Heterocyclic compound and use thereof

Abstract

Disclosed is a heterocyclic compound as represented by formula (I), a tautomer thereof, or a pharmaceutically acceptable salt thereof. The compound has better inhibitory activity on TRPC5, has good metabolic stability in liver micro-particles, and has good clinical pharmacokinetic properties.

Description

A heterocyclic compound and its application

[0001] This application claims priority to Chinese Patent Application No. 2020106363080, filed on July 3, 2020, and Chinese Patent Application No. 2020114601432, filed on December 11, 2020. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to a heterocyclic compound and its applications. Background Technology

[0003] Various ion channel proteins exist to regulate ion flow across the cell membrane. Proper expression and function of ion channel proteins are crucial for maintaining cellular function and intracellular communication. Many diseases result from abnormal regulation of membrane potential or aberrant calcium processing. Given the central importance of ion channels in regulating membrane potential and ion flow within cells, the identification of agents that can promote or inhibit specific ion channels is of great interest as a research tool and as potential therapeutic agents.

[0004] TRPC (Transient Receptor Potential Canonical) is one of the most important subfamilies in the TRP superfamily, including TRPC1-7, of which TRPC2 is a pseudogene and not expressed in humans. Based on amino acid sequence homology and structural characteristics, TRPCs can be divided into two subclasses: TRPC1, 4, and 5 are classified as one subclass, and TRPC3, 6, and 7 as another. According to their activation mode, functional TRPCs can be further divided into calcium channel channels controlled by calcium stores and calcium channels controlled by receptors. Both types of activated TRPC channels are non-specific cation channels, mediating sodium and calcium influx and potassium efflux.

[0005] Cation channels (such as the transient receptor potential (TRP) cation channel subfamily C, member 5 (TRPC5)) regulate the flow of calcium and sodium ions across the cell membrane. The influx of sodium and calcium leads to cellular depolarization. This increases the likelihood that voltage-gated ion channels will reach the threshold required for activation. Therefore, activation of nonselective cation channels can increase electrical excitability and the frequency of voltage-dependent events. Voltage-dependent events include, but are not limited to, neuronal action potentials, cardiac action potentials, smooth muscle contraction, cardiac contraction, and skeletal muscle contraction.

[0006] Calcium influx induced by activation of non-selective cation channels (such as TRPC5) also alters intracellular free calcium concentration. Calcium is a ubiquitous second messenger molecule in cells, and changes in intracellular calcium levels have profound effects on signal transduction and gene expression. Therefore, activation of non-selective cation channels (such as TRPC5) can lead to changes in gene expression and cell phenotype. Gene expression events include, but are not limited to, the production of mRNAs encoding cell surface receptors, ion channels, and kinases. These changes in gene expression can lead to hyperexcitability of the cell.

[0007] The homopolymer TRPC5 ion channel is a signal transduction gating and Ca2+ ion channel primarily expressed in neurons. 2+ TRPC5 can be formed through channels. It can form homopolymeric multi-subunit structures (such as tetramers (i.e., TRPC5 homopolymers)) and heteropolymeric multi-subunit structures (such as tetramers (i.e., TRPC5-TRPC1 heteropolymers)). Unless explicitly stated otherwise, when the term TRPC5 is used herein (e.g., when identifying modulators of TRPC5, such as TRPC5 antagonists), the term TRPC5 is used generally to include one or both of the TRPC5 homopolymers or heteropolymers (e.g., TRPC5-TPRC1 or TRPC5-TRPC4 heteropolymers). Examples of TRPC5 in the literature include the following: Nature. January 3, 2008; 451(7174): 69-72; Mol Pharmacol. January 2008; 73(1): 42-9; J Biol Chem. November 16, 2007; 282(46): 33868-78; Biochem Biophys Res Commun. January 11, 2008; 365(2): 239-45; J Biol Chem. November 3, 2006; 281(44): 33487-96; Eur J Pharmacol. March 14, 2005; 510(3): 217-22; J Biol Chem. February 24, 2006; 281(8): 4977-82; Biochem Soc Trans. February 2007; 35(Pt 1): 101-4; Handb ExpPharmacol. 2007; (179): 109-23; J Biol Chem. March 25, 2005; 280(12): 10997-1006; J Physiol. January 15, 2006; 570(Pt 2): 219-35; and Nat Neurosci. (2003) 6: 837-45.

[0008] Modulating the function of TRPC5 protein provides a means of regulating calcium homeostasis, sodium homeostasis, membrane polarization and / or intracellular calcium levels, and compounds that can modulate TRPC5 function can be used in many ways, including but not limited to maintaining calcium homeostasis, regulating intracellular calcium levels, regulating membrane polarization, and treating or preventing diseases, symptoms or conditions related to calcium and / or sodium homeostasis or dyshomeostasis.

[0009] Compounds that inhibit TRPC5 containing ion channels are suitable for treating conditions by modulating the activity of transient receptor potential cation channel subfamily C, member 5 (TRPC5), which can exist in homomeric form and heteromeric form with other ion channels (such as TRPC1 or TRPC3) (i.e., TRPC5-TRPC1 and TRPC1-TRPC3-TRPC5).

[0010] Focal segmental glomerulosclerosis (FSGS) is a clinicopathological syndrome characterized by massive proteinuria or nephrotic syndrome. Pathologically, it is characterized by focal segmental glomerular sclerosis and podocyte degeneration leading to fusion or disappearance of foot processes. FSGS accounts for approximately 5%–10% of nephrotic syndrome cases in Chinese adults, and is more common in young and middle-aged men. More than 50% of patients with persistent nephrotic syndrome progress to end-stage renal disease within 5–10 years.

[0011] In a healthy glomerulus, TRPC5 is isolated in the cytoplasm, maintaining normal filtration. When podocytes are injured, the injury activates RAC1, causing TRPC5 to translocate from the cytoplasm to the cell membrane. This promotes AT1 receptor-induced calcium ion influx through the TRPC5 channel, further promoting RAC1 activity. RAC1 activation induces actin remodeling and detachment of podocytes from the glomerulus. The loss of podocytes disrupts the filtration barrier, allowing serum proteins to leak into the urine.

[0012] Currently, the main drugs used in clinical practice to treat FSGS are hormones, immunosuppressants, CNIs, and alkylating agents, all of which have serious toxic side effects. Many of them need to be used in combination with other drugs to be effective, and they are prone to relapse.

[0013] Summary of the Invention

[0014] The technical problem this invention aims to solve is that existing TRPC5 inhibitors have relatively simple structures. Therefore, this invention provides a heterocyclic compound and its applications. This compound exhibits superior inhibitory activity against TRPC5, good metabolic stability in liver microsomes, and better clinical pharmacokinetic properties.

[0015] The present invention provides a heterocyclic compound as described in Formula I, its tautomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof;

[0016]

[0017] Where m is 1 or 2;

[0018] A independently is -(CR) 1 R 2 - or -(C=O)-;

[0019] R 1 Independently hydrogen, halogen, R 1-1 "By one, two or more R" 1-3 Replacement R 1-2 "、-(C=O)NHR 1-4 -NH(C=O)R 1-5 -(C=O)OR 1-6 -S(=O)2R 1-7 、or 、-S(=O)R 1-8 ;

[0020] R 1-1 and R 1-2 Independently amino, C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 aryl, C6-C 20 aryl-C1-C 40 Alkyl group, "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", or "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S" -C1-C 40 Alkyl groups;

[0021] R 1-3 R 1-4 R 1-5 R 1-6 R 1-7 and R 1-8 Independently, -CN, halogen, -OH, -NH2, -COOH, -NO2, -S(=O)2CH3, -C(=O)NHCH2CH3, oxo(=O), -NHC(=O)R 1-3-4 -C(=O)OR 1-3-5 R 1-3-1Or, "by one, two or more Rs" 1-3-2 Replacement R 1-3-2 ”;

[0022] R 1-3-1 and R 1-3-2 Independently for C1-C 40 Alkyl, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0023] R 1-3-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0024] R 1-3-4 Independently for hydrogen, R 1-3-4-1 Or, "by one, two or more Rs" 1-3-4-3 Replacement R 1-3-4-2 ”;

[0025] R 1-3-4-1 and R 1-3-4-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0026] R 1-3-4-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0027] R 1-3-5 Independently for hydrogen, R 1-3-5-1 Or, "by one, two or more Rs" 1-3-5-3 Replacement R 1-3-5-2 ”;

[0028] R 1-3-5-1 and R 1-3-5-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0029] R 1-3-5-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0030] R 2 Independently hydrogen, halogen, R 2-1 "By one, two or more R" 2-3 Replacement R 2-2 "、-(C=O)NHR 2-4 -NH(C=O)R 2-5 -(C=O)OR 2-6 -S(=O)2R 2-7 、or 、-S(=O)R 2-8 ;

[0031] R 2-1 and R 2-2 Independently amino, C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 aryl, C6-C 20 aryl-C1-C 40 Alkyl group, "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", or "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S" -C1-C 40 Alkyl groups;

[0032] R 2-3 R 2-4 R 2-5 R 2-6 R 2-7 and R 2-8 Independently, -CN, halogen, -OH, -NH2, -COOH, -NO2, -S(=O)2CH3, -C(=O)NHCH2CH3, oxo(=O), -NHC(=O)R 2-3-4 -C(=O)OR 2-3-5 R 2-3-1 Or, "by one, two or more Rs" 2-3-3 Replacement R 2-3-2 ”;

[0033] R 2-3-1 and R 2-3-2 Independently for C1-C 40 Alkyl, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0034] R 2-3-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0035] R 2-3-4 Independently for hydrogen, R 2-3-4-1Or, "by one, two or more Rs" 2-3-4-3 Replacement R 2-3-4-2 ”;

[0036] R 2-3-4-1 and R 2-3-4-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0037] R 2-3-4-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0038] R 2-3-5 Independently for hydrogen, R 2-3-5-1 Or, "by one, two or more Rs" 2-3-5-3 Replacement R 2-3-5-2 ”;

[0039] R 2-3-5-1 and R 2-3-5-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0040] R 2-2-5-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0041] n is 1 or 2;

[0042] G independently is -(CR) 3 R 4 - or -(C=O)-;

[0043] R 3 Independently hydrogen, halogen, R 3-1 "By one, two or more R" 3-3 Replacement R 3-2 "、-(C=O)NHR 3-4 -NH(C=O)R 3-5 -(C=O)OR 3-6 -S(=O)2R 3-7 、or 、-S(=O)R 3-8 ;

[0044] R 3-1 and R 3-2 Independently amino, C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 aryl, C6-C 20 aryl-C1-C 40 Alkyl group, "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", or "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S" -C1-C 40 Alkyl groups;

[0045] R 3-3 R 3-4 R 3-5 R 3-6 R 3-7 and R 3-8 Independently, -CN, halogen, -OH, -NH2, -COOH, -NO2, -S(=O)2CH3, -C(=O)NHCH2CH3, oxo(=O), -NHC(=O)R 3-3-4 -C(=O)OR3-3-5 R 3-3-1 Or, "by one, two or more Rs" 3-3-3 Replacement R 3-3-2 ”;

[0046] R 3-3-1 and R 3-3-2 Independently for C1-C 40 Alkyl, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0047] R 3-3-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0048] R 3-3-4 Independently for hydrogen, R 3-3-4-1 Or, "by one, two or more Rs" 3-3-4-3 Replacement R 3-3-4-2 ”;

[0049] R 3-3-4-1 and R 3-3-4-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0050] R 3-3-4-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0051] R 3-3-5 Independently for hydrogen, R 3-3-5-1 Or, "by one, two or more Rs" 3-3-5-3 Replacement R 3-3-5-2 ”;

[0052] R 3-3-5-1 and R 3-3-5-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0053] R 3-3-5-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0054] R 4 Independently hydrogen, halogen, R 4-1 "By one, two or more R" 4-3 Replacement R 4-2 "、-(C=O)NHR 4-4 -NH(C=O)R 4-5 -(C=O)OR 4-6 -S(=O)2R 4-7 、or 、-S(=O)R 4-8 ;

[0055] R 4-1 and R 4-2 Independently amino, C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 aryl, C6-C 20 aryl-C1-C 40 Alkyl group, "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", or "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S" -C1-C 40 Alkyl groups;

[0056] R 4-3 R 4-4 R 4-5 R 4-6 R 4-7 and R 4-8 Independently, -CN, halogen, -OH, -NH2, -COOH, -NO2, -S(=O)2CH3, -C(=O)NHCH2CH3, oxo(=O), -NHC(=O)R 4-3-4 -C(=O)OR 4-3-5 R 4-3-1 Or, "by one, two or more Rs" 4-3-3 Replacement R 4-3-2 ”;

[0057] R 4-3-1 and R 4-3-2 Independently for C1-C 40 Alkyl, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0058] R 4-3-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0059] R 4-3-4 Independently for hydrogen, R 4-3-4-1Or, "by one, two or more Rs" 4-3-4-3 Replacement R 4-3-4-2 ”;

[0060] R 4-3-4-1 and R 4-3-4-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0061] R 4-3-4-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0062] R 4-3-5 Independently for hydrogen, R 4-3-5-1 Or, "by one, two or more Rs" 4-3-5-3 Replacement R 4-3-5-2 ”;

[0063] R 4-3-5-1 and R 4-3-5-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0064] R 4-3-5-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0065] X is either N or CH;

[0066] When X is N, Z is CR 6 When X is CH, Z is N or CR. 7 ;

[0067] R 6 Hydrogen, halogen, amino, or with one or more R 6-2 Substituted C1-C4 alkyl, C1-C4 alkoxy, or -C(=O)-NH-R 6-1 ;R 6-1 It is a C1-C4 alkyl group; R 6-2 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0068] R7 is hydrogen, halogen, amino, or surrounded by one or more R... 7-2 Substituted C1-C4 alkyl, C1-C4 alkoxy, or -C(=O)-NH-R 7-1 ;R 7-1 It is a C1-C4 alkyl group; R 7-2 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0069] Y is -O-, -S-, -NR 8 -, -CH2-, -C(=O)- or -S(=O)-;

[0070] R 8 For hydrogen, by one or more R 8-2 Substituted C1-C4 alkyl, C1-C4 alkoxy, or -C(=O)-NH-R 8-1 ;R 8-1 It is a C1-C4 alkyl group; R8-2 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S (=O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0071] p is 1, 2, or 3;

[0072] R 5 Independently cyano, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, -NR 9 R 10 C3-C6 cycloalkyl groups, or C1-C4 alkyl groups substituted with one or more halogens;

[0073] R 9 and R 10 It is independently an H or C1-C4 alkyl group.

[0074] In one embodiment, the heterocyclic compound of formula I is shown as in formula II or formula III:

[0075]

[0076] Among them, A, X, Z, G, R 5 The definitions of m, n, and p are as described in any of the schemes.

[0077] In one embodiment, the heterocyclic compound of formula I is shown as in formula IV or V:

[0078]

[0079] Among them, A, G, R 5 R 6 The definitions of m, n, and p are as described in any of the schemes.

[0080] In one embodiment, the heterocyclic compound of formula I is shown as in formula VI or formula VII:

[0081]

[0082] Among them, R 5 R 6 Both p are as described in either scheme.

[0083] In one embodiment, certain groups in the heterocyclic compound of Formula I, its tautomers, or pharmaceutically acceptable salts thereof are defined as follows, and groups not covered below are defined as described in any of the preceding embodiments (hereinafter referred to as "in one embodiment"):

[0084] m is 1 or 2;

[0085] A independently is -(CR) 1 R 2 )-;

[0086] R 1 Independently hydrogen or R 1-1 ;R 1-1 Independently for C1-C 40 Alkyl groups;

[0087] R 2 It is hydrogen;

[0088] n is 2;

[0089] G independently is -(CR) 3 R 4 )-;

[0090] R 3 Independently for hydrogen, R 3-1 "By one, two or more R" 3-3 Replacement R 3-2 ”;R 3-1 and R 3-2 Independently for C1-C 40 Alkyl group; R 3-3 It is -OH;

[0091] R 4 It is hydrogen;

[0092] X is N, Z is CR 6 Or X is CH and Z is N;

[0093] R 6 It is hydrogen, halogen, or -C(=O)-NH-R 6-1 ;R 6-1 It is a C1-C4 alkyl group;

[0094] Y is -O-, -S-, -NR 8 -, -CH2-, -C(=O)- or -S(=O)-; R 8 It is hydrogen;

[0095] p is 1 or 2;

[0096] R 5 Independently cyano, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, -NR9 R 10 C3-C6 cycloalkyl groups, or C1-C4 alkyl groups substituted with one or more halogens; R 9 and R 10 It is an alkyl group that is independently C1-C4.

[0097] In one of the solutions,

[0098] m is 1 or 2;

[0099] A independently is -(CR) 1 R 2 )-;

[0100] R 1 Independently hydrogen or R 1-1 ;R 1-1 Independently for C1-C 40 Alkyl groups;

[0101] R 2 It is hydrogen;

[0102] n is 2;

[0103] G independently is -(CR) 3 R 4 )-;

[0104] R 3 Independently for hydrogen, R 3-1 "By one, two or more R" 3-3 Replacement R 3-2 ”;R 3-1 and R 3-2 Independently for C1-C 40 Alkyl group; R 3-3 It is -OH;

[0105] R 4 It is hydrogen;

[0106] X is N, Z is CR 6 ;

[0107] R 6 It is hydrogen, halogen, or -C(=O)-NH-R 6-1 ;R 6-1 It is a C1-C4 alkyl group;

[0108] Y is -NR 8 -or -CH2-; R 8 It is hydrogen;

[0109] p is 1 or 2;

[0110] R 5A C1-C4 alkyl group that is independently a halogen or is substituted with one or more halogens.

[0111] In one of the proposed solutions:

[0112] m is 1 or 2;

[0113] A is -(CR) 1 R 2 )-;

[0114] R 1 It is hydrogen;

[0115] R 2 It is hydrogen;

[0116] n is 2;

[0117] G is -(CR) 3 R 4 )-;

[0118] R 3 It is hydrogen;

[0119] R 4 It is hydrogen;

[0120] X is N, Z is CR 6 ;

[0121] R 6 It is hydrogen, halogen, or -C(=O)-NH-R 6-1 ;R 6-1 It is a C1-C4 alkyl group;

[0122] Y is -NR 8 -or -CH2-; R 8 It is hydrogen;

[0123] p is 1 or 2;

[0124] R 5 A C1-C4 alkyl group that is independently a halogen or is substituted with one or more halogens.

[0125] In one of the proposed solutions:

[0126] m is 1;

[0127] A is -(CR) 1 R 2 )-;

[0128] R 1 It is hydrogen;

[0129] R 2 It is hydrogen;

[0130] n is 2;

[0131] G is -(CR) 3 R 4 )-;

[0132] R 3 It is hydrogen;

[0133] R 4 It is hydrogen;

[0134] X is N, Z is CR 6 ;

[0135] R 6 It is hydrogen;

[0136] Y is -CH2-;

[0137] p is 1 or 2;

[0138] R 5 A C1-C4 alkyl group that is independently a halogen or is substituted with one or more halogens.

[0139] In one of the proposed solutions:

[0140] m is 1 or 2;

[0141] A is -(CR) 1 R 2 )-;

[0142] R 1 Independently hydrogen or R 1-1 ;R 1-1 Independently for C1-C 40 Alkyl groups;

[0143] R 2 It is hydrogen;

[0144] n is 2;

[0145] G is -(CR) 3 R 4 )-;

[0146] R 3 Independently for hydrogen, R 3-1 "By one, two or more R" 3-3 Replacement R 3-2 ”;R 3-1 and R 3-2 Independently for C1-C 40 Alkyl group; R 3-3 It is -OH;

[0147] R 4 It is hydrogen;

[0148] X is N, Z is CR 6 ;

[0149] R 6 It is hydrogen, halogen, or -C(=O)-NH-R 6-1 ;R 6-1 It is a C1-C4 alkyl group;

[0150] Y is -NR 8 -, -CH2-, -C(=O)- or -S(=O)-; R 8 It is hydrogen;

[0151] p is 1 or 2;

[0152] R 5 Independently cyano, halogen, -OH, C1-C4 alkoxy, -NR 9 R 10 C3-C6 cycloalkyl groups, or C1-C4 alkyl groups substituted with one or more halogens; R 9 and R 10 It is an alkyl group that is independently C1-C4.

[0153] In one of the proposed solutions:

[0154] m is 1 or 2;

[0155] A is -(CR) 1 R 2 )-;

[0156] R 1 Independently hydrogen or R 1-1 ;R 1-1 Independently methyl or ethyl;

[0157] R 2 It is hydrogen;

[0158] n is 2;

[0159] G is -(CR) 3 R 4 )-;

[0160] R 3 Independently for hydrogen, R 3-1 "By one, two or more R" 3-3 Replacement R 3-2 ”;R 3-1 and R 3-2 Independently methyl or ethyl; R 3-3 It is -OH;

[0161] R 4 It is hydrogen;

[0162] X is N, Z is CR 6 Or X is CH and Z is N;

[0163] R 6 It is hydrogen, halogen, or -C(=O)-NH-R 6-1 ;R 6-1 It is methyl or ethyl;

[0164] Y is -O-, -S-, -NR 8 -, -CH2-, -C(=O)- or -S(=O)-; R 8 It is hydrogen;

[0165] p is 1 or 2;

[0166] R 5 Independently cyano, halogen, -OH, methoxy, ethoxy, -NR 9 R 10 Cyclopropyl, methyl, difluoromethyl, or trifluoromethyl; R 9 and R 10 It can be methyl or ethyl on its own.

[0167] In one of the proposed solutions:

[0168] m is 1 or 2;

[0169] A is -(CR) 1 R 2 )-;

[0170] R 1 Independently hydrogen or R 1-1 ;R 1-1 Independently methyl or ethyl;

[0171] R 2 It is hydrogen;

[0172] n is 2;

[0173] G is -(CR) 3 R 4 )-;

[0174] R 3 Independently for hydrogen, R 3-1 "By one, two or more R" 3-3 Replacement R 3-2 ”;R 3-1 and R 3-2 Independently methyl or ethyl; R 3-3 It is -OH;

[0175] R 4 It is hydrogen;

[0176] X is N, Z is CR 6 ;

[0177] R 6It is hydrogen, halogen, or -C(=O)-NH-R 6-1 ;R 6-1 It is methyl or ethyl;

[0178] Y is -NR 8 -, -CH2-, -C(=O)- or -S(=O)-; R 8 It is hydrogen;

[0179] p is 1 or 2;

[0180] R 5 Independently cyano, halogen, -OH, methoxy, ethoxy, -NR 9 R 10 , cyclopropyl, or, methyl group substituted with one or more halogens; R 9 and R 10 It can be methyl or ethyl on its own.

[0181] In one of the proposed solutions:

[0182] m is 1;

[0183] A is -(CR) 1 R 2 )-;

[0184] R 1 It is hydrogen;

[0185] R 2 It is hydrogen;

[0186] n is 2;

[0187] G is -(CR) 3 R 4 )-;

[0188] R 3 It is hydrogen;

[0189] R 4 It is hydrogen;

[0190] X is N, Z is CR 6 ;

[0191] R 6 It is hydrogen;

[0192] Y is -CH2-, -C(=O)-, or -S(=O)-;

[0193] p is 1 or 2;

[0194] R 5 It is independently a halogen, cyano, -OH, or a C1-C4 alkyl group substituted with one or more halogens.

[0195] In one of the proposed solutions:

[0196] m is 1;

[0197] A is -(CR) 1 R 2 )-;

[0198] R 1 It is hydrogen;

[0199] R 2 It is hydrogen;

[0200] n is 2;

[0201] G is -(CR) 3 R 4 )-;

[0202] R 3 It is hydrogen;

[0203] R 4 It is hydrogen;

[0204] X is N, Z is CR 6 ;

[0205] R 6 It is hydrogen;

[0206] Y is -CH2-, -C(=O)-, or -S(=O)-;

[0207] p is 1 or 2;

[0208] R 5 Independently a halogen, cyano, -OH, or a C1-C4 alkyl group substituted with one or more halogens; when p is 1, R 5 It is a C1-C4 alkyl group substituted with one or more halogens; when p is 2, the C1-C4 alkyl group substituted with one or more halogens is a C1-C4 alkyl group substituted with three halogens.

[0209] In one of the solutions,

[0210] m is 1;

[0211] A is -(CR) 1 R 2 )-;

[0212] R 1 It is hydrogen;

[0213] R 2 It is hydrogen;

[0214] n is 2;

[0215] G is -(CR) 3 R 4 )-;

[0216] R 3 It is hydrogen;

[0217] R 4 It is hydrogen;

[0218] X is N, Z is CR 6 ;

[0219] R 6 It is hydrogen;

[0220] Y is -CH2- or -C(=O)-;

[0221] p is 1 or 2;

[0222] R 5 Independently a halogen, cyano, or methyl group substituted with one or more halogens;

[0223] When p is 2, the R 5 Located at the ortho and para positions of Y, the methyl group substituted by one or more halogens is a methyl group substituted by three halogens;

[0224] When Y is -CH2- and p is 1, R 5 A methyl group is substituted with one or more halogens.

[0225] In one particular scheme, m is 1.

[0226] In one possible solution, A is -(CR) 1 R 2 )-.

[0227] In one particular scheme, R 1 Independently hydrogen or R 1-1 ;R 1-1 Independently for C1-C 40 Alkyl groups.

[0228] In one particular scheme, R 1 Independently hydrogen or R 1-1 ;R 1-1 It can be methyl or ethyl on its own.

[0229] In one particular scheme, R 1 It is hydrogen.

[0230] In one particular scheme, R 2 It is hydrogen.

[0231] In one particular scheme, n is 2.

[0232] In one scheme, G is -(CR) 3 R 4 )-.

[0233] In one particular scheme, R 3 Independently for hydrogen, R 3-1 "By one, two or more R" 3-3 Replacement R 3-2 ”;R 3-1 and R 3-2 Independently for C1-C 40 Alkyl group; R 3-3 It is -OH.

[0234] In one particular scheme, R 3 Independently for hydrogen, R 3-1 "By one, two or more R" 3-3 Replacement R 3-2 ”;R 3-1 and R 3-2 Independently methyl or ethyl; R 3-3 It is -OH.

[0235] In one particular scheme, R 3 It is hydrogen.

[0236] In one particular scheme, R 4 It is hydrogen.

[0237] In a certain scheme, X is N and Z is CR. 6 ;R 6 It is hydrogen, halogen, or -C(=O)-NH-R 6-1 ;R 6-1 It is a C1-C4 alkyl group.

[0238] In a certain scheme, X is N and Z is CR. 6 ;R 6 It is hydrogen.

[0239] In a certain scheme, X is CH and Z is N.

[0240] In one scheme, Y is -O-, -S-, or -NR. 8 -, -CH2-, -C(=O)- or -S(=O)-; R 8 It is hydrogen.

[0241] In one particular scheme, Y is -NR 8 -, -CH2-, -C(=O)- or -S(=O)-; R 8 It is hydrogen.

[0242] In one scheme, Y is -CH2- or -C(=O)-.

[0243] In one particular scheme, Y is -C(=O)-.

[0244] In a certain scheme, p is 1 or 2.

[0245] In one particular scheme, R 5 Independently cyano, halogen, -OH, C1-C4 alkoxy, -NR 9 R 10 C3-C6 cycloalkyl groups, or C1-C4 alkyl groups substituted with one or more halogens; R 9 and R 10 It is an alkyl group that is independently C1-C4.

[0246] In one particular scheme, R 5 Independently cyano, halogen, C1-C4 alkoxy, -NR 9 R 10 C3-C6 cycloalkyl groups, or C1-C4 alkyl groups substituted with one or more halogens.

[0247] In one particular scheme, R 5 It can be cyano, halogen, -OH, methoxy, ethoxy, -N(CH3)2, cyclopropyl, methyl, difluoromethyl or trifluoromethyl.

[0248] In one particular scheme, R 5 It is independently a cyano, halogen, or a C1-C4 alkyl group substituted with one or more halogens.

[0249] In a certain scheme, when A is independently -(CR) 1 R 2 When )-, where R 1 and R 2 The connected carbon atoms can be R-configuration carbon atoms and / or S-configuration carbon atoms.

[0250] In a certain scheme, when R 1-1 Independently for C1-C 40 When alkyl, the C1-C 40 The alkyl group can be a C1-C4 alkyl group, or it can be methyl or ethyl.

[0251] In a certain scheme, when G is independently -(CR) 3 R 4 When )-, the carbon atoms bonded to R3 and R4 can be R-configuration carbon atoms and / or S-configuration carbon atoms.

[0252] In a certain scheme, when R 3-1 Independently for C1-C 40 When alkyl, the C1-C 40 The alkyl group can be a C1-C4 alkyl group, or it can be methyl or ethyl.

[0253] In a certain scheme, when R 3-2Independently for C1-C 40 When alkyl, the C1-C 40 The alkyl group can be a C1-C4 alkyl group, or it can be methyl or ethyl.

[0254] In a certain scheme, when R 3 Independently for "by an R" 3-3 Replacement R 3-2 When “”, the “being” mentioned above refers to “being an R”. 3-3 Replacement R 3-2 "Can be hydroxymethyl."

[0255] In a certain scheme, when R 6 When the halogen is halogen, the halogen can be fluorine, chlorine, or bromine, and it can also be bromine.

[0256] In a certain scheme, when R 6-1 When the alkyl group is C1-C4, the C1-C4 alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, or it can be methyl.

[0257] In one scheme, the R... 5 It can be independently located in the adjacent, intermediate, or opposite position of Y.

[0258] In one scheme, when p is 1, the R... 5 It can be located in the adjacent position of Y.

[0259] In one scheme, when p is 2, the R... 5 It can be located in the adjacent or opposite position of Y.

[0260] In one scheme, when p is 2, the R... 5 It can be located in the adjacent and opposite positions of Y, or it can be located in the adjacent and intermediate positions of Y.

[0261] In a certain scheme, when R 5 When it is a halogen on its own, the halogen can be fluorine, chlorine or bromine, or it can be fluorine or chlorine.

[0262] In a certain scheme, when R 5 When the plurality is independently a C1-C4 alkyl group substituted with one or more halogens, the plurality may be two or three.

[0263] In a certain scheme, when R 5 When independently a C1-C4 alkyl group substituted with one or more halogens, the halogen can be fluorine, chlorine, or bromine, or it can be fluorine.

[0264] In a certain scheme, when R 5When the C1-C4 alkyl group is independently substituted with one or more halogens, the C1-C4 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, or may be methyl.

[0265] In a certain scheme, when R 5 When the alkyl group is independently a C1-C4 alkyl group substituted with multiple halogens, the C1-C4 alkyl group substituted with multiple halogens may be difluoromethyl or trifluoromethyl.

[0266] In a certain scheme, when R 5 When the alkoxy group is independently C1-C4, the C1-C4 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0267] In a certain scheme, when R 5 When independently a C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0268] In a certain scheme, when R 5 When independently a C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is cyclopropyl.

[0269] In one particular scheme, the aforementioned Can be

[0270] In one particular scheme, the aforementioned It can be 2-trifluoromethylphenyl, 2-trifluoromethyl-4-fluorophenyl, 2-difluoromethyl-4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl,

[0271] In one particular scheme, the aforementioned It can be 2-trifluoromethylphenyl, 2-trifluoromethyl-4-fluorophenyl, 2-difluoromethyl-4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl,

[0272] In one particular scheme, the aforementioned It can be 2-trifluoromethylphenyl, 2-trifluoromethyl-4-fluorophenyl, 2-chloro-4-fluorophenyl,

[0273] In one particular scheme, the aforementioned Can be

[0274] In one particular scheme, the aforementioned Can be

[0275] In one particular scheme, the aforementioned Can be

[0276] In one particular scheme, the aforementioned Can be

[0277] In one particular scheme, the aforementioned Can be

[0278] In one particular scheme, the aforementioned Can be

[0279] In one embodiment, the heterocyclic compound as described in Formula I, its tautomers, its pharmaceutically acceptable salts, its solvates, or solvates of its pharmaceutically acceptable salts;

[0280]

[0281] Where m is 1 or 2;

[0282] A independently is -(CR) 1 R 2 - or -(C=O)-;

[0283] R 1 Independently hydrogen, halogen, R 1-1 "By one, two or more R" 1-3 Replacement R 1-2 "、-(C=O)NHR 1-4 -NH(C=O)R 1-5 -(C=O)OR 1-6 -S(=O)2R 1-7 、or 、-S(=O)R 1-8 ;

[0284] R 1-1 and R 1-2 Independently amino, C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 aryl, C6-C 20 aryl-C1-C 40 Alkyl group, "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", or "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S" -C1-C 40 Alkyl groups;

[0285] R 1-3 R 1-4 R 1-5 R 1-6 R 1-7 and R 1-8 Independently, -CN, halogen, -OH, -NH2, -COOH, -NO2, -S(=O)2CH3, -C(=O)NHCH2CH3, oxo(=O), -NHC(=O)R 1-3-4 -C(=O)OR 1-3-5 R 1-3-1 Or, "by one, two or more Rs" 1-3-3 Replacement R 1-3-2 ”;

[0286] R 1-3-1 and R 1-3-2 Independently for C1-C 40 Alkyl, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0287] R 1-3-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0288] R 1-3-4 Independently for hydrogen, R 1-3-4-1Or, "by one, two or more Rs" 1-3-4-3 Replacement R 1-3-4-2 ”;

[0289] R 1-3-4-1 and R 1-3-4-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0290] R 1-3-4-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0291] R 1-3-5 Independently for hydrogen, R 1-3-5-1 Or, "by one, two or more Rs" 1-3-5-3 Replacement R 1-3-5-2 ”;

[0292] R 1-3-5-1 and R 1-3-5-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0293] R 1-3-5-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0294] R 2 Independently hydrogen, halogen, R 2-1 "By one, two or more R" 2-3 Replacement R 2-2 "、-(C=O)NHR 2-4 -NH(C=O)R 2-5 -(C=O)OR 2-6 -S(=O)2R 2-7 、or 、-S(=O)R 2-8 ;

[0295] R 2-1 and R 2-2 Independently amino, C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 aryl, C6-C 20 aryl-C1-C 40 Alkyl group, "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", or "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S" -C1-C 40 Alkyl groups;

[0296] R 2-3 R 2-4 R 2-5 R 2-6 R 2-7 and R 2-8 Independently, -CN, halogen, -OH, -NH2, -COOH, -NO2, -S(=O)2CH3, -C(=O)NHCH2CH3, oxo(=O), -NHC(=O)R 2-3-4 -C(=O)OR 2-3-5 R 2-3-1 Or, "by one, two or more Rs" 2-3-3 Replacement R 2-3-2 ”;

[0297] R 2-3-1 and R2-3-2 Independently for C1-C 40 Alkyl, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0298] R 2-3-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0299] R 2-3-4 Independently for hydrogen, R 2-3-4-1 Or, "by one, two or more Rs" 2-3-4-3 Replacement R 2-3-4-2 ”;

[0300] R 2-3-4-1 and R 2-3-4-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0301] R 2-3-4-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0302] R 2-3-5Independently for hydrogen, R 2-3-5-1 Or, "by one, two or more Rs" 2-3-5-3 Replacement R 2-3-5-2 ”;

[0303] R 2-2-5-1 and R 2-3-5-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0304] R 2-3-5-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0305] n is 1 or 2;

[0306] G independently is -(CR) 3 R 4 - or -(C=O)-;

[0307] R 3 Independently hydrogen, halogen, R 3-1 "By one, two or more R" 3-3 Replacement R 3-2 "、-(C=O)NHR 3-4 -NH(C=O)R 3-5 -(C=O)OR 3-6 -S(=O)2R 3-7 、or 、-S(=O)R 3-8 ;

[0308] R 3-1 and R 3-2 Independently amino, C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 aryl, C6-C 20 aryl-C1-C 40 Alkyl group, "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", or "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S" -C1-C 40 Alkyl groups;

[0309] R 3-3 R 3-4 R 3-5 R 3-6 R 3-7 and R 3-8 Independently, -CN, halogen, -OH, -NH2, -COOH, -NO2, -S(=O)2CH3, -C(=O)NHCH2CH3, oxo(=O), -NHC(=O)R 3-3-4 -C(=O)OR 3-3-5 R 3-3-1 Or, "by one, two or more Rs" 3-3-3 Replacement R 3-3-2 ”;

[0310] R 3-3-1 and R 3-3-2 Independently for C1-C 40 Alkyl, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "having one, two or three heteroatoms, the heteroatoms being selected from one or more of N, O and S, and being a 5-20 membered heteroaryl group";

[0311] R 3-3-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0312] R 3-3-4 Independently for hydrogen, R 3-3-4-1Or, "by one, two or more Rs" 3-3-4-3 Replacement R 3-3-4-2 ”;

[0313] R 3-3-4-1 and R 3-3-4-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0314] R 3-3-4-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0315] R 3-3-5 Independently for hydrogen, R 3-3-5-1 Or, "by one, two or more Rs" 3-3-5-3 Replacement R 3-3-5-2 ”;

[0316] R 3-3-5-1 and R 3-3-5-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0317] R 3-3-5-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0318] R 4 Independently hydrogen, halogen, R 4-1 "By one, two or more R" 4-3 Replacement R 4-2 "、-(C=O)NHR 4-4 -NH(C=O)R 4-5 -(C=O)OR 4-6 -S(=O)2R 4-7 、or 、-S(=O)R 4-8 ;

[0319] R 4-1 and R 4-2 Independently amino, C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 aryl, C6-C 20 aryl-C1-C 40 Alkyl group, "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", or "5-20-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S" -C1-C 40 Alkyl groups;

[0320] R 4-3 R 4-4 R 4-5 R 4-6 R 4-7 and R 4-8 Independently, -CN, halogen, -OH, -NH2, -COOH, -NO2, -S(=O)2CH3, -C(=O)NHCH2CH3, oxo(=O), -NHC(=O)R 4-3-4 -C(=O)OR 4-3-5 R 4-3-2 Or, "by one, two or more Rs" 4-3-3 Replacement R 4-3-2 ”;

[0321] R 4-3-1 and R4-3-2 Independently for C1-C 40 Alkyl, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "having one, two or three heteroatoms, the heteroatoms being selected from one or more of N, O and S, and being a 5-20 membered heteroaryl group";

[0322] R 4-3-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0323] R 4-3-4 Independently for hydrogen, R 4-3-4-1 Or, "by one, two or more Rs" 4-3-4-3 Replacement R 4-3-4-2 ”;

[0324] R 4-3-4-1 and R 4-3-4-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C1-C 40 alkoxy groups, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0325] R 4-3-4-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0326] R 4-3-5Independently for hydrogen, R 4-3-5-1 Or, "by one, two or more Rs" 4-3-5-3 Replacement R 4-3-5-2 ”;

[0327] R 4-3-5-1 and R 4-3-5-2 Independently for C1-C 40 Alkyl, C2-C 40 alkenyl, C2-C 40 alkynyl group, C3-C 20 Cycloalkyl groups, "3-20 membered heterocycloalkyl groups having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", C6-C 20 The aryl group, or, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, which are 5-20 membered heteroaryl groups";

[0328] R 4-3-5-3 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0329] X is either N or CH;

[0330] When X is N, Z is CR 6 When X is CH, Z is N or CR. 7 ;

[0331] R 6 Hydrogen, halogen, amino, or with one or more R 6-2 Substituted C1-C4 alkyl, C1-C4 alkoxy, or -C(=O)-NH-R 6-1 ;R 6-1 It is a C1-C4 alkyl group; R 6-2 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0332] R 7 Hydrogen, halogen, amino, or with one or more R 7-2Substituted C1-C4 alkyl, C1-C4 alkoxy, or -C(=O)-NH-R 7-1 ;R 7-1 It is a C1-C4 alkyl group; R 7-2 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0333] Y is -O-, -S-, -NR 8 -or -CH2-;

[0334] R 8 For hydrogen, by one or more R 8-2 Substituted C1-C4 alkyl, C1-C4 alkoxy, or -C(=O)-NH-R 8-1 R 8-1 It is a C1-C4 alkyl group; R 8-2 Independently -CN, halogen, -OH, -NH2, oxo (=O), -S(O)2CH3, C1-C 40 Alkyl groups, C1-C substituted with one or more halogens 40 Alkyl group, C1-C 40 alkoxy groups, or C1-C atoms substituted with one or more halogens 40 "alkoxy group";

[0335] p is 1, 2, or 3;

[0336] R 5 It is independently a cyano, a halogen, a C1-C4 alkyl, or a C1-C4 alkyl substituted with one or more halogens.

[0337] In one embodiment, certain groups in the heterocyclic compound of Formula I, its tautomers, its pharmaceutically acceptable salts, its solvates, or solvates of its pharmaceutically acceptable salts are defined as follows, and groups not covered below are defined as described in any of the preceding embodiments (hereinafter referred to as "in one embodiment"):

[0338] m is 1 or 2;

[0339] A independently is -(CR) 1 R 2 )-;

[0340] R 1 Independently hydrogen or R1-1 ;R 1-1 Independently for C1-C 40 Alkyl groups;

[0341] R 2 It is hydrogen;

[0342] n is 2;

[0343] G independently is -(CR) 3 R 4 )-;

[0344] R 3 Independently for hydrogen, R 3-1 "By one, two or more R" 3-3 Replacement R 3-2 ”;R 3-1 and R 3-2 Independently for C1-C 40 Alkyl group; R 3-3 It is -OH;

[0345] R 4 It is hydrogen;

[0346] X is N, Z is CR 6 ;

[0347] R 6 It is hydrogen, halogen, or -C(=O)-NH-R 6-1 ;R 6-1 It is a C1-C4 alkyl group;

[0348] Y is -NR 8 -or -CH2-; R 8 It is hydrogen;

[0349] p is 1 or 2;

[0350] R 5 A C1-C4 alkyl group that is independently a halogen or is substituted with one or more halogens.

[0351] In one of the proposed solutions:

[0352] m is 1 or 2;

[0353] A is -(CR) 1 R 2 )-;

[0354] R 1 It is hydrogen;

[0355] R 2 It is hydrogen;

[0356] n is 2;

[0357] G is -(CR)3 R 4 )-;

[0358] R 3 It is hydrogen;

[0359] R 4 It is hydrogen;

[0360] X is N, Z is CR 6 ;

[0361] R 6 It is hydrogen, halogen, or -C(=O)-NH-R 6-1 ;R 6-1 It is a C1-C4 alkyl group;

[0362] Y is -NR 8 -or -CH2-; R 8 It is hydrogen;

[0363] p is 1 or 2;

[0364] R 5 A C1-C4 alkyl group that is independently a halogen or is substituted with one or more halogens.

[0365] In one of the proposed solutions:

[0366] m is 1;

[0367] A is -(CR) 1 R 2 )-;

[0368] R 1 It is hydrogen;

[0369] R 2 It is hydrogen;

[0370] n is 2;

[0371] G is -(CR) 3 R 4 )-;

[0372] R 3 It is hydrogen;

[0373] R 4 It is hydrogen;

[0374] X is N, Z is CR 6 ;

[0375] R 6 It is hydrogen;

[0376] Y is -CH2-;

[0377] p is 1 or 2;

[0378] R5 A C1-C4 alkyl group that is independently a halogen or is substituted with one or more halogens.

[0379] In one particular scheme, m is 1.

[0380] In a certain scheme, A is independently -(CR) 1 R 2 )-.

[0381] In one particular scheme, R 1 Independently hydrogen or R 1-1 ;R 1-1 Independently for C1-C 40 Alkyl groups.

[0382] In one particular scheme, R 1 It is hydrogen.

[0383] In one particular scheme, R 2 It is hydrogen.

[0384] In one particular scheme, n is 2.

[0385] In one particular scheme, G is independently -(CR) 3 R 4 )-.

[0386] In one particular scheme, R 3 Independently for hydrogen, R 3-1 "By one, two or more R" 3-3 Replacement R 3-2 ”;R 3-1 and R 3-2 Independently for C1-C 40 Alkyl group; R 3-3 It is -OH.

[0387] In one particular scheme, R 3 It is hydrogen.

[0388] In one particular scheme, R 4 It is hydrogen.

[0389] In a certain scheme, X is N and Z is CR. 6 ;R 6 It is hydrogen, halogen, or -C(=O)-NH-R 6-1 ;R 6-1 It is a C1-C4 alkyl group.

[0390] In a certain scheme, X is N and Z is CR. 6 ;R 6 It is hydrogen.

[0391] In one particular scheme, Y is -NR 8-or -CH2-; R 8 It is hydrogen.

[0392] In one particular scheme, Y is -CH2-.

[0393] In a certain scheme, p is 1 or 2.

[0394] In one particular scheme, R 5 A C1-C4 alkyl group that is independently a halogen or is substituted with one or more halogens.

[0395] In a certain scheme, when A is independently -(CR) 1 R 2 When )-, where R 1 and R 2 The connected carbon atoms can be R-configuration carbon atoms and / or S-configuration carbon atoms.

[0396] In a certain scheme, when R 1-1 Independently for C1-C 40 When alkyl, the C1-C 40 The alkyl group can be a C1-C4 alkyl group, or it can be methyl or ethyl.

[0397] In a certain scheme, when G is independently -(CR) 3 R 4 When )-, the carbon atoms bonded to R3 and R4 can be R-configuration carbon atoms and / or S-configuration carbon atoms.

[0398] In a certain scheme, when R 3-1 Independently for C1-C 40 When alkyl, the C1-C 40 The alkyl group can be a C1-C4 alkyl group, or it can be methyl or ethyl.

[0399] In a certain scheme, when R 3-2 Independently for C1-C 40 When alkyl, the C1-C 40 The alkyl group can be a C1-C4 alkyl group, or it can be methyl or ethyl.

[0400] In a certain scheme, when R 3 Independently for "by an R" 3-3 Replacement R 3-2 When “”, the “being” mentioned above refers to “being an R”. 3-3 Replacement R 3-2 "Can be hydroxymethyl."

[0401] In a certain scheme, when R 6 When the halogen is halogen, the halogen can be fluorine, chlorine, or bromine, and it can also be bromine.

[0402] In a certain scheme, when R 6-1 When the alkyl group is C1-C4, the C1-C4 alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, or it can be methyl.

[0403] In one scheme, the R... 5 It can be independently located in the adjacent, intermediate, or opposite position of Y.

[0404] In one scheme, when p is 1, the R... 5 It can be located in the adjacent position of Y.

[0405] In one scheme, when p is 2, the R... 5 It can be located in the adjacent or opposite position of Y.

[0406] In a certain scheme, when R 5 When it is a halogen on its own, the halogen can be fluorine, chlorine or bromine, or it can be fluorine or chlorine.

[0407] In a certain scheme, when R 5 When the plurality is independently a C1-C4 alkyl group substituted with one or more halogens, the plurality may be two or three.

[0408] In a certain scheme, when R 5 When independently a C1-C4 alkyl group substituted with one or more halogens, the halogen can be fluorine, chlorine, or bromine, or it can be fluorine.

[0409] In a certain scheme, when R 5 When the C1-C4 alkyl group is independently substituted with one or more halogens, the C1-C4 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, or may be methyl.

[0410] In a certain scheme, when R 5 When the alkyl group is independently a C1-C4 alkyl group substituted with multiple halogens, the C1-C4 alkyl group substituted with multiple halogens may be difluoromethyl or trifluoromethyl.

[0411] In one particular scheme, the aforementioned It can be 2-trifluoromethylphenyl, 2-trifluoromethyl-4-fluorophenyl, 2-difluoromethyl-4-fluorophenyl, 2,4-difluorophenyl or 2-chloro-4-fluorophenyl.

[0412] In one embodiment, the heterocyclic compound of Formula I, its tautomers, its pharmaceutically acceptable salts, its solvates, or solvates of its pharmaceutically acceptable salts, wherein the heterocyclic compound of Formula I is any one of the following compounds:

[0413]

[0414]

[0415]

[0416] The present invention also provides a pharmaceutical composition comprising substance Y and a pharmaceutical excipient, wherein substance Y is a heterocyclic compound as described in Formula I, its tautomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof.

[0417] This invention also provides the use of substance Y in the preparation of TRPC5 inhibitors, wherein substance Y is a heterocyclic compound as described in Formula I, its tautomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof.

[0418] The present invention also provides the use of substance Y in the preparation of a drug, wherein substance Y is a heterocyclic compound as described in Formula I, its tautomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, and the drug is a drug for treating and / or preventing TRPC5-mediated diseases.

[0419] In the aforementioned applications, the TRPC5-mediated diseases may be mental illnesses, neurological disorders, neurodegenerative diseases, or kidney diseases.

[0420] The mental illnesses, neurological disorders, or neurodegenerative disorders mentioned may be selected from: disorders related to disordered emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, severe depressive disorder, psychotic depression, dysphoric mood and postpartum depression, and bipolar disorder); disorders related to anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and separation anxiety); memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disabilities, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke, and Wechsler-Colombian syndrome); disorders related to impaired impulse control and addiction; Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy; and other brain disorders caused by trauma or other damage including aging.

[0421] The kidney disease mentioned may be focal segmental glomerulosclerosis (FSGS), minimal change disease, or diabetic nephropathy.

[0422] The present invention also provides the use of substance Y in the preparation of a drug, wherein substance Y is a heterocyclic compound as described in Formula I, its tautomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, and wherein the drug is a drug for treating and / or preventing mental illnesses, neurological disorders, neurodegenerative diseases, or kidney diseases.

[0423] In the described application, the mental illness, neurological illness, or neurodegenerative illness may be selected from: illnesses related to disordered emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, severe depressive disorder, psychotic depression, dysphoric mood and postpartum depression, and bipolar disorder), illnesses related to anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disabilities, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke, and Wechsler-Colombian syndrome), illnesses related to impaired impulse control and addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, and other brain illnesses caused by trauma or other damage including aging.

[0424] In the aforementioned applications, the kidney disease may be focal segmental glomerulosclerosis (FSGS), minimal change disease, or diabetic nephropathy.

[0425] The present invention also provides a method for treating and / or preventing TRPC5-mediated diseases, comprising administering to a patient a therapeutically effective amount of substance Y; said substance Y is a heterocyclic compound as described in Formula I, its tautomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof.

[0426] In the method described, the TRPC5-mediated disease may be a mental illness, a neurological disorder, a neurodegenerative disease, or a kidney disease.

[0427] The mental illnesses, neurological disorders, or neurodegenerative disorders mentioned may be selected from: disorders related to disordered emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, severe depressive disorder, psychotic depression, dysphoric mood and postpartum depression, and bipolar disorder); disorders related to anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and separation anxiety); memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disabilities, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke, and Wechsler-Colombian syndrome); disorders related to impaired impulse control and addiction; Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy; and other brain disorders caused by trauma or other damage including aging.

[0428] The kidney disease mentioned may be focal segmental glomerulosclerosis (FSGS), minimal change disease, or diabetic nephropathy.

[0429] The present invention also provides a method for treating and / or preventing mental illnesses, neurological disorders, neurodegenerative diseases, or kidney diseases, comprising administering to a patient a therapeutically effective amount of substance Y; said substance Y is a heterocyclic compound as described in Formula I, its tautomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof.

[0430] In the method described, the mental illness, neurological illness, or neurodegenerative illness may be selected from: illnesses related to disordered emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, severe depressive disorder, psychotic depression, dysphoric mood and postpartum depression, and bipolar disorder), illnesses related to anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disabilities, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke, and Wechsler-Colombian syndrome), illnesses related to impaired impulse control and addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, and other brain illnesses caused by trauma or other damage including aging.

[0431] In the method described, the kidney disease may be focal segmental glomerulosclerosis (FSGS), minimal change disease, or diabetic nephropathy.

[0432] Unless otherwise stated, the following terms appearing in this specification and claims have the following meanings:

[0433] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the prototype of such compounds with a sufficient amount of pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the prototype of such compounds with a sufficient amount of pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentic acid, fumaric acid, gluconic acid, succinic acid, formic acid, ethanesulfonic acid, dihydroxynaphthyl acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthylcarboxylic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0434] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[0435] As described above, the terms "pharmaceutical-acceptable salt" and "solvent" in the term "pharmaceutical-acceptable salt solvate" refer to substances formed by the following: 1) compounds of the present invention prepared with a relatively non-toxic, pharmaceutically acceptable acid or base; and 2) substances formed by combining with a stoichiometric or non-stoichiometric solvent. The term "pharmaceutical-acceptable salt solvate" includes, but is not limited to, hydrochloric acid monohydrates of the compounds of the present invention.

[0436] When any variable (e.g., R) 1-3 When a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Therefore, if a group is surrounded by one, two, or three R... 1-3 Group substitution, meaning that the group can be replaced by up to 3 R groups. 1-3 Replace, the position R 1-3 Definition and other positions R 1-3 The definitions are independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0437] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0438] The term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group having one to forty carbon atoms (e.g., C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.). Examples of alkyl groups include, but are not limited to: methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, and 1-octyl.

[0439] The term "alkenyl" refers to an alkenyl group having at least one carbon-carbon sp. 2 A monovalent hydrocarbon group (e.g., C2-C6 alkenyl, or C2-C4 alkenyl) with two to forty carbon atoms in a double bond, either straight-chain or branched, and including groups having “cis” and “trans” orientations or “E” and “Z” orientations. Examples of alkenyl groups include, but are not limited to, vinyl and allyl groups.

[0440] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group (e.g., C2-C6 alkynyl, or C2-C4 alkynyl) having two to forty carbon atoms and having at least one carbon-carbon sp triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl and propynyl.

[0441] The term "alkoxy" refers to an alkyl group linked by an oxygen bridge; the definition of the alkyl group is the same as above. Examples of alkoxy groups include, but are not limited to, methoxy and ethoxy groups.

[0442] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group having three to twenty carbon atoms, preferably containing three to twelve carbon atoms, and more preferably containing three to six carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0443] The term "heterocyclic alkyl" refers to a saturated cyclic group having 3 to 20 ring atoms, wherein at least one ring atom is a heteroatom independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon atoms. The group can be a carbon group or a heteroatom group (i.e., it can be a C-linked or N-linked group, whichever is possible). Examples of heterocyclic alkyl groups include, but are not limited to: pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, 4-thiomorpholinyl, thiaoxylalkyl, and piperazineyl.

[0444] The term "aryl" refers to a monocyclic, bicyclic, or polycyclic carbon ring having six to twenty carbon atoms, at least one of which is an aromatic ring. When one of the rings is non-aromatic, the group can be linked to other groups via either the aromatic or non-aromatic ring. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthracene, and acenaphthene.

[0445] The term "heteroaryl" refers to a monocyclic, bicyclic, or polycyclic cyclic system having 3 to 20 ring atoms, wherein at least one ring atom is a heteroatom independently selected from oxygen, sulfur, and nitrogen, the remaining ring atoms are carbon atoms, and at least one ring is an aromatic ring. The group can be a carbon group or a heteroatom group (i.e., it can be a C-linked or N-linked group, whichever is possible). When one of the rings is a non-aromatic ring, the group can be linked to other groups via an aromatic or non-aromatic ring. Examples of heteroaryl groups include, but are not limited to: acridinel, carbazolyl, borazolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thiophenyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrroleyl, and tetrahydroquinoline.

[0446] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. It includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0447] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0448] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0449] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has already received administration of the compound or composition according to embodiments of the invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.

[0450] The term "therapeutic effective amount" refers to the amount of a compound, when administered to a patient, sufficient to effectively treat the disease or condition described herein. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and may be adjusted as needed by those skilled in the art.

[0451] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0452] The reagents and raw materials used in this invention are all commercially available.

[0453] The positive and progressive effects of this invention are that the compound has better inhibitory activity against TRPC5, better metabolic stability in liver microsomes, and better clinical pharmacokinetic properties. Attached Figure Description

[0454] Figure 1 shows the distribution of blood drug concentration in tissues of CD-1 mice after a single oral gavage administration. Detailed Implementation

[0455] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0456] Nouns and representative reagents

[0457] The terms used in the following specific experimental descriptions refer to the following reagents (unless otherwise stated):

[0458] NBS: N-bromosuccinimide; DIEA: N,N-diisopropylethylamine; EA: ethyl acetate; DCM: dichloromethane; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; IV: intravenous injection; PO: oral administration.

[0459] Example 1: Preparation of compound 4-chloro-5-(3-(2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)one (L001)

[0460]

[0461] 1.1 Preparation of compound 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-tert-butyl carboxylate (L001-1)

[0462] 5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazine (700 mg, 5.68 mmol) and K₂CO₃ (1.57 g, 11.37 mmol) were added to a single-necked flask, followed by 8 mL of H₂O and 8 mL of THF. After complete dissolution, (Boc)₂O was added dropwise, and the reaction was allowed to proceed overnight at room temperature. TLC (DCM / MeOH = 10 / 1) showed that the reaction was complete. The reaction solution was saturated with NaCl, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give compound L001-1 (1.2 g), a brown solid.

[0463] 1.2 Preparation of compound 3-bromo-5,6-dihydroimidazole[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (L001-2)

[0464] 1.2 g (5.37 mmol) of 5,6-dihydroimidazolo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester was added to a single-necked flask, followed by the addition of DMF (10 mL). After complete dissolution, NBS (1.15 g (6.45 mmol) was slowly added, and the reaction was allowed to proceed overnight at room temperature. TLC (DCM / MeOH = 10 / 1) indicated that the reaction was complete. The reaction solution was prepared by separation (MeCN, H2O, 0.05% TFA) to give compound L001-2 (700 mg), a pale yellow solid.

[0465] 1.3 Preparation of compound 3-(2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (L001-3)

[0466] o-bromotrifluorotoluene (791.1 mg, 3.31 mmol) and Zn (8.27 mmol) were added to a single-necked flask, along with anhydrous THF (5 mL). The mixture was reacted overnight at room temperature under nitrogen protection. Pd2(dba)3 (91.6 mg), tris(o-methylphenyl)phosphine (50.3 mg), and tert-butyl 3-bromo-5,6-dihydroimidazole[1,2-a]pyrazine-7(8H)-carboxylic acid (500 mg, 1.65 mmol) were added to the single-necked flask. The mixture was reacted at 70 °C for 2 h under nitrogen protection. The reaction was complete according to TLC (EA). The mixture was extracted with EA, and the organic phase was washed with saturated brine and concentrated. The crude product was purified by silica gel column chromatography to obtain compound L001-3 (80 mg), a colorless liquid.

[0467] 1.4 Preparation of compound 3-(2-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (L001-4)

[0468] 60 mg (157.3 μmol) of 3-(2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester was dissolved in 2 mL of DCM. After complete dissolution, HCl / 1,4-dioxane (2 mL, 4N) was added while stirring. The reaction was allowed to proceed at room temperature for 3 h after the addition was complete. TLC (pure EA with 1 drop of ammonia) showed that the reaction was complete. The solution was concentrated to give compound L001-4 (45 mg) as a white solid.

[0469] 1.5 Preparation of compound 4-chloro-5-(3-(2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)one (L001)

[0470] 3-(2-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (43 mg, 152.9 μmol) was added to a single-necked flask, followed by 4,5-dichloropyridazin-3(2H)-one (211.1 mg, 1.28 mmol), DIEA (59.2 mg, 458.6 μmol), and DMF (2 mL). The reaction was carried out overnight at 100 °C under nitrogen protection. TLC (DCM / MeOH = 10 / 1) showed that the reaction was complete. The crude product was prepared and separated by preparative HPLC (H2O, MeCN, 0.05% TFA), and after lyophilization, compound L001 was obtained as a yellow solid (6.1 mg, purity 97.71%).

[0471] LC-MS[M+H] + =410.05.

[0472] 1 H NMR (400MHz, DMSO-d6) δ13.08 (s, 1H), 7.97 (s, 1H), 7.80 (d, J=7.9Hz, 1H), 7.65 (t, J=7.7Hz, 1H), 7.53 (t, J=7.6Hz , 1H), 7.33 (d, J=7.6Hz, 1H), 7.18 (s, 1H), 4.96 (s, 2H), 4.24 (s, 2H), 4.12 (d, J=4.9Hz, 2H), 3.93 (d, J=5.0Hz, 2H).

[0473] Example 2: Preparation of compound 5-(2-bromo-3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-4-chloropyridazin-3(2H)-one (L002)

[0474]

[0475]

[0476] 2.1 Preparation of compound imidazo[1,2-a]pyrazine-3-carboxaldehyde (L002-1)

[0477] Aminopyrazine (10.0 g, 0.11 mol) was dissolved in anhydrous ethanol (100 mL), and 2-bromomalondialdehyde (15.8 g, 0.11 mmol) was added. The mixture was stirred at 90 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was evaporated to obtain a black viscous substance. 30 mL of a 1,4-dioxane solution of hydrogen chloride (4 mmol / L) was added, and the mixture was stirred at 25 °C for 12 h. After the reaction was complete, 50 mL of water was added, and the pH was adjusted to approximately 8 with sodium carbonate solution. The mixture was extracted with ethyl acetate (50 mL * 4), and the organic phase was washed with saturated brine (30 mL * 2), dried over anhydrous sodium sulfate, and recrystallized three times with ethyl acetate after evaporation to obtain 3.5 g of a yellow solid, with a yield of 22%. LC-MS [M+H] + =148.0.

[0478] 2.2 Preparation of compound (4-fluoro-2-(trifluoromethyl)phenyl)(imidazo[1,2-a]pyrazin-3-yl)methanol (L002-2)

[0479] 2-Bromo-5-fluorotrifluorotoluene (7.47 g, 30.6 mmol) was dissolved in tetrahydrofuran (50 mL), and 2 mL of this solution was added dropwise to a tetrahydrofuran (20 mL) solution containing magnesium shavings (1.47 g, 61.2 mmol) and iodine (50 mg, 2 mmol) under nitrogen protection. The mixture was heated with a blower until the solution became clear and transparent. The remaining tetrahydrofuran solution of 2-bromo-5-fluorotrifluorotoluene was then added dropwise to the reaction system. The mixture was stirred at 70 °C for 1 h and cooled to room temperature. Under nitrogen protection at -70 °C, the resulting mixture was then added dropwise to a tetrahydrofuran solution of imidazo[1,2-a]pyrazin-3-carboxaldehyde (3.00 g, 20.4 mmol). The mixture was stirred at -70 °C for 2 h. After the reaction was complete, ammonium chloride solution (50 mL) was added, followed by extraction with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was then separated by silica gel column chromatography (DCM / MeOH = 100 / 1) to give 3.20 g of a yellow solid, with a yield of 41%. LC-MS [M+H] + =312.07.

[0480] 2.3 Preparation of compound (4-fluoro-2-(trifluoromethyl)phenyl)(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)methanol (L002-3)

[0481] (4-fluoro-2-(trifluoromethyl)phenyl)(imidazo[1,2-a]pyrazin-3-yl)methanol (1.10 g, 3.50 mmol) was dissolved in tetrahydrofuran (25 mL). Wet Pd / C (10%, 400 mg) was added, and the mixture was stirred at room temperature for 12 h under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the solvent was evaporated from the filtrate to give 1.00 g of a white solid (90% yield). LC-MS [M+H] + =316.2.

[0482] 2.4 Preparation of compound 3-((4-fluoro-2-(trifluoromethyl)phenyl)(hydroxy)methyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (L002-4)

[0483] (4-fluoro-2-(trifluoromethyl)phenyl)(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)methanol (1.00 g, 3.16 mmol) was dissolved in tetrahydrofuran (10 mL) / water (5 mL), and sodium carbonate (1.00 g, 9.48 mmol) and di-tert-butyl dicarbonate (0.83 g, 3.79 mmol) were added. The mixture was stirred at 25 °C for 2 h. After the reaction was complete, water (50 mL) and ethyl acetate (20 mL x 3) were added for extraction. The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.00 g of a yellow solid, yield 71%. LC-MS [M+H] + =416.4.

[0484] 2.5 Preparation of compound 3-(acetoxy(4-fluoro-2-(trifluoromethyl)phenyl)methyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (L002-5)

[0485] 1.00 g (2.40 mmol) of 3-((4-fluoro-2-(trifluoromethyl)phenyl)(hydroxy)methyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester was dissolved in pyridine (10 mL), and acetic anhydride (300 mg, 2.89 mmol) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the solvent was evaporated to dryness, yielding 1.10 g (90% product) of a pale yellow oil. LC-MS [M+H] + =457.9.

[0486] 2.6 Preparation of compound 3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (L002-6)

[0487] 1.10 g (2.40 mmol) of 3-(acetoxy-(4-fluoro-2-(trifluoromethyl)phenyl)methyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran (10 mL), and wet palladium / carbon (10%, 100 mg) was added. Hydrogen gas was introduced, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the palladium / carbon was filtered off, and the solvent was evaporated to dryness to give 800 mg of a white solid, yield 85%.

[0488] LC-MS[M+H] + =400.1.

[0489] 2.7 Preparation of compound 3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (L002-7)

[0490] 500 mg (1.25 mmol) of 3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester was dissolved in a solution of 1,4-dioxane (4 mmol / L, 5 mL) with hydrogen chloride. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the solvent was evaporated to dryness, yielding 450 mg of a pale yellow crude product. LC-MS [M+H] + =300.1.

[0491] 2.8 Preparation of compound 4-chloro-5-(3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (L002-8)

[0492] 3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (336 mg, 1.0 mmol) was dissolved in n-butanol (1.5 mL), and 4,5-dichloro-2-(oxa-2-yl)pyridazin-3-one (374 mg, 1.5 mmol) and N,N-diisopropylethylamine (388 mg, 3.0 mmol) were added. The mixture was stirred at 120 °C for 3 hours under nitrogen protection. After the reaction was complete, the n-butanol solvent was evaporated, and the crude product was separated by silica gel column chromatography (DCM / MeOH = 30). ∶ 1) A yellow solid of 200 mg was obtained. The yield was 71%. LC-MS [M+H] + =512.1.

[0493] 2.9 Preparation of compound 4-chloro-5-(3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L002)

[0494] 200 mg (0.39 mmol) of 4-chloro-5-(3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one was dissolved in 2 mL (4 mmol / L) of 1,4-dioxane hydrogen chloride solution and stirred at 25 °C for 1 hour. After the reaction was complete, the solvent was evaporated, and the residue was dissolved in dichloromethane (40 mL). The resulting solution was washed with saturated sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative chromatography to give 94.0 mg of a white solid, with a yield of 57%. LC-MS [M+H] + =427.9.

[0495] 1 H NMR (400MHz, DMSO-d6) δ13.13 (s, 1H), 7.99 (s, 1H), 7.73 (dd, J=9.3, 2.7Hz, 1H), 7.57 (td, J=8.5, 2.7Hz, 1H), 7. 44 (dd, J=8.6, 5.5Hz, 1H), 7.22 (s, 1H), 5.00 (s, 2H), 4.23 (s, 2H), 4.17 (d, J=5.1Hz, 2H), 3.96 (d, J=5.0Hz, 2H).

[0496] Example 3: Preparation of compound 7-(5-chloro-6-carbonyl-1,6-dihydropyridazin-4-yl)-3-(4-fluoro-2-(trifluoromethyl)benzyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide (L003)

[0497]

[0498]

[0499] 3.1 Preparation of compound 3-(4-fluoro-2-(trifluoromethyl)benzyl)-2-iodide-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (L003-1)

[0500] 3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (L002-6, 0.50 g, 1.25 mmol) was dissolved in dichloroethane (6 mL), and N-iodosuccinimide (0.42 g, 1.87 mmol) was added. Under nitrogen protection, the reaction mixture was stirred at 90 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, and sodium thiosulfate aqueous solution (10 mL) was added and stirred for five minutes. The mixture was then extracted with dichloromethane (10 mL * 3), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration of the filtrate was separated by silica gel column chromatography (dichloromethane / methanol = 100). ∶ 1) A yellow oily substance was obtained, 200 mg, in 27% yield. LC-MS [M+H] + =525.8.

[0501] 3.2 Preparation of compound 7-(tert-butoxycarbonyl)-3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-2-carboxylic acid methyl ester (L003-2)

[0502] 3-(4-fluoro-2-(trifluoromethyl)benzyl)-2-iodo-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (170 mg, 0.32 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (24 mg, 0.032 mmol), and triethylamine (162 mg, 1.6 mmol) were dissolved in methanol / N,N-dimethylformamide (3 mL / 3 mL). After nitrogen purging, carbon monoxide gas was introduced, and the mixture was stirred at 70 °C for 16 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to give 126 mg of a yellow solid product, yield 85%. LC-MS [M+H] + =458.

[0503] 3.3 Preparation of compound 3-(4-fluoro-2-(trifluoromethyl)benzyl)-2-(methylcarbamoyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (L003-3)

[0504] Methylamine (2M THF solution, 0.75 mL, 1.5 mmol) was added to trimethylaluminum (2M hexane solution, 0.75 mL, 1.5 mmol) at 0 °C and reacted for 0.25 h. Then, methyl 7-(tert-butoxycarbonyl)-3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-2-carboxylic acid (126 mg, 0.28 mmol) was added to the above reaction solution. After the addition was complete, the temperature was raised to 25 °C and stirred for 10 h. The pH was adjusted to neutral with hydrochloric acid (1 N), and the product was evaporated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give 80 mg of yellow solid product, yield 63%.

[0505] LC-MS[M+H] + =457.

[0506] 3.4 Preparation of compound 3-(4-fluoro-2-(trifluoromethyl)benzyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide hydrochloride (L003-4)

[0507] 80 mg (0.175 mmol) of 3-(4-fluoro-2-(trifluoromethyl)benzyl)-2-(methylcarbamoyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester was dissolved in dichloromethane (3 mL), and a solution of 1,4-dioxane in hydrogen chloride (3 mL, 4N) was added. The mixture was stirred at room temperature for 1 h. The reaction solution was evaporated to dryness to give 70 mg of a yellow solid. LC-MS [M+H] + =357.

[0508] 3.5 Preparation of compound 7-(5-chloro-6-carbonyl-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-4-yl)-3-(4-fluoro-2-(trifluoromethyl)benzyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide (L003-5)

[0509] 3-(4-fluoro-2-(trifluoromethyl)benzyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxamide hydrochloride (70 mg, 0.175 mmol), 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (50 mg, 0.192 mmol), and N,N-diisopropylethylamine (68 mg, 0.525 mmol) were dissolved in n-butanol (1 mL). The reaction mixture was stirred at 120 °C for 4 hours. After the reaction was complete, the solution was evaporated to dryness. The crude product was purified by thin-layer chromatography on silica gel (mobile phase: ethyl acetate) to give 60 mg of a white solid, yield 59%. LC-MS [M+H] +=569.

[0510] 3.6 Preparation of compound 7-(5-chloro-6-carbonyl-1,6-dihydropyridazin-4-yl)-3-(4-fluoro-2-(trifluoromethyl)benzyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide (L003-6)

[0511] 7-(5-chloro-6-carbonyl-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-4-yl)-3-(4-fluoro-2-(trifluoromethyl)benzyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxamide (60 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and a solution of 1,4-dioxane in hydrogen chloride (2 mL, 4 N) was added. The mixture was stirred at room temperature for 1 h. The reaction solution was evaporated to dryness, and the crude product was dissolved in methanol / dichloromethane solution (10 mL, 1 / 15). Solid sodium bicarbonate was added, and the mixture was stirred for 5 min. The mixture was filtered, and the filtrate was evaporated to dryness. The crude product was purified by thin-layer chromatography on silica gel (methanol / dichloromethane = 1 / 20) to give 30 mg of a white solid, with a yield of 59%.

[0512] LC-MS[M+H] + =485.

[0513] 1 H NMR (400MHz, CD3OD) δ7.94 (s, 1H), 7.51 (dd, J=9.1, 2.8Hz, 1H), 7.25 (t, J=8.5Hz, 1H), 6.96 (dd, J=8 .6, 5.2Hz, 1H), 4.75 (s, 2H), 4.67 (s, 2H), 3.87 (d, J=5.0Hz, 2H), 3.83 (d, J=5.0Hz, 2H), 2.87 (s, 3H).

[0514] Example 4 Preparation of compound 4-chloro-5-(3-((4-fluoro-2-(trifluoromethyl)phenyl)amino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L004)

[0515]

[0516] 4.1 Preparation of Compound 4-Methyl-N-(pyrazin-2-yl)benzenesulfonamide (L004-1) - Step 1

[0517] At room temperature, pyrazin-2-amine (6.4 g, 67.30 mmol) was added to pyridine (100 mL), followed by p-toluenesulfonyl chloride (15.4 g, 8.07 mmol). The mixture was stirred at room temperature for 18 h. The solution was concentrated under reduced pressure, and the crude product was washed with methanol (30 mL) and filtered to give 6.80 g of a gray solid, 4-methyl-N-(pyrazin-2-yl)benzenesulfonamide (L004-1), in 36% yield. LC-MS [M+H] + =249.9.

[0518] 4.2 Preparation of compound N-(cyanomethyl)-4-methyl-N-(pyrazin-2-yl)benzenesulfonamide (L004-2)

[0519] 4-Methyl-N-(pyrazin-2-yl)benzenesulfonamide (6.8 g, 27.20 mmol) was added to DMF (30 mL), followed by sodium hydride (1.6 g, 40.80 mmol, 60%). The reaction mixture was stirred at room temperature for 30 minutes, then bromoacetonitrile (4.9 g, 40.80 mmol) was added, and stirring continued for another 30 minutes. The mixture was then heated to 60 °C and reacted for 3 hours. After returning to room temperature, stirring was continued for 14 hours. The reaction mixture was poured into saturated ammonium chloride (200 mL), extracted with ethyl acetate (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate) to give a brown solid N-(cyanomethyl)-4-methyl-N-(pyrazin-2-yl)benzenesulfonamide (L004-2, 3.5 g, yield 45%).

[0520] LC-MS[M+H] +＝ 288.9.

[0521] 4.3 Preparation of compound imidazo[1,2-a]pyrazin-3-amine (L004-3)

[0522] N-(cyanomethyl)-4-methyl-N-(pyrazin-2-yl)benzenesulfonamide (1.8 g, 6.20 mmol) was added to a mixed solvent of trifluoroacetic acid (9.0 mL) and water (1.0 mL), and the mixture was heated to 40 °C and reacted for 2.5 h. The mixture was concentrated under reduced pressure, and the concentrated solid was added to saturated sodium acetate (40 mL). The mixture was stirred for 1 h, extracted with ethyl acetate (30 mL * 6), and the organic phases were combined. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give 0.5 g of a yellow solid imidazo[1,2-a]pyrazin-3-amine (L004-3), in 60% yield. LC-MS [M+H] + =315.1.

[0523] 4.4 Preparation of compound N-(4-fluoro-2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyrazine-3-amine (L004-4)

[0524] Imidazolo[1,2-a]pyrazin-3-amine (400 mg, 2.98 mmol), 1-bromo-4-fluoro-2-(trifluoromethyl)benzene (1.45 g, 5.96 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (142 mg, 0.30 mmol) and Cs2CO3 (1.94 g, 5.96 mmol) were added to 1,4-dioxane (20 mL). Under nitrogen protection, tridibenzylacetone dipalladium (273 mg, 0.30 mmol) was added. The resulting reaction solution was heated to 120 °C and stirred for 15 hours. The solution was cooled to room temperature, quenched with 30 mL of water, extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate) to give 250 mg of a brown solid, N-(4-fluoro-2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyrazin-3-amine (L004-4), in 23% yield. LC-MS [M+H] + =296.9.

[0525] 4.5 Preparation of compound N-(4-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-amine (L004-5)

[0526] N-(4-fluoro-2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyrazin-3-amine (150 mg, 0.50 mmol) was dissolved in t-BuOH (40 mL), Pd / C (50 mg) was added, and the mixture was stirred for 72 h under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated to obtain 150 mg of a brown solid, N-(4-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine (L004-5), crude product. LC-MS [M+H] + =300.9

[0527] 4.6 Preparation of compound 4-chloro-5-(3-((4-fluoro-2-(trifluoromethyl)phenyl)amino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (L004-6)

[0528] N-(4-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine (140 mg, 0.46 mmol) and 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (172 mg, 0.68 mmol) were dissolved in n-BuOH (0.7 mL), DIEA (178 mg, 1.40 mmol) was added, and the mixture was heated to 120 °C and reacted for 3 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel (ethyl acetate) to give 50 mg of brown solid 4-chloro-5-(3-((4-fluoro-2-(trifluoromethyl)phenyl)amino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (L004-6), yield 21%.

[0529] LC-MS[M+H] + =512.8.

[0530] 4.7 Preparation of compound 4-chloro-5-(3-((4-fluoro-2-(trifluoromethyl)phenyl)amino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L004)

[0531] At room temperature, 50 mg (0.06 mmol) of 4-chloro-5-(3-((4-fluoro-2-(trifluoromethyl)phenyl)amino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)one was added to DCM (3 mL), followed by the addition of 1,4-dioxane (4N, 1N) in HCl, and the mixture was stirred for 3 h. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (30 mL), then washed with saturated sodium bicarbonate (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative chromatography to obtain 12.5 mg of a white solid 4-chloro-5-(3-((4-fluoro-2-(trifluoromethyl)phenyl)amino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L004), with a yield of 47%.

[0532] LC-MS[M+H] + =428.8.

[0533] 1H NMR (400MHz, DMSO-d6) 13.04 (s, 1H), 7.96 (s, 1H), 7.42 (dd, J=8.9, 2.8Hz, 1H), 7.29 (d, J= 10.8Hz, 2H), 6.83 (s, 1H), 6.60 (dd, J=9.1, 4.6Hz, 1H), 4.65 (s, 2H), 3.78 (d, J=5.4Hz, 4H).

[0534] Example 5 Preparation of compound 5-(2-bromo-3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-4-chloropyridazin-3(2H)-one (L005)

[0535]

[0536] 5.1 Preparation of compound 2-bromo-3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (L005-1)

[0537] 3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (L002-6) (800 mg, 1.92 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen protection. N-bromosuccinimide (513 mg, 2.88 mmol) was added in portions at -70 °C, and the mixture was stirred at -70 °C for 1 hour. After the reaction was complete, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL * 4). The organic phases were combined, washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography (DCM / EA = 8). ∶ 1) A yellow solid of 300 mg was obtained. The yield was 32%. LC-MS [M+H] + =478.5.

[0538] 5.2 Preparation of compound 2-bromo-3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (L005-2)

[0539] 300 mg (0.63 mmol) of 2-bromo-3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester was dissolved in HCl / 1,4-dioxane (3 mL, 4 mmol / L), and the resulting solution was stirred at 25 °C for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure to give 260 mg of a pale yellow solid crude product. LC-MS [M+H]+ =377.8.

[0540] 5.3 Preparation of compound 5-(2-bromo-3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (L005-3)

[0541] 2-Bromo-3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (207 mg, 0.50 mmol) was dissolved in n-butanol (1 mL), and 4,5-dichloro-2-(oxa-2-yl)pyridazin-3-one (187 mg, 0.70 mmol) and N,N-diisopropylethylamine (256 mg, 2.00 mmol) were added. The reaction mixture was stirred at 120 °C for 3 hours under nitrogen protection. After the reaction was complete, the solution was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (DCM / MeOH = 30:1) to give 200 mg of a yellow solid, with a yield of 67%. LC-MS [M+H] + =590.4.

[0542] 5.4 Preparation of compound 5-(2-bromo-3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-4-chloropyridazin-3(2H)-one (L005-4)

[0543] 150 mg (0.25 mmol) of 5-(2-bromo-3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one was dissolved in HCl / 1,4-dioxane (2 mL, 4 mmol / L) and stirred at 25 °C for 1 hour. After concentration under reduced pressure, the solution was extracted with 25 mL of saturated sodium bicarbonate solution and 3 x 20 mL of ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was recrystallized twice from ethyl acetate to give 33.8 mg of a white solid, yield 25%. LC-MS [M+H] + =505.7.

[0544] 1H NMR (400MHz, DMSO-d6) δ13.05 (s, 1H), 7.94 (s, 1H), 7.68 (dd, J=9.2, 2.7Hz, 1H), 7.48 (td, J =8.4, 2.6Hz, 1H), 7.01 (dd, J=8.7, 5.5Hz, 1H), 4.66 (s, 2H), 4.10 (s, 2H), 3.86-3.77 (m, 4H).

[0545] Example 6 Preparation of compound 4-chloro-5-(3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,8,9-tetrahydro-7H-imidazo[1,2-d][1,4]diazoylheptan-7-yl)pyridazin-3(2H)-one (L006)

[0546]

[0547]

[0548] 6.1 Preparation of compound 5-methoxy-2,3,6,7-tetrahydro-1H-1,4-diazaphen-1-carboxylic acid tert-butyl ester (L006-1)

[0549] 1-Boc-1,4-diaza-5-cycloheptanone (500 mg, 2.32 mmol) was dissolved in dichloromethane (5 mL), and trimethyloxonium tetrafluoroboric acid (377 mg, 2.552 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 14 h under a nitrogen atmosphere. After the reaction was completed, saturated sodium bicarbonate solution (15 mL) was added, followed by extraction with ethyl acetate (20 mL x 2). The organic phases were combined, washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 400 mg of crude product L006-1, with a yield of 67.6%. No purification was required, and it was used directly in the next reaction.

[0550] 1 H NMR (300MHz, CDCl3) δ3.60 (s, 3H), 3.53-3.49 (m, 6H), 2.57-2.56 (m, 2H), 1.46 (s, 9H).

[0551] 6.2 Preparation of compound (3-(4-fluoro-2-(trifluoromethyl)phenyl)prop-2-yn-1-yl)carbamate tert-butyl ester (L006-2)

[0552] 2-Bromo-5-fluorotrifluorotoluene (2.00 g, 8.2 mmol) was dissolved in 1,4-dioxane (20 mL). N-Boc-aminopropyne (4.66 g, 32.8 mmol), cuprous iodide (15 mg, 0.082 mmol), diisopropylamine (960 mg, 9.51 mmol), palladium dichloride bis(triphenylphosphine) (230 mg, 0.33 mmol), and a 10% solution of tri-tert-butylphosphine in n-hexane (960 mg, 0.48 mmol) were added to the resulting solution. The reaction mixture was stirred at 45 °C for 15 h under a nitrogen atmosphere. After the reaction was complete, the solvent was evaporated, and the crude product was separated by silica gel column chromatography (PE / EA = 10:1) to give 1.2 g of a pale yellow solid containing the impurity N-Boc-aminopropyne (which could be removed in the next step), with a purity of approximately 30% and a yield of 14.6%. LC-MS [M+H] + =261.9.

[0553] 6.3 Preparation of compound 3-(4-fluoro-2-(trifluoromethyl)phenyl)prop-2-yn-1-amine (L006-3)

[0554] 1.2 g (1.1 mmol) of tert-butyl (3-(4-fluoro-2-(trifluoromethyl)phenyl)prop-2-yn-1-yl)carbamate was dissolved in dichloromethane (8 mL). HCl / 1,4-dioxane (4 N, 4.5 mL) was added at 0 °C, and the mixture was stirred at 25 °C for 15 h under nitrogen protection. After the reaction was complete, the solvent was evaporated to obtain the crude product. A saturated sodium bicarbonate solution (10 mL) was added to the crude product, and the mixture was extracted with ethyl acetate (10 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 0.2 g of a pale yellow liquid, with a yield of 72.7%. LC-MS [M+H] + =218.0.

[0555] 6.4 Preparation of compound 3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,8,9-tetrahydro-7H-imidazo[1,2-d][1,4]diazazo-7-carboxylic acid tert-butyl ester (L006-4)

[0556] 200 mg (0.92 mmol) of 3-(4-fluoro-2-(trifluoromethyl)phenyl)prop-2-yn-1-amine was dissolved in anhydrous methanol (4 mL). 316 mg (1.38 mmol) of 5-methoxy-2,3,6,7-tetrahydro-1H-1,4-diazaphen-1-carboxylic acid tert-butyl ester was added to the resulting solution. The reaction mixture was stirred at 66 °C for 5 h under nitrogen protection. After the reaction was complete, the solvent was evaporated, and the crude product was separated by silica gel column chromatography (DCM / MeOH = 50:1) to give 200 mg of a pale yellow oil, with a yield of 44.5%. LC-MS [M+H] +=414.0.

[0557] 6.5 Preparation of compound 3-(4-fluoro-2-(trifluoromethyl)benzyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-d][1,4]diazazolide (L006-5)

[0558] 200 mg (0.48 mmol) of 3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,8,9-tetrahydro-7H-imidazo[1,2-d][1,4]diazaphen-7-carboxylic acid tert-butyl ester was dissolved in DCM (3 mL), and HCl / 1,4-dioxane (4N, 2 mL) was added at 0 °C. The mixture was stirred at 25 °C for 15 h under nitrogen protection. The solution was concentrated under reduced pressure, and the resulting 200 mg crude product was used directly in the next reaction without further purification.

[0559] LC-MS[M+H] + =314.0.

[0560] 6.6 Preparation of compound 4-chloro-5-(3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,8,9-tetrahydro-7H-imidazo[1,2-d][1,4]diazo-heptan-7-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (L006-6)

[0561] Crude 3-(4-fluoro-2-(trifluoromethyl)benzyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-d][1,4]diazazopyridine (200 mg, 0.48 mmol) was dissolved in n-butanol (0.8 mL). 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (142 mg, 0.57 mmol) and N,N-diisopropylethylamine (186 mg, 1.44 mmol) were added to the resulting solution. The reaction mixture was stirred at 120 °C for 6 h under nitrogen protection. After the reaction was complete, the solvent was evaporated, and the crude product was separated by preparative TLC (DCM / MeOH = 20:1) to give 75 mg of a yellow oil, with a yield of 31.8%.

[0562] LC-MS[M+H] + =525.8.

[0563] 6.7 Preparation of compound 4-chloro-5-(3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,8,9-tetrahydro-7H-imidazo[1,2-d][1,4]diazoylheptan-7-yl)pyridazin-3(2H)-one (L006)

[0564] 75 mg (0.15 mmol) of 4-chloro-5-(3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,8,9-tetrahydro-7H-imidazo[1,2-d][1,4]diazo-heptan-7-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one was dissolved in dichloromethane (2 mL). HCl / 1,4-dioxane (4N, 1 mL) was added at 0 °C, and the mixture was stirred at 25 °C for 4 h under nitrogen protection. The solvent was evaporated, and the crude product was dissolved in a small amount of dichloromethane and methanol. Sodium bicarbonate was added for neutralization, and the mixture was filtered. The filtrate was concentrated, and the crude product was separated by preparative TLC (DCM / MeOH = 15:1) to obtain 25.5 mg of a pale yellow solid, with a yield of 37.9%.

[0565] LC-MS[M+H] + =441.9.

[0566] 1 H NMR (400MHz, CD3OD) δ7.89 (s, 1H), 7.52 (dd, J=8.8, 2.4Hz, 1H), 7.36-7.31 (m, 1H), 7.21 (dd , J=8.8, 5.2Hz, 1H), 6.53 (s, 1H), 4.16-4.13 (m, 4H), 3.70-3.65 (m, 4H), 3.28-3.25 (m, 2H).

[0567] Examples 7-12

[0568] The following compounds were prepared according to the preparation method in Example 6:

[0569]

[0570]

[0571] Example 13 Preparation of compound 4-chloro-5-(3-(5-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L013)

[0572]

[0573] 13.1 Preparation of compound L013-01

[0574] Compound L013-a (2.5 g, 10.2 mmol) was dissolved in 1,4-dioxane (25 mL), and compound L013-b (4.66 g, 32.8 mmol), bis(triphenylphosphine)palladium dichloride (230 mg, 0.328 mmol), cuprous iodide (15.6 mg, 0.082 mmol), triethylamine (962 mg, 9.512 mmol), and tri-tert-butylphosphine (10%) (1.20 g, 0.05 mmol) were added. The mixture was stirred at 45 °C for 12 hours under nitrogen protection. After the reaction was completed, water (20 mL) and ethyl acetate (20 mL * 3) were added for extraction. The organic phase was washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 1.90 g of compound L013-01. LC-MS[M-55]+=262.1.

[0575] 13.2 Preparation of compound L013-02

[0576] Compound L013-01 (1.90 g, 6.2 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (10 mL, 4 mol / L). The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the pH was adjusted to approximately 8 with an aqueous sodium carbonate solution (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated to give 450 mg of compound L013-02. LC-MS [M+H] + =218.0.

[0577] 13.3 Preparation of compound L013-03

[0578] Compound L013-02 (450 mg, 2.06 mmol) was dissolved in anhydrous methanol (4.5 mL), and L013-c (567 mg, 2.48 mmol) was added. The mixture was stirred at 70 °C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to give 160 mg of compound L013-03. LC-MS [M+H] + =399.8.

[0579] 13.4 Preparation of compound L013-04

[0580] Compound L013-03 (160 mg, 0.324 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (4 mol / L, 2 mL). The mixture was stirred at 25 °C for 1 h. After the reaction was completed, the pH was adjusted to approximately 8 with an aqueous sodium carbonate solution (10 mL), extracted with ethyl acetate (20 mL * 3), washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, and concentrated to give compound L013-04 (100 mg).

[0581] LC-MS[M+H] + =299.7.

[0582] 13.5 Preparation of compound L013-05

[0583] Compound L013-04 (100 mg, 0.33 mmol) was dissolved in n-butanol (0.5 mL), and N,N-diisopropylethylamine (129 mg, 0.1 mmol) and compound L013-d (100 mg, 0.40 mmol) were added. The mixture was stirred at 120 °C for 3 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give 60 mg of compound L013-05.

[0584] LC-MS[M+H] + =512.1.

[0585] 13.6 Preparation of compound 4-chloro-5-(3-(5-fluoro-2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L013)

[0586] Compound L013-05 (40 mg, 0.078 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (4 mmol / L, 1 mL). The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the solvent was evaporated, and the crude product was purified by high-performance liquid chromatography (HPLC) (acetonitrile-water (0.1% formic acid)) to give 15.8 mg of compound L013. LC-MS [M+H] + =427.7.

[0587] 1H NMR (400MHz, DMSO-d6) δ7.95 (s, 1H), 7.85 (dd, J=8.8, 5.6Hz, 1H), 7.34 (t, J=6.8Hz, 1H), 7.05 (d, J =9.5Hz, 1H), 6.54 (s, 1H), 4.64 (s, 2H), 4.12 (s, 2H), 3.91 (d, J = 5.1Hz, 2H), 3.83 (d, J = 5.0Hz, 2H).

[0588] Example 14 Preparation of compound 4-((7-(5-chloro-6-carbonyl-1,6-dihydropyridazin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)methyl)-3-(trifluoromethyl)benzonitrile (L014)

[0589]

[0590] 14.1 Preparation of compound L014-01

[0591] Compound L014-a (3.0 g, 12.0 mmol) was dissolved in 1,4-dioxane (30 mL), and compound L013-b (6.82 g, 48 mmol), bis(triphenylphosphine)palladium dichloride (340 mg, 0.04 mmol), cuprous iodide (20 mg, 0.01 mmol), triethylamine (1.41 g, 13.9 mmol), and tri-tert-butylphosphine (10%) (1.40 g, 0.06 mmol) were added. The mixture was stirred at 45 °C for 12 hours under nitrogen protection. After the reaction was completed, water (20 mL) and ethyl acetate (20 mL x 3) were added for extraction. The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give 4.0 g of compound L014-01.

[0592] LC-MS [M-55] + =269.

[0593] 14.2 Preparation of compound L014-02

[0594] Compound L014-01 (1.90 g, 6.2 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (20 mL, 4 mol / L). The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the pH was adjusted to approximately 8 with an aqueous sodium carbonate solution (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated to give 1.0 g of compound L014-02. LC-MS [M+H] + =225.0.

[0595] 14.3 Preparation of compound L014-03

[0596] Compound L014-02 (1.0 g, 4.4 mmol) was dissolved in anhydrous methanol (10 mL), and compound L013-c (1.21 g, 5.28 mmol) was added. The mixture was stirred at 70 °C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to give 500 mg of compound L014-03. LC-MS [M+H] + =407.2.

[0597] 14.4 Preparation of compound L014-04

[0598] Compound L014-03 (300 mg, 0.735 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (4 mol / L, 3 mL). The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the pH was adjusted to approximately 8 with an aqueous sodium carbonate solution (20 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated to give 200 mg of compound L014-04. LC-MS [M+H] + =306.8.

[0599] 14.5 Preparation of compound L014-05

[0600] Compound L014-04 (100 mg, 0.325 mmol) was dissolved in n-butanol (0.5 mL), and N,N-diisopropylethylamine (126 mg, 0.976 mmol) and compound L13-d (97 mg, 0.390 mmol) were added. The mixture was stirred at 120 °C for 3 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give 50 mg of compound L014-05. LC-MS [M+H] + =519.2.

[0601] 14.6 Preparation of compound 4-((7-(5-chloro-6-carbonyl-1,6-dihydropyridazin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)methyl)-3-(trifluoromethyl)benzonitrile (L014)

[0602] Compound L014-05 (50 mg, 0.10 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (4 mmol / L, 1 mL). The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the pH was adjusted to approximately 8 with an aqueous sodium carbonate solution (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, concentrated, washed with ethyl acetate, filtered, and the filter cake was dried to give 22 mg of compound L014.

[0603] LC-MS[M+H] + =435.1.

[0604] 1 H NMR (400MHz, DMSO-d6) δ7.95 (s, 1H), 7.48 (dd, J=8.8, 2.6Hz, 1H), 7.27 (dd, J=8.6, 6.3Hz, 1H), 7.20 (td, J=8.5, 2.6Hz, 1H), 6.52 (s, 1H), 4.62 (s, 2H), 4.01 (s, 2H), 3.96 (t, J=5.2Hz, 2H), 3.82 (t, J=5.2Hz, 2H).

[0605] Example 15 Preparation of compound 4-chloro-5-(3-(4-fluoro-2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L015)

[0606]

[0607] 15.1 Preparation of compound L015-01

[0608] Compound L015-a (10.0 g, 0.11 mol) was dissolved in anhydrous ethanol (100 mL), and compound L015-b (15.8 g, 0.11 mmol) was added. The mixture was stirred at 90 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was evaporated to obtain a black viscous substance. 30 mL of a 1,4-dioxane solution of hydrogen chloride (4 mmol / L) was added, and the mixture was stirred at 25 °C for 12 hours. After the reaction was completed, 50 mL of water was added, and the pH was adjusted to approximately 8 with sodium carbonate solution. The mixture was extracted with ethyl acetate (50 mL * 4), and the organic phase was washed with saturated brine (30 mL * 2). The organic phase was then dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent. After recrystallization three times with ethyl acetate, 3.5 g of compound L015-01 was obtained.

[0609] LC-MS[M+H] + =148.0.

[0610] 15.2 Preparation of compound L015-02

[0611] Compound L015-c (7.47 g, 30.6 mmol) was dissolved in tetrahydrofuran (50 mL). 2 mL of this solution was added dropwise to a tetrahydrofuran solution (20 mL) containing magnesium shavings (1.47 g, 61.2 mmol) and iodine (50 mg, 2 mmol) under nitrogen protection. The mixture was heated with a blower until the solution became clear and transparent. The remaining tetrahydrofuran solution of compound L015-c was then added dropwise to the reaction system. The mixture was stirred at 70 °C for 1 hour and cooled to room temperature. Then, under nitrogen protection at -70 °C, the mixture was added dropwise to a tetrahydrofuran solution of compound L015-01 (3.00 g, 20.4 mmol). The mixture was stirred at -70 °C for 2 hours. After the reaction was complete, ammonium chloride solution (50 mL) was added, followed by extraction with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered, and the crude product after concentration was subjected to silica gel column chromatography (dichloromethane / methanol = 100 / 1) to obtain 3.20 g of compound L015-02. LC-MS [M+H] + =312.07.

[0612] 15.3 Preparation of compound L015-03

[0613] Compound L015-02 (1.10 g, 3.50 mmol) was dissolved in tetrahydrofuran (25 mL). Wet Pd / C (10%, 400 mg) was added, and the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness to give 1.00 g of compound L015-03. LC-MS [M+H] + =316.2.

[0614] 15.4 Preparation of compound L015-04

[0615] Compound L015-03 (200 mg, 0.63 mmol) was dissolved in anhydrous butanol (1 mL), and L013-d (189 mg, 0.76 mmol) and N,N-diisopropylethylamine (245 mg, 1.90 mmol) were added. Under nitrogen protection, the mixture was stirred at 120 °C for 2 hours. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to give 160 mg of compound L015-04.

[0616] LC-MS[M+H] + =528.2.

[0617] 15.5 Preparation of compound L015-05

[0618] L015-04 (200 mg, 0.297 mmol) was dissolved in anhydrous dichloromethane (20 mL), and Dys-Martin oxidant (630 mg, 1.485 mmol) was added. Under nitrogen protection, the mixture was stirred at 40 °C for 8 hours. After the reaction was complete, sodium hydroxide solution was added to adjust the pH to approximately 9, and the mixture was extracted with dichloromethane (10 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to give 150 mg of compound L015-05.

[0619] LC-MS[M+H] + =526.2.

[0620] Preparation of compound 15.6: 4-chloro-5-(3-(4-fluoro-2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L015)

[0621] L015-05 (150 mg, 0.28 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (2 mL, 4 mol / L), and the mixture was stirred at 25 °C for 1 hour. After the solvent was evaporated, a crude product was obtained, which was purified by high-performance liquid chromatography to give 21.6 mg of compound L015.

[0622] LC-MS[M+H] + =441.8.

[0623] 1 H NMR (400MHz, DMSO-d6) δ13.08 (s, 1H), 8.02 (s, 1H), 7.85 (dd, J=9.3, 2.5Hz, 1H), 7.79 (dd, J=8.5, 5.5Hz, 1H), 7.68 (td, J=8.5, 2.5Hz, 1H), 7.35 (s, 1H), 4.83 (s, 2H), 4.52 (t, J=5.2Hz, 2H), 3.91 (t, J=5.3Hz, 2H).

[0624] Example 16 Preparation of compound 4-chloro-5-(3-(2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L016)

[0625]

[0626] 16.1 Preparation of compound L016-01

[0627] L016-a (2.55 g, 11.3 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), purged three times with nitrogen, and isopropyl magnesium bromide (2.8 M, 8.09 mL, 22.65 mmol) was added to the reaction solution at room temperature. The reaction solution was stirred for 2 hours. Then, L015-01 (2.0 g, 13.6 mmol) was added to the reaction solution, and the temperature was raised to 60 °C and stirred for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium chloride aqueous solution (20 mL), and then extracted with ethyl acetate (30 mL * 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 650 mg of compound L016-01.

[0628] LC-MS[M+H] + =294.0.

[0629] 16.2 Preparation of compound L016-02

[0630] Compound L016-01 (600 mg, 2.05 mmol) was dissolved in tetrahydrofuran (10 mL). Palladium on carbon (10%, 60 mg) was then added, and the reaction was carried out at 40 °C for 12 hours under a hydrogen atmosphere until completion. The reaction solution was filtered, and the filtrate was concentrated to give 540 mg of compound L016-02.

[0631] LC-MS[M+H] + =298.0.

[0632] 16.3 Preparation of compound L016-03

[0633] L016-02 (500 mg, 1.68 mmol), L016-b (915.05 mg, 2.52 mmol), and N,N-diisopropylethylamine (652 mg, 5.05 mol) were dissolved in dimethyl sulfoxide (10 mL), and the mixture was heated to 60 °C and reacted for 2 hours until the reaction was complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 510 mg of compound L016-03. LC-MS [M+H] + =510.1.

[0634] 16.4 Preparation of compound L016-04

[0635] L016-03 (500 mg, 0.98 mmol) was dissolved in dichloromethane (10 mL). Then, Desmartin reagent (831.8 mg, 1.96 mmol) was added in portions, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 210 mg of compound L016-04.

[0636] LC-MS[M+H] + =508.0.

[0637] Preparation of compound 16.5 4-chloro-5-(3-(2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L016)

[0638] L016-04 (200 mg, 0.39 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (2 mL, 4 mol / L), and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the solvent was evaporated to obtain the crude product, which was purified by high-performance liquid chromatography to obtain 16.1 mg of compound L016.

[0639] LC-MS[M+H] + =424.0;

[0640] 1 H NMR (400MHz, DMSO-d6) δ13.05 (s, 1H), 8.00 (s, 1H), 7.90-7.86 (m, 1H), 7.82-7.74 (m, 2H), 7.67 (d, J=7.2Hz, 1H), 7.25 (s, 1H), 4.81 (s, 2H), 4.51 (t, J=5.6Hz, 2H), 3.92-3.88 (m, 2H).

[0641] Example 17 Preparation of compound 4-chloro-5-(3-(4-chloro-2-(trifluoromethyl)benzoyl)-5,6-dedihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L017)

[0642]

[0643]

[0644] 17.1 Preparation of compound L017-01

[0645] Compound L017-a (4.36 g, 16.80 mmol) was weighed and added to anhydrous tetrahydrofuran (80 mL). Nitrogen gas was purged three times. Isopropyl magnesium bromide (2.8 M, 5 mL, 14.00 mmol) was slowly added at room temperature. After the addition was complete, the reaction was allowed to proceed for 2 hours at room temperature. Then, solid L015-01 (1.85 g, 12.60 mmol) was added to the reaction system, the temperature was raised to 40 °C, and the reaction was allowed to proceed for 4 hours. The reaction was then quenched by slowly adding saturated ammonium chloride aqueous solution (100 mL). The mixture was extracted with dichloromethane (100 mL x 3), washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 2.5 g of compound L017-01.

[0646] LC-MS[M+H] + =328.0.

[0647] 17.2 Preparation of compound L017-02

[0648] Compound L017-01 (2.4 g, 7.32 mmol) was weighed and dissolved in tetrahydrofuran (30 mL). Palladium / carbon (10%, 1.0 g) was then added, and hydrogen gas was purged three times. The reaction was carried out at 40 °C for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 1.0 g of compound L017-02. LC-MS [M+H] + =332.0.

[0649] 17.3 Preparation of compound L017-03

[0650] Compounds L017-02 (0.5 g, 1.06 mmol) and L016-b (0.54 g, 1.48 mmol) were weighed and dissolved in dimethyl sulfoxide (5.0 mL). Diisopropylethylamine (0.41 g, 3.17 mmol) was then added. The reaction mixture was stirred at 80 °C for 16 hours until the reaction was complete. The reaction mixture was then cooled to 30 °C, and ethyl acetate (30 mL) and water (20 mL) were added. After stirring, the mixture was separated into two phases. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the crude product was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 0.4 g of compound F017-03. LC-MS [M+H]+ = 544.0.

[0651] 17.4 Preparation of compound L017-04

[0652] Compound L017-03 (0.4 g, 734.81 mmol) was weighed and dissolved in dichloromethane (8.0 mL), and then Dys-Martin reagent (0.94 g, 2.2 mol) was added. The mixture was stirred at room temperature for 16 hours until the reaction was complete. The reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 0.35 g of compound L017-04.

[0653] LC-MS[M+H] + =542.0.

[0654] Preparation of compound 17.5: 4-chloro-5-(3-(4-chloro-2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L017)

[0655] Weigh 0.35 g (645.35 μmol) of L017-04 into a reaction flask, add 1,4-dioxane (4 M, 4 mL) of hydrogen chloride, and react at room temperature for 3 hours. After the reaction is complete, concentrate the reaction solution, and purify the crude product by high-performance liquid chromatography (HPLC) to obtain 42.8 mg of compound L017.

[0656] LC-MS[M+H] + =458.0;

[0657] 1 H NMR (400MHz, DMSO-d6) δ13.06 (s, 1H), 8.01 (d, J=3.4Hz, 2H), 7.90 (dd, J=8.2, 1.8Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.37 (s, 1H), 4.83 (s, 2H), 4.51 (t, J=5.2Hz, 2H), 3.91 (t, J=5.2Hz, 2H), 2.07 (s, 1H).

[0658] Example 18 Preparation of compound 4-chloro-5-(3-(5-fluoro-2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L018A) and compound 4-chloro-5-(3-(2-fluoro-5-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L018B)

[0659]

[0660]

[0661] 18.1 Preparation of compounds L018-01A & L018-01B

[0662] Compound L013-a (1 g, 4.11 mmol) was dissolved in tetrahydrofuran (15 mL), purged with nitrogen, and cooled to -78 °C. A 2.5 M solution of n-butyllithium in hexane (1.8 mL, 4.52 mmol) was added, and the mixture was reacted at -78 °C for one hour. Compound L015-01 (605 mg, 4.11 mmol) was added to the reaction system, and the mixture was allowed to rise to room temperature overnight. After the reaction was complete, the reaction solution was slowly diluted with water (80 mL) and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification was achieved by silica gel column chromatography (dichloromethane / methanol = 50 / 1 - 15 / 1) to obtain compounds L018-01A & L018-01B (600 mg). LC-MS [M+H] + =312.0.

[0663] 18.2 Preparation of compounds L018-02A & L018-02B

[0664] Compounds L018-01A and L018-01B (270 mg, 0.87 mmol) were dissolved in methanol (20 mL), and anhydrous palladium / carbon (10%) was added. After purging with hydrogen, the reaction was stirred at room temperature for 3 hours until completion. The reaction solution was filtered, washed three times with methanol (3 mL), and the filtrate was concentrated under reduced pressure to obtain the product. No purification was required, and it could be directly proceeded to the next step. Compounds L018-02A and L018-02B (230 mg) were obtained. LC-MS [M+H] + =316.0.

[0665] 18.3 Preparation of L018-03A & L018-03B

[0666] L018-02A & L018-02B (230 mg, 0.73 mmol) and L016-b (291 mg, 0.80 mmol) were dissolved in dimethyl sulfoxide (6 mL), and N,N-diisopropylethylamine (283 mg, 2.19 mmol) was added. The mixture was reacted overnight at 60 °C until the reaction was complete. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 50 / 1-20 / 1) to obtain L018-03A & L018-03B (270 mg). LC-MS [M+H] + =528.0.

[0667] 18.4 Preparation of compounds L018-04A & L018-04B

[0668] L018-03A & L018-03B (270 mg, 0.51 mmol) were dissolved in dichloromethane (10 mL), and Dys-Martin oxidant (434 mg, 1.02 mmol) was added in portions at 0 °C. The mixture was then heated to room temperature and reacted for 30 minutes. A saturated sodium thiosulfate aqueous solution (30 mL) was added to the reaction mixture, followed by extraction with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification was achieved by silica gel column chromatography (dichloromethane / methanol = 50 / 1 - 20 / 1) to obtain L018-04A & L018-04B (230 mg). LC-MS [M+H] + =526.0.

[0669] Preparation of compound 18.5: 4-chloro-5-(3-(5-fluoro-2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyrazin-3(2H)-one (L018A) and compound 4-chloro-5-(3-(2-fluoro-5-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyrazin-3(2H)-one (L018B)

[0670] Compounds L018-04A and L018-04B (230 mg, 0.44 mmol) were placed in a 25 mL single-necked flask, and 5 mL of 4 M dioxane solution of hydrogen chloride was added. The mixture was stirred at room temperature for 30 minutes until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) using a water / acetonitrile system. After lyophilization, compounds L018A (26.8 mg) and L018B (37.0 mg) were obtained.

[0671] L018A: LC-MS[M+H] + =442.0; 1 H NMR (400MHz, DMSO-d6) δ13.07 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.62 (t, J=8.4 Hz, 2H), 7.41 (s, 1H), 4.83 (s, 2H), 4.51 (t, J=5.2Hz, 2H), 3.91 (t, J=5.2Hz, 2H).

[0672] L018B: LC-MS[M+H] + =442.0; 1H NMR (400MHz, DMSO-d6) δ13.07 (s, 1H), 8.10-7.90 (m, 3H), 7.64 (t, J=9.2Hz, 1H), 7.55 (s, 1H), 4.83 (s, 2H), 4.52 (t, J=4.8Hz, 2H), 3.91 (t, J=4.8Hz, 2H).

[0673] Example 19 Preparation of compound 4-(7-(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carbonyl)-3-(trifluoromethyl)benzonitrile (L019)

[0674]

[0675]

[0676] 19.1 Preparation of compound L019-01

[0677] Compound L014-03 (2 g, 4.92 mmol), acetic acid (295.52 mg, 4.92 mmol), and ferrous chloride tetrahydrate (97.83 mg, 0.492 mmol) were dissolved in dimethyl sulfoxide (20 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 24 hours. After the reaction was completed, the reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 5) to obtain compound L019-01 (600 mg).

[0678] LC-MS[M+H] + =421.10.

[0679] 19.2 Preparation of compound L019-02

[0680] L019-01 (600 mg, 1.43 mmol) was dissolved in dioxane hydrochloride (4 M, 10 mL) and reacted at room temperature for 2 hours. After the reaction was complete, the mixture was filtered to obtain compound L019-02 (500 mg) as the filter cake. LC-MS [M+H] + =321.05.

[0681] 19.3 Preparation of compound L019-03

[0682] Compounds L019-02 (250 mg, 0.78 mmol), L013-d (233 mg, 0.94 mmol), and N,N-diisopropylethylamine (504 mg, 3.9 mmol) were dissolved in dimethyl sulfoxide (3 mL). The reaction was carried out at 80 °C for 4 hours until completion. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound L019-03 (200 mg). LC-MS [M+H] + =533.10.

[0683] 19.4 Preparation of compound 4-(7-(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-carbonyl)-3-(trifluoromethyl)benzonitrile (L019)

[0684] L019-03 (200 mg, 0.37 mmol) was dissolved in dioxane hydrochloride (4 M, 10 mL), and the reaction was carried out at room temperature for 2 hours until completion. The solvent was evaporated to obtain the crude product, which was purified by high-performance liquid chromatography (HPLC) to give 31 mg of compound L019. LC-MS [M+H] + =449.00;

[0685] 1 H NMR (400MHz, DMSO-d6) δ13.06 (s, 1H), 8.50 (s, 1H), 8.31 (d, J=8.0Hz, 1H), 8.01 (s, 1H), 7.9 1 (d, J=8.0Hz, 1H), 7.39 (s, 1H), 4.83 (s, 2H), 4.52 (t, J=5.2Hz, 2H), 3.92 (t, J=5.2Hz, 2H).

[0686] Example 20 Preparation of compound 4-chloro-5-(3-(4-methoxy-2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L020)

[0687]

[0688] 20.1 Preparation of compound L020-01

[0689] Compound L020-a (1.5 g, 6.22 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL). Under nitrogen protection, sodium hydride (298 mg, 60%, 7.46 mmol) was added at 0 °C. The reaction mixture was stirred for 0.5 hours, followed by the addition of iodomethane (2.65 g, 18.7 mmol). After the addition was complete, the mixture was slowly brought to room temperature and stirred for another 2 hours. After the reaction was complete, the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 6:1-2:1) to obtain 1.2 g of compound L020-01.

[0690] 20.2 Preparation of compound L020-02

[0691] Compound L020-01 (1.2 g, 4.71 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Under nitrogen protection, n-butyllithium (2.8 mL, 7.07 mmol) was added dropwise at -78 °C, and the mixture was stirred at this temperature for 1 hour. Then, compound L015-01 (692 mg, 4.71 mmol) was added. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (50 mL * 3), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain 400 mg of compound L020-02. LC-MS [M+H] + =324.05.

[0692] 20.3 Preparation of compound L020-03

[0693] Compound L020-02 (400 mg, 1.24 mmol) was dissolved in methanol (10 mL), and then dry palladium on carbon (10%, 50 mg) was added. The reaction mixture was stirred at 40 °C for 16 hours under hydrogen (15 Psi). After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 100 mg of crude compound L020-03. LC-MS [M+H] + =328.10.

[0694] 20.4 Preparation of compound L020-04

[0695] Compound L020-03 (100 mg, 0.306 mmol) and compound L016-b (91.4 mg, 0.367 mmol) were dissolved in dimethyl sulfoxide (1 mL), and then N,N-diisopropylethylamine (78.9 mg, 0.367 mmol) was added. The mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (30 mL * 3), and the organic phase was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane / methanol = 10 / 1) to obtain 60 mg of compound L020-04.

[0696] Preparation of compound L020-05 (20.5)

[0697] Compound L020-04 (60 mg, 0.111 mmol) was dispersed in dichloromethane (2 mL). At 25 °C, Desmartin reagent (71 mg, 0.167 mmol) was added in portions to the resulting suspension, and the mixture was stirred for 1 hour. After the reaction was complete, the reaction solution was quenched with saturated sodium sulfite aqueous solution (50 mL), extracted with ethyl acetate (30 mL x 3), and the organic phase was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane / methanol = 10 / 1) to obtain 30 mg of compound L020-05.

[0698] Preparation of compound 20.6 4-chloro-5-(3-(4-methoxy-2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L020)

[0699] Compound L020-05 (30 mg, 55.8 μmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (4 M, 2 mL), and the resulting solution was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure at room temperature, and the pH was adjusted to 9 with NaHCO3 aqueous solution. The solution was extracted with ethyl acetate (5 mL * 3), and the organic phase was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (HPLC) to obtain 3.3 mg of compound L020.

[0700] LC-MS[M+H] + =454.05;

[0701] 1 H NMR (400MHz, DMSO-d6) δ13.04 (br.s, 1H), 8.01 (s, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.36 (d, J = 2.4Hz, 1 H), 7.33 (dd, J=8.4, 2.5Hz, 1H), 7.29 (s, 1H), 4.82 (s, 2H), 4.53-4.48 (m, 2H), 3.94-3.88 (m, 5H).

[0702] Example 21 Preparation of compound 4-chloro-5-(3-(4-hydroxy-2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazolium[1,2-a]pyrazin-7(8H)-yl)pyridin-3(2H)-one (L021)

[0703]

[0704] 21.1 Preparation of compound L021-01

[0705] Compound L020-a (2 g, 8.3 mmol), 3,4-2H-dihydropyran (1.4 g, 16.6 mmol), pyridinium p-toluenesulfonate (41.6 mg, 0.83 mmol), and dichloromethane (20 mL) were added sequentially to a reaction flask. The mixture was stirred to dissolve the compounds, and the resulting reaction solution was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by rapid preparative chromatography (6% ethyl acetate in petroleum ether) to give 2.7 g of compound L021-01.

[0706] 1 H NMR (400MHz, CDCl3) δ10.48-10.37 (m, 3H), 10.17-10.10 (m, 2H), 10.07-10.00 (m, 1H), 8.41-8.36 (m, 1H), 8.20-8 .14 ​​(m, 1H), 6.58 (t, J=3.0Hz, 1H), 4.92 (dd, J1=8.8, J2=3.2Hz, 1H), 4.63 (d, J=3.2Hz, 1H), 4.44 (d, J=8.8Hz, 1H).

[0707] 21.2 Preparation of compound L021-02

[0708] The preparation of compound L021-02 was performed using the same method as compound L020-02, except that the starting material in step 20.2 was replaced with compound L021-01 instead of compound L020-01. 660 mg of compound L021-02 was obtained. LC-MS [M+H]+ = 394.10.

[0709] 21.3 Preparation of compound L021-03

[0710] The preparation of compound L021-03 was performed using the same method as compound L020-03, except that the starting material in step 20.3 was replaced with compound L021-02 instead of compound L020-02. 500 mg of crude compound L021-03 was obtained.

[0711] 21.4 Preparation of compound L021-04

[0712] The preparation of compound L021-04 followed the same method as compound L020-04, except that the starting material in step 20.4 was replaced with compound L021-03 instead of compound L020-03. 380 mg of compound L021-04 was obtained. LC-MS [M+H] + =610.15.

[0713] 21.5 Preparation of compound L021-05

[0714] Compound L021-04 (300 mg, 0.49 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of sodium bicarbonate (50 mg, 0.59 mmol) and sodium bromide (2.53 mg, 0.024 mmol), and the reaction mixture was cooled to 0 °C. Then, 2,2,6,6-tetramethylpiperidine-NOx (0.7 mg, 0.005 mmol) and sodium hypochlorite (366 mg, 0.49 mmol, 10% purity) were added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was slowly poured into an aqueous sodium bicarbonate solution (50 mL), extracted with ethyl acetate (30 mL x 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. 150 mg of compound L021-05 was obtained by rapid preparative chromatography (80-100% ethyl acetate in petroleum ether). LC-MS [M+H] + =608.20.

[0715] 21.6 Preparation of compound 4-chloro-5-(3-(4-hydroxy-2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazolium[1,2-a]pyrazin-7(8H)-yl)pyridin-3(2H)-one (L021)

[0716] L021-05 (150 mg, 0.34 mmol) was placed in a single-necked flask, and a 1,4-dioxane solution of hydrogen chloride (3 mL, 4 M) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was evaporated to dryness at low temperature and then slowly poured into an aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (10 mL * 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness. 37.5 mg of compound L021 was obtained by preparative HPLC purification.

[0717] LC-MS[M+H] + =440.05;

[0718] 1H NMR (400MHz, DMSO-d6): δ8.01 (s, 1H), 7.55 (d, J=8.4Hz, 1H), 7.30 (s, 1H), 7.19 (d, J=2.4Hz, 1H ), 7.10 (dd, J1=8.4, J2=2.4Hz, 1H), 4.81 (s, 2H), 4.49 (t, J=5.2Hz, 2H), 3.90 (t, J=5.2Hz, 2H).

[0719] Example 22 Preparation of compound 4-chloro-5-(3-(4-(dimethylamino)-2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L022)

[0720]

[0721]

[0722] Compound L015 (200 mg, 453 μmol), dimethylamine hydrochloride (110 mg, 1.36 mmol), and potassium carbonate (250 mg, 1.81 mmol) were sequentially added to N,N-dimethylformamide (3.0 mL), and the reaction was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, and ethyl acetate (10 mL) was added to the filtrate. The solution was then washed twice with saturated sodium chloride aqueous solution (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin-layer chromatography on silica gel plates. The crude product was then purified by preparative HPLC (pure water system) and lyophilized to obtain compound L022 (68.7 mg).

[0723] LC-MS[M+H] + =467.1;

[0724] 1 H NMR (400MHz, DMSO-d6): 13.04 (s, 1H), 8.01 (s, 1H), 7.55 (d, J = 8.8Hz, 1H), 7.28 (s, 1H), 7.01 (d, J = 2.4Hz, 1H), 6.94 (dd, J=8.8, 2.4Hz, 1H), 4.48 (t, J=5.2Hz, 2H), 3.89 (t, J=5.2Hz, 2H), 3.32 (s, 2H), 3.05 (s, 6H).

[0725] Example 23 Preparation of compound 4-chloro-5-(3-((4-fluoro-2-(trifluoromethyl)phenyl)thio)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L023)

[0726]

[0727]

[0728] 23.1 Preparation of compound L023-01

[0729] L001-2 (1 g, 3.55 mmol) and triphenylphosphine (2.8 g, 10.64 mmol) were dissolved in tetrahydrofuran (15 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was quenched with water (200 mL), extracted with ethyl acetate (200 mL * 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 450 mg of compound L023-01.

[0730] 1 H NMR (400MHz, DMSO-d6) δ7.85 (dd, J1=8Hz, J2=4Hz, 1H), 7.74 (dd, J1=12Hz, J2=4Hz, 1H), 7.64 (td, J1=8Hz, J2=4Hz, 1H).

[0731] 23.2 Preparation of compound L023-02

[0732] Compounds L023-01 (400 mg, 2.02 mmol), L023-b (2.8 g, 10.64 mmol), tris(dibenzylideneacetone)palladium (186 mg, 0.21 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (190 mg, 0.41 mmol), and cesium carbonate (1.33 g, 4.04 mmol) were dissolved in diethylene glycol dimethyl ether (5 mL). The mixture was purged with nitrogen three times and reacted at 140 °C for 5 hours. After the reaction was complete, the reaction solution was quenched with water (50 mL), extracted with ethyl acetate (50 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1). The crude product was then purified by preparative high-performance liquid chromatography to obtain 40 mg of compound L023-02. LC-MS[M+H] + =418.05.

[0733] 23.3 Preparation of compound L023-03

[0734] Compound L023-02 (40 mg, 0.10 mmol) was dissolved in 2 mL of 4 M hydrogen chloride solution of 1,4-dioxane. Palladium on carbon (10%, 60 mg) was then added. The reaction mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was concentrated to give 35 mg of compound L023-03.

[0735] LC-MS[M+H] + =318.05.

[0736] 23.4 Preparation of compound L23-04

[0737] Compounds L023-03 (30 mg, 0.094 mmol), L013-d (41 mg, 0.11 mmol), and N,N-diisopropylethylamine (61 mg, 0.47 mol) were dissolved in dimethyl sulfoxide (1 mL), and the mixture was heated to 60 °C and reacted for 2 hours until the reaction was complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 40 mg of crude compound L023-04.

[0738] 23.5 Preparation of compound 4-chloro-5-(3-((4-fluoro-2-(trifluoromethyl)phenyl)thio)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L023)

[0739] Compound L023-04 (35 mg, 0.07 mmol) was dissolved in 2 mL of 4 M hydrogen chloride solution of 1,4-dioxane. The reaction solution was reacted at room temperature for 2 hours until completion. The reaction solution was concentrated and purified by high-performance liquid chromatography (HPLC) to obtain 6 mg of compound L023.

[0740] LC-MS[M+H] + =445.00.

[0741] 1 H NMR (400MHz, DMSO-d6) δ13.01 (s, 1H), 7.93 (s, 1H), 7.70 (dd, J=9.0, 2.8Hz, 1H), 7.49 (s, 1H) ), 7.44 (td, J=8.5, 2.8Hz, 1H), 6.95 (dd, J=8.9, 5.1Hz, 1H), 4.71 (s, 2H), 3.89-3.75 (m, 4H).

[0742] Example 24 Preparation of compound 4-chloro-5-(3-((4-fluoro-2-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydroimidazolium[1,2-a]pyrazin-7(8H)-yl)pyridin-3(2H)-one (L024)

[0743]

[0744] Compound L023 (18 mg, 0.04 mmol) was dissolved in acetic acid:hydrogen peroxide = 1:1 (4 mL), and the reaction solution was stirred at room temperature for 36 hours. After the reaction was completed, the reaction solution was quenched with sodium sulfite (10 mL), and the pH was adjusted to 8 with sodium bicarbonate. The solution was extracted with ethyl acetate (30 mL * 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography to obtain 8.3 mg of compound L024.

[0745] LC-MS[M+H] + =462.00.

[0746] 1 H NMR (400MHz, DMSO-d6) δ13.06 (s, 1H), 8.42 (dd, J1=8Hz, J2=4Hz, 1H), 7.96-7.92 (m, 2H), 7.15 (d, J=5 2Hz, 1H), 6.93 (d, J = 20Hz, 1H), 4.73 (s, 2H), 4.37-4.32 (m, 1H), 4.12-4.06 (m, 1H), 3.95-3.82 (m, 2H).

[0747] Example 25 Preparation of compound 4-chloro-5-(3-(2-(difluoromethyl)-4-fluorobenzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L025)

[0748]

[0749] 25.1 Preparation of compound L025-01

[0750] Compound L025-a (10.00 g, 49.30 mmol) and diethylaminosulfur trifluoride (15.90 g, 98.30 mmol) were dissolved in dichloromethane (100 mL), and the reaction mixture was stirred at -10 °C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 7 g of compound L025-01.

[0751] 25.2 Preparation of compound L025-02

[0752] Compound L025-01 (2.00 g, 8.89 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), purged three times with nitrogen, and reacted with n-butyllithium (2.5 M, 3.91 mL, 9.78 mmol) at -78 °C for 0.5 h. Then, L015-01 (1.44 g, 9.78 mmol) was added to the reaction mixture and reacted at -78 °C for 2 h. After the reaction was complete, the reaction solution was quenched with saturated sodium chloride aqueous solution (20 mL), and extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 1.1 g of compound L025-02.

[0753] LC-MS[M+H] + =294.05.

[0754] 25.3 Preparation of compound L025-03

[0755] Compound L025-02 (244 mg, 0.85 mmol) was dissolved in methanol (3 mL). Platinum dioxide (38.70 mg, 0.17 mmol) was then added, and the reaction was carried out at 45 °C for 2 hours under a hydrogen atmosphere until completion. The reaction solution was filtered, and the filtrate was concentrated to obtain 300 mg of compound L025-03.

[0756] 25.4 Preparation of compound L025-04

[0757] Compounds L025-03 (300 mg, 1.04 mmol), L013-d (300 mg, 1.30 mmol), and N,N-diisopropylethylamine (250 mg, 2.00 mmol) were dissolved in dimethyl sulfoxide (5 mL). The mixture was heated to 80 °C and reacted for 2 hours until the reaction was complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 10 / 1) to give 220 mg of compound L025-04. LC-MS [M+H] + =510.20.

[0758] 25.5 Preparation of compound L025-05

[0759] Compound L025-04 (200 mg, 0.39 mmol), H2O (0.5 mL), sodium bicarbonate (49.40 mg, 0.59 mmol), and sodium bromide (2.00 mg, 0.02 mmol) were dissolved in dichloromethane (5 mL). 2,2,6,6-Tetramethylpiperidine oxide (2.00 mg, 0.01 mmol) was added at 0 °C, followed by dropwise addition of sodium hypochlorite (10%, 30 mg, 0.40 mmol). The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was quenched with a saturated aqueous sodium thiosulfate solution, extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 10 / 1) to give 110 mg of compound L025-05. LC-MS [M+H] + =508.05.

[0760] 25.6 Preparation of compound 4-chloro-5-(3-(2-(difluoromethyl)-4-fluorobenzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L025)

[0761] Compound L025-05 (80 mg, 0.16 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (3 mL, 4 mol / L), and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the solvent was evaporated to obtain the crude product, which was purified by high-performance liquid chromatography (HPLC) to obtain 18.1 mg of compound L025.

[0762] LC-MS[M+H] + =424.05;

[0763] 1 H NMR (400MHz, DMSO-d6) δ13.06 (s, 1H), 8.02 (s, 1H), 7.78-7.72 (m, 1H), 7.61-7.57 (m, 2H) , 7.41 (s, 1H), 7.04 (t, J=56Hz, 1H), 4.84 (s, 2H), 4.54 (t, J=8Hz, 2H), 3.92 (t, J=8Hz, 2H).

[0764] Example 26 Preparation of compound 4-chloro-5-(3-(4-methyl-2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L026)

[0765]

[0766] 26.1 Preparation of compound L026-01

[0767] The preparation of compound L026-01 followed the same method as compound L025-02, except that the starting material in step 25.2 was replaced with compound L026-a instead of compound L025-01. 130 mg of compound L026-01 was obtained. LC-MS [M+H] + =308.10.

[0768] 26.2 Preparation of compound L026-02

[0769] The preparation of compound L026-02 followed the same method as compound L025-03, except that the starting material in step 25.3 was replaced with compound L026-01 instead of compound L025-02. 100 mg of compound L026-02 was obtained. LC-MS [M+H] + =312.10.

[0770] 26.3 Preparation of compound L026-03

[0771] The preparation of compound L026-03 followed the same method as compound L025-04, except that in step 25.4, the starting material was replaced with compound L026-02 instead of compound L025-03, and compound L013-d was replaced with compound L016-b. 110 mg of compound L026-03 was obtained. LC-MS [M+H] + =524.15.

[0772] 26.4 Preparation of compound L026-04

[0773] L026-03 (100 mg, 0.19 mmol) was dissolved in dichloromethane (4 mL), and Dys-Martin oxidant (122 mg, 0.29 mmol) was added in portions at 0 °C. The mixture was then heated to room temperature and reacted for 30 minutes. A saturated sodium thiosulfate aqueous solution (30 mL) was added to the reaction solution, followed by extraction with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel plates (DCM / MeOH = 25 / 1) to give 80 mg of compound L026-04. LC-MS [M+H] + =522.15.

[0774] Preparation of compound 26.5 4-chloro-5-(3-(4-methyl-2-(trifluoromethyl)benzoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L026)

[0775] The preparation of compound L026 was performed by referring to the preparation method of compound L025, except that the starting material in step 25.6 was replaced with compound L026 instead of compound L025. 15.4 mg of compound L026 was obtained.

[0776] LC-MS[M+H] + =438.05;

[0777] 1 H NMR (400MHz, DMSO-d6) δ13.05 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.68-7.62 (m, 2H), 7.30 (s, 1H), 4.81 (s, 2H), 4.54 (t, J=5.2Hz, 2H), 3.90 (t, J=5.3Hz, 2H), 2.35 (s, 3H).

[0778] Example 27 Preparation of compound 5-(3-(2,4-bis(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-4-chloropyrazin-3(2H)-one (L027)

[0779]

[0780] 27.1 Preparation of compound L027-01

[0781] The preparation of compound L027-01 was carried out by referring to the preparation method of compound L006-2, except that the starting material in step 6.2 was replaced by compound L027-a instead of compound 2-bromo-5-fluorotrifluorotoluene, and the catalyst was replaced by Pd(dppf)Cl2 instead of bis(triphenylphosphine)palladium dichloride. 2.42 g of compound L027-01 was obtained.

[0782] 1 H NMR (400MHz, DMSO-d6) 8.05 (d, J=8.0Hz, 2H), 7.87 (d, J=8.0Hz, 1H), 7.42 (t, J=5.2Hz, 1H), 4.04 (d, J=5.6Hz, 2H), 1.40 (s, 9H).

[0783] 27.2 Preparation of compound L027-02

[0784] The preparation of compound L027-02 was performed using the same method as compound L006-3, except that the starting material in step 6.3 was replaced with compound L027-01 instead of compound (3-(4-fluoro-2-(trifluoromethyl)phenyl)prop-2-yn-1-yl)carbamate tert-butyl ester. 80.0 mg of compound L027-02 was obtained.

[0785] LC-MS[M+H] + =268.00.

[0786] 27.3 Preparation of compound L027-03

[0787] The preparation of compound L027-03 was performed using the same method as compound L006-4, except that the starting material in step 6.4 was replaced with compound L027-02 (3-(4-fluoro-2-(trifluoromethyl)phenyl)prop-2-yn-1-yl)carbamate tert-butyl ester, and compound L027-c was replaced with compound L027-c. 60.0 mg of compound L027-03 was obtained.

[0788] LC-MS[M+H] + =450.1.

[0789] 27.4 Preparation of compound L027-04

[0790] The preparation of compound L027-04 followed the method for compound L006-5, except that the starting material in step 6.5 was replaced with compound L027-03 instead of compound 3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,8,9-tetrahydro-7H-imidazo[1,2-d][1,4]diazaphen-7-carboxylic acid tert-butyl ester. 45.0 mg of compound L027-04 was obtained. LC-MS [M+H] + =350.0.

[0791] 27.5 Preparation of compound L027-05

[0792] The preparation of compound L027-05 followed the same method as compound L006-6, except that the starting material in step 6.6 was replaced with compound L027-03 instead of compound 3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,8,9-tetrahydro-7H-imidazo[1,2-d][1,4]diazaphen-7-carboxylic acid tert-butyl ester. 40 mg of compound L027-05 was obtained. LC-MS [M+H] + =562.10.

[0793] 27.6 Preparation of compound 5-(3-(2,4-bis(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-4-chloropyrazin-3(2H)-one (L027)

[0794] The preparation of compound L027 followed the method used for compound L006, except that the starting material in step 6.7 was replaced with compound L027-05 instead of compound 4-chloro-5-(3-(4-fluoro-2-(trifluoromethyl)benzyl)-5,6,8,9-tetrahydro-7H-imidazo[1,2-d][1,4]diazo-heptan-7-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one, yielding 15.2 mg of compound L027. LC-MS [M+H] + =478.00.

[0795] 1 H NMR (400MHz, DMSO-d6): 13.03 (s, 1H), 8.03 (d, J=8.8Hz, 2H), 7.95 (s, 1H), 7.49 (d, J=8.0Hz , 1H), 6.56 (s, 1H), 4.65 (s, 2H), 4.22 (s, 2H), 3.91 (t, J=5.2Hz, 2H), 3.82 (t, J=5.2Hz, 2H).

[0796] Example 28 Preparation of compound 4-chloro-5-(3-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L028)

[0797]

[0798] 28.1 Preparation of compound L028-01

[0799] Compound L028-a (2.2 g, 12.15 mmol) was dissolved in DMF (25 mL), and L028-b (2.63 g, 13.36 mmol) and potassium carbonate (3.36 g, 24.29 mmol) were added. The mixture was stirred at 70 °C for 2 hours under nitrogen protection. After the reaction was completed, water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL * 2). The organic phase was washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 2.5 g of compound L028-01.

[0800] 1H NMR (300MHz, CDCl3) δ7.28 (dd, J=8.7, 3.0Hz, 1H), 7.21-7.14 (m, 1H), 6.96 (dd, J=9.0, 3.9Hz, 1H), 4.8 3 (t, J=5.4Hz, 1H), 4.04 (d, J=5.1Hz, 2H), 3.84-3.74 (m, 2H), 3.70-3.60 (m, 2H), 1.24 (t, J=7.2Hz, 6H).

[0801] 28.2 Preparation of compound L028-02

[0802] Compound L028-01 (2.5 g, 8.41 mmol) was dissolved in THF (5 mL), and concentrated hydrochloric acid (12.06 mol / L, 5 mL) was added dropwise. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the pH was adjusted to approximately 8 with sodium carbonate solution (20 mL), extracted with dichloromethane (20 mL * 3), washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 1.5 g of compound L028-02. 1 H NMR (300MHz, CDCl3) δ9.86 (s, 1H), 7.35 (dd, J=8.1, 3.0Hz, 1H), 7.22-7.17 (m, 1H), 6.84 (dd, J=9.0, 3.9Hz, 1H), 4.62 (d, J=0.9Hz, 2H).

[0803] 28.3 Preparation of compound L028-03

[0804] Compound L028-02 (600 mg, 2.68 mmol) was dissolved in chloroform (6 mL). D-proline (62 mg, 0.54 mmol) and N-chlorosuccinimide (359 mg, 2.69 mmol) were added. The mixture was stirred at 0°C for 30 minutes under nitrogen protection, then heated to room temperature and stirred for 2 hours. Aminopyrazine (256 mg, 2.69 mmol) was added, and stirring continued at room temperature for 1 hour. The solvent was then evaporated to dryness. n-Butanol (4 mL) was added, and the mixture was stirred at 100°C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated, and the crude product was separated by silica gel column chromatography (dichloromethane / ethyl acetate = 2 / 1) to give 180 mg of compound L028-03. LC-MS [M+H] + =298.1.

[0805] 28.4 Preparation of compound L028-04

[0806] Compound L028-03 (180 mg, 0.60 mmol) was dissolved in THF (3 mL), and Pd / C (10%, 32 mg, 0.30 mmol) was added. The mixture was stirred at 25 °C for 9 h under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain 180 mg of compound L028-04.

[0807] LC-MS[M+H] + =301.8.

[0808] 28.5 Preparation of compound L028-05

[0809] Compound L028-04 (180 mg, 0.59 mmol) was dissolved in n-butanol (1.0 mL), and N,N-diisopropylethylamine (231 mg, 1.78 mmol) and compound L013-d (223 mg, 0.89 mmol) were added. The mixture was stirred at 120 °C for 3 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated, and the crude product was separated by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 90 mg of compound L028-05. LC-MS [M+H] + =514.2.

[0810] 28.6 Preparation of compound 4-chloro-5-(3-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L028)

[0811] Compound L028-05 (90 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), and a solution of 1,4-dioxane hydrogen chloride (4 mmol / L, 2 mL) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was concentrated to give 75.7 mg of compound L028.

[0812] LC-MS[M+H] + =430.1.

[0813] 1 H NMR (400MHz, DMSO-d6) δ13.11 (s, 1H), 8.01 (s, 1H), 7.83 (dd, J=8.0, 3.2Hz, 1H), 7.71-7.65 (m, 1H), 7.52 (dd, J=9.2, 4.4Hz, 1H), 7.42 (s, 1H), 4.94 (s, 2H), 4.05 (t, J=4.8Hz, 2H), 3.94 (t, J=5.2Hz, 2H).

[0814] Example 29 Preparation of compound 4-chloro-5-(3-(5-fluoro-2-(trifluoromethyl)phenoxy)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L029)

[0815]

[0816] 29.1 Preparation of compound L029-01

[0817] The preparation of compound L029-01 was carried out by referring to the preparation method of compound L028-01, except that the raw material in step 28.1 was replaced by compound L029-a instead of compound L028-a, to obtain 1.2g of compound L029-01.

[0818] 1 H NMR (300MHz, DMSO-d6) 7.69 (dd, J=8.5, 6.6Hz, 1H), 7.28 (d, J=11.2Hz, 1H), 6.95 (s, 1H), 4.82 (t, J= 5.3Hz, 1H), 4.11 (d, J=5.4Hz, 2H), 3.64 (dddd, J=16.5, 14.1, 7.1, 2.4Hz, 4H), 1.13 (t, J=7.0Hz, 6H).

[0819] 29.2 Preparation of compound L029-02

[0820] The preparation of compound L029-02 was carried out by referring to the preparation method of compound L028-02, except that the raw material in step 28.2 was replaced by compound L029-01 instead of compound L028-01, resulting in 1.2g of crude product of compound L029-02, which was used directly in the next step without purification.

[0821] 29.3 Preparation of compound L029-03

[0822] The preparation of compound L029-03 followed the same method as compound L028-03, except that the starting material in step 28.3 was replaced with compound L029-02, yielding 200 mg of compound L029-03. LC-MS [M+H] + =297.8.

[0823] 29.4 Preparation of compound L029-04

[0824] The preparation of compound L029-04 followed the same method as compound L028-04, except that the starting material in step 28.4 was replaced with compound L029-03, yielding 50 mg of compound L029-04. LC-MS [M+H]+ =301.8.

[0825] 29.5 Preparation of compound L029-05

[0826] The preparation of compound L029-05 followed the same method as compound L028-05, except that the starting material in step 28.5 was replaced with compound L029-04, yielding 40 mg of compound L029-04. LC-MS [M+H] + =513.6.

[0827] 29.6 Preparation of compound 4-chloro-5-(3-(5-fluoro-2-(trifluoromethyl)phenoxy)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L029)

[0828] The preparation of compound L029 was carried out by referring to the preparation method of compound L028, except that the raw material in step 28.6 was replaced by compound L029-05 instead of compound L028-05, to obtain 12.0 mg of compound L029.

[0829] LC-MS[M+H] + =429.6.

[0830] 1 H NMR (400MHz, CD3OD): 7.97 (s, 1H), 7.80 (dd, J=8.7, 6.0Hz, 1H), 7.10-7.04 (m, 1H), 7 .01 (dd, J=9.8, 2.1Hz, 1H), 6.77 (s, 1H), 4.73 (s, 2H), 3.97 (dd, J=10.6, 4.3Hz, 4H).

[0831] Example 30 Preparation of compound 4-chloro-5-(3-(2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L030)

[0832]

[0833] 30.1 Preparation of compound L030-01

[0834] Compound L030-a (1.0 g, 9.17 mmol) was weighed and added to a reaction flask. Then, compounds L030-b (1.87 g, 9.17 mmol), HATU (5.23 g, 13.7 mmol), and DIPEA (3.55 g, 27.5 mmol) were added sequentially to the flask. DMF (20 mL) was then added to dissolve the reactants. The resulting reaction solution was stirred at 50 °C for 2 h. EtOAc (50 mL) and water (20 mL) were added to the reaction solution. After stirring, the mixture was separated. The aqueous phase was extracted twice with EtOAc (30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA = 4:1 to 2:1) and concentrated to obtain 2.5 g of compound L030-01.

[0835] 30.2 Preparation of compound L030-02

[0836] Compound L030-01 (2.4 g, 8.13 mmol) was weighed and dissolved in POCl3 (20 mL). The resulting reaction solution was stirred at 90 °C for 2 h. The reaction solution was cooled to 20 °C and slowly added dropwise to ice water (30 mL). EtOAc (50 mL) was added, and the pH was adjusted to 7-8 with 0.5 M NaOH aqueous solution. After stirring, the mixture was separated. The aqueous phase was extracted twice with EtOAc (50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 3:1 to 1:1) and concentrated to obtain 1.1 g of compound L030-02. LC-MS [M+H] + =278.05.

[0837] 30.3 Preparation of compound L030-03

[0838] Compound L030-02 (500 mg, 1.8 mmol) was weighed, and Pd / C (50 mg, 10%) and MeOH (20 mL) were added. The mixture was purged with hydrogen three times, and stirred at 50 °C for 16 h under a hydrogen atmosphere. The reaction solution was filtered, and the filter cake was washed twice with MeOH (10 mL). The filtrates were combined and concentrated under reduced pressure at 45 °C to obtain 440 mg of compound L030-03. LC-MS [M+H] + =282.10.

[0839] Preparation of compound 30.4: 4-chloro-5-(3-(2-(trifluoromethyl)benzyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)pyridazin-3(2H)-one (L030)

[0840] Compounds L030-03 (440 mg, 1.56 mmol) and L030-c (284 mg, 1.7 mmol) were weighed, and DIPEA (600 mg, 4.7 mmol) and DMF (10 mL) were added. The mixture was stirred at 100 °C for 16 h. EtOAc (50 mL) and water (20 mL) were added to the reaction mixture, and the mixture was stirred and separated. The aqueous phase was extracted twice with EtOAc (30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an H2O / acetonitrile system. The purified solution was concentrated at 45 °C and then lyophilized to obtain 89 mg of compound L030. LC-MS [M+H] + =410.00;

[0841] 1 H NMR (400MHz, DMSO-d6) δ13.13 (s, 1H), 7.95 (s, 1H), 7.85 (d, J=7.6Hz, 1H), 7.71 (t, J=7.6Hz, 1H), 7.61 (t, J=7.6Hz , 1H), 7.51 (s, 1H), 7.32 (d, J=7.6Hz, 1H), 4.79 (s, 2H), 4.56 (s, 2H), 4.24 (t, J=5.4Hz, 2H), 3.91 (t, J=5.4Hz, 2H).

[0842] Comparative Example

[0843] Compounds C001 and C002 are TRPC5 inhibitors disclosed in patent WO2019055966A2.

[0844] Table 1

[0845]

[0846] Example 1: Biological Activity Test

[0847] TRPC5 is a non-selective cation channel that is permeable to calcium ions. Therefore, this experiment used the TRPC5 agonist Englerin A (EA) and the TRPC5 inhibitor Pico145 as positive controls. Fluo-4AM fluorescent dye was used to detect the effects of these compounds on intracellular calcium ions in TRPC5-HEK 293 cells. 2+ This method indirectly reflects the effect of compounds on TRPC5 channels.

[0848] 1. Cell Culture

[0849] 1.1 TRPC5 recovery

[0850] Resuscitation fluid: 100% DMEM high glucose

[0851] Selective culture medium: DMEM high glucose + 10% FBS + 1% P / S + 1% HEPES + Blasticidin (5 μg / mL) + Hygromycine (50 μg / mL)

[0852] Induction medium: DMEM high glucose + 10% FBS + 1% P / S + 1% HEPES + doxycycline (1 μg / mL)

[0853] Resuscitation process: Remove from liquid nitrogen tank, transfer to water bath in ice box, stir in a circular motion to dissolve until a small piece of ice is present, then transfer the cryopreservation solution to the resuscitation solution, centrifuge at 1000 rpm for 5 min, discard the supernatant, transfer to selective culture medium, and expand culture in CO2 incubator (5% CO2, 95% humidity, 37℃).

[0854] 1.2 TRPC5 cell grafting plate

[0855] 14 hours before the real-time fluorescence experiment, the cells were washed with PBS, digested with TE, and diluted with induction medium to 200,000 cells / mL. The cells were then transferred to 96-well black-walled bottom permeable plates coated with PDL (stock solution 10 mg / mL, final concentration 10 μg / mL), 100 μL / well, which is 20,000 cells / well.

[0856] 2. Buffer solution preparation

[0857] 500mL TRPC5 calcium signal detection external solution: 4.0908g NaCl, 0.1864g KCl, 0.111CaCl2, 0.0476g MgCl2, 0.9g Glucose, 1.1915HEPES.

[0858] Calcium fluorescent dye: TRPC5, used for calcium signal detection, contains a final concentration of 4 μM Fluo-4 (containing 0.5% BSA).

[0859] 3. Compound preparation

[0860] Agonist: Englerin A (EA)

[0861] Concentration: Due to EA activating TRPC5 in EC 50 At approximately 0.35 nM, using 0.3 nM EA

[0862] Positive inhibitor: Pico145 (HC608)

[0863] Concentration: 100 nM

[0864] Test compound

[0865] Standard preparation, 8× solution, 60μL per bottom plate well.

[0866] 4. Data Processing

[0867] Water reduction hole, baseline removal, AUC

[0868] The results are shown in Table 2:

[0869] Table 2

[0870] Compound number TRPC5 inhibition, IC 50 (nM)L00110.75L0026.52L0077.37L00939.43L01314.56L01418.23L01511.5L01924

[0871] Example 2: Liver microsomal half-life test

[0872] The in vitro metabolic stability of the compounds in this invention was determined using a liver microsomal incubation method for various genera. An appropriate amount of the test compound was added to a liver microsomal reaction system (1 mg / mL liver microsomal protein, 25 U / mL glucose-6-phosphate dehydrogenase, 1 mM NADP, 6 mM D-6-phosphate glucose, 5 mM MgCl2), and the reaction was initiated by incubation in a 37°C water bath. At each time point, 100 μL of the reaction solution was added to a centrifuge tube containing 400 μL of pre-cooled internal standard working solution at 0°C (acetonitrile solution containing 200 ng / mL dexamethasone, diclofenac, tolbutamide, and labetalol). The reaction was then terminated, and the mixture was centrifuged at 10000 g for 10 min at 4°C. The supernatant was then analyzed by LC-MS to obtain the in vitro metabolic half-life of the test compound in various genera of liver microsomes.

[0873] The results are shown in Table 3:

[0874] Table 3

[0875]

[0876]

[0877] The data in Table 3 show that the metabolic stability of the compounds of the present invention in liver microsomes is significantly improved compared with the comparative compounds C001 and C002, indicating that the compounds of the present invention have better metabolic stability in liver microsomes and better clinical pharmacokinetic properties.

[0878] Example 3: Pharmacokinetic study of the compound of the present invention in mice.

[0879] SPF-grade mice (Beijing Speford Biotechnology Co., Ltd.) were fasted overnight after acclimatization (with no restriction on water) and administered the compound of this invention at 3 mg / kg or 1 mg / kg via gavage and tail vein bolus, respectively. Plasma samples were collected at specific time points after administration, and the concentration of the compound in the plasma was detected by LC-MS / MS (AB SCIEX Qtrap4500). PK parameters of each compound were statistically analyzed and calculated (WinNonlin V5.2, Pharsight) to demonstrate the pharmacokinetic properties of the compound of this invention in mice.

[0880] The above experiments were conducted on the compounds of the embodiments of the present invention. The results showed that the compounds of the present invention all have good pharmacokinetic properties in mice, and can achieve high in vivo exposure and high oral bioavailability at low doses. The oral bioavailability of some compounds is >30%, and that of some compounds is >50%. Table 4 below shows the experimental data of representative compounds.

[0881] Table 4: PK experiment of the compounds of the present invention in mice

[0882]

[0883] Example 4: Study on tissue distribution of the compound of the present invention in CD-1 mice after a single oral gavage administration.

[0884] Experimental plan:

[0885] 1.1 Experimental Apparatus

[0886] Table 5

[0887] Name, Model / Specification, Manufacturer: Electronic Analytical Balance MS105DUMettler-Toledo Electronic Scale YP2001 Shanghai Youke Instruments High-Speed ​​Refrigerated Centrifuge STR16 Thermo Fisher Scientific Ultrafine Homogenizer F6 / 10-8G Shanghai Fluke

[0888] 1.2 Experimental Preparation

[0889] Mice: CD-1 mice, SPF grade, 9 males, weighing 18-22g (Source: Beijing Speford Biotechnology Co., Ltd., Certificate No.: 110324200103036532).

[0890] Householding conditions: Standard animal room, free access to food and water, 3 animals per cage, 12 / 12-hour light / dark cycle (7:00 am / 7:00 pm), temperature 23±1℃.

[0891] Preparation: Accurately weigh compound L015, add the required volume of 20% solubilol, sonicate for 20 min, stir for 1.5 h until no visible particles are visible to the naked eye, and take the middle layer of the drug solution for administration; take two portions each of the upper, middle and lower layers of the suspension, and two portions of the middle layer of the clear solution. Accurately pipette 100 μL into a 1.5 mL EP tube for each portion, take the sample before administration, and store it in a -80℃ refrigerator after sampling. Send it for bioanalysis along with the plasma sample.

[0892] 1.3 Dosing regimen

[0893] Animals were randomly divided into 3 groups, with 3 male mice in each group receiving compound L015 at 3 different time points. All mice were administered the compound via a single gavage, with a dosage of 10 mL / kg. The specific grouping and administration details are as follows:

[0894]

[0895] Notes: ① Animal certificate number: 110324200103036532, CD-1 mouse, Beijing Sibefore Biotechnology Co., Ltd.; ② The three groups of rats were fasted overnight but allowed free water before administration; food was returned 4 hours after administration; ③ The tissue collection time points were based on previous 1, 3, and 10 mpk mouse PK results: L015, after oral administration of 10 mg / kg to mice, the absorption phase was 0.167 h, the blood concentration of the test substance reached its peak at 1 h, and it was in the elimination phase at around 10 h.

[0896] 1.4 Sample Collection and Preparation

[0897] Five minutes prior to the administration of the drug, each group of animals was anesthetized by an intraperitoneal injection of 1% sodium pentobarbital (0.06 mL / 10 g). Approximately 0.3 mL of blood was collected into an anticoagulant EP tube (containing 4 μL of EDTA-K2, 375 mg / mL, slowly inverted three times, and stored in an ice box for no more than 30 minutes). The tube was then centrifuged at 3500 × g for 10 minutes at 4°C. The supernatant was transferred to a labeled EP tube for bioanalytical analysis. If testing could not be performed on the same day, the sample should be stored at -80°C until testing (avoid repeated freezing / thawing).

[0898] After blood collection, the abdominal cavity was quickly opened, the rat's abdominal aorta and vein were cut open, and the blood was drained. The rat's heart, liver, spleen, lungs, kidneys, and brain were then harvested. After all tissues were collected, the surface blood was immediately washed away with physiological saline, dried with filter paper, and connective tissue was removed. The samples were then weighed. The homogenization tubes were placed in an ice-water bath, and the tissue samples were thoroughly homogenized using a high-speed homogenizer to prepare a tissue sample homogenate, which was then sent for bioanalytical analysis. If testing could not be performed on the same day, the samples should be stored at -80°C until testing (note that repeated thawing / freezing processes should be avoided).

[0899] 1.5 Sample Analysis Methods

[0900] 1.5.1 Experimental Apparatus:

[0901] High-performance liquid chromatography pump: Exion LC AD Pump, Sciex Corporation

[0902] Autosampler (Exion LC AD Autosampler, Sciex Corporation)

[0903] Column Oven: Exion LC AD Column Oven, Sciex Corporation

[0904] Mass spectrometer: AB Sciex Qtrap 4500

[0905] High-speed refrigerated centrifuge: Thermo Fisher, ST16R, GG1206085-093

[0906] Analytical balance (electronic balance): Mettler Toledo, MS-105D, GG1206363

[0907] Miniature Vortex Analyzer: Shanghai Huxi Analytical Instrument Factory, WH-2, GG1206487

[0908] 1.5.2 Experimental materials: Mouse plasma and tissues

[0909] 1.5.3 Analyte: L015

[0910] 1.5.4 Internal Standard: Labetalol

[0911] 1.5.5 Analytical Method: Liquid Chromatography-Mass Spectrometry (LC-MS)

[0912] 1.5.6 Mass spectrometry conditions:

[0913] 1.5.6.1 Mass Spectrometry Parameters

[0914] Ion source: Ion Electrospray (ESI)

[0915] Ionization mode: Positive ion mode

[0916] Detection Mode: Multiple Response Monitoring (MRM)

[0917] Ion Spray Voltage: 5500

[0918] Turbo Ion Spray Temperature: 550℃

[0919] Curtain Gas: 35

[0920] Collision pool gas (CAD Gas): Medium

[0921] Nebulizing Gas (Gas1): 55.00

[0922] Auxiliary Gas (Gas 2): 55.00

[0923] 1.5.6.2. Detection of ion pairs

[0924]

[0925] 1.5.7 Liquid phase methods:

[0926] Column: Agilent Poroshell 120 EC-C18 (4.6 × 50 mm, 2.7 μm)

[0927] Mobile Phase A: 0.1% aqueous solution of formic acid

[0928] Mobile Phase B: A methanol solution of 0.1% formic acid

[0929] Rinse Port Wash Solution (Methanol:Water:Acetonitrile:Isopropanol = 1:1:1:1)

[0930] Column temperature: 40℃

[0931] Flow Rate: 0.8mL / min

[0932] Automated sampler temperature (Sample Tray Temp): 15℃

[0933] Injection volume: 10 μL (L015)

[0934] Needle Stroke Lift: 49mm

[0935] Rinse Pump Setting: Cleans only the inlet.

[0936] Rinse Mode: Pre-absorption cleaning for autosampler

[0937] Automated syringe rinse volume: 500 μL

[0938] Rinse Dip Time during needle cleaning: 2 seconds

[0939] Elution gradient:

[0940]

[0941] 1.5.8 Preprocessing method:

[0942] Sample pretreatment: Take 3 μL of working solution, add 57 μL of blank matrix to a 1.5 mL centrifuge tube, add 240 μL of acetonitrile containing 200 ng / mL tolbutamide and labetalol mixed standard in 2.1% formic acid to precipitate the protein, vortex mix for 1 minute, and centrifuge the sample at 13000 rpm for 15 minutes at 4 °C. Take 100 μL of the supernatant to another 96-well plate, add 100 μL of methanol:water (1:3, v:v) solution containing 0.1% FA, vortex mix for 1 minute, centrifuge at 3500 rpm for 5 minutes in a 96-well plate centrifuge, and then inject directly.

[0943] 1.6 Data Analysis

[0944] The concentrations of compound L015 in plasma and tissues at each time point were calculated, and the data were analyzed.

[0945] 1.7 Experimental Conclusions:

[0946] Using 20% ​​solubilol as the solvent, male CD-1 mice were administered compound L015 at a single gavage dose of 10 mg / kg. At 0.167 h post-administration, compound L015 showed significant distribution in the liver (3260 ng / g) and kidneys (1467 ng / g) (5.55 times and 2.50 times the plasma concentration, respectively), while the brain concentration was relatively low (706 ng / g, 0.05 times the plasma concentration). At 1 h and 10 h post-administration, compound L015 was still mainly distributed in the liver and kidneys (4.53-5.05 times and 2.51-1.50 times the plasma concentration, respectively), with brain concentrations of 161 ng / g and 25.9 ng / g, respectively (0.19-0.09 times the plasma concentration, respectively). This suggests that L015 at 10 mg / kg has limited distribution in the brain (see Figure 1). This indicates that the compounds of the present invention are mainly distributed in the liver and target organs (kidneys). The high distribution of the compounds in the target organs can reduce the dosage and lower the safety risks.

Claims

1. A heterocyclic compound as described by Formula I, its tautomer, its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt; Wherein, m is 1 or 2; A is independently -(CR 1 R 2 )- or -(C═O)-; R 1 are independently hydrogen, halogen, R 1-1 , "by one, two or more R 1-3 Replaced by R 1-2 ", -(C=O)NHR 1-4 、-NH(C=O)R 1-5 、-(C=O)OR 1-6 、-S(=O) 2 R 1-7 , or, -S(=O)R 1-8 ; R 1-1 and R 1-2 independently represent amino, C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, C 6 -C 20 aryl-C 1 -C 40 alkyl, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"-C 1 -C 40 alkyl; R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 and R 1-8 are independently -CN, halogen, -OH, -NH 2 、-COOH, -NO 2 、-S(=O) 2 CH 3 、-C(=O)NHCH 2 CH 3 、oxo(=O), -NHC(=O)R 1-3-4 、-C(=O)OR 1-3-5 、R 1-3-1 、or, "R 1-3-3 substituted by one, two or more R 1-3-2 "; R 1-3-1 and R 1-3-2 are independently C 1 -C 40 alkyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 1-3-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 C 1 -C 40 alkyl of, "C alkyl substituted by one or more halogens 1 -C 40 C 1 -C 40 alkoxy of, or, "C alkoxy substituted by one or more halogens 1 -C 40 "; R 1-3-4 independently hydrogen, R 1-3-4-1 , or "R substituted by one, two or more R 1-3-4-3 "; 1-3-4-2 ​ R 1-3-4-1 and R 1-3-4-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 1-3-4-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 C 1 -C 40 alkyl, "C 1 -C 40 alkyl substituted by one or more halogens", C 1 -C 40 alkoxy, or, "C 1 -C 40 alkoxy substituted by one or more halogens"; R 1-3-5 independently hydrogen, R 1-3-5-1 , or, "R substituted with one, two or more R 1-3-5-3 "; 1-3-5-2 ​ R 1-3-5-1 and R 1-3-5-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 1-3-5-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 C 1 -C 40 alkyl of, "C alkyl substituted by one or more halogens 1 -C 40 alkyl", C 1 -C 40 alkoxy of, or, "C alkoxy substituted by one or more halogens 1 -C 40 "; R 2 independently is hydrogen, a halogen, R 2-1 ,"R substituted by one, two or more R 2-3 ", -(C=O)NHR 2-2 ,"-NH(C=O)R 2-4 ,"-(C=O)OR 2-5 ,"-S(=O) 2-6 R 2 ,"or -S(=O)R 2-7 ","; 2-8 ; R 2-1 and R 2-2 are independently amino, C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, C 6 -C 20 aryl-C 1 -C 40 alkyl, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"-C 1 -C 40 alkyl; R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 are independently -CN, halogen, -OH, -NH 2 、-COOH, -NO 2 、-S(=O) 2 CH 3 、-C(=O)NHCH 2 CH 3 、oxo(=O), -NHC(=O)R 2-3-4 、-C(=O)OR 2-3-5 、R 2-3-1 、or, "R 2-3-3 substituted by one, two or more R 2-3-2 "; R 2-3-1 and R 2-3-2 are independently C 1 -C 40 alkyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 2-3-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 C 1 -C 40 alkyl of, "C alkyl substituted by one or more halogens 1 -C 40 alkyl", C 1 -C 40 alkoxy of, or, "C alkoxy substituted by one or more halogens 1 -C 40 alkoxy"; R 2-3-4 independently is hydrogen, R 2-3-4-1 , or, "R substituted by one, two or more R 2-3-4-3 "; 2-3-4-2 " R 2-3-4-1 and R 2-3-4-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 2-3-4-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 C 1 -C 40 alkyl, "C 1 -C 40 alkyl substituted by one or more halogens", C 1 -C 40 alkoxy, or, "C 1 -C 40 alkoxy substituted by one or more halogens"; R 2-3-5 independently hydrogen, R 2-3-5-1 , or, "R substituted by one, two or more R 2-3-5-3 "; 2-3-5-2 ​ R 2-3-5-1 and R 2-3-5-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 2-3-5-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 C 1 -C 40 alkyl, "C 1 -C 40 alkyl substituted by one or more halogens", C 1 -C 40 alkoxy, or, "C 1 -C 40 alkoxy substituted by one or more halogens"; n is 1 or 2; G is independently -(CR 3 R 4 )- or -(C═O)-; R 3 are independently hydrogen, halogen, R 3-1 , "by one, two or more R 3-3 Replaced by R 3-2 ", -(C=O)NHR 3-4 、-NH(C=O)R 3-5 、-(C=O)OR 3-6 、-S(=O) 2 R 3-7 , or, -S(=O)R 3-8 ; R 3-1 and R 3-2 are independently amino, C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, C 6 -C 20 aryl-C 1 -C 40 alkyl, "5- to 20-membered heteroaryl with 1, 2 or 3 heteroatoms selected from one or more of N, O and S", or, "5- to 20-membered heteroaryl with 1, 2 or 3 heteroatoms selected from one or more of N, O and S"-C 1 -C 40 alkyl; R 3-3 、R 3-4 、R 3-5 、R 3-6 、R 3-7 and R 3-8 are independently -CN, halogen, -OH, -NH 2 , -COOH, -NO 2 , -S(=O) 2 CH 3 , -C(=O)NHCH 2 CH 3 , oxo(=O), -NHC(=O)R 3-3-4 , -C(=O)OR 3-3-5 、R 3-3-1 、or, "R substituted by one, two or more R 3-3-3 s" 3-3-2 "; R 3-3-1 and R 3-3-2 are independently C 1 -C 40 alkyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 3-3-3 Independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 C 1 -C 40 alkyl of, "C alkyl substituted by one or more halogens 1 -C 40 alkyl", C 1 -C 40 alkoxy of, or, "C alkoxy substituted by one or more halogens 1 -C 40 "; R 3-3-4 independently hydrogen, R 3-3-4-1 , or, "R substituted by one, two or more R 3-3-4-3 "; 3-3-4-2 ​ R 3-3-4-1 and R 3-3-4-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 3-3-4-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 C 1 -C 40 alkyl of, "C alkyl substituted by one or more halogens 1 -C 40 alkyl", C 1 -C 40 alkoxy of, or, "C alkoxy substituted by one or more halogens 1 -C 40 alkoxy"; R 3-3-5 independently hydrogen, R 3-3-5-1 , or, "R substituted by one, two or more R 3-3-5-3 "; 3-3-5-2 ​ R 3-3-5-1 and R 3-3-5-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 3-3-5-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 C 1 -C 40 alkyl of, "C substituted by one or more halogens 1 -C 40 alkyl", C 1 -C 40 alkoxy of, or, "C substituted by one or more halogens 1 -C 40 alkoxy"; R 4 are independently hydrogen, halogen, R 4-1 , "by one, two or more R 4-3 Replaced by R 4-2 ", -(C=O)NHR 4-4 、-NH(C=O)R 4-5 、-(C=O)OR 4-6 、-S(=O) 2 R 4-7 , or, -S(=O)R 4-8 ; R 4-1 and R 4-2 independently is amino, C 1 -C 40 alkyl of 2 -C 40 alkenyl of 2 -C 40 alkynyl of 1 -C 40 alkoxy of 3 -C 20 cycloalkyl of, "heterocycloalkyl with 1, 2 or 3 heteroatoms, and the heteroatoms are selected from one or more of N, O and S, with 3-20 ring atoms", C 6 -C 20 aryl of 6 -C 20 aryl-C 1 -C 40 alkyl of, "heteroaryl with 1, 2 or 3 heteroatoms, and the heteroatoms are selected from one or more of N, O and S, with 5-20 ring atoms", or, "heteroaryl with 1, 2 or 3 heteroatoms, and the heteroatoms are selected from one or more of N, O and S, with 5-20 ring atoms"-C 1 -C 40 alkyl of; R 4-3 、R 4-4 、R 4-5 、R 4-6 、R 4-7 and R 4-8 are independently -CN, halogen, -OH, -NH 2 , -COOH, -NO 2 , -S(=O) 2 CH 3 , -C(=O)NHCH 2 CH 3 , oxo(=O), -NHC(=O)R 4-3-4 , -C(=O)OR 4-3-5 、R 4-3-1 、or, "R substituted by one, two or more R 4-3-3 s 4-3-2 "; R 4-3-1 and R 4-3-2 are independently C 1 -C 40 alkyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heteroalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 4-3-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 C 1 -C 40 alkyl of, "C alkyl substituted by one or more halogens 1 -C 40 alkyl", C 1 -C 40 alkoxy of, or, "C alkoxy substituted by one or more halogens 1 -C 40 alkoxy"; R 4-3-4 independently hydrogen, R 4-3-4-1 , or "R substituted by one, two or more R 4-3-4-3 "; 4-3-4-2 ​ R 4-3-4-1 and R 4-3-4-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 4-3-4-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 C 1 -C 40 alkyl of, "C 1 -C 40 alkyl" substituted with one or more halogens, C 1 -C 40 alkoxy of, or, "C 1 -C 40 alkoxy" substituted with one or more halogens; R 4-3-5 independently hydrogen, R 4-3-5-1 , or, "R substituted by one, two or more R 4-3-5-3 "; 4-3-5-2 ​ R 4-3-5-1 and R 4-3-5-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 4-3-5-3 Independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 C 1 -C 40 alkyl, "C 1 -C 40 alkyl substituted by one or more halogens", C 1 -C 40 alkoxy, or, "C 1 -C 40 alkoxy substituted by one or more halogens"; X is N or CH; When X is N, Z is CR 6 ; when X is CH, Z is N or CR 7 ; R 6 is hydrogen, a halogen, an amino group, a C 6-2 alkyl group substituted by one or more R 1 -C 4 , a C 1 -C 4 alkoxy group, or -C(=O)-NH-R 6-1 ; R 6-1 is a C 1 -C 4 alkyl group; R 6-2 is independently -CN, a halogen, -OH, -NH 2 , oxo (=O), -S(=O) 2 CH 3 , a C 1 -C 40 alkyl group, "a C 1 -C 40 alkyl group substituted by one or more halogens", a C 1 -C 40 alkoxy group, or, "a C 1 -C 40 alkoxy group substituted by one or more halogens"; R 7 is hydrogen, a halogen, an amino group, a C 7-2 alkyl group substituted by one or more R 1 -C 4 , a C 1 -C 4 alkoxy group or -C(=O)-NH-R 7-1 ; R 7-1 is a C 1 -C 4 alkyl group; R 7-2 is independently -CN, a halogen, -OH, -NH 2 , oxo(=O), -S(=O) 2 CH 3 , a C 1 -C 40 alkyl group, "a C 1 -C 40 alkyl group substituted by one or more halogens", a C 1 -C 40 alkoxy group, or, "a C 1 -C 40 alkoxy group substituted by one or more halogens"; Y is -O-, -S-, -NR 8 -, -CH 2 -, -C(=O)- or -S(=O)-; R 5 is hydrogen, a C 8-2 alkyl group substituted by one or more R 1 -C 4 , a C 1 -C 4 alkoxy group, or -C(=O)-NH-R 8-1 ; R 8-1 is a C 1 -C 4 alkyl group; R 8-2 is independently -CN, halogen, -OH, -NH 2 , oxo (=O), -S(=O) 2 CH 3 , a C 1 -C 40 alkyl group, "a C 1 -C 40 alkyl group substituted by one or more halogens", a C 1 -C 40 alkoxy group, or, "a C 1 -C 40 alkoxy group substituted by one or more halogens"; p is 1, 2, or 3; R 5 Independently a cyano group, a halogen, -OH, C 1 -C 4 alkyl group of 1 -C 4 alkoxy group of 9 R 10 , C 3 -C 6 cycloalkyl group of 1 -C 4 alkyl group; R 9 and R 10 independently are H or C 1 -C 4 alkyl group of.

2. The heterocyclic compound as described by Formula I, its tautomer, or its pharmaceutically acceptable salt according to Claim 1, Characterized in that m is 1 or 2; A is independently -(CR 1 R 2 )- or -(C=O)-; R 1 are independently hydrogen, halogen, R 1-1 , "by one, two or more R 1-3 Replaced by R 1-2 ", -(C=O)NHR 1-4 、-NH(C=O)R 1-5 、-(C=O)OR 1-6 、-S(=O) 2 R 1-7 , or, -S(=O)R 1-8 ; R 1-1 and R 1-2 independently are amino group, C 1 -C 40 alkyl group of 2 -C 40 alkenyl group of 2 -C 40 alkynyl group of 1 -C 40 alkoxy group of 3 -C 20 cycloalkyl group, "3- to 20-membered hetero cycloalkyl group with 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl group, C 6 -C 20 aryl-C 1 -C 40 alkyl group of 1 -C 40 ; R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 and R 1-8 are independently -CN, halogen, -OH, -NH 2 、-COOH, -NO 2 、-S(=O) 2 CH 3 、-C(=O)NHCH 2 CH 3 、oxo(=O), -NHC(=O)R 1-3-4 、-C(=O)OR 1-3-5 、R 1-3-1 、or, "R 1-3-3 substituted by one, two or more R 1-3-2 "; R 1-3-1 and R 1-3-2 are independently C 1 -C 40 alkyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 1-3-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 C 1 -C 40 alkyl of, "C 1 -C 40 alkyl substituted by one or more halogens", C 1 -C 40 alkoxy of, or, "C 1 -C 40 alkoxy substituted by one or more halogens"; R 1-3-4 independently hydrogen, R 1-3-4-1 , or "R substituted by one, two or more R 1-3-4-3 "; 1-3-4-2 ​ R 1-3-4-1 and R 1-3-4-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl with 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 1-3-4-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 C 1 -C 40 alkyl of, "C alkyl substituted by one or more halogens 1 -C 40 alkyl", C 1 -C 40 alkoxy of, or, "C alkoxy substituted by one or more halogens 1 -C 40 alkoxy"; R 1-3-5 independently hydrogen, R 1-3-5-1 , or, "R substituted by one, two or more R 1-3-5-3 "; 1-3-5-2 ​ R 1-3-5-1 and R 1-3-5-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 1-3-5-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 C 1 -C 40 alkyl of, "C substituted by one or more halogens 1 -C 40 alkyl", C 1 -C 40 alkoxy of, or, "C substituted by one or more halogens 1 -C 40 alkoxy"; R 2 are independently hydrogen, halogen, R 2-1 , "by one, two or more R 2-3 Replaced by R 2-2 ", -(C=O)NHR 2-4 、-NH(C=O)R 2-5 、-(C=O)OR 2-6 、-S(=O) 2 R 2-7 , or, -S(=O)R 2-8 ; R 2-1 and R 2-2 independently are amino, C 1 -C 40 alkyl of 2 -C 40 alkenyl of 2 -C 40 alkynyl of 1 -C 40 alkoxy of 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, C 6 -C 20 aryl-C 1 -C 40 alkyl of, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"-C 1 -C 40 alkyl; R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 are independently -CN, halogen, -OH, -NH 2 , -COOH, -NO 2 , -S(=O) 2 CH 3 , -C(=O)NHCH 2 CH 3 , oxo(=O), -NHC(=O)R 2-3-4 , -C(=O)OR 2-3-5 , R 2-3-1 , or, "R 2-3-3 substituted by one, two or more R 2-3-2 "; R 2-3-1 and R 2-3-2 are independently C 1 -C 40 alkyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 2-3-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 C 1 -C 40 alkyl, "C 1 -C 40 alkyl substituted by one or more halogens", C 1 -C 40 alkoxy, or, "C 1 -C 40 alkoxy substituted by one or more halogens"; R 2-3-4 independently is hydrogen, R 2-3-4-1 , or, "R substituted by one, two or more R 2-3-4-3 "; 2-3-4-2 " R 2-3-4-1 and R 2-3-4-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 2-3-4-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 C 1 -C 40 alkyl of, "C alkyl substituted by one or more halogens 1 -C 40 alkyl", C 1 -C 40 alkoxy of, or, "C alkoxy substituted by one or more halogens 1 -C 40 alkoxy"; R 2-3-5 independently hydrogen, R 2-3-5-1 , or, "R substituted by one, two or more R 2-3-5-3 "; 2-3-5-2 ​ R 2-3-5-1 and R 2-3-5-2 are independently C 1 -C 40 alkyl of, C 2 -C 40 alkenyl of, C 2 -C 40 alkynyl of, C 3 -C 20 cycloalkyl of, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl of, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 2-3-5-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 C 1 -C 40 alkyl of, "C 1 -C 40 alkyl" substituted by one or more halogens, C 1 -C 40 alkoxy of, or, "C 1 -C 40 alkoxy" substituted by one or more halogens; n is 1 or 2; G is independently -(CR 3 R 4 )- or -(C═O)-; R 3 are independently hydrogen, halogen, R 3-1 , "by one, two or more R 3-3 Replaced by R 3-2 ", -(C=O)NHR 3-4 、-NH(C=O)R 3-5 、-(C=O)OR 3-6 、-S(=O) 2 R 3-7 , or, -S(=O)R 3-8 ; R 3-1 and R 3-2 independently is amino, C 1 -C 40 alkyl of 2 -C 40 alkenyl of 2 -C 40 alkynyl of 1 -C 40 alkoxy of 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, C 6 -C 20 aryl-C 1 -C 40 alkyl of, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"-C 1 -C 40 alkyl; R 3-3 、R 3-4 、R 3-5 、R 3-6 、R 3-7 and R 3-8 are independently -CN, halogen, -OH, -NH 2 、-COOH, -NO 2 、-S(=O) 2 CH 3 、-C(=O)NHCH 2 CH 3 、oxo(=O), -NHC(=O)R 3-3-4 、-C(=O)OR 3-3-5 、R 3-3-1 、or, "R substituted by one, two or more R 3-3-3 s 3-3-2 "; R 3-3-1 and R 3-3-2 are independently C 1 -C 40 alkyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 3-3-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 C 1 -C 40 alkyl, "C 1 -C 40 alkyl substituted by one or more halogens", C 1 -C 40 alkoxy, or, "C 1 -C 40 alkoxy substituted by one or more halogens"; R 3-3-4 independently hydrogen, R 3-3-4-1 , or, "R substituted by one, two or more R 3-3-4-3 "; 3-3-4-2 ​ R 3-3-4-1 and R 3-3-4-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 3-3-4-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 C 1 -C 40 alkyl of, "C alkyl substituted by one or more halogens 1 -C 40 alkyl", C 1 -C 40 alkoxy of, or, "C alkoxy substituted by one or more halogens 1 -C 40 "; R 3-3-5 independently hydrogen, R 3-3-5-1 , or, "R substituted by one, two or more R 3-3-5-3 "; 3-3-5-2 ​ R 3-3-5-1 and R 3-3-5-2 are independently C 1 -C 40 alkyl of, C 2 -C 40 alkenyl of, C 2 -C 40 alkynyl of, C 3 -C 20 cycloalkyl of, "heterocycloalkyl with 1, 2 or 3 heteroatoms, and the heteroatoms are selected from one or more of N, O and S, having 3 to 20 members", C 6 -C 20 aryl of, or, "heteroaryl with 1, 2 or 3 heteroatoms, and the heteroatoms are selected from one or more of N, O and S, having 5 to 20 members"; R 3-3-5-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 C 1 -C 40 alkyl, "C 1 -C 40 alkyl substituted by one or more halogens", C 1 -C 40 alkoxy, or, "C 1 -C 40 alkoxy substituted by one or more halogens"; R 4 independently is hydrogen, a halogen, R 4-1 、" substituted by one, two or more R 4-3 substituted R 4-2 ", -(C=O)NHR 4-4 、-NH(C=O)R 4-5 、-(C=O)OR 4-6 、-S(=O) 2 R 4-7 、or, -S(=O)R 4-8 ; R 4-1 and R 4-2 independently is amino, C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "heterocycloalkyl with 1, 2 or 3 heteroatoms, and the heteroatoms are selected from one or more of N, O and S, with 3-20 ring atoms", C 6 -C 20 aryl, C 6 -C 20 aryl-C 1 -C 40 alkyl, "heteroaryl with 1, 2 or 3 heteroatoms, and the heteroatoms are selected from one or more of N, O and S, with 5-20 ring atoms", or, "heteroaryl with 1, 2 or 3 heteroatoms, and the heteroatoms are selected from one or more of N, O and S, with 5-20 ring atoms"-C 1 -C 40 alkyl; R 4-3 、R 4-4 、R 4-5 、R 4-6 、R 4-7 and R 4-8 are independently -CN, halogen, -OH, -NH 2 、-COOH, -NO 2 、-S(=O) 2 CH 3 、-C(=O)NHCH 2 CH 3 、oxo(=O), -NHC(=O)R 4-3-4 、-C(=O)OR 4-3-5 、R 4-3-1 、or, "R substituted by one, two or more R 4-3-3 s 4-3-2 "; R 4-3-1 and R 4-3-2 are independently C 1 -C 40 alkyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 4-3-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 C 1 -C 40 alkyl, "C 1 -C 40 alkyl substituted by one or more halogens", C 1 -C 40 alkoxy, or, "C 1 -C 40 alkoxy substituted by one or more halogens"; R 4-3-4 independently hydrogen, R 4-3-4-1 , or "R substituted by one, two or more R 4-3-4-3 "; 4-3-4-2 ​ R 4-3-4-1 and R 4-3-4-2 are independently C 1 -C 40 alkyl, C 2 -C 40 alkenyl, C 2 -C 40 alkynyl, C 1 -C 40 alkoxy, C 3 -C 20 cycloalkyl, "3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl, or, "5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 4-3-4-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 C 1 -C 40 alkyl, "C 1 -C 40 alkyl substituted by one or more halogens", C 1 -C 40 alkoxy, or, "C 1 -C 40 alkoxy substituted by one or more halogens"; R 4-3-5 independently hydrogen, R 4-3-5-1 , or, "R substituted by one, two or more R 4-3-5-3 "; 4-3-5-2 ”; R 4-3-5-1 and R 4-3-5-2 are independently C 1 -C 40 alkyl of, C 2 -C 40 alkenyl of, C 2 -C 40 alkynyl of, C 3 -C 20 cycloalkyl of, "a 3- to 20-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S", C 6 -C 20 aryl of, or, "a 5- to 20-membered heteroaryl having 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; R 4-3-5-3 independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 C 1 -C 40 alkyl, "C 1 -C 40 alkyl substituted by one or more halogens", C 1 -C 40 alkoxy, or, "C 1 -C 40 alkoxy substituted by one or more halogens"; X is N or CH; When X is N, Z is CR 6 ; when X is CH, Z is N or CR 7 ; R 6 is hydrogen, halogen, amino, C substituted by one or more R 6-2 -C 1 -C 4 alkyl, C 1 -C 4 alkoxy or -C(=O)-NH-R 6-1 ; R 6-1 is C 1 -C 4 alkyl; R 6-2 is independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 , C 1 -C 40 alkyl, "C substituted by one or more halogens 1 -C 40 alkyl", C 1 -C 40 alkoxy, or, "C substituted by one or more halogens 1 -C 40 alkoxy"; R 7 is hydrogen, a halogen, an amino group, a C 7-2 alkyl group substituted by one or more R 1 -C 4 alkyl, a C 1 -C 4 alkoxy or -C(=O)-NH-R 7-1 ; R 7-1 is a C 1 -C 4 alkyl; R 7-2 is independently -CN, a halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 alkyl, a C 1 -C 40 alkyl group substituted by one or more halogens, a C 1 -C 40 alkyl group substituted by one or more halogens, a C 1 -C 40 alkoxy group substituted by one or more halogens, or a C 1 -C 40 alkoxy group substituted by one or more halogens; Y is -O-, -S-, -NR 8 -, or -CH 2 -; R 8 is hydrogen, C substituted by one or more R 8-2 -C 1 -C 4 alkyl, C 1 -C 4 alkoxy or -C(=O)-NH-R 8-1 ; R 8-1 is C 1 -C 4 alkyl; R 8-2 is independently -CN, halogen, -OH, -NH 2 , oxo(=O), -S(O) 2 CH 3 alkyl, C 1 -C 40 alkyl substituted by one or more halogens, "C 1 -C 40 alkyl", C 1 -C 40 alkoxy, or, "C 1 -C 40 alkoxy substituted by one or more halogens"; p is 1, 2, or 3; R 5 Independently a cyano group, a halogen, C 1 -C 4 alkyl group, or C 1 -C 4 alkyl group substituted by one or more halogens.

3. The heterocyclic compound as described by Formula I, its tautomer, its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt according to Claim 1, Characterized in that m is 1; and / or, A is -(CR 1 R 2 )-; and / or, R 1 is independently hydrogen or R 1-1 ; R 1-1 is independently C 1 -C 40 alkyl; and / or, R 2 is hydrogen; and / or, n is 2; and / or, G is independently -(CR 3 R 4 )-; and / or, R 3 is independently hydrogen, R 3-1 , "R substituted by one, two or more R 3-3 "; R 3-2 ; R 3-1 and R 3-2 are independently C 1 -C 40 alkyl; R 3-3 is -OH; and / or, R 4 is hydrogen; and / or, X is N, Z is CR 6 ; R 6 is hydrogen, halogen or -C(=O)-NH-R 6-1 ; R 6-1 is C 1 -C 4 alkyl of; and / or, Y is -NR 8 -, -CH 2 -, -C(=O)- or -S(=O)-; R 8 is hydrogen; and / or, p is 1 or 2; and / or, R 5 is independently cyano, halogen, C 1 -C 4 alkoxy, -NR 9 R 10 , C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl substituted with one or more halogens; R 9 and R 10 are independently H, methyl or ethyl.

4. The heterocyclic compound as described by Formula I, its tautomer, or its pharmaceutically acceptable salt according to Claim 3, Characterized in that R 1 is hydrogen; and / or, R 3 is hydrogen; and / or, X is N, Z is CR 6 ; R 6 is hydrogen; and / or, Y is -CH 2 - or -C(=O)-; and / or, R 5 independently is cyano, halogen, or a C 1 -C 4 alkyl group substituted by one or more halogens.

5. The heterocyclic compound as described by Formula I, its tautomer, or its pharmaceutically acceptable salt according to Claim 1, Characterized in that R 1 independently hydrogen or R 1-1 ; R 1-1 independently methyl or ethyl; and / or, R 3 is independently hydrogen, R 3-1 , "R substituted by one, two or more R 3-3 "; R 3-2 ; R 3-1 and R 3-2 are independently methyl or ethyl; R 3-3 is -OH; and / or, X is CH and Z is N; and / or, Y is -O-, -S-, -NR 8 -, -CH 2 -, -C(=O)- or -S(=O)-; R 8 is hydrogen; and / or, R 5 is independently cyano, halogen, -OH, C 1 -C 4 alkoxy, -NR 9 R 10 , C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl substituted by one or more halogens; R 9 and R 10 are independently C 1 -C 4 alkyl; preferably, R 5 is independently cyano, halogen, -OH, methoxy, ethoxy, -N(CH 3 ) 2 , cyclopropyl, methyl, difluoromethyl or trifluoromethyl.

6. The heterocyclic compound as described by Formula I, its tautomer, its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt according to Claim 1, Characterized in that It is as described in any of the following schemes: Scheme 1: m is 1 or 2; A is independently -(CR 1 R 2 )-; R 1 independently hydrogen or R 1-1 ; R 1-1 independently is C 1 -C 40 alkyl group of R 2 is hydrogen; n is 2; G is independently -(CR 3 R 4 )-; R 3 independently hydrogen, R 3-1 ,"R substituted by one, two or more R 3-3 "; R 3-2 ”;R 3-1 and R 3-2 independently are C 1 -C 40 alkyl of; R 3-3 is -OH; R 4 is hydrogen; X is N, and Z is CR 6 ; R 6 is hydrogen, a halogen or -C(=O)-NH-R 6-1 ; R 6-1 is C 1 -C 4 alkyl; Y is -NR 8 - or -CH 2 -; R 8 is hydrogen; p is 1 or 2; R 5 independently a halogen, or a C 1 -C 4 alkyl group substituted by one or more halogens; Scheme 2: m is 1 or 2; A is -(CR 1 R 2 )-; R 1 is hydrogen; R 2 is hydrogen; n is 2; G is -(CR 3 R 4 )-; R 3 is hydrogen; R 4 is hydrogen; X is N, and Z is CR 6 ; R 6 is hydrogen, a halogen or -C(=O)-NH-R 6-1 ; R 6-1 is C 1 -C 4 alkyl; Y is -NR 8 - or -CH 2 -; R 8 is hydrogen; p is 1 or 2; R 5 independently is halogen, or a C 1 -C 4 alkyl group substituted by one or more halogens; Scheme 3: m is 1; A is -(CR 1 R 2 )-; R 1 is hydrogen; R 2 is hydrogen; n is 2; G is -(CR 3 R 4 )-; R 3 is hydrogen; R 4 is hydrogen; X is N, and Z is CR 6 ; R 6 is hydrogen; Y is -CH 2 -; p is 1 or 2; R 5 independently a halogen, or a C 1 -C 4 alkyl group substituted by one or more halogens; Scheme 4: m is 1 or 2; A is -(CR 1 R 2 )-; R 1 independently hydrogen or R 1-1 ; R 1-1 independently is C 1 -C 40 alkyl group of R 2 is hydrogen; n is 2; G is -(CR 3 R 4 )-; R 3 independently hydrogen, R 3-1 ; "R substituted by one, two or more 3-3 R 3-2 "; R 3-1 and R 3-2 independently are C 1 -C 40 alkyl; R 3-3 is -OH; R 4 is hydrogen; X is N, and Z is CR 6 ; R 6 is hydrogen, a halogen or -C(=O)-NH-R 6-1 ; R 6-1 is C 1 -C 4 alkyl; Y is -NR 8 -, -CH 2 -, -C(=O)- or -S(=O)-; R 8 is hydrogen; p is 1 or 2; R 5 Independently a cyano group, a halogen, -OH, C 1 -C 4 alkoxy group of, -NR 9 R 10 , C 3 -C 6 cycloalkyl group of, or, C substituted by one or more halogens 1 -C 4 alkyl group of; R 9 and R 10 Independently C 1 -C 4 alkyl group of; Scheme 5: m is 1 or 2; A is -(CR 1 R 2 )-; R 1 independently hydrogen or R 1-1 ; R 1-1 independently methyl or ethyl; R 2 is hydrogen; n is 2; G is -(CR 3 R 4 )-; R 3 independently is hydrogen, R 3-1 ," substituted by one, two or more R 3-3 substituted R 3-2 "; R 3-1 and R 3-2 independently are methyl or ethyl; R 3-3 is -OH; R 4 is hydrogen; X is N, and Z is CR 6 ; R 6 is hydrogen, a halogen or -C(=O)-NH-R 6-1 ; R 6-1 is methyl or ethyl; Y is -NR 8 -, -CH 2 -, -C(=O)- or -S(=O)-; R 8 is hydrogen; p is 1 or 2; R 5 Independently a cyano group, a halogen, -OH, a methoxy group, an ethoxy group, -NR 9 R 10 , a cyclopropyl group, or a methyl group substituted by one or more halogens; R 9 and R 10 Independently a methyl group or an ethyl group; Scheme 6: m is 1; A is -(CR 1 R 2 )-; R 1 is hydrogen; R 2 is hydrogen; n is 2; G is -(CR 3 R 4 )-; R 3 is hydrogen; R 4 is hydrogen; X is N, and Z is CR 6 ; R 6 is hydrogen; Y is -CH 2 -, -C(=O)- or -S(=O)-; p is 1 or 2; R 5 independently a halogen, cyano, -OH, or a C 1 -C 4 alkyl group substituted by one or more halogens; Scheme 7: m is 1; A is -(CR 1 R 2 )-; R 1 is hydrogen; R 2 is hydrogen; n is 2; G is -(CR 3 R 4 )-; R 3 is hydrogen; R 4 is hydrogen; X is N, and Z is CR 6 ; R 6 is hydrogen; Y is -CH 2 -, -C(=O)- or -S(=O)-; p is 1 or 2; R 5 Independently a halogen, a cyano group, -OH, or a C 1 -C 4 alkyl group; when p is 1, R 5 is a C 1 -C 4 alkyl group substituted by one or more halogens; when p is 2, the C 1 -C 4 alkyl group substituted by one or more halogens is a C 1 -C 4 alkyl group substituted by 3 halogens; Scheme 8: The structure shown by Formula I is as shown by Formula II or Formula III: Scheme 9: The structure shown by Formula I is as shown by Formula IV or Formula V: Scheme 10: The structure shown by Formula I is as shown by Formula VI or Formula VII: Scheme 11: m is 1 or 2; A is independently -(CR 1 R 2 )-; R 1 independently hydrogen or R 1-1 ; R 1-1 independently is C 1 -C 40 alkyl group of R 2 is hydrogen; n is 2; G is independently -(CR 3 R 4 )-; R 3 independently is hydrogen, R 3-1 ,"R substituted by one, two or more R 3-3 "; R 3-2 and R 3-1 independently are C 3-2 -C 1 alkyl of 40 ; R 3-3 is -OH; R 4 is hydrogen; X is N, and Z is CR 6 ; or X is CH and Z is N; R 6 is hydrogen, a halogen or -C(=O)-NH-R 6-1 ; R 6-1 is C 1 -C 4 alkyl of Y is -O-, -S-, -NR 8 -, -CH 2 -, -C(=O)- or -S(=O)-; R 8 is hydrogen; p is 1 or 2; R 5 Independently a cyano group, a halogen, -OH, C 1 -C 4 alkyl group of 1 -C 4 alkoxy group of 9 R 10 , C 3 -C 6 cycloalkyl group of 1 -C 4 alkyl group; R 9 and R 10 Independently C 1 -C 4 alkyl group of Scheme 12: m is 1 or 2; A is -(CR 1 R 2 )-; R 1 independently hydrogen or R 1-1 ; R 1-1 independently methyl or ethyl; R 2 is hydrogen; n is 2; G is -(CR 3 R 4 )-; R 3 independently is hydrogen, R 3-1 ,"R substituted by one, two or more R 3-3 "; R 3-2 ”;R 3-1 and R 3-2 independently are methyl or ethyl; R 3-3 is -OH; R 4 is hydrogen; X is N, and Z is CR 6 ; or X is CH and Z is N; R 6 is hydrogen, a halogen or -C(=O)-NH-R 6-1 ; R 6-1 is methyl or ethyl; Y is -O-, -S-, -NR 8 -, -CH 2 -, -C(=O)- or -S(=O)-; R 8 is hydrogen; p is 1 or 2; R 5 Independently a cyano group, a halogen, -OH, a methoxy group, an ethoxy group, -NR 9 R 10 , a cyclopropyl group, a methyl group, a difluoromethyl group or a trifluoromethyl group; R 9 and R 10 Independently a methyl group or an ethyl group; Scheme 13: m is 1; A is -(CR 1 R 2 )-; R 1 is hydrogen; R 2 is hydrogen; n is 2; G is -(CR 3 R 4 )-; R 3 is hydrogen; R 4 is hydrogen; X is N, and Z is CR 6 ; R 6 is hydrogen; Y is -CH 2 - or -C(=O)-; p is 1 or 2; R 5 independently a halogen, a cyano group, or a methyl group substituted by one or more halogens; When p is 2, the R 5 is located at the ortho and para positions of the Y, and the methyl group substituted by one or more halogens is a methyl group substituted by 3 halogens; When Y is -CH 2 -, and p is 1, R 5 is methyl substituted by one or more halogens.

7. The heterocyclic compound as described by Formula I, its tautomer, its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt according to any one of Claims 1-6, Characterized in that When A is independently -(CR 1 R 2 )-, wherein the carbon atom linked to R 1 and R 2 is an R-configured carbon atom and / or an S-configured carbon atom; and / or, when R 1-1 is independently C 1 -C 40 alkyl, the C 1 -C 40 alkyl is C 1 -C 4 alkyl; and / or, when G is independently -(CR 3 R 4 )-, wherein the carbon atom linked to R 3 and R 4 is an R-configured carbon atom and / or an S-configured carbon atom; And / or, when R 3-1 is independently C 1 -C 40 alkyl, the C 1 -C 40 alkyl is C 1 -C 4 alkyl; and / or, when R 3-2 is independently C 1 -C 40 alkyl, the C 1 -C 40 alkyl is C 1 -C 4 alkyl; and / or, when R 6 is a halogen, the halogen is fluorine, chlorine or bromine; and / or, when R 6-1 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and / or, said R 5 is independently located at the ortho, meta or para position of said Y; and / or, when R 5 is independently a halogen, the halogen is fluorine, chlorine or bromine; and / or, when R 5 is independently C substituted by one or more halogens 1 -C 4 alkyl, the plurality is two or three; and / or, when R 5 is independently C substituted by one or more halogens 1 -C 4 alkyl, the halogen is fluorine, chlorine or bromine; and / or, when R 5 is independently C substituted by one or more halogens 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

8. The heterocyclic compound as described by Formula I, its tautomer, or its pharmaceutically acceptable salt according to Claim 7, Characterized in that When R 1-1 is independently C 1 -C 40 alkyl, the C 1 -C 40 alkyl is methyl or ethyl; And / or, when R 3-1 is independently C 1 -C 40 alkyl, the C 1 -C 40 alkyl is methyl or ethyl; and / or, when R 3-2 is independently C 1 -C 40 alkyl, the C 1 -C 40 alkyl is methyl or ethyl; and / or, when R 6 is a halogen, the halogen is bromine; and / or, when R 6-1 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl; and / or, when p is 1, said R 5 is in the ortho position to said Y; and / or, when p is 2, said R 5 is located at the ortho- and para-positions of said Y; and / or, when R 5 is independently halogen, the halogen is fluorine or chlorine; and / or, when R 5 is independently C substituted by multiple halogens 1 -C 4 alkyl, the C substituted by multiple halogens 1 -C 4 alkyl is difluoromethyl or trifluoromethyl.

9. The heterocyclic compound as described by Formula I, its tautomer, or its pharmaceutically acceptable salt according to Claim 8, Characterized in that When p is 2, the said R 5 is located at the ortho and para positions of the said Y, or at the ortho and meta positions of the said Y; and / or, the For and / or, the said For 10. The heterocyclic compound as described by Formula I, its tautomer, or its pharmaceutically acceptable salt according to Claim 9, Characterized in that The described For and / or, the For 11. The heterocyclic compound as described by Formula I, its tautomer, or its pharmaceutically acceptable salt according to Claim 8, Characterized in that When R 3 is independently "R substituted by one R 3-3 ", the "R substituted by one R 3-2 " is hydroxymethyl; 3-3 When the "R substituted by one R 3-2 " is hydroxymethyl; and / or, when R 5 is independently a halogen, the halogen is fluorine or chlorine; and / or, the is 2-trifluoromethylphenyl, 2-trifluoromethyl-4-fluorophenyl, 2-difluoromethyl-4-fluorophenyl, 2,4-difluorophenyl or 2-chloro-4-fluorophenyl, and / or, the For 12. The heterocyclic compound of formula I as described in claim 11, its tautomer, its pharmaceutically acceptable salt, its solvate or its solvate of pharmaceutically acceptable salt, characterized in that, The described and / or, the said For 13. The heterocyclic compound of formula I as described in claim 12, its tautomer, its pharmaceutically acceptable salt, its solvate or its solvate of pharmaceutically acceptable salt, characterized in that, The described and / or, the For 14. The heterocyclic compound of formula I as described in claim 1, its tautomer, its pharmaceutically acceptable salt, its solvate or its solvate of pharmaceutically acceptable salt, characterized in that, the heterocyclic compound of formula I is any of the following compounds:

15. A pharmaceutical composition comprising substance Y and a pharmaceutical excipient, wherein the substance Y is the heterocyclic compound of formula I as described in any one of claims 1-14, its tautomer, its pharmaceutically acceptable salt, its solvate or its solvate of pharmaceutically acceptable salt.

16. Use of a substance Y in the preparation of a TRPC5 inhibitor, wherein the substance Y is the heterocyclic compound of formula I as described in any one of claims 1-14, its tautomer, its pharmaceutically acceptable salt, its solvate or its solvate of pharmaceutically acceptable salt.

17. Use of a substance Y in the preparation of a drug, wherein the substance Y is the heterocyclic compound of formula I as described in any one of claims 1-14, its tautomer, its pharmaceutically acceptable salt, its solvate or its solvate of pharmaceutically acceptable salt, and the drug is a drug for treating and / or preventing TRPC5-mediated diseases.

18. The use as described in claim 17, wherein the TRPC5-mediated diseases are mental disorders, neurological disorders, neurodegenerative disorders or kidney diseases; the mental disorders, neurological disorders or neurodegenerative disorders may be selected from: diseases related to dysregulated emotion processing (e.g., borderline personality disorder or depression, such as major depressive disorder, severe depressive disorder, psychotic depression, dysthymia and postpartum depression, and bipolar disorder), disorders related to anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disorder, sleep disorder, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injury, stroke and Wernicke-Korsakoff syndrome), disorders related to impaired impulse control and addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, and other brain disorders caused by trauma or other injuries including aging; the kidney disease may be focal segmental glomerulosclerosis, minimal change nephropathy or diabetic nephropathy.

19. Use of a substance Y in the preparation of a medicament, wherein the substance Y is a heterocyclic compound of formula I as described in any one of claims 1-14, its tautomer, its pharmaceutically acceptable salt, its solvate or its solvate of a pharmaceutically acceptable salt, and the medicament is a medicament for treating and / or preventing mental disorders, neurological disorders, neurodegenerative disorders or kidney diseases.

20. The use according to claim 19, wherein the mental disorder, neurological disorder or neurodegenerative disorder is selected from: diseases related to dysregulated emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, severe depressive disorder, psychotic depression, dysthymia and postpartum depression, and bipolar disorder), disorders related to anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disorder, sleep disorder, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injury, stroke and Wernicke-Korsakoff syndrome), disorders related to impaired impulse control and addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, and other brain disorders caused by trauma or other injuries including aging; and / or, the kidney disease is focal segmental glomerulosclerosis, minimal change nephropathy or diabetic nephropathy.

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