product, followed by extraction and separation. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:4) to afford 849 mg of a colorless oil in a 64.81% yield. LC-MS (ESI) m / z: 257.17 (M+H).+ .

[0288] Synthesis of intermediate a7:

[0289] Synthesis of Intermediate a7-2: To a clean, dry flask, 3-cyano-4-methyl-2,6-dichloropyridine (Compound a7-1) (7.80 g, 41.71 mmol) and concentrated sulfuric acid (40 mL) were added sequentially. The reaction system was reacted in an 80°C oil bath for 6 hours. The reaction mixture was then slowly poured into an ice-water mixture (400 mL). The precipitated solid was collected by filtration and dried under vacuum to yield 7.80 g of a yellow solid, with a yield of 91.23%. LC-MS (ESI) m / z: 205.0 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ8.08(s,1H),7.90(s,1H),7.55(s,1H),2.31(s,3H).

[0290] Synthesis of Intermediate a7-3: Intermediate a7-2 (9.8 g, 47.80 mmol) was placed in a 250 mL sealed flask. Ammonia (20 mL) and dioxane solution (40 mL) were added at room temperature. The mixture was sealed in an oil bath at 130°C under nitrogen for 40 hours. The reaction mixture was concentrated in vacuo to dryness and purified on a silica gel column (mobile phase: dichloromethane and methanol, volume ratio 20 / 1 to 10 / 1) to obtain 4.01 g of a white solid, with a yield of 45.72%. LC-MS (ESI) m / z: 186.07 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ7.79(s,1H),7.61(s,1H),6.50(s,1H),6.15(s,2H),2.19(s,3H).

[0291] Synthesis of Intermediate a7-4: To a clean, dry flask, add Intermediate a7-3 (2.00 g, 10.78 mmol) and triethyl orthoformate (80 mL) sequentially. The mixture was reacted in an oil bath at 140°C under nitrogen for 48 hours. The reaction mixture was concentrated in vacuo to dryness and purified on a silica gel column (mobile phase: dichloromethane and methanol, 10 / 1 to 5 / 1 volume ratio) to afford 1.40 g of a yellow solid in a 66.35% yield. LC-MS (ESI) m / z: 196.03 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ12.56(s,1H),8.27(s,1H),7.45(s,1H),2.76(s,3H).

[0292] Synthesis of Intermediate a7: To a clean, dry flask, add N,N-dimethylformamide (20 mL), followed by Intermediate a7-4 (1.30 g, 6.65 mmol), zinc cyanide (1.17 g, 9.97 mmol), tris(dibenzylideneacetone)dipalladium (304 mg, 0.33 mmol), and 1,1-bis(diphenylphosphino)ferrocene (737 mg, 1.33 mmol). The mixture was reacted at 100°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to dryness. The crude product was purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, volume ratio: 10 / 1 to 5 / 1), followed by reverse phase preparative separation (alkaline) to obtain 282 mg of a yellow solid, in a yield of 22.78%. LC-MS (ESI) m / z: 187.04 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ12.66(s,1H),8.34(s,1H),7.93(s,1H),2.82(s,3H).

[0293] Synthesis of intermediate a8:

[0294] Synthesis of Intermediate a8-2: To a clean, dry flask were added 1-(4-cyclopropylphenyl)ethanone (a8-1) (500 mg, 3.12 mmol), dichloromethane (5 mL), and methanol (5 mL). A solution of tetrabutylammonium tribromide (1.66 g, 3.43 mmol) in dichloromethane (5 mL) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 12 hours. TLC indicated that the reaction was essentially complete. The solvent was removed by rotary evaporation under reduced pressure. Water (15 mL) and ethyl acetate (10 mL x 3) were added to the crude product, followed by extraction and separation. The combined organic phases were washed sequentially with saturated sodium bicarbonate solution (25 mL) and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure on a rotary evaporator to remove the solvent. The crude product was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether, volume ratio: 1:15) to obtain 564 mg of a light yellow solid, in a yield of 75.61%. LC-MS (ESI) m / z: 239.11 (M+H) + .

[0295] Synthesis of intermediate a8-3: To a clean, dry flask were added 5-chloromethyltetrazole (a1-1) (280 mg, 2.36 mmol), N,N-dimethylacetamide (5 mL), intermediate a8-2 (564 mg, 2.36 mmol), and anhydrous potassium carbonate (488 mg, 3.54 mmol). The reaction system was stirred at room temperature for 12 hours. TLC indicated that the starting materials had essentially reacted completely. The reaction solution was diluted with water (20 mL), then extracted with ethyl acetate (20 mL x 3). The resulting mixture was separated, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:6) to obtain 353 mg of an oily substance in a yield of 54.13%. LC-MS (ESI) m / z: 277.13 (M+H). + .

[0296] Synthesis of Intermediate a8: To a clean, dry flask, add Intermediate a8-3 (353 mg, 1.27 mmol), replace the atmosphere with nitrogen three times, and add methanol (5 mL). In an ice-water bath, slowly add sodium borohydride (72 mg, 1.91 mmol). The reaction mixture was brought to room temperature and stirred for 12 hours. TLC indicated that the reaction of the starting material was essentially complete. The solvent was removed by rotary evaporation under reduced pressure. Water (20 mL) and ethyl acetate (20 mL × 3) were added to the crude product, and the mixture was extracted and separated. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio 1:5) to obtain 234 mg of an oily substance, with a yield of 65.77%. LC-MS (ESI) m / z: 279.15 (M+H) + .

[0297] Synthesis of intermediate a9:

[0298] Synthesis of intermediate a9-2: To a clean, dry flask were added 5-chloromethyltetrazole (a1-1) (533 mg, 4.50 mmol), N,N-dimethylacetamide (10 mL), 2-bromo-4'-(trifluoromethyl)acetophenone (a9-1) (1.00 g, 3.74 mmol), and anhydrous potassium carbonate (1.02 g, 7.49 mmol). The reaction system was stirred at room temperature for 1 hour. TLC indicated that the starting materials had essentially reacted completely. The reaction solution was diluted with water (30 mL), then extracted with ethyl acetate (30 mL x 3). The resulting mixture was separated, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:9) to obtain 0.59 g of a yellow solid in a yield of 52.35%. LC-MS (ESI) m / z: 305.11 (M+H). + .

[0299] Synthesis of intermediate a9: To a clean, dry flask, add intermediate a9-2 (300 mg, 0.98 mmol), replace the atmosphere with nitrogen three times, and add methanol (5 mL). In an ice-water bath, slowly add sodium borohydride (56 mg, 1.48 mmol). After the reaction mixture was brought to room temperature and stirred for 1 hour, TLC confirmed that the reaction of the starting material was essentially complete. The solvent was removed by rotary evaporation under reduced pressure, and water (10 mL) and ethyl acetate (10 mL × 3) were added to the crude product. Extraction and separation were performed, and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio 1:9) to obtain 290 mg of a white solid, with a yield of 96.12%. LC-MS (ESI) m / z: 307.08 (M+H) + .

[0300] Synthesis of intermediate a10:

[0301] Synthesis of intermediate a10-2: To a clean, dry flask were added 5-chloromethyltetrazole (a1-1) (423 mg, 3.57 mmol), N,N-dimethylacetamide (10 mL), 2-bromo-3',4'-difluoroacetophenone (a10-1) (700 mg, 2.98 mmol), and anhydrous potassium carbonate (618 mg, 4.47 mmol). The reaction system was stirred at room temperature for 1 hour. TLC indicated that the starting materials were essentially reacted. The reaction solution was diluted with water (30 mL), then extracted with ethyl acetate (15 mL x 3). The layers were separated, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:9) to obtain 528 mg of a yellow solid in a yield of 65.05%. LC-MS (ESI) m / z: 273.11 (M+H). + .

[0302] Synthesis of Intermediate a10: To a clean, dry flask, add Intermediate a10-2 (300 mg, 1.10 mmol), replace the atmosphere with nitrogen three times, and add methanol (5 mL). In an ice-water bath, slowly add sodium borohydride (62 mg, 1.65 mmol). After stirring the reaction mixture at room temperature for 1 hour, TLC confirmed that the reaction was essentially complete. The solvent was removed by rotary evaporation under reduced pressure. Water (10 mL) and ethyl acetate (10 mL x 3) were added to the crude product, followed by extraction and separation. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:9) to obtain 218 mg of a white solid in a yield of 72.18%. LC-MS (ESI) m / z: 275.10 (M+H) + .

[0303] Synthesis of intermediate a11:

[0304] Synthesis of intermediate a11-2: To a clean, dry flask were added 5-chloromethyltetrazole (a1-1) (330 mg, 2.78 mmol), N,N-dimethylacetamide (10 mL), 2-bromo-3'-chloro-4'-fluoroacetophenone (a11-1) (700 mg, 2.78 mmol), and anhydrous potassium carbonate (576 mg, 4.18 mmol). The reaction system was stirred at room temperature for 12 hours. TLC indicated that the starting materials were essentially reacted. The reaction solution was diluted with water (30 mL), then extracted with ethyl acetate (15 mL x 3). The layers were separated, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:4) to obtain 582 mg of a yellow solid in a yield of 72.32%. LC-MS (ESI) m / z: 289.07 (M+H). + .

[0305] Synthesis of Intermediate a11: To a clean, dry flask, add Intermediate a11-2 (582 mg, 2.01 mmol), replace the atmosphere with nitrogen three times, and add methanol (6 mL). In an ice-water bath, slowly add sodium borohydride (114 mg, 3.02 mmol). The reaction mixture was brought to room temperature and stirred for 12 hours. TLC confirmed that the reaction was essentially complete. The solvent was removed by rotary evaporation under reduced pressure. Water (20 mL) and ethyl acetate (20 mL × 3) were added to the crude product, extracted, and separated. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio 1:3) to obtain 309 mg of a yellow oil in a yield of 52.75%. LC-MS (ESI) m / z: 291.04 (M+H) + .

[0306] Example 1: Synthesis of 6-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-1-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (1)

[0307] To a clean, dry flask were added intermediate 1-1 (120 mg, 0.80 mmol), intermediate a1 (261 mg, 0.96 mmol), acetonitrile (3 mL), and anhydrous potassium carbonate (221 mg, 1.60 mmol). The reaction system was stirred at room temperature for 14 hours. TLC indicated that the reaction of the starting materials was essentially complete. The reaction solution was filtered, the filter cake was washed with dichloromethane, and the filtrate was evaporated on a rotary evaporator under reduced pressure to remove the solvent. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio: 1:40) to obtain 174 mg of a yellow solid, with a yield of 56.31%. LC-MS (ESI) m / z: 387.28 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ8.01 (s, 1H), 7.88 (s, 1H), 7.34 (m, 4H), 5.48 (s, 2H), 5.31 (dd, J = 8.7, 3.8Hz, 1H), 4.85–4.68 (m, 2H), 4.29 (s, 3H).

[0308] Example 2: Synthesis of 5-chloro-3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-6-methylpyrimidin-4(3H)-one (2)

[0309] To a clean, dry flask, intermediate 2-1 (100 mg, 0.69 mmol), intermediate a1 (225 mg, 0.83 mmol), N,N-dimethylacetamide (2 mL), and anhydrous potassium carbonate (190 mg, 1.38 mmol) were added sequentially. The reaction system was stirred at 40°C for 14 hours, and TLC indicated that the reaction of the starting materials was essentially complete. The reaction solution was cooled to room temperature, diluted with water, and then extracted with ethyl acetate and separated. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio: 1:50) to obtain 185 mg of a white solid with a yield of 70.34%. LC-MS (ESI) m / z: 381.21 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ8.17(s,1H),7.35(m,4H),5.40(s,2H),5.30(dd,J=8.8,3.7Hz,1H),4.88–4.59(m,2H),3.25(s,1H),2.45(s,3H).

[0310] Example 3: Synthesis of 6-chloro-3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrimidin-4(3H)-one (3)

[0311] To a clean, dry flask, intermediate 3-1 (100 mg, 0.69 mmol), intermediate a1 (225 mg, 0.83 mmol), N,N-dimethylacetamide (2 mL), and anhydrous potassium carbonate (190 mg, 1.38 mmol) were added in sequence. The reaction system was stirred at 40°C for 14 hours, and TLC indicated that the reaction of the raw materials was essentially complete. The reaction solution was cooled to room temperature, diluted with water, and then extracted with ethyl acetate and separated. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio: 1:50) to obtain 226 mg of a white solid with a yield of 85.93%. LC-MS (ESI) m / z: 381.18 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ8.11 (s, 1H), 7.35 (m, 4H), 5.36 (s, 2H), 5.30 (dd, J = 8.9, 3.6Hz, 1H), 4.85–4.62 (m, 2H), 3.28 (s, 1H), 2.16 (s, 3H).

[0312] Referring to the similar preparation methods of Examples 1-3, the present invention also synthesized the following compounds:

[0313] Example 4: Synthesis of 6-((2-(2-(Benzothiophene-2-yl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-1-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (4)

[0314] To a clean, dry flask were added 1-methyl-1H-pyrazolo[4,3-D]pyrimidin-7-ol (1-1) (55 mg, 0.37 mmol), intermediate a2 (121 mg, 0.41 mmol), N,N-dimethylformamide (1 mL), and anhydrous potassium carbonate (102 mg, 0.74 mmol). The reaction system was stirred at 40°C for 12 hours, and TLC indicated that the starting material had essentially reacted completely. The reaction solution was cooled to room temperature, diluted with water (3 mL), and extracted with ethyl acetate (3 mL x 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 48 mg of a yellow solid in a yield of 31.79%. LC-MS (ESI) m / z: 409.40 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ7.99(s,1H),7.87(s,1H),7.83–7.75(m,1H),7.74–7.65(m,1H),7.41–7.31(m,2H),7. 26(s,1H),5.67(dt,J=8.5,4.1Hz,1H),5.47(s,2H),5.13–4.87(m,2H),4.27(s,3H),3.45(d,J=4.5Hz,1H).

[0315] Example 5: Synthesis of 3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one (5)

[0316] To a clean, dry flask were added intermediate a4 (120 mg, 0.74 mmol), N,N-dimethylformamide (1.5 mL), intermediate a1 (245 mg, 0.90 mmol), and anhydrous potassium carbonate (207 mg, 1.50 mmol). The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials were essentially reacted. The reaction solution was cooled to room temperature and diluted with water (3 mL). Extraction was performed with ethyl acetate (3 mL × 3) and the layers separated. The combined organic phases were washed with saturated brine (6 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 172 mg of a yellow solid, in a yield of 58.07%. LC-MS (ESI) m / z: 398.26 (M+H). + ; 1H NMR (400MHz, DMSO-d6) δ8.84–8.67(m,2H),7.42–7.31(m,5H),5.94(d,J=4 .9Hz,1H),5.48(s,2H),5.20–5.03(m,1H),4.83–4.74(m,2H),2.77(s,3H).

[0317] Example 6: Synthesis of 6-((2-(2-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-1-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (6)

[0318] To a clean, dry flask were added 1-methyl-1H-pyrazolo[4,3-D]pyrimidin-7-ol (1-1) (103 mg, 0.69 mmol), intermediate a3 (200 mg, 0.69 mmol), acetonitrile (10 mL), and anhydrous potassium carbonate (190 mg, 1.20 mmol). The reaction system was stirred at 50°C for 24 hours. TLC confirmed that the reaction was essentially complete. The reaction solution was cooled to room temperature and the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 160 mg of a yellow solid in a yield of 57.35%. LC-MS (ESI) m / z: 405.2 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.04(s,1H),7.66–7.07(m,3H),6.04(d, J=5.0Hz,1H),5.52(s,2H),5.21–5.09(m,1H),4.95–4.71(m,2H),4.19(s,3H).

[0319] Example 7: Synthesis of 2-amino-3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrazolo[5,1-f][1,2,4]triazine-4(3H)-one (7)

[0320] Synthesis of Intermediate 7-2: Place ethyl 4-methyl-1H-pyrazole-3-carboxylate (7-1) (2.00 g, 12.97 mmol) in a clean, dry flask, replace the atmosphere with nitrogen three times, and add tetrahydrofuran (60 mL). Place the reaction system at -20°C and slowly add a 1.0 mmol / mL solution of lithium bistrimethylsilylamide in tetrahydrofuran (14.27 mL, 14.27 mmol) dropwise. After the addition is complete, warm the reaction system to 0°C and continue stirring for 20 minutes. Add diphenylphosphonohydroxylamine (3.63 g, 15.56 mmol). Stir the reaction system at room temperature for 12 hours. TLC indicates that the starting material has essentially reacted. The solvent was removed under reduced pressure on a rotary evaporator. Dichloromethane and ethyl acetate (50 mL, volume ratio of 2:1) were added to the residue, stirred, and filtered. The solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio of 1:4) to obtain 1.10 g of a white solid, with a yield of 50.23%. LC-MS (ESI) m / z: 170.17 (M+H) + .

[0321] Synthesis of Intermediate 7-3: To a clean, dry microwave reaction tube (10 mL) were added intermediate 7-2 (200 mg, 1.18 mmol), 1,2-dichloroethane (5 mL), chloroformamidine hydrochloride (271 mg, 2.36 mmol), and N,N-diisopropylethylamine (381 mg, 2.95 mmol). The reaction system was placed in a microwave reactor and stirred at 160°C for 3 hours. TLC monitoring indicated that the reaction of the raw materials was essentially complete. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane and dried to obtain 80 mg of a yellow solid with a yield of 41.17%. LC-MS (ESI) m / z: 166.13 (M+H) + .

[0322] Synthesis of Compound 7: To a clean, dry flask were added intermediate 7-3 (80 mg, 0.48 mmol), N,N-dimethylformamide (1 mL), intermediate a1 (158 mg, 0.58 mmol), and anhydrous potassium carbonate (132 mg, 0.96 mmol). The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials were essentially reacted. The reaction solution was cooled to room temperature and diluted with water (3 mL). Extraction was performed with ethyl acetate (3 mL × 3) and the layers separated. The combined organic phases were washed with saturated brine (6 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 88 mg of a yellow solid, with a yield of 45.62%. LC-MS (ESI) m / z: 402.25 (M+H) + ;1 H NMR(400MHz,DMSO-d6)δ7.50–7.30(m,5H),6.79(s,2H),5.92(d,J=4.8Hz,1H ), 5.46 (s, 2H), 5.11 (dt, J = 7.3, 5.4Hz, 1H), 4.87–4.69 (m, 2H), 2.30 (s, 3H).

[0323] Example 8: Synthesis of 3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrazolo[5,1-f][1,2,4]triazine-4(3H)-one (8)

[0324] Synthesis of Intermediate 8-1: To a clean, dry flask, intermediate 7-2 (300 mg, 1.77 mmol) and formamide (1 mL) were added sequentially. The reaction system was stirred at 150°C for 12 hours. TLC confirmed that the starting materials were essentially reacted. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate and dried to obtain 95 mg of a yellow solid, a yield of 35.62%. LC-MS (ESI) m / z: 151.13 (M+H). + .

[0325] Synthesis of Compound 8: To a clean, dry flask were added intermediate 8-1 (79 mg, 0.52 mmol), N,N-dimethylformamide (1 mL), intermediate a1 (170 mg, 0.62 mmol), and anhydrous potassium carbonate (144 mg, 1.04 mmol). The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials were essentially reacted. The reaction solution was cooled to room temperature and diluted with water (3 mL). Extraction was performed with ethyl acetate (3 mL × 3) and the layers separated. The combined organic phases were washed with saturated brine (6 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:50) to obtain 84 mg of a white solid in a yield of 41.94%. LC-MS (ESI) m / z: 387.23 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.75(s,1H),7.50–7.21(m,4H),5.93(d,J=4.8Hz, 1H), 5.42 (s, 2H), 5.13 (dt, J = 7.6, 5.1Hz, 1H), 4.79 (dd, J = 6.4, 2.4Hz, 2H), 2.36 (s, 3H).

[0326] Example 9: Synthesis of 5-amino-6-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-1-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (9)

[0327] Synthesis of intermediate 9-2: To a clean, dry microwave reaction tube (10 mL) were added 4-amino-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (9-1) (300 mg, 1.93 mmol), 1,2-dichloroethane (5 mL), chloroformamidine hydrochloride (444 mg, 3.86 mmol) and N,N-diisopropylethylamine (622 mg, 4.83 mmol). The reaction system was placed in a microwave reactor and stirred at 130°C for 2 hours. TLC monitoring showed that the reaction of the raw materials was basically complete. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane and dried to obtain 252 mg of a yellow solid with a yield of 79.07%. LC-MS (ESI) m / z: 166.16 (M+H) + .

[0328] Synthesis of Compound 9: To a clean, dry flask were added intermediate 9-2 (200 mg, 1.21 mmol), N,N-dimethylformamide (3 mL), intermediate a1 (395 mg, 1.45 mmol), and anhydrous potassium carbonate (334 mg, 2.42 mmol). The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted. The reaction solution was cooled to room temperature and diluted with water (9 mL). Extraction was performed with ethyl acetate (6 mL × 3) and the layers separated. The combined organic phases were washed with saturated brine (6 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:30) to obtain 142 mg of a white solid, in a yield of 29.34%. LC-MS (ESI) m / z: 402.29 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ7.55 (s, 1H), 7.46–7.21 (m, 4H), 6.68 (s, 2H), 5.92 (d, J = 4. 8Hz, 1H), 5.50 (s, 2H), 5.10 (dt, J = 7.3, 5.4Hz, 1H), 4.87–4.69 (m, 2H), 4.08 (s, 3H).

[0329] Example 10: Synthesis of 3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-2,5-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one (10)

[0330] Synthesis of Intermediate 10-2: 2-Amino-4-methylpyridine-3-carboxylic acid (10-1) (300 mg, 1.97 mmol) and acetic anhydride (3 mL) were placed in a clean, dry flask (25 mL). The atmosphere was replaced with nitrogen three times, and the reaction system was stirred at 130°C for 12 hours. TLC monitoring indicated that the reaction of the starting materials was essentially complete. The solvent was removed under reduced pressure on a rotary evaporator, and the crude product was purified by silica gel chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:30) to obtain 294 mg of a light yellow solid, with a yield of 76.65%. LC-MS (ESI) m / z: 195.14 (M+H) + ;

[0331] Synthesis of Intermediate 10-3: To a clean, sealed reaction tube, intermediate 10-2 (294 mg, 1.51 mmol) and aqueous ammonia (7 mL) were added sequentially. The reaction system was stirred at 90°C for 12 hours. TLC indicated that the reaction of the starting materials was essentially complete. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:20) to obtain 215 mg of a white solid, with a yield of 81.46%. LC-MS (ESI) m / z: 176.13 (M+H) + ;

[0332] Synthesis of Compound 10: To a clean, dry flask were added intermediate 10-3 (215 mg, 1.23 mmol), N,N-dimethylformamide (5 mL), intermediate a1 (403 mg, 1.48 mmol), and anhydrous potassium carbonate (339 mg, 2.46 mmol). The reaction system was stirred at 30°C for 12 hours. TLC indicated that the starting materials were essentially reacted. The reaction solution was cooled to room temperature and diluted with water (20 mL). Extraction was performed with ethyl acetate (15 mL × 3) and the layers separated. The combined organic phases were washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:30) to obtain 73 mg of a white solid, with a yield of 14.41%. LC-MS (ESI) m / z: 412.25 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ8.73(d,J=4.8Hz,1H),7.49–7.13(m,5H),5.93(d,J=4.8Hz,1H),5.5 5(s,2H),5.12(dt,J=7.3,5.2Hz,1H),4.95–4.59(m,2H),2.76(d,J=0.8Hz,3H),2.62(s,3H).

[0333] Example 11: Synthesis of 3-((2-(2-(3-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one (11)

[0334] To a clean, dry flask were added intermediate a4 (100 mg, 0.62 mmol), N,N-dimethylformamide (1.2 mL), intermediate a5 (202 mg, 0.74 mmol), and anhydrous potassium carbonate (171 mg, 1.24 mmol). The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted completely. The reaction solution was cooled to room temperature and diluted with water (5 mL). The mixture was extracted with ethyl acetate (3 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 146 mg of a white solid, with a yield of 59.21%. LC-MS (ESI) m / z: 398.26 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ8.78(d,J=4.8Hz,1H),8.74(s,1H),7.47(d,J=2.1Hz,1H),7.39(dd,J=4.8,0.9Hz,1H),7. 35–7.26(m,3H),5.97(d,J=4.9Hz,1H),5.49(s,2H),5.14(dt,J=7.8,4.8Hz,1H),4.87–4.75(m,2H),2.77(s,3H).

[0335] Example 12: Synthesis of 3-((2-(2-(4-fluorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one (12)

[0336] To a clean, dry flask were added intermediate a4 (100 mg, 0.62 mmol), N,N-dimethylformamide (1.2 mL), intermediate a6 (190 mg, 0.74 mmol), and anhydrous potassium carbonate (171 mg, 1.24 mmol). The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials were essentially reacted. The reaction mixture was cooled to room temperature and diluted with water (5 mL). The mixture was extracted with ethyl acetate (3 mL x 3). The organic phases were combined, washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 171 mg of a white solid in a yield of 72.34%. LC-MS (ESI) m / z: 382.24 (M+H)+; 1 H NMR (400MHz, DMSO-d6) δ8.77(d,J=4.8Hz,1H),8.73(s,1H),7.45–7.29(m,3H),7.20–7.06(m,2H),5. 87 (d, J = 4.9 Hz, 1H), 5.48 (s, 2H), 5.11 (q, J = 6.1 Hz, 1H), 4.78 (d, J = 6.5 Hz, 2H), 2.77 (d, J = 0.8 Hz, 3H).

[0337] Example 13: Synthesis of 3-((2-(2-(Benzothiophene-2-yl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one (13)

[0338] To a clean, dry flask were added intermediate a4 (80 mg, 0.50 mmol), N,N-dimethylformamide (1 mL), intermediate a2 (176 mg, 0.60 mmol), and anhydrous potassium carbonate (138 mg, 1.00 mmol). The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted completely. The reaction solution was cooled to room temperature and diluted with water (5 mL). The mixture was extracted with ethyl acetate (3 mL x 3). The organic phases were combined, washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 170 mg of a white solid in an 81.12% yield. LC-MS (ESI) m / z: 420.27 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ8.78(d,J=4.8Hz,1H),8.75(s,1H),7.91(dd,J=7.8,1.5Hz,1H),7.80–7.63(m,1H ),7.41–7.22(m,4H),6.46(d,J=5.2Hz,1H),5.65–5.32(m,3H),5.06–4.82(m,2H),2.77(d,J=7.2Hz,3H).

[0339] Example 14: Synthesis of 3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-7-carbonitrile (14)

[0340] To a clean, dry flask were added intermediate a7 (40 mg, 0.21 mmol), N,N-dimethylformamide (2 mL), intermediate a1 (60 mg, 0.22 mmol), and anhydrous potassium carbonate (55 mg, 0.40 mmol). The reaction system was stirred at room temperature for 12 hours. TLC indicated that the starting materials were essentially reacted. The reaction solution was diluted with water (6 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:50 to 1:20) to obtain 52 mg of a light yellow oil, with a yield of 58.70%. LC-MS (ESI) m / z: 423.2 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ8.49(s,1H),7.55(s,1H),7.39–7.31(m,4H),5.46(s,2H),5.33(dd,J=8.8,3.7Hz,1H),4.89–4.67(m,2H),2.92(s,3H).

[0341] Example 15: Synthesis of 3-((2-(2-(4-cyclopropylphenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one (15)

[0342] To a clean, dry flask were added intermediate a4 (135 mg, 0.84 mmol), N,N-dimethylformamide (5 mL), intermediate a8 (234 mg, 0.84 mmol), and anhydrous potassium carbonate (173 mg, 1.26 mmol). The reaction system was stirred at room temperature for 12 hours. TLC indicated that the starting materials had essentially reacted. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:30) to obtain 161 mg of a white solid, with a yield of 47.65%. LC-MS (ESI) m / z: 404.26 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.79–8.75(m,1H),8.75–8.71(m,1H),7.38(dt,J=6.3,3.2Hz,1H) ,7.23(dd,J=8.3,2.3Hz,2H),7.00(dd,J=8.3,2.4Hz,2H),5.73(dd,J=4.7,2.2Hz,1H),5.4 8(t,J=1.5Hz,2H),5.04(t,J=6.3Hz,1H),4.73(dd,J=6.6,2.2Hz,2H),2.81–2.73(m,3H),1 .86(ddt,J=8.3,5.7,2.8Hz,1H), 0.91(dt,J=8.6,2.7Hz,2H), 0.61(dd,J=5.4,2.7Hz,2H).

[0343] Example 16: Synthesis of 3-((2-(2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one (16)

[0344] To a clean, dry flask were added intermediate a4 (80 mg, 0.50 mmol), N,N-dimethylformamide (2 mL), intermediate a9 (184 mg, 0.60 mmol), and anhydrous potassium carbonate (104 mg, 0.75 mmol). The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted completely. The reaction solution was cooled to room temperature and diluted with water (8 mL). The mixture was extracted with ethyl acetate (8 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 87 mg of a white solid, in a yield of 40.38%. LC-MS (ESI) m / z: 432.20 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.77(dd,J=5.0,2.3Hz,1H),8.73(d,J=2.4Hz,1H),7.67(dd,J=8.5,2.3Hz,2H),7.60(d,J=7.8Hz,2H),7 .41–7.33(m,1H),6.04(s,1H),5.48(d,J=2.4Hz,2H),5.23(d,J=8.1Hz,1H),4.84(tq,J=12.3,4.1Hz,2H),2.77(d,J=2.3Hz,3H).

[0345] Example 17: Synthesis of 3-((2-(2-(3,4-difluorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one (17)

[0346] To a clean, dry flask were added intermediate a4 (80 mg, 0.50 mmol), N,N-dimethylformamide (2 mL), intermediate a10 (165 mg, 0.60 mmol), and anhydrous potassium carbonate (104 mg, 0.75 mmol). The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted completely. The reaction solution was cooled to room temperature and diluted with water (8 mL). The mixture was extracted with ethyl acetate (8 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 121 mg of a white solid in a 60.70% yield. LC-MS (ESI) m / z: 400.19 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ8.77(d,J=2.4Hz,1H),8.72(d,J=2.4Hz,1H),7.51–7.26(m,3H),7.21(t,J=6.2Hz ,1H),6.01(s,1H),5.47(d,J=2.3Hz,2H),5.12(d,J=6.5Hz,1H),4.87–4.70(m,2H),2.76(d,J=2.3Hz,3H).

[0347] Example 18: Synthesis of 3-((2-(2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one (18)

[0348] To a clean, dry flask were added intermediate a4 (100 mg, 0.62 mmol), N,N-dimethylformamide (5 mL), intermediate a11 (199 mg, 0.68 mmol), and anhydrous potassium carbonate (129 mg, 0.93 mmol). The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted completely. The reaction solution was cooled to room temperature and diluted with water (20 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:25) to obtain 163 mg of a white solid in a yield of 62.90%. LC-MS (ESI) m / z: 416.17 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.77(dd,J=4.9,2.1Hz,1H),8.72(d,J=2.1Hz,1H),7.60(dd,J=7.3,2.3Hz,1H),7.42–7.27(m ,3H),5.99(dd,J=5.0,2.1Hz,1H),5.47(d,J=2.2Hz,2H),5.24–5.02(m,1H),4.95–4.57(m,2H),2.76(d,J=2.2Hz,3H).

[0349] Example 19: Synthesis of 3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one (19)

[0350] To a clean, dry flask, pyrrolo[2,3-D]pyrimidin-4(hydrogen)-one (19-1) (100 mg, 0.68 mmol), N,N-dimethylformamide (4 mL), intermediate a1 (224 mg, 0.82 mmol), and anhydrous potassium carbonate (141 mg, 1.02 mmol) were added sequentially. The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted completely. The reaction solution was cooled to room temperature and diluted with water (20 mL). The solution was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 230 mg of a waxy solid in an 88.16% yield. LC-MS (ESI) m / z: 384.13 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ9.02(dt,J=4.5,2.1Hz,1H),8.79(d,J=2.0Hz,1H),8.56(dt,J=8.0,2.1Hz,1H),7.62(ddd,J=7.7,4.5,2 .0Hz,1H),7.49–7.21(m,4H),5.91(dd,J=4.9,2.0Hz,1H),5.53(d,J=2.0Hz,2H),5.11(dt,J=8.4,5.2Hz,1H),4.90–4.59(m,2H).

[0351] Example 20: Synthesis of 8-chloro-3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyridone[3,4-d]pyrimidin-4(3H)-one (20)

[0352] Synthesis of Intermediate 20-2: Compound 20-1 (10.00 g, 47.52 mmol) was dissolved in anhydrous tetrahydrofuran (300 mL), and the reaction system was purged with nitrogen three times. A 2M solution of lithium diisopropylamine in tetrahydrofuran (47.5 mL, 90 mmol) was slowly added dropwise while stirring in a dry ice-ethanol bath at -78°C. The mixture was allowed to react at -78°C for 4 hours. The dry ice-ethanol bath was removed, and dry ice (41.80 g, 950 mmol) was added to the reaction system. The reaction was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride (200 mL) and water (200 mL) were slowly poured into the reaction system. The reaction solution was washed with ethyl acetate (300 mL) and acidified with 6M aqueous hydrochloric acid (5 mL). The reaction solution was concentrated under reduced pressure to obtain 9.00 g of crude yellow solid compound 20-2. 1H NMR (400MHz, DMSO-d6) 8.60 (s, 1H). LC-MS(ESI)m / z:255.8(M+H+2) + .

[0353] Synthesis of Intermediate 20-3: Compound 20-2 (7.40 g, 29.08 mmol) was dissolved in acetonitrile (100 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (5.31 g, 34.88 mmol) was added at room temperature. The reaction system was purged with nitrogen three times. Methyl iodide (4.95 g, 34.88 mmol) was slowly added dropwise with stirring at 0°C. The reaction was allowed to react at room temperature for 4 hours. Water (300 mL) was poured into the reaction system, and the mixture was extracted three times with ethyl acetate (300 mL). The organic phase was washed twice with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column (mobile phase: petroleum ether and ethyl acetate, volume ratio: 20 / 1 to 10 / 1) afforded 3.80 g of compound 20-3 as a colorless oil, with a two-step yield of 36.21%. 1 H NMR (400MHz, DMSO-d6) 8.67 (s, 1H), 3.99 (s, 3H). LC-MS(ESI)m / z:269.9(M+H+2) + .

[0354] Synthesis of Intermediate 20-4: Compound 20-3 (3.58 g, 13.33 mmol), compound 20-3a (4.35 g, 17.33 mmol, 50% by mass solution in tetrahydrofuran), potassium carbonate (5.53 g, 40.01 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (488 mg, 0.67 mmol) were placed in a 250 mL flask. Dioxane solution (60 mL) and water (6 mL) were added at room temperature. The atmosphere in the flask was replaced with nitrogen three times, and the reaction was stirred in an oil bath at 80°C for 12 hours. Water (100 mL) was poured into the reaction system, and the mixture was extracted three times with ethyl acetate (100 mL). The organic phase was washed twice with saturated brine and twice with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column (mobile phase: petroleum ether and ethyl acetate, volume ratio of 20 / 1 to 10 / 1) gave 1.45 g of compound 20-4 as a white solid, with a yield of 53.43%. LC-MS (ESI) m / z: 204.0 (M+H) + ; 1 H NMR (400MHz, DMSO-d6)8.32(s,1H),3.95(s,3H),2.34(s,3H).

[0355] Synthesis of Intermediate 20-5: Compound 20-4 (700 mg, 3.44 mmol) was dissolved in dioxane (10 mL) and aqueous ammonia (3 mL) in a 50 mL flask. Under nitrogen, the mixture was stirred in an oil bath at 100°C for 12 hours. The reaction mixture was concentrated under reduced pressure to yield 641 mg of crude yellow solid compound 20-5. LC-MS (ESI) m / z: 187.1 (M+H) + .

[0356] Synthesis of Intermediate 20-6: Compound 20-5 (641 mg, 3.44 mmol) and compound 20-5a (7.15 g, 68.68 mmol) were placed in a 50 mL flask and triethyl orthoformate (20 mL) was added at room temperature. Under nitrogen, the mixture was stirred in an oil bath at 140°C for 2 hours. The reaction solution was concentrated under reduced pressure. Purification by silica gel column chromatography (mobile phase: dichloromethane and methanol, volume ratio: 20 / 1 to 10 / 1) afforded 46.0 mg of 20-6 as a white solid, with a two-step yield of 7%. 1 H NMR (400MHz, DMSO-d6)12.67(s,1H),8.31-8.16(m,2H),2.67(s,3H). LC-MS(ESI)m / z:196.0(M+H) + .

[0357] Synthesis of Final Product 20: 20-6 (40 mg, 0.20 mmol) and N,N-dimethylformamide (2 mL) were placed in a clean, dry reaction tube (15 mL). Anhydrous potassium carbonate (50 mg, 0.36 mmol) was added. After stirring at room temperature for 1 hour, intermediate a1 (68 mg, 0.25 mmol) was added. TLC indicated that the starting materials were essentially reacted. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and washed with silica gel. Purification was performed by silica gel chromatography (mobile phase: dichloromethane and methanol, 50:1 volume ratio) to obtain 52 mg of a white solid, in a yield of 59.09%. LC-MS (ESI) m / z: 432.0 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.30(s,1H),7.50–7.22(m,4H),5.92(dd,J=4.9,1. 8Hz, 1H), 5.55–5.44 (m, 2H), 5.17–5.04 (m, 1H), 4.79 (d, J = 6.3Hz, 2H), 2.70–2.60 (m, 3H).

[0358] Example 21: Synthesis of (R)-2-amino-3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyridone[2,3-d]pyrimidin-4(3H)-one (21)

[0359] Synthesis of Intermediate 21-3: Compound 21-1 (2.00 g, 8.55 mmol), compound 20-3a (3.22 g, 12.83 mmol, 50% by mass in tetrahydrofuran), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (625 mg, 0.85 mmol), and potassium carbonate (3.54 g, 25.63 mmol) were placed in a 50 mL flask. Anhydrous dioxane (20 mL) and water (2 mL) were added. Under nitrogen, the mixture was stirred at 80°C for 12 hours. The reaction solution was diluted with water (100 mL), and the aqueous phase was extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Compound 21-3 was purified by silica gel column chromatography (mobile phase: petroleum ether and ethyl acetate, volume ratio: 20 / 1 to 3 / 1) to obtain 1.20 g of a white solid in an 83.00% yield. LC-MS (ESI) m / z: 170.1 (M+H) + : 1 HNMR (400MHz, CDCl3) δ8.13 (d, J = 5.2 Hz, 1H), 7.07 (d, J = 5.2 Hz, 1H), 3.95 (s, 3H), 2.47 (s, 3H).

[0360] Synthesis of Intermediate 21-5: Compound 21-4 (1.36 g, 14.24 mmol) was placed in a 250 mL flask, and N,N-dimethylacetamide (50 mL) was added. Under nitrogen, 60% sodium hydride (568 mg, 14.24 mmol) was added. After stirring at room temperature for 1 hour, compound 21-3 (800 mg, 4.73 mmol) was added, and the mixture was stirred at 110°C for 11 hours. The reaction was quenched with water (150 mL) in an ice bath, and the aqueous phase was washed twice with dichloromethane, and the organic phase was discarded. The aqueous phase was adjusted to a pH of approximately 7 with 1 M aqueous hydrochloric acid, resulting in the precipitation of a white solid. The filtered solid was purified by slurrying with dichloromethane / methanol (200 mL, 1 / 20 volume ratio) to afford 514 mg of compound 21-5 as a yellow solid in a 61.70% yield. LC-MS (ESI) m / z: 177.1 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.46-8.32(m,1H),6.93-6.79(m,1H),6.71-6.44(m,2H),2.66(s,3H).

[0361] Synthesis of Compound 21: 21-5 (176 mg, 1.00 mmol) and N-methylpyrrolidone (4 mL) were placed in a clean, dry reaction tube (15 mL). Anhydrous potassium carbonate (207 mg, 1.50 mmol) was added. After stirring at room temperature for 1 hour, intermediate a1-R (300 mg, 1.10 mmol) was added. TLC indicated that the starting materials had essentially reacted. The reaction mixture was quenched with water (8 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 10:1) to obtain 160 mg of a white solid, in a yield of 38.76%. LC-MS (ESI) m / z: 413.1 (M+H) + : 1 H NMR (400MHz, DMSO-d6) δ8.4–8.3(m,1H),7.60–7.12(m,7H),5.92(dd,J=4.9,1.8Hz, 1H),5.75–5.64(m,2H),5.17–5.04(m,1H),4.77(d,J=6.3Hz,2H),2.70–2.60(m,3H).

[0362] Example 22: Synthesis of 2-amino-3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4(3H)-one (22)

[0363] Synthesis of Intermediate 22-2: 22-1 (300 mg, 1.46 mmol) and ethanol (5 mL) were placed in a clean, dry, single-necked flask (50 mL). Formamidine acetate (455 mg, 4.37 mmol) was then added and stirred at 100°C overnight. TLC confirmed the reaction was essentially complete. After cooling to room temperature, the formamidine acetate was removed by filtration. The reaction mixture was then quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure on a rotary evaporator to remove the solvent, affording the crude product. The crude product was then purified by silica gel chromatography (mobile phase: dichloromethane: methanol, 25:1 volume ratio) to afford 166 mg of a white solid in a 52.87% yield. LC-MS (ESI) m / z: 216.13 (M+H) + .

[0364] Synthesis of Final Product 22: 22-2 (166 mg, 0.77 mmol) and N,N-dimethylformamide (5 mL) were placed in a clean, dry reaction tube (25 mL). Compound a1 (232 mg, 0.85 mmol) and anhydrous potassium carbonate (160 mg, 1.16 mmol) were added and stirred at room temperature overnight. TLC indicated that the reaction was essentially complete. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (8 mL × 3). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure on a rotary evaporator to obtain the crude product. Purification by silica gel chromatography (mobile phase: dichloromethane and methanol, 25:1 volume ratio) afforded 100 mg of a clear oily liquid in a yield of 28.74%. LC-MS (ESI) m / z: 452.14 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ9.24(d,J=4.8Hz,1H),8.91(s,1H),7.99(d,J=4.9Hz,1H ),7.45–7.27(m,4H),5.94(s,1H),5.54(s,2H),5.12(s,1H),4.83–4.74(m,2H).

[0365] Example 23: Synthesis of 3-(1-(2-(4-chlorophenyl)-2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)methyl)-5-methylpyridone[2,3-d]pyrimidin-4(3H)-one (23)

[0366] Synthesis of Intermediate 23-3: 23-1 (800 mg, 6.29 mmol) and N,N-dimethylformamide (10 mL) were placed in a clean, dry reaction flask (50 mL). Anhydrous potassium carbonate (1.70 g, 12.31 mmol) was added and stirred at room temperature for 1 hour. Intermediate 23-2 (1.46 g, 6.25 mmol) was added and stirred at room temperature for 6 hours. TLC indicated that the starting materials were essentially reacted. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and washed with silica gel. Purification was performed by silica gel chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:5) to obtain 580 mg of a solid, in a yield of 33.33%. LC-MS (ESI) m / z: 280.0 (M+H). + .

[0367] Synthesis of Intermediate 23-4: Intermediate 23-3 (280 mg, 1.00 mmol) and anhydrous tetrahydrofuran (4 mL) were placed in a clean, dry reaction flask (25 mL). A solution of lithium aluminum hydride in tetrahydrofuran (1 mol / L, 3 mL) was added under ice-cooling and stirred for 2 h. TLC confirmed the substantial reaction. Water (5 mL) was slowly added to the reaction mixture to quench the reaction. Extraction afforded 251 mg of an oily product, which was then used in the next step without further purification. LC-MS (ESI) m / z: 254.7 (M+H) + .

[0368] Synthesis of Compound 23: Intermediate a4 (161 mg, 1.00 mmol), 23-4 (304 mg, 1.20 mmol), triphenylphosphine (582 mg, 2.20 mmol), and N,N-dimethylformamide (3 mL) were placed in a clean, dry reaction flask (25 mL) and stirred under an ice bath. Diisopropyl azodicarboxylate (0.44 mL, 2.22 mmol) was added dropwise to the mixture under a nitrogen atmosphere. After the addition was complete, the mixture was stirred at room temperature for 5 hours. TLC confirmed that the reaction was essentially complete. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (8 mL × 3). The organic phases were combined, washed with saturated brine (8 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and mixed with silica gel. Purification was performed by silica gel chromatography (mobile phase: dichloromethane and methanol, volume ratio 20:1) to obtain 62 mg of the oily product in a yield of 15.62%. LC-MS (ESI) m / z: 397.1 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ8.76–8.70(m,1H),8.66(d,J=2.5Hz,1H),7.75(d,J=2.4Hz,1H),7.40–7.20(m,5H ),5.80–5.70(m,1H),5.53(d,J=2.4Hz,2H),5.21(d,J=2.4Hz,1H),4.54–4.34(m,3H),2.85–2.78(m,2H).

[0369] Example 24: Synthesis of 2-amino-3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)pteridin-4(3H)-one (24)

[0370] Synthesis of Final Product 24: 2-Amino-4-hydroxypteridine (24-1) (400 mg, 2.45 mmol) and DMSO (3 mL) were placed in a clean, dry reaction tube (25 mL). Anhydrous potassium carbonate (679 mg, 4.90 mmol) was added and stirred at 40°C. Alpha 1 (558 mg, 2.04 mmol) was dissolved in DMSO (2 mL) and added to the reaction system in four portions. After 15 hours, TLC confirmed that the starting material had reacted substantially completely. The reaction solution was cooled to room temperature, quenched with water (3 mL), filtered, and the filter cake was collected. The filter cake was purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, 40:1 volume ratio) to obtain 106 mg of a white solid, with a yield of 12.97%. LC-MS (ESI) m / z: 400.20. 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=2.1Hz,1H),8.42(d,J=2.1Hz,1H),7.80–7.65(m,2H),7.36(d, J=1.5Hz,4H),5.92(d,J=4.8Hz,1H),5.53(s,2H),5.10(dt,J=7.3,5.3Hz,1H),4.84–4.63(m,2H).

[0371] Example 25: Synthesis of 6-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)pyrimido[4,5-c]pyridazin-5(6H)-one (25)

[0372] Synthesis of Final Product 25: Pyrimido[4,5-C]pyridazin-5(1H)-one (25-1) (60 mg, 0.41 mmol) and N,N-dimethylformamide (2 mL) were added to a clean, dry reaction tube (25 mL). Compound a1 (122 mg, 0.45 mmol) and anhydrous potassium carbonate (84 mg, 0.61 mmol) were added and stirred at room temperature overnight. TLC confirmed the reaction was essentially complete. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. Purification by silica gel chromatography (mobile phase: dichloromethane and methanol, 20:1 volume ratio) afforded 103 mg of a white solid in a 65.19% yield. LC-MS (ESI) m / z: 385.17 (M+H) + ; 1 H NMR(400MHz, DMSO-d6)δ9.56(d,J=5.2Hz,1H),8.91(s,1H),8.33(d,J=5.2Hz,1H),7.53–7.2 0(m,4H),5.91(d,J=4.8Hz,1H),5.54(s,2H),5.11(dt,J=7.4,5.2Hz,1H),4.88–4.69(m,2H).

[0373] Example 26: Synthesis of 6-chloro-3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one (26)

[0374] Synthesis of Intermediate 26-2: 26-1 (200 mg, 1.00 mmol) was placed in a clean, dry reaction tube (25 mL). Formamide (3 mL) was added and stirred at 150°C for 48 hours. TLC indicated that the reaction was essentially complete. The reaction solution was cooled to room temperature and then placed in an ice-water bath. A yellow solid precipitated and was filtered. The filter cake was washed with ethyl acetate and dried to yield 68 mg of a yellow solid, a yield of 37.22%. LC-MS (ESI) m / z: 182.13 (M+H). + .

[0375] Synthesis of Final Product 26: 26-2 (60 mg, 0.33 mmol) and N,N-dimethylformamide (1 mL) were placed in a clean, dry reaction tube (25 mL). Compound a1 (109 mg, 0.40 mmol) and anhydrous potassium carbonate (91.08 mg, 0.66 mmol) were added and stirred at 40°C for 12 hours. TLC indicated that the reaction was essentially complete. The reaction mixture was cooled to room temperature and quenched with water (3 mL). The mixture was extracted with ethyl acetate (3 mL × 3). The organic phases were combined, washed with saturated brine (6 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent removed by rotary evaporation under reduced pressure to obtain the crude product. Purification by silica gel chromatography (mobile phase: dichloromethane and methanol, 40:1 volume ratio) afforded 95 mg of a white solid in a 68.84% yield. LC-MS (ESI) m / z: 418.21 (M+H) + ; 1 H NMR(400MHz, DMSO-d6)δ9.04(d,J=2.7Hz,1H),8.81(s,1H),8.57(d,J=2.8Hz,1H),7.39–7.3 2(m,4H),5.91(d,J=4.8Hz,1H),5.53(s,2H),5.11(dt,J=7.3,5.2Hz,1H),4.88–4.71(m,2H).

[0376] Example 27: Synthesis of (R)-3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrimido[4,5-d]pyrimidin-4(3H)-one (27)

[0377] Synthesis of Intermediate 27-2: 27-1 (2.00 g, 8.69 mmol) was placed in a clean, dry reaction flask (250 mL). Ethanol (20 mL) was added, along with formamidine acetate (1.085 g, 10.42 mmol) and potassium tert-butoxide (2.144 g, 19.11 mmol). The mixture was stirred overnight at room temperature. TLC confirmed that the reaction was essentially complete. The solvent was removed by rotary evaporation to obtain the crude product, which was then purified by silica gel chromatography (mobile phase: dichloromethane and methanol, volume ratio 20:1) to afford 1.16 g of a pale yellow oily liquid in a yield of 73.28%. LC-MS (ESI) m / z: 183.11 (M+H). + .

[0378] Synthesis of Intermediate 27-3: 27-2 (660 mg, 3.62 mmol) was placed in a clean, dry reaction flask (50 mL). Toluene (12 mL) and phosphorus oxychloride (1.11 g, 7.25 mmol) were added, and the mixture was stirred at 120°C for 1 hour. TLC confirmed that the reaction was essentially complete. Saturated sodium bicarbonate solution was added dropwise to the reaction mixture until the pH was 7-8. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator to obtain the crude product. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:8) to obtain 300 mg of a white solid in a yield of 41.28%. LC-MS (ESI) m / z: 201.10 (M+H) + .

[0379] Synthesis of Intermediate 27-4: 27-3 (300 mg, 1.50 mmol) was placed in a clean, dry reaction flask (50 mL). Ethanol (5 mL) and aqueous ammonia (5 mL) were added and stirred at 120°C overnight. TLC indicated that the reaction was essentially complete. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator to obtain the crude product. The crude product was separated and purified by silica gel chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:4) to obtain 200 mg of a white solid, with a yield of 73.81%. LC-MS (ESI) m / z: 182.16 (M+H) + .

[0380] Synthesis of Intermediate 27-5: 27-4 (200 mg, 1.10 mmol) was placed in a clean, dry reaction flask (50 mL). Ethanol (5 mL) and formamidine acetate (288 mg, 2.77 mmol) were added. The mixture was stirred at 130°C for 4 hours under microwave conditions. TLC indicated that the reaction was essentially complete. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator to obtain the crude product. The crude product was separated and purified by silica gel chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:10) to obtain 35 mg of a white solid, with a yield of 19.61%. LC-MS (ESI) m / z: 163.15 (M+H) + .

[0381] Synthesis of Final Product 27: 27-5 (67 mg, 0.41 mmol) and N,N-dimethylformamide (1 mL) were placed in a clean, dry reaction tube (25 mL). Al-R (124 mg, 0.45 mmol) and anhydrous potassium carbonate (86 mg, 0.62 mmol) were added and stirred at room temperature overnight. TLC indicated that the reaction was essentially complete. The reaction mixture was cooled to room temperature and quenched with water (3 mL). The mixture was extracted with ethyl acetate (3 mL × 3). The organic phases were combined, washed with saturated brine (6 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. Purification by silica gel chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:25) afforded 20 mg of a white solid in a yield of 12.20%. LC-MS (ESI) m / z: 399.21 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ9.21 (s, 1H), 8.96 (s, 1H), 7.41–7.33 (m, 4H), 5.93 (d, J = 4. 8Hz, 1H), 5.51 (s, 2H), 5.12 (dt, J = 7.4, 5.2Hz, 1H), 4.92–4.56 (m, 2H), 2.91 (s, 3H).

[0382] Example 28: Synthesis of (S)-3-((2-(2-(5-chlorothiophen-2-yl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyridone[2,3-d]pyrimidin-4(3H)-one (28)

[0383] Synthesis of Intermediate 28-2: 28-1 (300 mg, 1.25 mmol) was placed in a clean, dry reaction flask (50 mL). N,N-dimethylformamide (3 mL) was added, along with a1-1 (149 mg, 1.25 mmol) and anhydrous potassium carbonate (259 mg, 1.88 mmol). The mixture was stirred at room temperature overnight. TLC indicated that the reaction was essentially complete. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator to obtain the crude product. The crude product was purified by silica gel chromatography (mobile phase: ethyl acetate and petroleum ether, 1:4 volume ratio) to afford 200 mg of a white solid in a 57.60% yield. LC-MS (ESI) m / z: 277.04 (M+H). + .

[0384] Synthesis of intermediate 28-3: 28-2 (200 mg, 0.72 mmol) was placed in a clean, dry reaction flask (50 mL), the atmosphere was replaced with nitrogen three times, acetonitrile (4 mL) was added, and under a nitrogen atmosphere, (mesitylene) chloride [(S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]ruthenium (II) (4.43 mg, 0.007 mmol) and formic acid-triethylamine (5:2) addition compound (310 mg, 2.17 mmol) were added in sequence. The reaction was stirred at room temperature overnight. TLC detected that the raw materials were basically reacted. The solvent was evaporated under reduced pressure, and the reaction system was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure on a rotary evaporator to obtain the crude product. The crude product was separated and purified by silica gel chromatography (mobile phase: ethyl acetate and petroleum ether, volume ratio: 1:4) to obtain 114 mg of a light yellow oily liquid, with a yield of 56.56%. LC-MS (ESI) m / z: 279.05 (M+H) + .

[0385] Synthesis of final product 28: Compound a4 (66 mg, 0.41 mmol) and N,N-dimethylformamide (1 mL) were placed in a clean, dry reaction tube (25 mL). Compound 28-3 (114 mg, 0.41 mmol) and anhydrous potassium carbonate (85 mg, 0.61 mmol) were added and stirred at room temperature overnight. TLC confirmed the reaction was essentially complete. The reaction mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:20) to afford 34 mg of a white solid in a yield of 20.53%. LC-MS (ESI) m / z: 404.21 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.77(d,J=4.8Hz,1H),8.74(s,1H),7.46–7.34(m,1H),6.94(d,J=3.8Hz,1H),6.87(dd,J=3. 9,0.9Hz,1H),6.41(d,J=5.2Hz,1H),5.49(s,2H),5.29(dt,J=9.0,4.8Hz,1H),4.92–4.79(m,2H),2.78–2.72(m,3H).

[0386] Example 29: Synthesis of 8-chloro-3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylquinazolin-4(3H)-one (29)

[0387] Synthesis of Intermediate 29-2: Compound 29-1 (1.60 g, 6.39 mmol) was dissolved in triethyl orthoformate (50 mL) and ammonium acetate (2.46 g, 31.91 mmol) was added at room temperature. The reaction was stirred at 130°C for 12 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. 10 mL of dichloromethane and 10 mL of water were then added to slurry. The resulting mixture was filtered, and the filter cake was washed with 10 mL of water, 10 mL of dichloromethane, and 10 mL of acetonitrile, respectively. The filter cake was concentrated under reduced pressure to obtain 1.33 g of a gray solid, with a yield of 80.22%. LC-MS (ESI) m / z: 260.9 (M+2+H). + ; 1 H NMR (400MHz, DMSO-d6) δ 12.57 (brs, 1H), 8.22 (s, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.70 (d, J = 8.0Hz, 1H).

[0388] Synthesis of Intermediate 29-3: Intermediate 29-2 (500 mg, 1.93 mmol) and compound 20-3a (1.45 g, 5.78 mmol, 50% by mass in tetrahydrofuran) were dissolved in dimethyl sulfoxide (10 mL) and water (1 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (163 mg, 0.19 mmol) and potassium carbonate (799 mg, 5.78 mmol) were added at room temperature. The atmosphere was replaced with nitrogen three times and the reaction was stirred at 100°C for 12 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain 146 mg of a white solid, with a yield of 38.83%. LC-MS (ESI) m / z: 195.0 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.12 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 2.73 (s, 3H).

[0389] Synthesis of Compound 29: Intermediate 29-3 (26 mg, 0.13 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL). Compound a1-R (44 mg, 0.16 mmol) and potassium carbonate (55 mg, 0.40 mmol) were added at room temperature. The reaction was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:20) to obtain 49 mg of a white solid, with a yield of 87.50%. LC-MS (ESI) m / z: 431.0 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.63 (s, 1H), 7.87 (d, J = 8.4Hz, 1H), 7.39-7.30 (m, 5H), 5. 95-5.93(m,1H),5.47(s,2H),5.15-5.08(m,1H),4.81-4.74(m,2H),2.71(s,3H).

[0390] Example 30: Synthesis of (R)-3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one (5-R)

[0391] To a clean, dry flask were added intermediate a4 (120 mg, 0.74 mmol), N,N-dimethylformamide (1.5 mL), intermediate a1-R (245 mg, 0.90 mmol), and anhydrous potassium carbonate (207 mg, 1.50 mmol). The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials were essentially reacted. The reaction solution was cooled to room temperature and diluted with water (3 mL). Extraction and separation were performed with ethyl acetate (3 mL × 3). The combined organic phases were washed with saturated brine (6 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 170 mg of a yellow solid, in a yield of 57.82%. LC-MS (ESI) m / z: 398.26 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ8.84–8.67(m,2H),7.42–7.31(m,5H),5.94(d,J=4 .9Hz,1H),5.48(s,2H),5.20–5.03(m,1H),4.83–4.74(m,2H),2.77(s,3H).

[0392] Example 31: Synthesis of (R)-2-amino-3-((2-(2-(4-chlorophenyl)-2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)-5-methylpyrazolo[5,1-f][1,2,4]triazine-4(3H)-one (7-R)

[0393] To a clean, dry flask were added intermediate 7-3 (80 mg, 0.48 mmol), N,N-dimethylformamide (1 mL), intermediate a1-R (158 mg, 0.58 mmol), and anhydrous potassium carbonate (132 mg, 0.96 mmol). The reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted. The reaction solution was cooled to room temperature and diluted with water (3 mL). The mixture was extracted with ethyl acetate (3 mL × 3) and separated. The combined organic phases were washed with saturated brine (6 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 80 mg of a yellow solid in a yield of 41.88%. LC-MS (ESI) m / z: 402.25 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ7.50–7.30(m,5H),6.79(s,2H),5.92(d,J=4.8Hz,1H ), 5.46 (s, 2H), 5.11 (dt, J = 7.3, 5.4Hz, 1H), 4.87–4.69 (m, 2H), 2.30 (s, 3H).

[0394] Biological activity test

[0395] Experimental Example 1: Determination of the inhibitory activity of the compounds of the present invention on TRPA1

[0396] Experimental purpose: The inhibitory effect of the compounds of the present invention on TRPA1 can be evaluated by measuring calcium flux after incubation in stably transfected TRPA1 cells in vitro.

[0397] method:

[0398] A HEK293 cell line stably expressing the human TRPA1 ion channel (constructed by the Cell Biology Group of Aisiyi) was used as a test system for compound potency and efficacy. The effects of the compounds on allyl isothiocyanate (AITC) (Sigma, 36682)-induced intracellular calcium concentration were determined using a FLIPR Penta system (Molecular Devices).

[0399] Cell culture:

[0400] HEK-293 cells stably expressing the human TRPA1 ion channel were cultured in DMEM (Hyclone, SH30243.01) containing 10% fetal bovine serum (AusGeneX, FBS500-S), 10 μg / mL Blasticidin S (Solarbio B9300), and 100 μg / mL Zeocin (Solarbio Z8020) at 37°C and a carbon dioxide concentration of 5%.

[0401] Remove the old culture medium and wash once with PBS, then add 1 mL of 0.25%-Trypsin-EDTA solution and incubate at 37°C for about 1 minute. When the cells detach from the bottom of the flask, add about 3 mL of complete culture medium preheated at 37°C. Gently pipette the cell suspension to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect the cells. For expansion or maintenance culture, inoculate the cells into T25 cell culture flasks, with 5×10 cells in each cell culture dish. 5 To maintain the physiological activity of cells, the experimental cell confluence was 80%-90%.

[0402] Compound preparation:

[0403] The test compound was dissolved in 100% DMSO at a concentration of 10 mM, followed by a three-fold serial dilution step in 100% DMSO to prepare 10 different concentrations. The test compound was then diluted 1:100 in 1x Hank's Balanced Salt Solution (HBSS) buffer containing 20 mM HEPES (preparation method: HBSS containing 20 mM HEPES is prepared using 1X HBSS and 1M HEPES, where HBSS, Gibco, Cat. 14025092; 1M HEPES, Solarbio, Cat. H1095) to prepare a 10x intermediate solution of the test compound.

[0404] Cell plating:

[0405] Before the test, cells were detached with 0.25%-Trypsin-EDTA, and the required cell suspension was calculated based on a density of 8000 cells per well. After induction with tetracycline (the final concentration of tetracycline was 2 μg / ml), the cells were plated into a black bottom transparent 384-well plate (Corning, Cat.3764). After culturing in the 384-well plate (final volume: 25 μL) for 12 hours, the test was performed.

[0406] Detection:

[0407] Prepare a buffer solution of 1x Hank's Balanced Salt Solution (HBSS) containing 20 mM HEPES according to the kit instructions, and then use the buffer solution to prepare 2x dye for use.

[0408] The culture medium in the 384-well plate was removed by low-speed inverted centrifugation. 18 μL of buffer and 18 μL of 2X dye were added to each experimental well, and the plates were incubated at 37°C in the dark for 2 hours.

[0409] The prepared 10× test substance intermediate solution was transferred to the corresponding 384-well plate (Nunc, 264573). The detection concentration of A-967079 and the test substance was 10 μM, and three-fold serial dilution was performed.

[0410] Prepare agonist AITC EC according to 5× agonist intermediate solution 80 Solution (concentration of 25 μM). Transfer the prepared 5× agonist intermediate solution to the corresponding 384-well plate. Agonist AITC EC 80 The working solution concentration is 5 μM.

[0411] After incubation, use FLIPR Penta The instrument takes 4 μL of the prepared 10× test substance intermediate solution and adds it to the test well. The data is collected and recorded for 5 minutes. Incubate in the dark for 20 minutes. Then take 10 μL of the prepared 5× agonist intermediate solution and collect data and record for 5 minutes. The excitation light for calcium flow detection is 470-515 nm, and the emission light is 515-575 nm. The maximum value after adding AITC is used for IC 50 calculate.

[0412] Data evaluation and calculation:

[0413] Data analysis was performed by calculating the maximum value of the signal of the experimental wells. 50 The values ​​were calculated using GraphPad software and the results are shown in Table 1 below.

[0414] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0415] Table 1 hTRPA1 IC values ​​of the compounds of the present invention 50 value

[0416] Test Example 2: Pharmacokinetics of the compound of the present invention in rats after intravenous and oral administration

[0417] Three SPF male SD rats (Beijing Weitonglihua Experimental Animal Technology Co., Ltd.) were used for each dosing group. The test compound was prepared with 5% DMSO, 10% HS15 and 85% normal saline (vehicle). The rat intravenous administration group had an intravenous dose of 1 mg / kg; the rat oral administration group fasted overnight before administration and had an oral dose of 5 mg / kg. Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood samples were placed on ice and plasma was separated within 1 hour (centrifugation conditions 6000g, 3 minutes, 2-8°C). The separated plasma was stored at -80°C. For testing, all samples were thawed, mixed for 10-30 seconds, and centrifuged at 4000 rpm at 4°C for 0.5 minutes. Plasma was collected at each time point and added to a 10-fold volume of 50% methanol-acetonitrile solution containing an internal standard. The sample was vortexed for 5 minutes and centrifuged at 4000 rpm at 4°C for 10 minutes. The supernatant was added to an equal volume of water, mixed, and analyzed by LC-MS / MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 software, as shown in Table 2.

[0418] Table 2: Pharmacokinetic test results in rats

[0419] From the results in Table 2, it can be seen that the rat clearance rate of the compound of the present invention is low, and the exposure amount after oral administration and oral bioavailability are good.

[0420] Test Example 3: Determination of the efficacy of the compound of the present invention in the citric acid-induced guinea pig cough model

[0421] Test method:

[0422] Cough sensitivity screening: Hartley guinea pigs (Beijing Weitong Lihua Co., Ltd.), male, SPF grade, weighing 280-340g, that have passed quarantine, were taken for sensitivity testing one day before administration. The guinea pigs were placed in a YSL-8A cough and wheeze induction apparatus. A 0.5 mol / L citric acid solution was added to the nebulizer as a cough inducing solution. The nebulization was continued for 60 seconds and then stopped. While the citric acid was being introduced, a stopwatch was used to time the number of coughs in the guinea pig within 12 minutes of the nebulization (a cough was counted as one cough when the guinea pig opened its mouth and heard a loud cough). Guinea pigs that did not cough or coughed more than 35 times (continuous coughing with severe symptoms) were eliminated.

[0423] Test: Guinea pigs that passed the screening were selected and randomly divided into vehicle control group (5% DMSO, 10% HS15 and 85% saline), 7-R group and 5-R group. They were given the corresponding drug solution by oral gavage at a dose of 10 mg / kg, and the vehicle control group was given an equal volume of vehicle. One hour before the drug was given, the guinea pigs were placed in a YLS-8A cough and asthma induction instrument, and 0.5 mol / L citric acid solution was added as a cough induction solution. The nebulizer was used at the maximum spray level (7 L / min) and the nebulizer was used to spray for 60 seconds to stimulate the guinea pigs to cough. A stopwatch was used while the citric acid solution was introduced. The cough latency (s - the time when the guinea pig first coughed) and the number of coughs within 12 minutes from the start of the spray were recorded.

[0424] Data processing: Quantitative data are presented as mean ± standard deviation. GraphPad 9 software was used for statistical analysis. Normality and lognormativity tests were used to test for normality and homogeneity of variance. If the results were not statistically significant (P>0.05), one-way analysis of variance (ANOVA) was used for statistical analysis. If the ANOVA results were statistically significant (P≤0.05), Dunnett's test was used for comparative analysis. If the variances were not homogeneous (P≤0.05), the Kruskal-Wallis test was used. If the Kruskal-Wallis test was statistically significant (P≤0.05), Dunnett's test (nonparametric method) was used for comparative analysis. Statistical results were tested with an α = 0.05 threshold, where P≤0.05 indicated statistical significance and P≤0.01 indicated highly significant differences.

[0425] Table 3 Statistical data of cough latency and total number of coughs of the compounds of the present invention in guinea pig cough model

[0426] Note: Statistical analysis was performed using ANOVA, *P ≤ 0.05, **P ≤ 0.01.

[0427] From the results in Table 3, it can be seen that compared with the vehicle control, the compound of the present invention exhibits a better antitussive effect at a dosage of 10 mg / kg, with a significant difference.

[0428] Although the embodiments disclosed in this application are as described above, the contents described are merely embodiments adopted to facilitate understanding of this application and are not intended to limit this application. Any person skilled in the art to which this application belongs may make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in this application, but the scope of protection of this application shall still be based on the scope defined by the attached claims.

Claims

1. A compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; in, Ring A is selected from: X1, X2, X3 and X4 are N or CR 5 , and the number of N in X1, X2, X3 and X4 is 0, 1 or 2; Ring B is selected from 5-membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 3 R a1 substituted; wherein the heteroaryl group contains 1 to 4 heteroatoms selected from N, O and S; Ring C is selected from C 6-14 aryl, 5- to 14-membered heteroaryl, 5- to 14-membered heterocyclyl, wherein the heteroaryl and heterocyclyl each contain 1 to 4 heteroatoms selected from N, O and S; R is independently selected from H, halogen, cyano, -SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 5- to 7-membered heterocyclic group, -C(O)NR b R c 、-NR b R c 、-P(O)R b R c 、-S(O)2NR b R c 、-NR d C(O)R e 、-C(O)R e 、-C(O)OR e 、-S(NH)(O)R e , wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1- 3-alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 5 to 7 membered heterocyclic group optionally substituted by 1 to 3 R a2 substituted; wherein the 5- to 7-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S; R 1 、R 2 、R 3 and R 4 Each independently selected from H, D, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 R a3 replace; X is selected from N and CR 10 ; R 5 Each independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3- 6-cycloalkyl, -C(O)NR b R c 、-NR b R c 、C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted with 1 to 3 R a4 replace; R 6 Each independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3- 6-cycloalkyl, -C(O)NR b R c 、-NR b R c 、C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted with 1 to 3 R a5 replace; R 7 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 R a6 replace; R 8 Selected from H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C(O)NR b R c 、-NR b R c 、-OC 1-6 Alkyl, -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 The alkyl group is optionally substituted with 1 to 3 R a7 replace; R 9 Selected from H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)NR b R c 、-NR b R c 、-NR d C(O)R e 、-C(O)R e 、-C(O)OR e , wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted with 1 to 3 R a8 replace; R 10 Selected from H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C(O)NR b R c 、-NR b R c 、-OC 1-6 Alkyl, -SC 1-6 Alkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 The alkyl group is optionally substituted with 1 to 3 R a9 replace; p is an integer selected from 0, 1, 2, 3, 4 and 5; m is an integer selected from 0, 1 and 2; R b and R c Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, or R b and R c and the atoms to which they are attached together form a 5- to 7-membered heterocycloalkyl group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, 5 to 7 membered heterocycloalkyl optionally substituted by 1 to 3 R a10 replace; R d and R e Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3- 6-cycloalkyl, -C 1-3 Alkylene-C 3-6 The cycloalkyl group is optionally substituted with 1 to 3 R a11 replace; R a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R a11 Each independently selected from halogen, cyano, hydroxy, amino, C 1-3 Haloalkyl or C 1-3 alkyl; * The configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration; It is provided that when ring A is selected from When ring B is not And when ring A is When the number of N in X1, X2, X3 and X4 is 0, the ring B is not 2. The compound represented by formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from n is an integer selected from 0, 1, 2 and 3; It is provided that when ring A is selected from When ring B is not 3. The compound represented by formula (I) according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1) Ring C is C 6-14 aryl or 5- to 14-membered heteroaryl; wherein the 5- to 14-membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; (2) R is independently H, halogen, cyano, -SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 5- to 7-membered heterocyclic group, -C(O)NR b R c 、-NR b R c 、-P(O)R b R c 、-S(O)2NR b R c 、-NR d C(O)R e 、-C(O)R e 、-C(O)OR e or -S(NH)(O)R e ; Preferably, R is each independently H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 R a2 substituted; more preferably, R is each independently halogen; (3)R 1 、R 2 、R 3 and R 4 Each independently represents H, D, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl; preferably, R 1 、R 2 、R 3 and R 4 are each independently H, D, halogen or C 1-6 Alkyl; more preferably R 1 、R 2 、R 3 and R 4 is H; (4) X is N or CH; (5)R 5 are independently H, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C(O)NR b R c 、-NR b R c 、C 2-6 Alkenyl or C 2-6 Alkynyl; preferably, R 5 are independently H, halogen, C 1-6 Alkyl or cyano; More preferably, R 5 are each independently H, halogen or C 1-6 alkyl; (6)R 6 are independently H, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C(O)NR b R c 、-NR b R c 、C 2-6 Alkenyl or C 2-6 Alkynyl; preferably, R 6 Each independently is H, C 1-6 Alkyl or -NR b R c ; (7)R 7 H, C 1-6 Alkyl, C 3-6 Cycloalkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl; preferably, R 7 H, C 1-6 Alkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl; (8)R 8 H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C(O)NR b R c 、-NR b R c 、-OC 1-6 Alkyl or -SC 1-6 Alkyl; preferably, R 8 is H, halogen or C 1-6 alkyl; (9)R 9 H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)NR b R c 、-NR b R c 、-NR d C(O)R e 、-C(O)R e or-C(O)OR e ; R 9 is H, halogen or C 1-6 alkyl; (10)R 10 H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C(O)NR b R c 、-NR b R c 、-OC 1-6 Alkyl or -SC 1-6 Alkyl; preferably, R 10 is H, halogen or C 1-6 Alkyl; more preferably, R 10 is H; (11) p is 1 or 2; (12) m is 0 or 1; (13) n is 0 or 1; (14)R b and R c Each independently is H, C 1-6 Alkyl, C 3-6 Cycloalkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl; preferably, R b and R c Each independently is H or C 1-6 alkyl; (15)R d and R e Each independently is H, C 1-6 Alkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl; preferably, R d and R e Each independently is H or C 1-6 alkyl; and (16)R a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R a11 Halogen or C 1-3 alkyl.

4. The compound represented by formula (I) according to claim 1 or 2, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1) Ring A is Preferably More preferably (2) Ring B is selected from one of the following structures: Preferably, ring B is selected from one of the following structures: (3) Ring C is selected from one of the following structures: Preferably, ring C is selected from one of the following structures: More preferably, ring C is and (4) Fragment for Preferably 5. The compound represented by formula (I) according to claim 1 or 2, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1) The 5-membered heteroaryl group is one of the following structures: Preferably, the 5-membered heteroaryl group is (2) C 6-14 Aryl is C 6-10 Aryl, such as phenyl or naphthyl, preferably phenyl; (3) the 5- to 14-membered heteroaryl group is a 5- to 10-membered heteroaryl group; (4) The 5- to 14-membered heteroaryl group is independently monocyclic or polycyclic; the polycyclic rings may be fused rings; the polycyclic rings may be bicyclic or tricyclic; preferably, the 5- to 14-membered heteroaryl group is a 5- to 6-membered monocyclic heteroaryl group or a 9- to 10-membered bicyclic heteroaryl group; (5) The 5- to 14-membered heteroaryl group is one of the following structures: (6) The 5- to 14-membered heterocyclic group is a 5- to 10-membered heterocyclic group; (7) In the 5- to 14-membered heterocyclic group, the heterocyclic group is independently a heterocycloalkyl group or a heterocycloalkenyl group; When the heterocyclic group is a heterocycloalkyl group, the heterocycloalkyl group does not contain an unsaturated bond; When the heterocyclic group is a heterocycloalkenyl group, the heterocycloalkenyl group contains 1, 2, 3 or 4 unsaturated bonds, and the heterocycloalkenyl group is not aromatic; (8) The 5- to 14-membered heterocyclic group is independently monocyclic or polycyclic; the polycyclic rings may be fused rings; the polycyclic rings may be bicyclic or tricyclic; preferably, the 5- to 14-membered heterocyclic group is a 5- to 6-membered monocyclic heterocyclic group or a 9- to 10-membered bicyclic heterocyclic group; (9) The halogen is independently fluorine, chlorine, bromine or iodine; (10) C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (11) C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (12) C 1-3 Alkylene is independently methylene, ethylene, n-propylene or isopropylene; (13) -OC 1-6 Alkyl is independently -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-isobutyl or -O-tert-butyl; (14)-SC 1-6 Alkyl is independently -S-methyl, -S-ethyl, -S-n-propyl, -S-isopropyl, -S-n-butyl, -S-isobutyl or -S-tert-butyl; (15) C 2-6 Alkenyl is independently C 2-4 alkenyl, such as ethenyl, propenyl or butenyl; (16) C 2-6 Alkynyl is independently C 2-4 Alkynyl, such as ethynyl, propynyl or butynyl; (17) In the 5- to 7-membered heterocyclic group, the heterocyclic group is independently a heterocycloalkyl group or a heterocycloalkenyl group; When the heterocyclic group is a heterocycloalkyl group, the heterocycloalkyl group does not contain an unsaturated bond; When the heterocyclic group is a heterocycloalkenyl group, the heterocycloalkenyl group contains one or two unsaturated bonds and the heterocycloalkenyl group is not aromatic; (18) C 1-3 Haloalkyl is independently -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3; and (19) C 1-3 Alkyl groups are independently methyl, ethyl, n-propyl or isopropyl.

6. The compound represented by formula (I) according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1) Ring A is Preferably, ring A is (2) Ring B is Preferably More preferably (3) Ring C is The configuration of the carbon atom at position (4)* is R configuration.

7. The compound represented by formula (I) according to any one of claims 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) satisfies one of the following schemes: Option 1: Ring A is selected from: Ring B is n is an integer selected from 0, 1, 2 and 3; Option 2: Ring A is selected from: Ring B is n is an integer selected from 0, 1, 2 and 3.

8. The compound represented by formula (I) according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) satisfies one of the following schemes: Option 1: The compound represented by formula (I) has the structural characteristics of general formula (II-1): Among them, R, p, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 , Ring B, * and Ring C are defined as any one of claims 1 to 7; Option 2: The compound represented by formula (I) has the structural characteristics of formula (II-2): Among them, R, p, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 , * and ring C are defined as any one of claims 1 to 7; Option 3: The compound represented by formula (I) has the structural characteristics of formula (II-3): in, R is a halogen; P is 0, 1, or 2; X is N or CH, preferably N; R 5 is H, halogen or C 1-6 alkyl; R 6 H, C 1-6 Alkyl or -NH2; R 7 H, C 1-6 Alkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl; * The configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration; Option 4: The compound represented by formula (I) has the structural characteristics (II-4): in, R is a halogen; P is 0, 1, or 2; X is N or CH, preferably N; R 5 is H, halogen or C 1-6 alkyl; R 6 H, C 1-6 Alkyl or -NH2; R 7 H, C 1-6 Alkyl or -C 1-3 Alkylene-C 3-6 Cycloalkyl; * The configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration; Option 5: The compound represented by formula (I) has the structural characteristics of formula (III-1): Among them, R, p, X, m, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , Ring B, * and Ring C are defined as any one of claims 1 to 7; Option 6: The compound represented by formula (I) has the structural characteristics of formula (III-2): Among them, R, p, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 , * and ring C are defined as any one of claims 1 to 7; Option 7: The compound represented by formula (I) has the structural characteristics of formula (III-3): Among them, in the general formula (III-3), R is a halogen; P is 0, 1, or 2; m is 0 or 1; R 5 is H, halogen or C 1-6 alkyl; R 6 H, C 1-6 Alkyl or -NH2; * The configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration; Preferably, the structural fragment for Option 8: The compound represented by formula (I) has the structural characteristics of formula (IV-1): Among them, R, p, X, n, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , Ring B, * and Ring C are defined as any one of claims 1 to 7; Option 9: The compound represented by formula (I) has the structural characteristics of formula (IV-2): Among them, R, p, X, n, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , * and ring C are defined as any one of claims 1 to 7; Option 10: The compound represented by formula (I) has the structural characteristics of formula (IV-3): Among them, in the general formula (IV-3), R is a halogen; P is 0, 1, or 2; n is 0 or 1; R 5 is H, halogen or C 1-6 alkyl; R 6 H, C 1-6 Alkyl or -NH2; * The configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration; Plan 11: The compound represented by formula (I) has the structural characteristics of formula (IV-4): Among them, in the general formula (IV-4), R is a halogen; P is 0, 1, or 2; n is 0 or 1; R 5 is H, halogen or C 1-6 alkyl; R 6 H, C 1-6 Alkyl or -NH2; * The configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration; Plan 12: The compound represented by formula (I) has the structural characteristics of formula (IV-5): Among them, in the general formula (IV-5), R is halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 R a2 replace; R a2 are independently halogen; P is 0, 1, or 2; n is 0, 1, or 2; R 5 H, halogen, C 1-6 Alkyl or cyano; R 6 H, C 1-6 Alkyl or -NH2; * The configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration; Preferably, ring C is Preferably, the structural fragment for Plan 13: The compound represented by formula (I) has the structural characteristics of formula (V-1): Among them, R, p, X, R 1 、R 2 、R 3 、R 4 、R 6 、R 8 、R 9 , Ring B, * and Ring C are defined as any one of claims 1 to 7; Plan 14: The compound represented by formula (I) has the structural characteristics of formula (V-2): Among them, R, p, X, R 1 、R 2 、R 3 、R 4 、R 6 、R 8 、R 9 , * and ring C are defined as described in any one of claims 1 to 7; Scheme 15: The compound represented by formula (I) has the structural characteristics of formula (V-3): Among them, in the general formula (V-3), R is a halogen; P is 0, 1, or 2; R 6 H, C 1-6 Alkyl or -NH2; R 8 is H, halogen or C 1-6 alkyl; R 9 is H, halogen or C 1-6 alkyl; * The configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration; Plan 16: The compound represented by formula (I) has the structural characteristics of formula (VI): Among them, ring A is Ring C, R, p, n, R 5 、R 6 and * are as defined in any one of claims 1 to 7; Plan 17: The compound represented by formula (I) has the structural characteristics of formula (VI): Among them, ring A is Ring C is R is halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; P is 0, 1, or 2; n is 0, 1, or 2; R 5 is H, halogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R 6 H, C 1-6 Alkyl or -NH2; * The configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration; Plan 18: The compound represented by formula (I) has the structural characteristics of formula (VI): Among them, ring A is Ring C is R is halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; P is 0, 1, or 2; n is 0, 1, or 2; The configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.

9. The compound represented by formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) is selected from any one of the following compounds:

10. A pharmaceutical composition comprising a compound represented by formula (I) according to any one of claims 1 to 9, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

11. Use of a compound of formula (I) according to any one of claims 1 to 9, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing and / or treating diseases and / or disorders associated with TRPA1.

12. The use according to claim 11, characterized in that The TRPA1-related diseases and / or disorders are pain, respiratory diseases, fibrotic diseases, urinary system diseases, autoimmune diseases, central nervous system (CNS) diseases, inflammatory diseases, gastrointestinal diseases or cardiovascular diseases; The pain is preferably postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain or pain caused by inflammation; and the respiratory disease is preferably asthma, cough, chronic pulmonary obstruction or sleep apnea.

13. Use of a compound of formula (I) according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, in the preparation of a medicament for preventing and / or treating a disease and / or disorder; the disease and / or disorder being pain, respiratory disease, fibrotic disease, urinary system disease, autoimmune disease, central nervous system (CNS) disease, inflammatory disease, gastrointestinal disease, or cardiovascular disease; The pain is preferably postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain or pain caused by inflammation; the respiratory disease is preferably asthma, cough, chronic pulmonary obstruction or sleep apnea.

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