Heterocyclic compounds, intermediates, methods for producing the same, and applications

Abstract

To provide a heterocyclic compound having a high P2X3 antagonistic activity, an intermediate, and a preparation method therefor and an application therefor.SOLUTION: The present invention provides a heterocyclic compound as shown in formula I, and a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt. The heterocyclic compound has a high P2X3 antagonistic activity, and has good selectivity, low toxicity, good metabolic stability, and minimal taste influence.SELECTED DRAWING: Figure 8

Description

[Technical Field]

[0001] This application claims priority based on Chinese patent application CN 201811642319, filed on December 29, 2018; Chinese patent application CN201910440214.3, filed on May 24, 2019; and Chinese patent application CN201911016158.7, filed on October 24, 2019. The entire text of the above Chinese patent applications is incorporated herein by reference.

[0002] (Technical field) This invention relates to heterocyclic compounds, intermediates, methods for producing the same, and applications thereof. [Background technology]

[0003] Based on molecular structure, signaling mechanism, and pharmacological properties, ATP receptors are classified into two major families: P2Y- and P2X-purine receptors. P2X-purine receptors are a family of ATP-dependent cation channels, and several subtypes have been cloned, including six homopolymer receptors (P2X1; P2X2; P2X3; P2X4; P2X5; and P2X7) and three heteromeric receptors (P2X2 / 3, P2X4 / 6, and P2X1 / 5). Studies have shown that the P2X3 receptor is particularly expressed on primary afferent nerve fibers in "hollow viscera," such as the lower urinary tract and respiratory tract.

[0004] Coughing is a major symptom of respiratory diseases, with 70% to 80% of patients presenting with coughing symptoms in respiratory outpatient clinics. With the increasing prevalence of COPD, IPF, and other respiratory illnesses, coughing has become a primary symptom of most respiratory diseases, and the demand for treatment is also increasing. As a defensive nerve reflex, coughing helps to clear airway secretions and harmful substances, but frequent and severe coughing can have a serious impact on a patient's work, life, and social activities.

[0005] There are still few types of P2X3 antagonists specifically developed for the treatment of cough. Currently, Roche's AF-219 project is progressing rapidly, and in a newly completed Phase II clinical trial, it showed relatively good efficacy for refractory cough, but the problem of taste disturbance is serious.

[0006] Currently, there are no commercially available drugs that treat many diseases, including chronic cough, via the P2X3 inhibitory pathway. Therefore, the development of new compounds that can inhibit P2X3 activity has positive implications for the treatment of these diseases. [Overview of the project]

[0007] The technical problem that this invention aims to solve is the shortcomings of conventional P2X3 antagonists, and provides heterocyclic compounds, intermediates, methods for producing the same, and applications. The heterocyclic compounds of this invention have high P2X3 antagonistic activity, as well as better selectivity, lower toxicity, good metabolic stability, and minimal impact on taste.

[0008] This invention solves the above technical problems with the following technical proposal.

[0009] The present invention provides heterocyclic compounds represented by formula I, stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts, or prodrugs thereof.

[0010] [ka]

[0011] Eventually,

[0012] [ka]

[0013] is a 5-member heteroaryl group or a 5-member heterocyclic alkenyl group; in the said 5-member heteroaryl group, the heteroatom is one or more selected from N, O and S, and the number of heteroatoms is 1 to 2; in the said 5-member heterocyclic alkenyl group, the heteroatom is one or more selected from N, O and S, and the number of heteroatoms is 1 to 3;

[0014]

Chemical formula

[0015] is a phenyl group, a 5- to 6-member heterocycloalkyl group, a 5- to 6-member heterocyclic alkenyl group, or a 5- to 6-member heteroaryl group; in the said 5- to 6-member heterocycloalkyl group, the heteroatom is one or more selected from N, O and S, and the number of heteroatoms is 1 to 3; in the said 5- to 6-member heterocyclic alkenyl group, the heteroatom is one or more selected from N, O and S, and the number of heteroatoms is 1 to 3; in the said 5- to 6-member heteroaryl group, the heteroatom is one or more selected from N, O and S, and the number of heteroatoms is 1 to 3; Z , , , 3 , 6 , , , ,

[0017] , 9 、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 、Z 7 、Z 8 and Z 9 each independently represents a ring atom;

[0016]

Chemical formula

[0017] When is a 5-member heterocycloalkyl group, a 5-member heterocyclic alkenyl group, or a 5-member heteroaryl group, Z 6 or Z 9 represents a single bond; m is 1, 2, 3 or 4; R 3 is H, halogen, -OH, halo C1-C6 alkyl group, -CN or C1-C6 alkyl group; when m is not 1, R3 are independently homologous or different; or two R 3 If adjacent, then two adjacent R 3 These, in cooperation with cycloatoms directly bonded to them, form C3-C6 cycloalkyl groups, C3-C6 cycloalkenyl groups, C3-C9 heterocycloalkyl groups, C3-C9 heterocycloalkenyl groups, phenyl groups, or 5-6 membered heteroaryl groups; the C3-C9 heterocycloalkyl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C3-C9 heterocycloalkenyl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; and the 5-6 membered heteroaryl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3. W is either a single bond or -C(=O)-NH-;

[0018] [ka]

[0019] The group is a phenyl group, a 5-6 membered heteroaryl group, or a C3-C9 heterocycloalkyl group; the 5-6 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the C3-C9 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; n is 1, 2, 3, or 4; R 1is independently H, halogen, -OH, -CN, unsubstituted or substituted C1-C6 alkyl group, or unsubstituted or substituted C1-C6 alkyl group-O-; the substituted C1-C6 alkyl group, or the substituted C1-C6 alkyl group-O-, each substitution is independently one or more substitutions selected from substituent halogen, -OH, -CF3, -CN, -COOH, -C(=O)NH2, C1-C6 alkyl group, C1-C6 alkyl group-O-, or =O (i.e., two geminal hydrogens on the carbon atom are substituted with the group O); if there are multiple substituents, the substituents are homologous or different; if n is not 1, R 1 They are independently homologous or different; Q is H, halogen, -OH, -CF3, -CN, -NH-C(=O)-R 1-1 -C(=O)-R 1-2 -OC(=O)-N(R 1-3 R 1-4 ), -C(=O)-N(R 1-5 R 1-6 ), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), -S(=O)-N(R 1-11 R 1-12 ), -OC(=O)-R 1-13 , -N(R 1-14 R 1-15 ), -NH-S(=O)2-R 1-16 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C1-C6 alkyl groups-O-, unsubstituted or substituted C2-C6 alkenyl groups, unsubstituted or substituted C2-C6 alkenyl groups-O-, unsubstituted or substituted C3-C 10 Cycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkenyl groups, unsubstituted or substituted C6-C 10The aryl group is an aryl group, or an unsubstituted or substituted 5-10 membered heteroaryl group; the C3-C9 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C3-C9 heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5-10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C1-C6 alkyl group, the substituted C1-C6 alkyl group-O-, the substituted C2-C6 alkenyl group, the substituted C2-C6 alkenyl group-O-, the substituted C3-C 10 Cycloalkyl groups, the aforementioned substituted C6-C 10 The aryl group, the substituted C3-C9 heterocycloalkyl group, the substituted C3-C9 heterocycloalkenyl group, or the substituted 5-10 membered heteroaryl group are each independently of the substituent halogen, -OH, -CF3, -CN, -COOH, -C(=O)NH2, =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), -N(R 1-21 R 1-22 ), -C(=O)-N(R 1-23 R 1-24 ), -S(=O)2-N(R 1-25 R 1-26 ), -C(=O)-OR 1-27 , or unsubstituted or one or more R a Substitutions: One or more substitutions selected from C1-C6 alkyl groups, C1-C6 alkyl-O-, or C3-C6 cycloalkyl groups, R a If there are multiple, they are either identical or different, R a is a halogen, -OH, =O, -CF3, -CN, -COOH, -C(=O)NH2; if there are multiple substituents, the substituents are homologous or homologous; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 These are independently H, unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C1-C6 alkyl group-O-, unsubstituted or substituted C2-C6 alkenyl groups, unsubstituted or substituted C2-C6 alkenyl groups-O-, unsubstituted or substituted C2-C6 alkynyl groups, and unsubstituted or substituted C3-C 10 The C3-C9 heterocycloalkyl group is a cycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkenyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted 5-10 membered heteroaryl group; the C3-C9 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C3-C9 heterocycloalkenyl group has heteroatoms The heteroatoms are one or more selected from oxygen, sulfur, and nitrogen, with 1 to 3 heteroatoms; the 5 to 10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, with 1 to 3 heteroatoms; the substituted C1 to C6 alkyl group, the substituted C1 to C6 alkyl-O-, the substituted C2 to C6 alkenyl group, the substituted C2 to C6 alkenyl-O-, the substituted C2 to C6 alkynyl group, the substituted C3 to C 10 The cycloalkyl group, the substituted C3-C9 heterocycloalkyl group, the substituted C3-C9 heterocycloalkenyl group, the substituted phenyl group, or the substituted 5-10 membered heteroaryl group may have the following substitutions independently: a substituent halogen, -OH, -CF3, -CN, -COOH, -COOCH3, -NH2, =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), or unsubstituted or with one or more R groups. dReplaced by: one or more substituents selected from a C1-C6 alkyl group, a C1-C6 alkyl group -O-, or a C3-C6 cycloalkyl group, R d When there are a plurality of them, they are the same or different, R d is independently H, halogen, -OH, =O, -CF3, -CN, -COOH, -C(=O)NH2; when there are a plurality of substituents, the substituents are the same or different; Or, R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , R 1-11 and R 1-12 , R 1-14 and R 1-15 , R 1-21 and R 1-22 , R 1-23 and R 1-24 , or, R 1-25 and R 1-26independently forms, together with nitrogen directly bonded thereto, an unsubstituted or substituted C3-C9 heterocycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkenyl group, or an unsubstituted or substituted 5- to 10-membered heteroaryl group; the C3-C9 heterocycloalkyl group contains no heteroatom other than the nitrogen or further contains one or more, 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen; the C3-C9 heterocycloalkenyl group contains no heteroatom other than the nitrogen or further contains one or more, 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen; the 5- to 10-membered heteroaryl group contains no heteroatom other than the nitrogen or further contains one or more, 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen; the substitution of the substituted C3-C9 heterocycloalkyl group, the substituted C3-C9 heterocycloalkenyl group, or the substituted 5- to 10-membered heteroaryl group is each independently a halogen, -OH, -CF3, -CN, a C1-C6 alkyl group, a C1-C6 alkyl group -O-, =O (i.e., two geminal hydrogens on a carbon atom are substituted by the group O), or an unsubstituted or one or more R b substituted with: one or more substitutions selected from a C1-C6 alkyl group, a C1-C6 alkyl group -O-, or a C3-C6 cycloalkyl group, where R b when there are a plurality, are the same or different, and R b is halogen, -OH, =O, -CF3, -CN, -COOH, -C(=O)NH2; when there are a plurality of substituents, the substituents are the same or different; R 2 is independently

[0020]

Chemical formula

[0021] , -C(=O)N(R 2-5 R 2-6), or an unsubstituted or substituted 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substitutions are, independently, a substituent halogen, -OH, -CN, an unsubstituted or halogen-substituted C1-C6 alkyl group, an unsubstituted or halogen-substituted C1-C6 alkyl group-O-, and -C(=O)R 2-7 , or -C(=O)N(R 2-8 R 2-9 ) is one or more substitutions selected from; if there are multiple substituents, the substituents are homologous or different; R 2-1 and R 2-2 Each of the substituents is independently H, a halogen, -OH, -CN, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C1-C6 alkyl group-O-, or =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O); the substituted C1-C6 alkyl group, or the substituted C1-C6 alkyl group-O-, is independently one or more substituents selected from the substituent halogen, -OH, -CF3, -CN, a C1-C6 alkyl group, a C1-C6 alkyl group-O-, or =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O); if there are multiple substituents, the substituents are homologous or different; X and Y are independently single bonds, methylene, -O-, -N(R) 2-3 )-, or

[0022] [ka]

[0023] and; R 2-3 , R 2-4 , R 2-5 and R 2-6Each of the substituents is independently H, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C3-C8 cycloalkyl group, an unsubstituted or substituted C3-C8 cycloalkyl group-O-, or an unsubstituted or substituted C1-C6 alkyl group-O-; each of the substituted C1-C6 alkyl groups, substituted C3-C8 cycloalkyl groups, substituted C3-C8 cycloalkyl group-O-, or substituted C1-C6 alkyl group-O- is independently one or more substituents selected from a substituent halogen, -OH, -CF3, -CN, C1-C6 alkyl group, C1-C6 alkyl group-O-, or =O (i.e., two geminal hydrogens on the carbon atom are substituted with the group O); if there are multiple substituents, the substituents are homologous or homologous; R 2-7 These are independently H, halogen, -OH, -CN, unsubstituted or halogen-substituted C1-C6 alkyl groups, or unsubstituted or halogen-substituted C1-C6 alkyl groups-O-; R 2-8 and R 2-9 These are independently H, or unsubstituted or halogenated C1-C6 alkyl groups.

[0024] In the present invention, some substituents in the heterocyclic compound shown in formula I are defined as follows, and the definitions of substituents not mentioned are as described in any of the above embodiments.

[0025] Preferred embodiments of the present invention include,

[0026] [ka]

[0027] The group is a 5-membered heteroaryl group or a 5-membered heterocyclic alkenyl group; the 5-membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2; the 5-membered heterocyclic alkenyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3;

[0028] [ka]

[0029] The group is a phenyl group, a 5-6 member heterocycloalkyl group, a 5-6 member heterocyclic alkenyl group, or a 5-6 member heteroaryl group; the 5-6 member heterocycloalkyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the 5-6 member heterocyclic alkenyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the 5-6 member heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 These independently represent cycloatoms;

[0030] [ka]

[0031] If Z is a 5-membered heterocycloalkyl group, a 5-membered heterocyclic alkenyl group, or a 5-membered heteroaryl group, 6 or Z 9 This indicates a single bond; m is 1, 2, 3, or 4; R 3 is H, halogen, -OH, halo C1-C6 alkyl, -CN, or C1-C6 alkyl; if m is not 1, R 3 are independently homologous or different; or two R 3 If adjacent, then two adjacent R 3These, in cooperation with cycloatoms directly bonded to them, form C3-C6 cycloalkyl groups, C3-C6 cycloalkenyl groups, C3-C9 heterocycloalkyl groups, C3-C9 heterocycloalkenyl groups, phenyl groups, or 5-6 membered heteroaryl groups; the C3-C9 heterocycloalkyl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C3-C9 heterocycloalkenyl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; and the 5-6 membered heteroaryl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3. W is either a single bond or -C(=O)-NH-;

[0032] [ka]

[0033] The group is a phenyl group, a 5-6 membered heteroaryl group, or a C3-C9 heterocycloalkyl group; the 5-6 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the C3-C9 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; n is 1, 2, 3, or 4; R 1 is independently H, halogen, -OH, -CN, unsubstituted or substituted C1-C6 alkyl group, or unsubstituted or substituted C1-C6 alkyl group-O-; the substituted C1-C6 alkyl group, or the substituted C1-C6 alkyl group-O-, each substitution is independently one or more substitutions selected from substituent halogen, -OH, -CF3, -CN, -COOH, -C(=O)NH2, C1-C6 alkyl group, C1-C6 alkyl group-O-, or =O (i.e., two geminal hydrogens on the carbon atom are substituted with the group O); if there are multiple substituents, the substituents are homologous or different; if n is not 1, R 1They are independently homologous or different; Q is H, halogen, -OH, -CF3, -CN, -NH-C(=O)-R 1-1 -C(=O)-R 1-2 -OC(=O)-N(R 1-3 R 1-4 ), -C(=O)-N(R 1-5 R 1-6 ), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), -S(=O)-N(R 1-11 R 1-12 ), -OC(=O)-R 1-13 , -N(R 1-14 R 1-15 ), -NH-S(=O)2-R 1-16 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C1-C6 alkyl groups-O-, unsubstituted or substituted C2-C6 alkenyl groups, unsubstituted or substituted C2-C6 alkenyl groups-O-, unsubstituted or substituted C3-C 10 Cycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkenyl groups, unsubstituted or substituted C6-C 10 The aryl group is an aryl group, or an unsubstituted or substituted 5-10 membered heteroaryl group; the C3-C9 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C3-C9 heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5-10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C1-C6 alkyl group, the substituted C1-C6 alkyl group-O-, the substituted C2-C6 alkenyl group, the substituted C2-C6 alkenyl group-O-, the substituted C3-C 10 Cycloalkyl groups, the aforementioned substituted C6-C 10The aryl group, the substituted C3-C9 heterocycloalkyl group, the substituted C3-C9 heterocycloalkenyl group, or the substituted 5-10 membered heteroaryl group are each independently of the substituent halogen, -OH, -CF3, -CN, -COOH, -C(=O)NH2, =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), -N(R 1-21 R 1-22 ), -C(=O)-N(R 1-23 R 1-24 ), -S(=O)2-N(R 1-25 R 1-26 ), -C(=O)-OR 1-27 , or unsubstituted or one or more R a Substitutions: One or more substitutions selected from C1-C6 alkyl groups, C1-C6 alkyl-O-, or C3-C6 cycloalkyl groups, R a If there are multiple, they are either identical or different, R a is a halogen, -OH, =O, -CF3, -CN, -COOH, -C(=O)NH2; if there are multiple substituents, the substituents are homologous or homologous; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 These are independently H, unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C1-C6 alkyl group-O-, unsubstituted or substituted C2-C6 alkenyl groups, unsubstituted or substituted C2-C6 alkenyl groups-O-, unsubstituted or substituted C2-C6 alkynyl groups, and unsubstituted or substituted C3-C610 The C3-C9 heterocycloalkyl group is a cycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkenyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted 5-10 membered heteroaryl group; the C3-C9 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C3-C9 heterocycloalkenyl group has heteroatoms The heteroatoms are one or more selected from oxygen, sulfur, and nitrogen, with 1 to 3 heteroatoms; the 5 to 10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, with 1 to 3 heteroatoms; the substituted C1 to C6 alkyl group, the substituted C1 to C6 alkyl-O-, the substituted C2 to C6 alkenyl group, the substituted C2 to C6 alkenyl-O-, the substituted C2 to C6 alkynyl group, the substituted C3 to C 10 The cycloalkyl group, the substituted C3-C9 heterocycloalkyl group, the substituted C3-C9 heterocycloalkenyl group, the substituted phenyl group, or the substituted 5-10 membered heteroaryl group may have the following substitutions independently: a substituent halogen, -OH, -CF3, -CN, -COOH, -COOCH3, -NH2, =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), or unsubstituted or with one or more R groups. d Substitutions: One or more substitutions selected from C1-C6 alkyl groups, C1-C6 alkyl-O-, or C3-C6 cycloalkyl groups, R d If there are multiple, they are either identical or different, R d These are independently H, halogen, -OH, =O, -CF3, -CN, -COOH, and -C(=O)NH2; if there are multiple substituents, the substituents are homologous or distinct; Or, R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , R 1-11 and R 1-12 , R 1-14and R 1-15 , R 1-21 and R 1-22 , R 1-23 and R 1-24 , or R 1-25 and R 1-26 Each of these groups independently, in cooperation with nitrogen directly bonded to them, forms an unsubstituted or substituted C3-C9 heterocycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkenyl group, or an unsubstituted or substituted 5-10 membered heteroaryl group; the C3-C9 heterocycloalkyl group contains no heteroatoms other than nitrogen, or one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and further contains 1-2 heteroatoms other than nitrogen; the C3-C9 heterocycloalkenyl group contains no heteroatoms other than nitrogen, or one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and The 5-10 membered heteroaryl group further contains no heteroatoms other than nitrogen, or one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and one or more heteroatoms; the substituted C3-C9 heterocycloalkyl group, the substituted C3-C9 heterocycloalkenyl group, or the substituted 5-10 membered heteroaryl group each independently contains a substituent halogen, -OH, -CF3, -CN, C1-C6 alkyl group, C1-C6 alkyl-O-, =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), or unsubstituted or one or more R b Substitutions: One or more substitutions selected from C1-C6 alkyl groups, C1-C6 alkyl-O-, or C3-C6 cycloalkyl groups, R b If there are multiple, they are either identical or different, R b is a halogen, -OH, =O, -CF3, -CN, -COOH, -C(=O)NH2; if there are multiple substituents, the substituents are homologous or homologous; R 2 teeth

[0034] [ka]

[0035] or -C(=O)N(R 2-5 R 2-6 ) and; R 2-1 and R 2-2 Each of the substituents is independently H, a halogen, -OH, -CN, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C1-C6 alkyl group-O-, or =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O); the substituted C1-C6 alkyl group, or the substituted C1-C6 alkyl group-O-, is independently one or more substituents selected from the substituent halogen, -OH, -CF3, -CN, a C1-C6 alkyl group, a C1-C6 alkyl group-O-, or =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O); if there are multiple substituents, the substituents are homologous or different; X and Y are independently single bonds, methylene, -O-, -N(R) 2-3 )-, or

[0036] [ka]

[0037] and; R 2-3 , R 2-4 , R 2-5 and R 2-6 Each of the substituents is independently H, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C3-C8 cycloalkyl group, an unsubstituted or substituted C3-C8 cycloalkyl group-O-, or an unsubstituted or substituted C1-C6 alkyl group-O-; the substituted C1-C6 alkyl group, the substituted C3-C8 cycloalkyl group, the substituted C3-C8 cycloalkyl group-O-, or the substituted C1-C6 alkyl group-O- is independently one or more substituents selected from a substituent halogen, -OH, -CF3, -CN, a C1-C6 alkyl group, a C1-C6 alkyl group-O-, or =O (i.e., two geminal hydrogens on the carbon atom are substituted with the group O); and if there are multiple substituents, the substituents are homologous or homologous.

[0038] In the present invention, some substituents in the heterocyclic compound shown in Formula I, its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts, or prodrugs are defined as follows, and the definitions of substituents not mentioned are as described in any embodiment.

[0039] A preferred embodiment of the present invention is Z 6 It is a single bond, Z 9 is NH, O, or S; or Z 9 It is a single bond, Z 6 It is NH, O, or S.

[0040] Preferred embodiments of the present invention include:

[0041] [ka]

[0042] If it is a 5-membered heteroaryl group, the 5-membered heteroaryl group is a pyrazolyl group (for example)

[0043] [ka]

[0044] ), furan group (for example)

[0045] [ka]

[0046] ), pyrazole group (for example)

[0047] [ka]

[0048] ), thienyl group (for example)

[0049] [ka]

[0050] ) or imidazolyl group (for example)

[0051] [ka]

[0052] ) (In the structural formula, the bond on the right is connected to W.) Preferred embodiments of the present invention include:

[0053] [ka]

[0054] If it is a 5-membered heterocyclic alkenyl group, the 5-membered heterocyclic alkenyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2; a 2,3-dihydro-1H-pyrazolyl group (for example)

[0055] [ka]

[0056] ) (In the structural formula, the bond on the right is connected to W.) Preferred embodiments of the present invention include:

[0057] [ka]

[0058] If is a 5-6 member heterocycloalkyl group, then the 5-6 member heterocycloalkyl group is a 6 member heterocycloalkyl group, and the heteroatom in the 6 member heterocycloalkyl group is N, and the number of heteroatoms is 1 to 3; preferably a piperazine group (for example)

[0059] [ka]

[0060] ) or piperidine group (for example)

[0061] [ka]

[0062] ) (The structural formula shows the carbon-nitrogen bond on the right side)

[0063] [ka]

[0064] teeth

[0065] [ka]

[0066] (Indicates the position where a ring-closing bond is formed) Preferred embodiments of the present invention include:

[0067] [ka]

[0068] When is a 5-6 member heterocyclic alkenyl group, the 5-6 member heterocyclic alkenyl group is a 6 member heterocyclic alkenyl group, and the heteroatom in the 6 member heterocyclic alkenyl group is N, and the number of heteroatoms is 1 to 3; preferably 1,2-dihydropyridine (for example)

[0069] [ka]

[0070] ) or 1,6-dihydropyrimidine (for example)

[0071] [ka]

[0072] ) (The structural formula shows the carbon-nitrogen bond on the right side)

[0073] [ka]

[0074] teeth

[0075] [ka]

[0076] (Indicates the position where a ring-closing bond is formed) Preferred embodiments of the present invention include:

[0077] [ka]

[0078] When is a 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group is a 6 membered heteroaryl group, and the heteroatom in the 6 membered heteroaryl group is N, and the number of heteroatoms is 1 to 3 (for example, a pyridinyl group or a pyrimidinyl group), preferably a pyridinyl group (for example,

[0079] [ka]

[0080] ) is. (The structural formula shows a carbon-carbon double bond on the right side.)

[0081] [ka]

[0082] teeth

[0083] [ka]

[0084] (Indicates the position where a ring-closing bond is formed) Preferred embodiments of the present invention include:

[0085] [ka]

[0086] teeth

[0087] [ka]

[0088] That is the case.

[0089] Preferred embodiments of the present invention include:

[0090] [ka]

[0091] teeth

[0092] [ka]

[0093] That is the case.

[0094] In preferred embodiments of the present invention, m is 1 or 2; A preferred embodiment of the present invention is Z 7 is R 3 Replaced with Z 8 is R 3 Replaced or not replaced, Z 6 and Z 9 is unsubstituted, multiple R 3 If R 3They are homologous or different; preferably, Z 7 is R 3 Replaced with Z 6 , Z 8 and Z 9 It has not been replaced.

[0095] A preferred embodiment of the present invention is R 3 If the halogen is a halogen, then the halogen is fluorine, chlorine, bromine, or iodine.

[0096] A preferred embodiment of the present invention is R 3 When the C1-C6 alkyl group is a C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group), the C1-C6 alkyl group is a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group), preferably a methyl group.

[0097] A preferred embodiment of the present invention is R 3 When the halogen is a C1-C6 alkyl group, the halogen is fluorine, chlorine, bromine, or iodine; preferably chlorine.

[0098] A preferred embodiment of the present invention is R 3 When the halo is a C1-C6 alkyl group, the number of halos may be one or more (for example, 1, 2, 3, 4, or 5), preferably 1, 2, or 3.

[0099] A preferred embodiment of the present invention is R 3 It is -CF3, -CH2F, or -CHF2.

[0100] A preferred embodiment of the present invention includes two R 3 Two adjacent Rs 3 When these atoms, in cooperation with cyclo atoms directly bonded to them, form a C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0101] A preferred embodiment of the present invention includes two R 3 Two adjacent Rs 3 When these atoms, in cooperation with cyclo atoms directly bonded to them, form a C3-C6 cycloalkenyl group, the C3-C6 cycloalkenyl group is a cyclopropene group, a cyclobutylene group, a cyclopentenyl group, a cyclohexene group, or a cyclohexadienyl group.

[0102] A preferred embodiment of the present invention includes two R 3 Two adjacent Rs 3 When these atoms form a C3-C9 heterocycloalkyl group in cooperation with cyclo atoms that are directly bonded to them, the C3-C9 heterocycloalkyl group is a C4-C5 heterocycloalkyl group, and the C4-C5 heterocycloalkyl group consists of one or more heteroatoms selected from N, O, and S, with a total of 1-2 heteroatoms.

[0103] A preferred embodiment of the present invention includes two R 3 Two adjacent Rs 3 When these atoms form a C3-C9 heterocycloalkenyl group in cooperation with cyclo atoms that are directly bonded to them, the C3-C9 heterocycloalkenyl group is a C4-C5 heterocycloalkenyl group, and the C4-C5 heterocycloalkenyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2.

[0104] A preferred embodiment of the present invention includes two R 3 Two adjacent Rs 3 When these atoms form a 5-6 membered heteroaryl group in cooperation with cyclo atoms that are directly bonded to them, the 5-6 membered heteroaryl group consists of one or more heteroatoms selected from N, O, and S, and has 1 to 2 heteroatoms.

[0105] Preferred embodiments of the present invention include:

[0106] [ka]

[0107] teeth

[0108] [ka]

[0109] (As mentioned above, R 3 (They are either identical or different.)

[0110] Preferred embodiments of the present invention include:

[0111] [ka]

[0112] teeth

[0113] [ka]

[0114] (The structural formula shows the carbon-hydrogen bond on the right side.)

[0115] [ka]

[0116] teeth

[0117] [ka]

[0118] (and is ring-bound) Preferred embodiments of the present invention include:

[0119] [ka]

[0120] teeth

[0121] [ka]

[0122] (The structural formula shows the carbon-hydrogen bond on the right side.)

[0123] [ka]

[0124] teeth

[0125] [ka]

[0126] (and is ring-bound) Preferred embodiments of the present invention include:

[0127] [ka]

[0128] teeth

[0129] [ka]

[0130] (The structural formula shows the carbon-nitrogen bond on the right side.)

[0131] [ka]

[0132] or carbon-carbon double bond

[0133] [ka]

[0134] teeth

[0135] [ka]

[0136] (and is ring-bound) Preferred embodiments of the present invention include:

[0137] [ka]

[0138] teeth

[0139] [ka]

[0140] (The structural formula shows the carbon-hydrogen bond on the right side.)

[0141] [ka]

[0142] teeth

[0143] [ka]

[0144] (and is ring-bound) Preferred embodiments of the present invention include:

[0145] [ka]

[0146] teeth

[0147] [ka]

[0148] (The structural formula shows the carbon-nitrogen bond on the right side.)

[0149] [ka]

[0150] or carbon-carbon double bond

[0151] [ka]

[0152] teeth

[0153] [ka]

[0154] (and is ring-bound) Preferred embodiments of the present invention include:

[0155] [ka]

[0156] teeth

[0157] [ka]

[0158] That is the case.

[0159] Preferred embodiments of the present invention include:

[0160] [ka]

[0161] teeth

[0162] [ka]

[0163] That is the case.

[0164] Preferred embodiments of the present invention include:

[0165] [ka]

[0166] teeth

[0167] [ka]

[0168] That is the case.

[0169] Preferred embodiments of the present invention include:

[0170] [ka]

[0171] teeth

[0172] [ka]

[0173] That is the case.

[0174] Preferred embodiments of the present invention include:

[0175] [ka]

[0176] teeth

[0177] [ka]

[0178] That is the case.

[0179] Preferred embodiments of the present invention include:

[0180] [ka]

[0181] teeth

[0182] [ka]

[0183] That is the case.

[0184] In preferred embodiments of the present invention, n is 1 or 2.

[0185] A preferred embodiment of the present invention is R 1 The above are each

[0186] [ka]

[0187] and Z 2 The α-position of the bond (Z 2 (ortho position) or β position (Z 2 It is located in the meta position.

[0188] A preferred embodiment of the present invention includes at least one R 1 The above

[0189] [ka]

[0190] and Z 2 Located at the α-position of the bond; preferably, when n is 2, R 1 Each of the above is independent of the above

[0191] [ka]

[0192] and Z 2 It is located at the α-position of the bond.

[0193] A preferred embodiment of the present invention is R 1 If the halogen is a halogen, then the halogen is fluorine, chlorine, bromine, or iodine.

[0194] A preferred embodiment of the present invention is R 1 When is an unsubstituted or substituted C1-C6 alkyl group, or an unsubstituted or substituted C1-C6 alkyl group-O-, the C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group), preferably a methyl group.

[0195] A preferred embodiment of the present invention is R 1 If is a substituted C1-C6 alkyl group or a substituted C1-C6 alkyl-O-, and each substituent is independently a halogen, then the halogen is fluorine, chlorine, bromine, or iodine.

[0196] A preferred embodiment of the present invention is R 1If the substituent is a substituted C1-C6 alkyl group or a substituted C1-C6 alkyl-O-, and each substitution is independently a C1-C6 alkyl group or a C1-C6 alkyl-O-, then the C1-C6 alkyl group in the substituent (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group), preferably a methyl group.

[0197] A preferred embodiment of the present invention is R 1 If is a substituted C1-C6 alkyl group or a substituted C1-C6 alkyl-O-, the number of substituents is independently 1, 2, or 3.

[0198] A preferred embodiment of the present invention is R 1 If is a substituted C1-C6 alkyl group or a substituted C1-C6 alkyl-O-, and each substituent is independently a halogen, then the substituted C1-C6 alkyl group in the substituted C1-C6 alkyl group or the substituted C1-C6 alkyl-O- is independently -CF3.

[0199] In a preferred embodiment of the present invention, Q is the above

[0200] [ka]

[0201] It is located at the β or γ position of the W bond.

[0202] Preferred embodiments of the present invention include:

[0203] [ka]

[0204] When is a 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group is a 5 membered heteroaryl group, and the 5 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2; preferably an imidazolyl group

[0205] [ka]

[0206] , thienyl group

[0207] [ka]

[0208] furan group

[0209] [ka]

[0210] or pyrazolyl group

[0211] [ka]

[0212] (In the structural formula, the bond on the left is bonded to W, and the bond on the right is bonded to Q.) Preferred embodiments of the present invention include:

[0213] [ka]

[0214] When is a 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group is a 6 membered heteroaryl group, and the 6 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2; preferably a pyridinyl group

[0215] [ka]

[0216] or pyrazinyl group

[0217] [ka]

[0218] (In the structural formula, the bond on the left is bonded to W, and the bond on the right is bonded to Q.) Preferred embodiments of the present invention include:

[0219] [ka]

[0220] If the C3-C9 heterocycloalkyl group is a C3-C9 heterocycloalkyl group, the heteroatoms are one or more selected from N, O, and S, and the number of heteroatoms is 1 to 3; preferably a C4-C5 heterocycloalkyl group, the C4-C5 heterocycloalkyl group has one or more selected heteroatoms from N, O, and S, and the number of heteroatoms is 1 to 2; preferably a piperidine group

[0221] [ka]

[0222] (In the structural formula, the bond on the left is bonded to W, and the bond on the right is bonded to Q.) A preferred embodiment of the present invention is R 1 The above

[0223] [ka]

[0224] and Z 2 It is located at the β-position of the bond. Preferably, when n is 2, R 1 Each of the above is independent of the above

[0225] [ka]

[0226] and Z 2 It is located at the β-position of the bond.

[0227] A preferred embodiment of the present invention is the aforementioned

[0228] [ka]

[0229] If it is a phenyl group,

[0230] [ka]

[0231] And R 1’ The definition is R 1 It is the same as R 1’ and R 1 They are identical or different; preferably

[0232] [ka]

[0233] (In the structural formula, the bond on the left is bonded to W, and the bond on the right is bonded to Q.) A preferred embodiment of the present invention is the aforementioned

[0234] [ka]

[0235] If it is a phenyl group,

[0236] [ka]

[0237] teeth

[0238] [ka]

[0239] And R 1’ The definition is R 1 It is the same as R 1’ and R 1 They are identical or different; preferably

[0240] [ka]

[0241] (In the structural formula, the bond on the left is bonded to W, and the bond on the right is bonded to Q.) A preferred embodiment of the present invention is the aforementioned

[0242] [ka]

[0243] If it is a phenyl group,

[0244] [ka]

[0245] teeth

[0246] [ka]

[0247] (In the structural formula, the bond on the left is bonded to W, and the bond on the right is bonded to Q.) A preferred embodiment of the present invention is the aforementioned

[0248] [ka]

[0249] If it is a phenyl group,

[0250] [ka]

[0251] teeth

[0252] [ka]

[0253] (In the structural formula, the bond on the left is Z 2 (It is joined with, and the join on the right is joined with Q.) A preferred embodiment of the present invention is the aforementioned

[0254] [ka]

[0255] If it is a phenyl group,

[0256] [ka]

[0257] teeth

[0258] [ka]

[0259] Preferably

[0260] [ka]

[0261] And R 1’ The definition is R 1 It is the same as R 1’ and R 1 They are homologous or different; more

[0262] [ka]

[0263] (In the structural formula, the bond on the left is Z 2 (It is joined with, and the join on the right is joined with Q.) Preferred embodiments of the present invention include:

[0264] [ka]

[0265] teeth

[0266] [ka]

[0267] Preferably

[0268] [ka]

[0269] And R 1’ The definition is R 1 It is the same as R 1’ and R 1 They are homologous or different; more

[0270] [ka]

[0271] (In the structural formula, the bond on the left is Z 2 (It is joined with, and the join on the right is joined with Q.) Preferred embodiments of the present invention include:

[0272] [ka]

[0273] teeth

[0274] [ka]

[0275] That is the case.

[0276] Preferred embodiments of the present invention include:

[0277] [ka]

[0278] teeth

[0279] [ka]

[0280] That is the case.

[0281] A preferred embodiment of the present invention is the aforementioned

[0282] [ka]

[0283] If it is a 5-6 member heteroaryl group,

[0284] [ka]

[0285] teeth

[0286] [ka]

[0287] (In the structural formula, the bond on the left is bonded to W, and the bond on the right is bonded to Q.) A preferred embodiment of the present invention is the aforementioned

[0288] [ka]

[0289] If it is a 5-6 member heteroaryl group,

[0290] [ka]

[0291] teeth

[0292] [ka]

[0293] (In the structural formula, the bond on the left is bonded to W, and the bond on the right is bonded to Q.) A preferred embodiment of the present invention is the aforementioned

[0294] [ka]

[0295] If it is a 5-6 member heteroaryl group,

[0296] [ka]

[0297] teeth

[0298] [ka]

[0299] (In the structural formula, the bond on the left is bonded to W, and the bond on the right is bonded to Q.) A preferred embodiment of the present invention is the aforementioned

[0300] [ka]

[0301] If it is a 5-6 member heteroaryl group,

[0302] [ka]

[0303] teeth

[0304] [ka]

[0305] (In the structural formula, the bond on the left is bonded to W, and the bond on the right is bonded to Q.) Preferred embodiments of the present invention include:

[0306] [ka]

[0307] teeth

[0308] [ka]

[0309] That is the case.

[0310] Preferred embodiments of the present invention include:

[0311] [ka]

[0312] teeth

[0313] [ka]

[0314] That is the case.

[0315] A preferred embodiment of the present invention is the aforementioned

[0316] [ka]

[0317] If it is a C3-C5 heterocycloalkyl group,

[0318] [ka]

[0319] (In the structural formula, the bond on the left is bonded to W, and the bond on the right is bonded to Q.) In a preferred embodiment of the present invention, when Q is a halogen, the halogen is fluorine, chlorine, bromine, or iodine.

[0320] In preferred embodiments of the present invention, when Q is an unsubstituted or substituted C1-C6 alkyl group, or an unsubstituted or substituted C1-C6 alkyl group-O-, the C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group).

[0321] In preferred embodiments of the present invention, when Q is an unsubstituted or substituted C2-C6 alkenyl group, or an unsubstituted or substituted C2-C6 alkenyl group-O-, the C2-C6 alkenyl group is a C2-C4 alkenyl group {e.g., a vinyl group, a propenyl group (e.g., a 1-propenyl group or a 2-propenyl group), or a butenyl group (e.g., a 2-butenyl group, a 1-butenyl group, or a butadiene group)}.

[0322] In preferred embodiments of the present invention, Q is either unsubstituted or substituted C3-C 10 In the case of a cycloalkyl group, the C3-C 10 The cycloalkyl group is a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, or cyclooctyl group.

[0323] In preferred embodiments of the present invention, Q is an unsubstituted or substituted C3-C9 heterocycloalkyl group, wherein the C3-C9 heterocycloalkyl group is a C3-C5 heterocycloalkyl group, wherein the heteroatoms of the C3-C5 heterocycloalkyl group are one or more selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; preferably a C4-C5 heterocycloalkyl group, wherein the heteroatoms of the C4-C5 heterocycloalkyl group are one or more selected from N, O, and S, and the number of heteroatoms is 1 to 2; preferably a propylene oxide group (e.g.

[0324] [ka]

[0325] ), pyrrolidinyl group (for example)

[0326] [ka]

[0327] ) or piperazine group (for example)

[0328] [ka]

[0329] )

[0330] In preferred embodiments of the present invention, Q is an unsubstituted or substituted C3-C9 heterocycloalkenyl group, the C3-C9 heterocycloalkenyl group is a C3-C5 heterocycloalkenyl group; the C3-C5 heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; preferably it is a C4-C5 heterocycloalkenyl group, the C4-C5 heterocycloalkenyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2; preferably

[0331] [ka]

[0332] That is the case.

[0333] In preferred embodiments of the present invention, Q is either unsubstituted or substituted C6-C 10 In the case of an aryl group, the above C6~C 10 The aryl group is a phenyl group.

[0334] In preferred embodiments of the present invention, when Q is an unsubstituted or substituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group, preferably an imidazolyl group. (for example

[0335] [ka]

[0336] ), oxazolyl group (for example)

[0337] [ka]

[0338] ), furan group (for example)

[0339] [ka]

[0340] ), thienyl group (for example)

[0341] [ka]

[0342] ), pyrazolyl group (for example)

[0343] [ka]

[0344] ), pyrazole group (for example)

[0345] [ka]

[0346] ), isoxazolyl group (for example)

[0347] [ka]

[0348] ), pyridinyl group (for example)

[0349] [ka]

[0350] ), pyrimidinyl group (for example)

[0351] [ka]

[0352] ), triazolyl group

[0353] [ka]

[0354] That is the case.

[0355] In preferred embodiments of the present invention, when Q is an unsubstituted or substituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group, preferably an imidazolyl group (for example)

[0356] [ka]

[0357] ), oxazolyl group (for example)

[0358] [ka]

[0359] ), furan group (for example)

[0360] [ka]

[0361] ), thienyl group (for example)

[0362] [ka]

[0363] ), pyrazolyl group (for example)

[0364] [ka]

[0365] ), pyrazole group (for example)

[0366] [ka]

[0367] ), isoxazolyl group (for example)

[0368] [ka]

[0369] ), pyridinyl group (for example)

[0370] [ka]

[0371] ), pyrimidinyl group (for example)

[0372] [ka]

[0373] ) or triazolyl group

[0374] [ka]

[0375] That is the case.

[0376] In preferred embodiments of the present invention, when Q is an unsubstituted or substituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group, preferably a triazolyl group.

[0377] [ka]

[0378] That is the case.

[0379] In preferred embodiments of the present invention, Q is a substituted C1-C6 alkyl group, a substituted C1-C6 alkyl group-O-, a substituted C2-C6 alkenyl group, a substituted C2-C6 alkenyl group-O-, or a substituted C3-C 10 Cycloalkyl groups, substituted C6-C 10 When the substituent is an aryl group, a substituted C3-C9 heterocycloalkyl group, a substituted C3-C9 heterocycloalkenyl group, or a substituted 5-10 membered heteroaryl group, the number of substituents is independently 1, 2, 3, or 4.

[0380] In preferred embodiments of the present invention, Q is a substituted C1-C6 alkyl group, a substituted C1-C6 alkyl group-O-, a substituted C2-C6 alkenyl group, a substituted C2-C6 alkenyl group-O-, or a substituted C3-C 10 Cycloalkyl groups, substituted C6-C 10 The group is an aryl group, a substituted C3-C9 heterocycloalkyl group, a substituted C3-C9 heterocycloalkenyl group, or a substituted 5-10 membered heteroaryl group, and if the substitution is a halogen, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine.

[0381] A preferred embodiment of the present invention includes the unsubstituted or one or more R a The C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) in the substituted C1-C6 alkyl group or C1-C6 alkyl group-O- is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group), preferably a methyl group or an isopropyl group.

[0382] A preferred embodiment of the present invention includes the unsubstituted or one or more R a In the C3-C6 cycloalkyl groups substituted with , the C3-C6 cycloalkyl group is independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0383] A preferred embodiment of the present invention is R a If the halogen is a halogen, then the halogen is independently fluorine, chlorine, bromine, or iodine.

[0384] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27When is an unsubstituted or substituted C1-C6 alkyl group, or an unsubstituted or substituted C1-C6 alkyl group-O-, the C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group) or a t-pentyl group (1,1-dimethylpropyl group).

[0385] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 When is an unsubstituted or substituted C2-C6 alkenyl group, or an unsubstituted or substituted C2-C6 alkenyl group-O-, the C2-C6 alkenyl group is a C2-C4 alkenyl group {for example, a vinyl group, a propenyl group (for example, a 1-propenyl group or a 2-propenyl group), or a butenyl group (for example, a 2-butenyl group, a 1-butenyl group, or a butadiene group)}, and is preferably a vinyl group.

[0386] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 When is an unsubstituted or substituted C2-C6 alkynyl group, the C2-C6 alkynyl group is a C2-C4 alkynyl group {e.g., ethynyl group, propynyl group (e.g., 1-propynyl group or 2-propynyl group), or butynyl group (e.g., 2-butynyl group, 1-butynyl group or diacetylene group)}, preferably an ethynyl group.

[0387] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 C3~C is either unsubstituted or substituted. 10 If it is a cycloalkyl group, then C3~C 10 The cycloalkyl group is a C3-C6 cycloalkyl group, preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0388] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6, R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 If is an unsubstituted or substituted C3-C9 heterocycloalkyl group, the C3-C9 heterocycloalkyl group is a C3-C5 heterocycloalkyl group, and the C3-C5 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; preferably it is a C4-C5 heterocycloalkyl group, and the C4-C5 heterocycloalkyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2; for example, a propylene oxide group (for example)

[0389] [ka]

[0390] ), tetrahydrofuran group (for example)

[0391] [ka]

[0392] ), tetrahydropyran group (for example)

[0393] [ka]

[0394] ) or a tetrahydrothienyl group (for example)

[0395] [ka]

[0396] )

[0397] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 When is an unsubstituted or substituted C3-C9 heterocycloalkenyl group, the C3-C9 heterocycloalkenyl group is a C3-C5 heterocycloalkenyl group, and the C3-C5 heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, with 1 to 3 heteroatoms; preferably, it is a C4-C5 heterocycloalkenyl group, and the C4-C5 heterocycloalkenyl group has one or more heteroatoms selected from N, O, and S, with 1 to 2 heteroatoms.

[0398] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 When is an unsubstituted or substituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group, of which the heteroatoms are one or two selected from N, O, and S, and the number of heteroatoms is 1 to 2; preferably a furan group (for example)

[0399] [ka]

[0400] ) or pyridinyl group (for example)

[0401] [ka]

[0402] )

[0403] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27Substituted C1-C6 alkyl group, substituted C1-C6 alkyl group-O-, substituted C2-C6 alkenyl group, substituted C2-C6 alkenyl group-O-, substituted C2-C6 alkynyl group, substituted C3-C 10 The group is a cycloalkyl group, a substituted phenyl group, a substituted C3-C9 heterocycloalkyl group, a substituted C3-C9 heterocycloalkenyl group, or a substituted 5-10 membered heteroaryl group, and if the substitution is a halogen, the halogen is independently fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0404] A preferred embodiment of the present invention is R d When the halogen is independently a halogen, the halogen is independently fluorine, chlorine, bromine, or iodine, and is preferably fluorine.

[0405] A preferred embodiment of the present invention is R d The number of each is independently 1, 2, 3, or 4; preferably 1 or 2.

[0406] A preferred embodiment of the present invention includes unsubstituted or one or more R d The C1-C6 alkyl groups (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) in the C1-C6 alkyl groups or C1-C6 alkyl group-O- are independently C1-C4 alkyl groups (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group).

[0407] A preferred embodiment of the present invention includes the unsubstituted or one or more R d In the C3-C6 cycloalkyl groups substituted with , the C3-C6 cycloalkyl group is independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0408] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 Substituted C1-C6 alkyl group, substituted C1-C6 alkyl group-O-, substituted C2-C6 alkenyl group, substituted C2-C6 alkenyl group-O-, substituted C2-C6 alkynyl group, substituted C3-C 10 In the case of a cycloalkyl group, a substituted phenyl group, a substituted C3-C9 heterocycloalkyl group, a substituted C3-C9 heterocycloalkenyl group, or a substituted 5-10 membered heteroaryl group, the number of substituents is independently 1, 2, 3, or 4; preferably 1 or 2.

[0409] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , R 1-11 and R 1-12 , R 1-14 and R 1-15 , R 1-21 and R 1-22 , R 1-23 and R 1-24 , or R 1-25 and R 1-26 When each of these independently forms an unsubstituted or substituted C3-C9 heterocycloalkyl group with a nitrogen atom that is directly bonded to them, the C3-C9 heterocycloalkyl group may contain no heteroatoms other than the nitrogen atom, or may further contain one heteroatom selected from oxygen, sulfur, and nitrogen; preferably, it is a C3-C5 heterocycloalkyl group.

[0410] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , R 1-11 and R 1-12 , R 1-14 and R 1-15 , R 1-21 and R 1-22 , R 1-23 and R 1-24 , or R 1-25 and R 1-26 When each of these atoms independently forms an unsubstituted or substituted C3-C9 heterocycloalkenyl group in cooperation with nitrogen atoms that are directly bonded to them, the C3-C9 heterocycloalkenyl group contains no heteroatoms other than nitrogen, or further contains one heteroatom selected from oxygen, sulfur, and nitrogen; preferably it is a C3-C5 heterocycloalkenyl group.

[0411] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , R 1-11 and R 1-12 , R 1-14 and R 1-15 , R 1-21 and R 1-22 , R 1-23 and R 1-24 , or R 1-25 and R 1-26 When each of these independently forms an unsubstituted or substituted 5-10 membered heteroaryl group in cooperation with nitrogen that is directly bonded to them, the 5-10 membered heteroaryl group contains no heteroatoms other than nitrogen, or further contains one heteroatom selected from oxygen, sulfur, and nitrogen; preferably it is a 5-6 membered heteroaryl group.

[0412] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , R 1-11 and R 1-12 , R 1-14 and R 1-15 , R 1-21 and R 1-22 , R 1-23 and R 1-24 , or R 1-25 and R 1-26 Each of these groups independently forms a substituted C3-C9 heterocycloalkyl group, a substituted C3-C9 heterocycloalkenyl group, or a substituted 5-10 membered heteroaryl group in cooperation with the nitrogen directly bonded to them, and when the substitution is a halogen, the halogen is independently fluorine, chlorine, bromine, or iodine.

[0413] A preferred embodiment of the present invention includes the unsubstituted or one or more R b The C1-C6 alkyl groups (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) in the C1-C6 alkyl groups or C1-C6 alkyl group-O- are independently C1-C4 alkyl groups (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group).

[0414] A preferred embodiment of the present invention includes the unsubstituted or one or more R b In the C3-C6 cycloalkyl groups substituted with cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0415] A preferred embodiment of the present invention is R b If the halogen is a halogen, then the halogen is independently fluorine, chlorine, bromine, or iodine.

[0416] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , R 1-11 and R 1-12 , R 1-14 and R 1-15 , R 1-21 and R 1-22 , R 1-23 and R 1-24 , or R 1-25 and R 1-26 When each of these substituents independently forms a substituted C3-C9 heterocycloalkyl group, a substituted C3-C9 heterocycloalkenyl group, or a substituted 5-10 membered heteroaryl group in cooperation with the nitrogen directly bonded to them, the number of substituents is independently 1, 2, 3, or 4; preferably 1 or 2.

[0417] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 If is a substituted C1-C6 alkyl group, then the substituted C1-C6 alkyl group is

[0418] [ka]

[0419] That is the case.

[0420] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 If is a substituted C1-C6 alkyl group, then the substituted C1-C6 alkyl group is

[0421] [ka]

[0422] That is the case.

[0423] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27If is a substituted C2-C6 alkenyl group, then the substituted C2-C6 alkenyl group is

[0424] [ka]

[0425] That's fine.

[0426] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 If is a substituted C2-C6 alkynyl group, then the substituted C2-C6 alkynyl group is

[0427] [ka]

[0428] That is the case.

[0429] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 is the substitution C3~C 10 In the case of a cycloalkyl group, the substituted C3-C 10 Cycloalkyl groups are

[0430] [ka]

[0431] That is the case.

[0432] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 is a substitution

[0433]

number

[0434] In that case, the substituted C3-C9 heterocycloalkyl group is

[0435] [ka]

[0436] That is the case.

[0437] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 If is an unsubstituted or substituted phenyl group, the substituted phenyl group is

[0438] [ka]

[0439] That is the case.

[0440] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R1-25 , R 1-26 and R 1-27 If is an unsubstituted or substituted 5-10 member heteroaryl group, then the substituted 5-10 member heteroaryl group is

[0441] [ka]

[0442] That is the case.

[0443] A preferred embodiment of the present invention includes one or more R a The C1-C6 alkyl groups substituted with

[0444] [ka]

[0445] That is the case.

[0446] A preferred embodiment of the present invention includes one or more R a The C1-C6 alkyl groups substituted with

[0447] [ka]

[0448] That is the case.

[0449] A preferred embodiment of the present invention includes one or more R a The C3-C6 cycloalkyl groups substituted with are

[0450] [ka]

[0451] That is the case.

[0452] A preferred embodiment of the present invention includes one or more R aThe C3-C6 cycloalkyl groups substituted with are

[0453] [ka]

[0454] That is the case.

[0455] A preferred embodiment of the present invention includes the one or more R d The C3-C6 cycloalkyl groups substituted with are

[0456] [ka]

[0457] That is the case.

[0458] A preferred embodiment of the present invention is -N(R 1-21 R 1-22 ) is either -NHCH3 or -NH2.

[0459] Preferred embodiments of the present invention include:

[0460]

number

[0461] That is the case.

[0462] A preferred embodiment of the present invention is -S(=O)2-N(R 1-25 R 1-26 ) is -S(=O)2-NH2.

[0463] A preferred embodiment of the present invention is -C(=O)-OR 1-27 These are -COOH, -COOCH3, or -COOC2H5.

[0464] A preferred embodiment of the present invention is -C(=O)-OR 1-27 It is -COOH or -COOCH3.

[0465] A preferred embodiment of the present invention is -NH-C(=O)-R 1-1 is -NH-C(=O)-CH3, -NH-C(=O)-O-CH3,

[0466] [ka]

[0467] That is the case.

[0468] A preferred embodiment of the present invention is -NH-C(=O)-R 1-1 teeth

[0469] [ka]

[0470] That is the case.

[0471] A preferred embodiment of the present invention is -C(=O)-R 1-2 This is -C(=O)-CH3 or -C(=O)-O-CH3.

[0472] A preferred embodiment of the present invention is -OC(=O)-N(R 1-3 R 1-4 ) is -OC(=O)-NH-CH3.

[0473] A preferred embodiment of the present invention is -C(=O)-N(R 1-5 R 1-6 ) is -C(=O)-NH-CH3.

[0474] A preferred embodiment of the present invention is -C(=NH)-N(R 1-7 R 1-8 ) is -C(=NH)-NH-CH3.

[0475] A preferred embodiment of the present invention is -S(=O)2-N(R 1-9 R 1-10) is -S(=O)2-NH-CH3 or -SO2NH2.

[0476] A preferred embodiment of the present invention is -OC(=O)-R 1-13 It is -OC(=O)-NH-CH3.

[0477] A preferred embodiment of the present invention is -N(R 1-14 R 1-15 )teeth

[0478] [ka]

[0479] That is the case.

[0480] In a preferred embodiment of the present invention, Q is -N(R 1-14 R 1-15 ) is, for example, -NH2.

[0481] A preferred embodiment of the present invention is -NH-S(=O)2-R 1-16 It is -NH-S(=O)2-CH3.

[0482] In a preferred embodiment of the present invention, if Q is a substituted C1-C6 alkyl group, then the substituted C1-C6 alkyl group is

[0483] [ka]

[0484] That is the case.

[0485] In a preferred embodiment of the present invention, Q is substituted with C3~C 10 In the case of a cycloalkyl group, the substituted C3-C 10 Cycloalkyl groups are

[0486] [ka]

[0487] That is the case.

[0488] In a preferred embodiment of the present invention, when Q is a substituted C3-C9 heterocycloalkyl group, the substituted C3-C9 heterocycloalkyl group is

[0489] [ka]

[0490] That is the case.

[0491] In a preferred embodiment of the present invention, when Q is a substituted C3-C9 heterocycloalkyl group, the substituted C3-C9 heterocycloalkyl group is

[0492] [ka]

[0493] That is the case.

[0494] In a preferred embodiment of the present invention, when Q is a substituted C3-C9 heterocycloalkenyl group, the substituted C3-C9 heterocycloalkenyl group is

[0495] [ka]

[0496] That is the case.

[0497] In a preferred embodiment of the present invention, when Q is a substituted 5-10 membered heteroaryl group, the substituted 5-10 membered heteroaryl group is

[0498] [ka]

[0499] [ka]

[0500] That is the case.

[0501] In a preferred embodiment of the present invention, when Q is a substituted 5-10 membered heteroaryl group, the substituted 5-10 membered heteroaryl group is

[0502] [ka]

[0503] [ka]

[0504] That is the case.

[0505] In a preferred embodiment of the present invention, when Q is a substituted 5-10 membered heteroaryl group, the substituted 5-10 membered heteroaryl group is

[0506] [ka]

[0507] [ka]

[0508] That is the case.

[0509] In preferred embodiments of the present invention, Q is H, -OH, -CF3, -CN, -NH2, -NH-C(=O)-CH3, -NH-C(=O)-O-CH3,

[0510] [ka]

[0511] , -C(=O)-CH3, -C(=O)-C2H5, -C(=O)-O-CH3, -OC(=O)-NH-CH3, -C(=O)-NH-CH3, -C(=NH)-NH-CH3, -S(=O)2-NH-CH3,

[0512] [ka]

[0513] [ka]

[0514] -NH-S(=O)2-CH3, -S(=O)2-NH2,

[0515] [ka]

[0516] That is the case.

[0517] In preferred embodiments of the present invention, Q is H, -OH, -CF3, -CN, -NH-C(=O)-CH3, -NH-C(=O)-O-CH3,

[0518] [ka]

[0519] , -C(=O)-CH3, -C(=O)-C2H5, -C(=O)-O-CH3, -OC(=O)-NH-CH3, -C(=O)-NH-CH3, -C(=NH)-NH-CH3, -S(=O)2-NH-CH3,

[0520] [ka]

[0521] [ka]

[0522] That is the case.

[0523] In a preferred embodiment of the present invention, Q is

[0524] [ka]

[0525] [ka]

[0526] That is the case.

[0527] A preferred embodiment of the present invention is R 2-1 or R 2-2 If the halogen is a halogen, then the halogen is independently fluorine, chlorine, bromine, or iodine.

[0528] A preferred embodiment of the present invention is R 2-1 or R 2-2 When is an unsubstituted or substituted C1-C6 alkyl group, or an unsubstituted or substituted C1-C6 alkyl group-O-, the C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group).

[0529] A preferred embodiment of the present invention is R 2-1 or R 2-2 If is a substituted C1-C6 alkyl group or a substituted C1-C6 alkyl group-O-, and the substitution is a halogen, then the halogen is independently fluorine, chlorine, bromine, or iodine.

[0530] A preferred embodiment of the present invention is R 2-1 or R 2-2If the substituent is a substituted C1-C6 alkyl group or a substituted C1-C6 alkyl-O-, and the substitution is a C1-C6 alkyl group or a substituted C1-C6 alkyl-O-, then the C1-C6 alkyl group in the substituent (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group).

[0531] A preferred embodiment of the present invention is R 2-1 or R 2-2 When is a substituted C1-C6 alkyl group or a substituted C1-C6 alkyl-O-, the number of substituents is independently 1, 2, 3, or 4; preferably 1 or 2.

[0532] A preferred embodiment of the present invention is R 2-3 , R 2-4 , R 2-5 or R 2-6 When is an unsubstituted or substituted C1-C6 alkyl group, or an unsubstituted or substituted C1-C6 alkyl group-O-, the C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group).

[0533] A preferred embodiment of the present invention is R 2-3 , R 2-4 , R 2-5 or R 2-6 If is an unsubstituted or substituted C3-C8 cycloalkyl group, or an unsubstituted or substituted C3-C8 cycloalkyl group-O-, then the C3-C8 cycloalkyl group is a C3-C6 cycloalkyl group (e.g., a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group).

[0534] A preferred embodiment of the present invention is R 2-3 , R 2-4, R 2-5 or R 2-6 If is a substituted C1-C6 alkyl group, a substituted C3-C8 cycloalkyl group, a substituted C3-C8 cycloalkyl group-O-, or a substituted C1-C6 alkyl group-O-, and the substitution is a halogen, then the halogen is independently fluorine, chlorine, bromine, or iodine.

[0535] A preferred embodiment of the present invention is R 2-3 , R 2-4 , R 2-5 or R 2-6 If the substituent is a substituted C1-C6 alkyl group, a substituted C3-C8 cycloalkyl group, a substituted C3-C8 cycloalkyl group-O-, or a substituted C1-C6 alkyl group-O-, and the substitution is a C1-C6 alkyl group or a substituted C1-C6 alkyl group-O-, then the C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) in the substituent is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group), preferably a methyl group or an ethyl group.

[0536] A preferred embodiment of the present invention is R 2-3 , R 2-4 , R 2-5 or R 2-6 If the substituent is a substituted C1-C6 alkyl group, a substituted C3-C8 cycloalkyl group, a substituted C3-C8 cycloalkyl group-O-, or a substituted C1-C6 alkyl group-O-, and the substitution is a C1-C6 alkyl group or a substituted C1-C6 alkyl group-O-, the number of substituents is independently 1, 2, 3, or 4; preferably 1 or 2.

[0537] A preferred embodiment of the present invention is R 2-7 R is an independent halogen, 2-7 is an independently halogen-substituted C1-C6 alkyl group, or R 2-7The halogens in the C1-C6 alkyl-O- groups, which are independently substituted with halogens, are independently fluorine, chlorine, bromine, or iodine.

[0538] A preferred embodiment of the present invention is R 2-7 R is independently an unsubstituted or substituted C1-C6 alkyl group, or R 2-7 Independently, the C1-C6 alkyl groups (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) in the unsubstituted or substituted C1-C6 alkyl-O- are independently C1-C4 alkyl groups (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group).

[0539] A preferred embodiment of the present invention is R 2-8 or R 2-9 In the C1-C6 alkyl groups in which halogens are independently substituted, the halogens are independently fluorine, chlorine, bromine, or iodine.

[0540] A preferred embodiment of the present invention is R 2-8 or R 2-9 In C1-C6 alkyl groups that are independently unsubstituted or halogenated, the C1-C6 alkyl groups (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) are independently C1-C4 alkyl groups (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group).

[0541] A preferred embodiment of the present invention is -C(=O)N(R 2-5 R 2-6 ) is -C(=O)NH2.

[0542] A preferred embodiment of the present invention is -C(=O)N(R 2-8 R 2-9 ) is -C(=O)NHCH3.

[0543] Preferred embodiments of the present invention include:

[0544] [ka]

[0545] teeth

[0546] [ka]

[0547] However, carbon atoms marked with an asterisk (*) are chiral carbons and are in the S configuration, R configuration, or a mixture thereof; preferably, they exist in the form of a single (R) or (S) enantiomer or in the form of a kind of enantiomer enrichment.

[0548] Preferred embodiments of the present invention include:

[0549] [ka]

[0550] teeth

[0551] [ka]

[0552] (Of these, X is either methylene or -NH-).

[0553] A preferred embodiment of the present invention is R 2 but

[0554] [ka]

[0555] If that is the case, then one of X and Y is

[0556] [ka]

[0557] And the other is a single bond, methylene, or -O- (for example)

[0558] [ka]

[0559] , of which X is a single bond, methylene, or -O-); preferably X is -O-, i.e., R 2 teeth

[0560] [ka]

[0561] It is; moreR 2 teeth

[0562] [ka]

[0563] That is the case.

[0564] A preferred embodiment of the present invention is R 2 but

[0565] [ka]

[0566] If so, X or Y is -N(R 2-3 )- and preferably one of X and Y is -N(R 2-3 )- and the other is -O-, -N(R 2-3 )-, or

[0567] [ka]

[0568] It is; moreR2 teeth

[0569] [ka]

[0570] That is the case.

[0571] A preferred embodiment of the present invention is R 2 teeth

[0572] [ka]

[0573] That is the case.

[0574] A preferred embodiment of the present invention is R 2 In the case of unsubstituted or substituted 5-6 membered heteroaryl groups, the 5-6 membered heteroaryl groups are independently pyridinyl groups.

[0575] [ka]

[0576] That is the case.

[0577] A preferred embodiment of the present invention is R 2 When is independently a substituted 5-6 membered heteroaryl group, the halogen in the substituent, the halogen-substituted C1-C6 alkyl group, or the halogen in the halogen-substituted C1-C6 alkyl-O- is independently fluorine, chlorine, bromine, or iodine.

[0578] A preferred embodiment of the present invention is R 2If the substituent is independently a substituted 5-6 member heteroaryl group, then the unsubstituted or halogen-substituted C1-C6 alkyl group in the substituent, or the C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) in the unsubstituted or halogen-substituted C1-C6 alkyl-O-, is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group). A preferred embodiment of the present invention is R 2 These are independently unsubstituted or substituted 5-6 membered heteroaryl groups, and the substituted 5-6 membered heteroaryl groups are independently

[0579] [ka]

[0580] That is the case.

[0581] Preferred embodiments of the present invention include:

[0582] [ka]

[0583] teeth

[0584] [ka]

[0585] isn't it.

[0586] Preferred embodiments of the present invention include:

[0587] [ka]

[0588] teeth

[0589] [ka]

[0590] That is the case.

[0591] A preferred embodiment of the present invention is the heterocyclic compound shown in formula I, as shown in formula IA:

[0592] [ka]

[0593] Eventually,

[0594] [ka]

[0595] teeth

[0596] [ka]

[0597] and; Preferably, the heterocyclic compound shown in formula I is as shown in formula IA-1:

[0598] [ka]

[0599] , eventually, R 1’ The definition is R 1 It is the same as R 1’ and R 1 are homologous or different, and W is a single bond;

[0600] [ka]

[0601] teeth

[0602] [ka]

[0603] and; Preferably, the heterocyclic compound shown in formula I is as shown in formula IA-2:

[0604] [ka]

[0605] , eventually, R 1’ The definition is R 1 It is the same as R 1’ and R 1 are homologous or different; W is a single bond; X is a single bond, methylene, or -O-;

[0606] [ka]

[0607] teeth

[0608] [ka]

[0609] That is the case.

[0610] A preferred embodiment of the present invention is the heterocyclic compound shown in formula I, as shown in formula IB:

[0611] [ka]

[0612] , eventually, R 2 teeth

[0613] [Chemical formula]

[0614] or -C(=O)N(R 2-5 R 2-6 ) and X or Y is -N(R 2-3 )-; Preferably, the heterocyclic compound represented by Formula I is as shown in Formula I-B-1:

[0615] [Chemical formula]

[0616] , wherein the definition of R 1’ is the same as R 1 , R 1’ and R 1 are identical or different; W is a single bond; R 2 is

[0617] [Chemical formula]

[0618] or -C(=O)N(R 2-5 R 2-6 ) and X or Y is -N(R 2-3 )-; Preferably, the heterocyclic compound represented by Formula I is as shown in Formula I-B-2:

[0619] [Chemical formula]

[0620] , wherein the definition of R 1’ is the same as R 1 , R 1’ and R 1 are identical or different, W is a single bond; R 2 is

[0621] [Chemical formula]

[0622] or -C(=O)N(R 2-5 R 2-6 ) and X or Y is -N(R 2-3 ).

[0623] In a preferred embodiment of the present invention, in the heterocyclic compound represented by the formula I, Q is H, halogen, -OH, -CF3, -CN, -NH-C(=O)-R 1-1 , -C(=O)-R 1-2 , -O-C(=O)-N(R 1-3 R 1-4 ), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), -S(=O)-N(R 1-11 R 1-12 ), -O-C(=O)-R 1-13 , -N(R 1-14 R 1-15 ), -NH-S(=O)2-R 1-16 , an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C1-C6 alkyl group -O-, an unsubstituted or substituted C2-C6 alkenyl group, an unsubstituted or substituted C2-C6 alkenyl group -O-, an unsubstituted or substituted C3-C 10 cycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkenyl group, an unsubstituted or substituted C6-C 10 aryl group, or an unsubstituted or substituted 5-10 member heteroaryl group.

[0624] In a preferred embodiment of the present invention, the heterocyclic compound represented by the formula I is as shown in formula I-C:

[0625]

Chemical formula

[0626] , wherein Q is H, halogen, -OH, -CF3, -CN, -NH-C(=O)-R1-1 -C(=O)-R 1-2 -OC(=O)-N(R 1-3 R 1-4 ), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), -S(=O)-N(R 1-11 R 1-12 ), -OC(=O)-R 1-13 , -N(R 1-14 R 1-15 ), -NH-S(=O)2-R 1-16 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C1-C6 alkyl groups-O-, unsubstituted or substituted C2-C6 alkenyl groups, unsubstituted or substituted C2-C6 alkenyl groups-O-, unsubstituted or substituted C3-C 10 Cycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkenyl groups, unsubstituted or substituted C6-C 10 An aryl group, or an unsubstituted or substituted 5-10 membered heteroaryl group; Preferably, the heterocyclic compound shown in formula I is as shown in formula IC-1:

[0627] [ka]

[0628] ; Preferably, the heterocyclic compound shown in formula I is as shown in formula IC-2:

[0629] [ka]

[0630] , eventually, R 1’ The definition is R 1 It is the same as R 1’ and R 1 The atoms are homologous or different, and X is a single bond, a methylene group, or an O- group.

[0631] A preferred embodiment of the present invention includes the heterocyclic compound shown in formula I, as shown in formula ID:

[0632] [ka]

[0633] Eventually,

[0634] [ka]

[0635] This is a 5-6 membered heteroaryl group or a C3-C5 heterocycloalkyl group; Preferably, the heterocyclic compound shown in formula I is as shown in formula ID-1:

[0636] [ka]

[0637] Eventually,

[0638] [ka]

[0639] This is a 5-6 membered heteroaryl group, or a C3-C5 heterocycloalkyl group; Preferably, the heterocyclic compound shown in formula I is as shown in formula ID-2:

[0640] [ka]

[0641] Of these, X is a single bond, methylene, or -O-; W is a single bond;

[0642] [ka]

[0643] This is a 5-6 membered heteroaryl group or a C3-C5 heterocycloalkyl group.

[0644] A preferred embodiment of the present invention is the heterocyclic compound shown in formula I, as shown in formula IE:

[0645] [ka]

[0646] Eventually, R 2 Independently

[0647] [ka]

[0648] , or an unsubstituted or substituted 5-6 membered heteroaryl group; for example, W is a single bond; Preferably, the heterocyclic compound shown in formula I is as shown in formula IE-1:

[0649] [ka]

[0650] ;for example

[0651] [ka]

[0652] is a phenyl group or a 6-membered heteroaryl group; Preferably, the heterocyclic compound shown in formula I is as shown in formula IE-2:

[0653] [ka]

[0654] ;for example

[0655] [ka]

[0656] It is a phenyl group.

[0657] Preferred embodiments of the present invention include:

[0658] [ka]

[0659] It is a 5-membered heteroaryl group;

[0660] [ka]

[0661] The group is a phenyl group, a 5-6 member heterocycloalkyl group, a 5-6 member heterocyclic alkenyl group, or a 5-6 member heteroaryl group; the 5-6 member heterocycloalkyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the 5-6 member heterocyclic alkenyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the 5-6 member heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 These independently represent cycloatoms;

[0662] [ka]

[0663] When Z is a 5-member heterocycloalkyl group, a 5-member heterocyclic alkenyl group, or a 5-member heteroaryl group 6 or Z 9 represents a single bond; m is 1, 2, 3 or 4; R 3 is H, halogen, -OH, a halo C1-C6 alkyl group or a C1-C6 alkyl group; W is a single bond or -C(=O)-NH-;

[0664]

Chemical formula

[0665] is a phenyl group, a 5-6 member heteroaryl group, or a C3-C9 heterocycloalkyl group; n is 1, 2, 3 or 4; R 1 is independently H, halogen, -OH, -CN, or an unsubstituted or substituted C1-C6 alkyl group; Q is H, halogen, -OH, -CN, -NH-C(=O)-R 1-1 , -C(=O)-R 1-2 , -O-C(=O)-N(R 1-3 R 1-4 ), -C(=O)-N(R 1-5 R<000096?), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), -N(R 1-14 R 1-15 ), -NH-S(=O)2-R 1-16 , an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C3-C 10 cycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkyl group, an unsubstituted or substituted C3-C9 heterocyclic alkenyl group, or an unsubstituted or substituted 5-10 member heteroaryl group; R 2 is independently It seems there is a typo in the original text where "? " is present in ID=46. I've translated it as "? " for now. If this is incorrect, please provide the correct text.

[0666] [ka]

[0667] -C(=O)N(R 2-5 R 2-6 ), or an unsubstituted or substituted 5-6 member heteroaryl group; Preferably,

[0668] [ka]

[0669] This is a phenyl group, a 6-membered heterocycloalkyl group, a 6-membered heterocyclic alkenyl group, or a 6-membered heteroaryl group; m is either 1 or 2; R 1 The substituents in each are one or more substitutions independently selected from halogens, -OH, -CN, or -C(=O)NH2 substituents; for example, halogens; R 3 is H, halogen, -OH, -CF3, or C1-C6 alkyl group; R 2 Independently

[0670] [ka]

[0671] or -C(=O)N(R 2-5 R 2-6 )

[0672] Preferred embodiments of the present invention include:

[0673] [ka]

[0674] It is a 5-membered heteroaryl group.

[0675] Preferred embodiments of the present invention include:

[0676] [ka]

[0677] This group is a phenyl group, a 6-membered heterocycloalkyl group, a 6-membered heterocyclic alkenyl group, or a 6-membered heteroaryl group.

[0678] In preferred embodiments of the present invention, m is 1 or 2.

[0679] A preferred embodiment of the present invention is R 3 is H, halogen, -OH, haloC1-C6 alkyl group or C1-C6 alkyl group; preferably R 3 is H, halogen, -OH, -CF3, or C1-C6 alkyl group.

[0680] In a preferred embodiment of the present invention, W is a single bond.

[0681] In preferred embodiments of the present invention, n is 1 or 2.

[0682] A preferred embodiment of the present invention is R 1 These are independently H, a halogen, -OH, -CN, or an unsubstituted or substituted C1-C6 alkyl group; preferably H, a halogen, or an unsubstituted or substituted C1-C6 alkyl group.

[0683] A preferred embodiment of the present invention is R 1 The substituents in each are one or more substitutions independently selected from halogens, -OH, -CN, or -C(=O)NH2 substituents; for example, halogens.

[0684] In preferred embodiments of the present invention, Q is H, halogen, -OH, -CN, -NH-C(=O)-R 1-1 -C(=O)-R 1-2 -OC(=O)-N(R1-3 R 1-4 ), -C(=O)-N(R 1-5 R 1-6 ), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), -N(R 1-14 R 1-15 ), -NH-S(=O)2-R 1-16 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C3-C 10 The group is a cycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkenyl group, or an unsubstituted or substituted 5-10 membered heteroaryl group.

[0685] In preferred embodiments of the present invention, Q is H, halogen, -OH, -CF3, -CN, -NH-C(=O)-R 1-1 -C(=O)-R 1-2 -OC(=O)-N(R 1-3 R 1-4 ), -C(=O)-N(R 1-5 R 1-6 ), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), -S(=O)-N(R 1-11 R 1-12 ), -OC(=O)-R 1-13 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C1-C6 alkyl groups-O-, unsubstituted or substituted C2-C6 alkenyl groups, unsubstituted or substituted C2-C6 alkenyl groups-O-, unsubstituted or substituted C3-C9 heterocycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkenyl groups, unsubstituted or substituted C6-C 10 An aryl group, or an unsubstituted or substituted 5-6 membered heteroaryl group; Preferably, H, halogen, -OH, -CN, -NH-C(=O)-R 1-1 -C(=O)-R 1-2 -OC(=O)-N(R 1-3 R 1-4), -C(=O)-N(R 1-5 R 1-6 ), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C3-C9 heterocycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkenyl group, or an unsubstituted or substituted 5-10 membered heteroaryl group.

[0686] Preferred embodiments of the present invention include the substituted C1-C6 alkyl group, the substituted C1-C6 alkyl group-O-, the substituted C2-C6 alkenyl group, the substituted C2-C6 alkenyl group-O-, and the substituted C6-C 10 The aryl group, the substituted C3-C5 heterocycloalkyl group, the substituted C3-C5 heterocycloalkenyl group, or the substituted 5-6 membered heteroaryl group may have the following substitutions independently: a substituent halogen, -OH, -CF3, -CN, -COOH, -C(=O)NH2, =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), or unsubstituted or with one or more R a Substituted with: C1-C6 alkyl groups, C1-C6 alkyl-O- or C3-C6 cycloalkyl groups, R a If there are multiple, they are either identical or different, R a is one or more substitutions selected from halogen, -OH, =O, -CF3, -CN, -COOH, and -C(=O)NH2; if there are multiple substituents, the substituents are homologous or homologous.

[0687] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13The members are independently H, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C1-C6 alkyl group-O-, an unsubstituted or substituted C2-C6 alkenyl group, an unsubstituted or substituted C2-C6 alkenyl group-O-, an unsubstituted or substituted C3-C6 cycloalkyl group, an unsubstituted or substituted C3-C5 heterocycloalkyl group, an unsubstituted or substituted C3-C5 heterocycloalkenyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted 5-6 membered heteroaryl group; the C3-C5 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C3-C5 heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5-6 membered heteroaryl group The heteroatoms in the aryl group are one or more selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substitutions in the substituted C1-C6 alkyl group, the substituted C1-C6 alkyl-O-, the substituted C2-C6 alkenyl group, the substituted C2-C6 alkenyl-O-, the substituted C3-C6 cycloalkyl group, the substituted C3-C5 heterocycloalkyl group, the substituted C3-C5 heterocycloalkenyl group, the substituted phenyl group, or the substituted 5-6 membered heteroaryl group are each independently one or more substitutions selected from substituent halogen, -OH, -CF3, -CN, C1-C6 alkyl group, C1-C6 alkyl-O-, C3-C6 cycloalkyl group, -COOH, or =O; if there are multiple substituents, the substituents are homologous or homologous.

[0688] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , or R 1-11 and R 1-12Each of these groups independently, in cooperation with nitrogen directly bonded to them, forms an unsubstituted or substituted C3-C5 heterocycloalkyl group, an unsubstituted or substituted C3-C5 heterocycloalkenyl group, or an unsubstituted or substituted 5-6 membered heteroaryl group; the C3-C5 heterocycloalkyl group contains no heteroatoms other than nitrogen, or one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and further contains 1-2 heteroatoms other than nitrogen; the C3-C5 heterocycloalkenyl group contains no heteroatoms other than nitrogen, or one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and The 5-6 membered heteroaryl group further contains no heteroatoms other than nitrogen, or one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and one or more heteroatoms; the substituted C3-C5 heterocycloalkyl group, the substituted C3-C5 heterocycloalkenyl group, or the substituted 5-6 membered heteroaryl group each independently contains a substituent halogen, -OH, -CF3, -CN, C1-C6 alkyl group, C1-C6 alkyl-O-, =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), or unsubstituted or with one or more R a Substitutions: One or more substitutions selected from C1-C6 alkyl groups, C1-C6 alkyl-O-, or C3-C6 cycloalkyl groups, R b If there are multiple, they are either identical or different, R b The substituents are halogen, -OH, =O, -CF3, -CN, -COOH, and -C(=O)NH2; if there are multiple substituents, the substituents are homologous or different.

[0689] A preferred embodiment of the present invention is R 2 Independently

[0690] [ka]

[0691] or -C(=O)N(R 2-5 R 2-6 )

[0692] A preferred embodiment of the present invention includes Q being H, halogen, -OH, -CF3, -CN, -NH-C(=O)-R 1-1 -C(=O)-R 1-2 -OC(=O)-N(R 1-3 R 1-4 ), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), -S(=O)-N(R 1-11 R 1-12 ), -OC(=O)-R 1-13 , -N(R 1-14 R 1-15 ), -NH-S(=O)2-R 1-16 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C1-C6 alkyl groups-O-, unsubstituted or substituted C2-C6 alkenyl groups, unsubstituted or substituted C2-C6 alkenyl groups-O-, unsubstituted or substituted C3-C 10 Cycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkenyl groups, unsubstituted or substituted C6-C 10 In the case of an aryl group, or an unsubstituted or substituted 5-10 membered heteroaryl group,

[0693] [ka]

[0694] teeth

[0695] [ka]

[0696] is; or R 2 teeth

[0697] [ka]

[0698] X and Y are independently single bonds, methylene, -O-, or

[0699] [ka]

[0700] That is the case.

[0701] Preferred embodiments of the present invention include:

[0702] [ka]

[0703] but

[0704] [ka]

[0705] If that is the case,

[0706] [ka]

[0707] teeth

[0708] [ka]

[0709] is; or, R 2 Independently

[0710] [ka]

[0711] -C(=O)N(R 2-5 R 2-6 ), or an unsubstituted or substituted 5-6 member heteroaryl group; X or Y is -N(R2-3 )-is.

[0712] A preferred embodiment of the present invention is R 2 Independently

[0713] [ka]

[0714] -C(=O)N(R 2-5 R 2-6 ), or an unsubstituted or substituted 5-6 member heteroaryl group; X or Y is -N(R 2-3 )-is.

[0715] A preferred embodiment of the present invention is R 2 Independently

[0716] [ka]

[0717] And preferably, X and Y are independently single bonds, methylene, -O- or

[0718] [ka]

[0719] is; more

[0720] [ka]

[0721] That is the case.

[0722] Preferred embodiments of the present invention include:

[0723] [ka]

[0724] teeth

[0725] [ka]

[0726] That is the case.

[0727] A preferred embodiment of the present invention is R 3 These are halogens, C1-C6 alkyl groups, or C1-C6 alkyl groups; Q is -NH-C(=O)-R 1-1 -C(=O)-N(R 1-5 R 1-6 ), -S(=O)2-N(R 1-9 R 1-10 ), -N(R 1-14 R 1-15 ), -NH-S(=O)2-R 1-16 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C3-C 10 The C3-C9 heterocycloalkyl groups are cycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkenyl groups, or unsubstituted or substituted 5-10 membered heteroaryl groups; the C3-C9 heterocycloalkyl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C3-C9 heterocycloalkenyl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5-10 membered heteroaryl groups have one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C1-C6 alkyl groups, the substituted C3-C 10 In the case of a cycloalkyl group, the substituted C3-C9 heterocycloalkyl group, the substituted C3-C9 heterocycloalkenyl group, or the substituted 5-10 membered heteroaryl group, the substitutions are each independently substituents.

[0728]

number

[0729] (That is, the two geminal hydrogens on the carbon atom are substituted with the group O), or unsubstituted or with one or more R a Substitutions: One or more substitutions selected from C1-C6 alkyl groups, C1-C6 alkyl-O-, or C3-C6 cycloalkyl groups, R a If there are multiple, they are either identical or different, R a is a halogen, -OH, or -COOH; if there are multiple substituents, the substituents are homologous or different; R 2 Independently

[0730] [ka]

[0731] -C(=O)N(R 2-5 R 2-6 ), or an unsubstituted or substituted 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substitutions are, independently, a substituent halogen, -OH, -CN, an unsubstituted or halogen-substituted C1-C6 alkyl group, an unsubstituted or halogen-substituted C1-C6 alkyl group-O-, and -C(=O)R 2-7 , or -C(=O)N(R 2-8 R 2-9 ) is one or more substitutions selected from; if there are multiple substituents, the substituents are homologous or different; Preferably, Q is -S(=O)2-N(R 1-9 R 1-10 ) and; W is a single bond;

[0732] [ka]

[0733] It is a phenyl group; R 2Independently

[0734] [ka]

[0735] Alternatively, it is an unsubstituted or substituted 5-6 member heteroaryl group.

[0736] A preferred embodiment of the present invention is R 3 These are halogens, C1-C6 alkyl groups, or C1-C6 alkyl groups; Q is -NH-C(=O)-R 1-1 -C(=O)-N(R 1-5 R 1-6 ), -N(R 1-14 R 1-15 ), -NH-S(=O)2-R 1-16 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C3-C 10 The C3-C9 heterocycloalkyl groups are cycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkyl groups, unsubstituted or substituted C3-C9 heterocycloalkenyl groups, or unsubstituted or substituted 5-10 membered heteroaryl groups; the C3-C9 heterocycloalkyl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C3-C9 heterocycloalkenyl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5-10 membered heteroaryl groups have one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C1-C6 alkyl groups, the substituted C3-C 10 In the case of a cycloalkyl group, the substituted C3-C9 heterocycloalkyl group, the substituted C3-C9 heterocycloalkenyl group, or the substituted 5-10 membered heteroaryl group, the substitutions are each independently substituents.

[0737]

number

[0738] (That is, the two geminal hydrogens on the carbon atom are substituted with the group O), or unsubstituted or with one or more R a Substitutions: One or more substitutions selected from C1-C6 alkyl groups, C1-C6 alkyl-O-, or C3-C6 cycloalkyl groups, R a If there are multiple, they are either identical or different, R a If there are multiple substituents, the substituents are homologous or different; R 1-1 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 Each of these is independently H, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C2-C6 alkenyl group, an unsubstituted or substituted C2-C6 alkynyl group, or an unsubstituted or substituted C3-C6 alkyl group. 10 The C3-C5 heterocycloalkyl group is a cycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted 5-10 membered heteroaryl group; the C3-C5 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5-10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C1-C6 alkyl group, the substituted C2-C6 alkenyl group, the substituted C2-C6 alkynyl group, the substituted C3-C 10 For cycloalkyl groups, the substituted C3-C9 heterocycloalkyl groups, the substituted phenyl groups, or the substituted 5-10 membered heteroaryl groups, each substitution is independently a halogen substituent.

[0739]

number

[0740] Alternatively, unsubstituted or one or more R d Substitutions: One or more substitutions selected from C1-C6 alkyl groups, C1-C6 alkyl-O-, or C3-C6 cycloalkyl groups, R d If there are multiple, they are either identical or different, R d These are independently H, halogen, -OH, =O, -CF3, -CN, -COOH, and -C(=O)NH2; if there are multiple substituents, the substituents are homologous or distinct.

[0741] A preferred embodiment of the present invention is R 3 is a halogen, -CHF2, -CH2F, or C1-C6 alkyl group; Q is -NH-C(=O)-R 1-1 , -N(R 1-14 R 1-15 ), -NH-S(=O)2-R 1-16 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C3-C 10 The C3-C9 heterocycloalkyl group is a cycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkyl group, or an unsubstituted or substituted 5-10 membered heteroaryl group; the C3-C9 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5-10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C1-C6 alkyl group, the substituted C3-C 10 For cycloalkyl groups, the substituted C3-C9 heterocycloalkyl groups, or the substituted 5-10 membered heteroaryl groups, the substitutions are, in each case, independently of the substituent -N(R 1-21 R 1-22 ), -C(=O)-N(R 1-23 R 1-24 ), -S(=O)2-N(R 1-25 R 1-26 ), -C(=O)-OR 1-27 One or more substitutions selected from; if there are multiple substituents, the substituents are homologous or different; R 1-1 , R 1-14 , R1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 Each of these is independently H, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C2-C6 alkynyl group, or an unsubstituted or substituted C3-C6 alkyl group. 10 The group is a cycloalkyl group, an unsubstituted or substituted C3-C9 heterocycloalkyl group, or an unsubstituted or substituted 5-10 membered heteroaryl group; the C3-C9 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5-10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C1-C6 alkyl group, the substituted C2-C6 alkynyl group, the substituted C3-C9 heterocycloalkyl group, or the substituted 5-10 membered heteroaryl group has a substitution that is a halogen, -OH, -CN, =O, -COOH, -C(=O)NH2, -COOCH3, -NH2, or unsubstituted or with one or more R atoms. d Substitutions: One or more substitutions selected from C1-C6 alkyl groups, C1-C6 alkyl-O-, or C3-C6 cycloalkyl groups, R d If there are multiple, they are either identical or different, R d These are independently H, halogen, -OH, =O, -CF3, -CN, -COOH, and -C(=O)NH2; if there are multiple substituents, the substituents are homologous or distinct.

[0742] Preferred embodiments of the present invention include,

[0743] [ka]

[0744] The group is a 5-membered heteroaryl group or a 5-membered heterocyclic alkenyl group; the 5-membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2; the 5-membered heterocyclic alkenyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3;

[0745] [ka]

[0746] The group is a phenyl group, a 5-6 member heterocycloalkyl group, a 5-6 member heterocyclic alkenyl group, or a 5-6 member heteroaryl group; the 5-6 member heterocycloalkyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the 5-6 member heterocyclic alkenyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the 5-6 member heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 These independently represent cycloatoms;

[0747] [ka]

[0748] If Z is a 5-membered heterocycloalkyl group, a 5-membered heterocyclic alkenyl group, or a 5-membered heteroaryl group, 6 or Z 9 This indicates a single bond; m is 1, 2, 3, or 4; R 3 is H, halogen, -OH, -CF3, -CN, or C1-C6 alkyl group; if m is not 1, R3 are independently homologous or different; or two R 3 If adjacent, then two adjacent R 3 These, in cooperation with cyclo atoms directly bonded to them, form C3-C6 cycloalkyl groups, C3-C6 cycloalkenyl groups, C3-C5 heterocycloalkyl groups, C3-C5 heterocycloalkenyl groups, phenyl groups, or 5-6 membered heteroaryl groups; the C3-C5 heterocycloalkyl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C3-C5 heterocycloalkenyl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; and the 5-6 membered heteroaryl groups have one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3. W is either a single bond or -C(=O)-NH-;

[0749] [ka]

[0750] The group is a phenyl group, a 5-6 membered heteroaryl group, or a C3-C5 heterocycloalkyl group; the 5-6 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the C3-C5 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; n is 1, 2, 3, or 4; R 1is independently H, halogen, -OH, -CN, unsubstituted or substituted C1-C6 alkyl group, or unsubstituted or substituted C1-C6 alkyl group-O-; the substituted C1-C6 alkyl group, or the substituted C1-C6 alkyl group-O-, each substitution is independently one or more substitutions selected from substituent halogen, -OH, -CF3, -CN, -COOH, -C(=O)NH2, C1-C6 alkyl group, C1-C6 alkyl group-O-, or =O (i.e., two geminal hydrogens on the carbon atom are substituted with the group O); if there are multiple substituents, the substituents are homologous or different; if n is not 1, R 1 They are independently homologous or different; Q is H, halogen, -OH, -CF3, -CN, -NH2, -NH-C(=O)-R 1-1 -C(=O)-R 1-2 -OC(=O)-N(R 1-3 R 1-4 ), -C(=O)-N(R 1-5 R 1-6 ), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), -S(=O)-N(R 1-11 R 1-12 ), -OC(=O)-R 1-13 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C1-C6 alkyl groups-O-, unsubstituted or substituted C2-C6 alkenyl groups, unsubstituted or substituted C2-C6 alkenyl groups-O-, unsubstituted or substituted C6-C 10The aryl group is an aryl group, an unsubstituted or substituted C3-C5 heterocycloalkyl group, an unsubstituted or substituted C3-C5 heterocycloalkenyl group, or an unsubstituted or substituted 5-6 membered heteroaryl group; the C3-C5 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C3-C5 heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5-6 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C1-C6 alkyl group is a substituted C1-C6 alkyl group-O-, the substituted C2-C6 alkenyl group is a substituted C2-C6 alkenyl group-O-, and the substituted C6-C 10 The aryl group, the substituted C3-C5 heterocycloalkyl group, the substituted C3-C5 heterocycloalkenyl group, or the substituted 5-6 membered heteroaryl group may have the following substitutions independently: a substituent halogen, -OH, -CF3, -CN, -COOH, -C(=O)NH2, =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), or unsubstituted or with one or more R a Substitutions: One or more substitutions selected from C1-C6 alkyl groups, C1-C6 alkyl-O-, or C3-C6 cycloalkyl groups, R a If there are multiple, they are either identical or different, R a is a halogen, -OH, =O, -CF3, -CN, -COOH, -C(=O)NH2; if there are multiple substituents, the substituents are homologous or homologous; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13The members are independently H, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C1-C6 alkyl group-O-, an unsubstituted or substituted C2-C6 alkenyl group, an unsubstituted or substituted C2-C6 alkenyl group-O-, an unsubstituted or substituted C3-C6 cycloalkyl group, an unsubstituted or substituted C3-C5 heterocycloalkyl group, an unsubstituted or substituted C3-C5 heterocycloalkenyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted 5-6 membered heteroaryl group; the C3-C5 heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C3-C5 heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5-6 membered heteroaryl group has N, O One or more types selected from and S, with 1 to 3 heteroatoms; the substituted C1-C6 alkyl group, the substituted C1-C6 alkyl-O-, the substituted C2-C6 alkenyl group, the substituted C2-C6 alkenyl group-O-, the substituted C3-C6 cycloalkyl group, the substituted C3-C5 heterocycloalkyl group, the substituted C3-C5 heterocycloalkenyl group, the substituted phenyl group, or the substituted 5-6 membered heteroaryl group, each substitution is independently one or more substitutions selected from substituent halogens, -OH, -CF3, -CN, C1-C6 alkyl groups, C1-C6 alkyl-O-, C3-C6 cycloalkyl groups, -COOH, or =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O); if there are multiple substituents, the substituents are homologous or homologous; Or, R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , or R 1-11 and R 1-12Each of these groups independently, in cooperation with nitrogen directly bonded to them, forms an unsubstituted or substituted C3-C5 heterocycloalkyl group, an unsubstituted or substituted C3-C5 heterocycloalkenyl group, or an unsubstituted or substituted 5-6 membered heteroaryl group; the C3-C5 heterocycloalkyl group contains no heteroatoms other than nitrogen, or one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and further contains 1-2 heteroatoms other than nitrogen; the C3-C5 heterocycloalkenyl group contains no heteroatoms other than nitrogen, or one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and The 5-6 membered heteroaryl group further contains no heteroatoms other than nitrogen, or one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and one or more heteroatoms; the substituted C3-C5 heterocycloalkyl group, the substituted C3-C5 heterocycloalkenyl group, or the substituted 5-6 membered heteroaryl group each independently contains a substituent halogen, -OH, -CF3, -CN, C1-C6 alkyl group, C1-C6 alkyl-O-, =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), or unsubstituted or with one or more R b Substitutions: One or more substitutions selected from C1-C6 alkyl groups, C1-C6 alkyl-O-, or C3-C6 cycloalkyl groups, R b If there are multiple, they are either identical or different, R b is a halogen, -OH, =O, -CF3, -CN, -COOH, -C(=O)NH2; if there are multiple substituents, the substituents are homologous or homologous; R 2 teeth

[0751] [ka]

[0752] or -C(=O)N(R 2-5 R 2-6 ) and; R 2-1 and R 2-2Each of the substituents is independently H, a halogen, -OH, -CN, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C1-C6 alkyl group-O-, or =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O); the substituted C1-C6 alkyl group, or the substituted C1-C6 alkyl group-O-, is independently one or more substituents selected from the substituent halogen, -OH, -CF3, -CN, a C1-C6 alkyl group, a C1-C6 alkyl group-O-, or =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O); if there are multiple substituents, the substituents are homologous or different; X and Y are independently single bonds, methylene, -O-, -N(R) 2-3 )-, or

[0753] [ka]

[0754] and; R 2-3 , R 2-4 , R 2-5 and R 2-6 Each of the substituents is independently H, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C3-C8 cycloalkyl group, an unsubstituted or substituted C3-C8 cycloalkyl group-O-, or an unsubstituted or substituted C1-C6 alkyl group-O-; the substituted C1-C6 alkyl group, the substituted C3-C8 cycloalkyl group, the substituted C3-C8 cycloalkyl group-O-, or the substituted C1-C6 alkyl group-O- is independently one or more substituents selected from a substituent halogen, -OH, -CF3, -CN, a C1-C6 alkyl group, a C1-C6 alkyl group-O-, or =O (i.e., two geminal hydrogens on the carbon atom are substituted with the group O); and if there are multiple substituents, the substituents are homologous or homologous.

[0755] Preferred embodiments of the present invention include:

[0756] [ka]

[0757] If it is a 5-membered heteroaryl group, the 5-membered heteroaryl group is a pyrazolyl group (for example)

[0758] [ka]

[0759] ), furan group (for example)

[0760] [ka]

[0761] ), pyrazole group (for example)

[0762] [ka]

[0763] ), thienyl group (for example)

[0764] [ka]

[0765] ) or imidazolyl group (for example)

[0766] [ka]

[0767] ) (In the structural formula, the bond on the right is connected to W.) Preferred embodiments of the present invention include:

[0768] [ka]

[0769] teeth

[0770] [ka]

[0771] That is the case.

[0772] A preferred embodiment of the present invention includes two R 3 Two adjacent Rs 3 When these atoms form a C3-C5 heterocycloalkyl group in cooperation with cyclo atoms that are directly bonded to them, the C3-C5 heterocycloalkyl group is a C4-C5 heterocycloalkyl group, and the C4-C5 heterocycloalkyl group consists of one or more heteroatoms selected from N, O, and S, with a total of 1-2 heteroatoms.

[0773] A preferred embodiment of the present invention includes two R 3 Two adjacent Rs 3 When these atoms form a C3-C5 heterocycloalkenyl group in cooperation with cyclo atoms that are directly bonded to them, the C3-C5 heterocycloalkenyl group is a C4-C5 heterocycloalkenyl group, and the C4-C5 heterocycloalkenyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2.

[0774] Preferred embodiments of the present invention include:

[0775] [ka]

[0776] If the C3-C5 heterocycloalkyl group is a C3-C5 heterocycloalkyl group, the C4-C5 heterocycloalkyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2; preferably a piperidine group

[0777] [ka]

[0778] (In the structural formula, the bond on the left is bonded to W, and the bond on the right is bonded to Q.) In preferred embodiments of the present invention, when Q is an unsubstituted or substituted C3-C5 heterocycloalkyl group, the C3-C5 heterocycloalkyl group is a C4-C5 heterocycloalkyl group, and the C4-C5 heterocycloalkyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2; preferably a pyrrolidinyl group (e.g.

[0779] [ka]

[0780] ) or piperazine group (for example)

[0781] [ka]

[0782] )

[0783] In preferred embodiments of the present invention, when Q is an unsubstituted or substituted C3-C5 heterocycloalkenyl group, the C3-C5 heterocycloalkenyl group is a C4-C5 heterocycloalkenyl group, and the C4-C5 heterocycloalkenyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2; preferably a 2,5-dihydro-1H-pyrazolyl group (for example)

[0784] [ka]

[0785] )

[0786] In preferred embodiments of the present invention, when Q is an unsubstituted or substituted 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group is an imidazolyl group (for example)

[0787] [ka]

[0788] ), oxazolyl group (for example)

[0789] [ka]

[0790] ), furan group (for example)

[0791] [ka]

[0792] ), thienyl group (for example)

[0793] [ka]

[0794] ), pyrazolyl group (for example)

[0795] [ka]

[0796] ), pyrazole group (for example)

[0797] [ka]

[0798] ), isoxazolyl group (for example)

[0799] [ka]

[0800] ), pyridinyl group (for example)

[0801] [ka]

[0802] ) or pyrimidinyl group (for example)

[0803] [ka]

[0804] )

[0805] In preferred embodiments of the present invention, Q is a substituted C1-C6 alkyl group, a substituted C1-C6 alkyl group-O-, a substituted C2-C6 alkenyl group, a substituted C2-C6 alkenyl group-O-, or a substituted C6-C 10 When the substituent is an aryl group, a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group, the number of substituents is independently 1, 2, 3, or 4.

[0806] In preferred embodiments of the present invention, Q is a substituted C1-C6 alkyl group, a substituted C1-C6 alkyl group-O-, a substituted C2-C6 alkenyl group, a substituted C2-C6 alkenyl group-O-, or a substituted C6-C 10 The group is an aryl group, a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group, and if the substitution is a halogen, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine.

[0807] In preferred embodiments of the present invention, Q is a substituted C1-C6 alkyl group, a substituted C1-C6 alkyl group-O-, a substituted C2-C6 alkenyl group, a substituted C2-C6 alkenyl group-O-, or a substituted C6-C 10 The R is an aryl group, a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group, with one or more substitutions. a When the substituent is a C1-C6 alkyl group or a C1-C6 alkyl group-O-, the C1-C6 alkyl group in the substituent (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group), preferably a methyl group.

[0808] In preferred embodiments of the present invention, Q is a substituted C1-C6 alkyl group, a substituted C1-C6 alkyl group-O-, a substituted C2-C6 alkenyl group, a substituted C2-C6 alkenyl group-O-, or a substituted C6-C 10 The R is an aryl group, a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group, with one or more substitutions. a In the case of a C3-C6 cycloalkyl group substituted with a C3-C6 group, the C3-C6 cycloalkyl group in the substituent (e.g., a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group) is a cyclopropyl group.

[0809] In preferred embodiments of the present invention, Q is a substituted C1-C6 alkyl group, a substituted C1-C6 alkyl group-O-, a substituted C2-C6 alkenyl group, a substituted C2-C6 alkenyl group-O-, or a substituted C6-C 10 The R is an aryl group, a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group, with one or more substitutions. aSubstituted with: C1-C6 alkyl groups, C1-C6 alkyl-O- or C3-C6 cycloalkyl groups, R a If the halogen is a halogen, then the halogen is independently fluorine, chlorine, bromine, or iodine.

[0810] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 or R 1-13 When is an unsubstituted or substituted C1-C6 alkyl group, or an unsubstituted or substituted C1-C6 alkyl group-O-, the C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group), preferably a methyl group or an ethyl group.

[0811] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 or R 1-13 When is an unsubstituted or substituted C2-C6 alkenyl group, or an unsubstituted or substituted C2-C6 alkenyl group-O-, the C2-C6 alkenyl group is a C2-C4 alkenyl group {for example, a vinyl group, a propenyl group (for example, a 1-propenyl group or a 2-propenyl group), or a butenyl group (for example, a 2-butenyl group, a 1-butenyl group, or a butadiene group)}, and is preferably a vinyl group.

[0812] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 or R 1-13 The C3-C5 heterocycloalkyl group is an unsubstituted or substituted C3-C5 heterocycloalkyl group, and the C4-C5 heterocycloalkyl group contains one or more heteroatoms selected from N, O, and S, with a total number of heteroatoms of 1 to 2.

[0813] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 or R 1-13 When is an unsubstituted or substituted C3-C5 heterocycloalkenyl group, the C3-C5 heterocycloalkenyl group is a C4-C5 heterocycloalkenyl group, and the C4-C5 heterocycloalkenyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2.

[0814] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 or R 1-13If the group is an unsubstituted or substituted 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group has one or two heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2.

[0815] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 or R 1-13 If the substitution is a substituted C1-C6 alkyl group, a substituted C1-C6 alkyl-O-, a substituted C2-C6 alkenyl group, and a substituted C2-C6 alkenyl-O-, a substituted phenyl group, a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group, and the substitution is a halogen, the halogen is independently fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0816] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 or R 1-13If the substituent is a substituted C1-C6 alkyl group, a substituted C1-C6 alkyl-O-, a substituted C2-C6 alkenyl group, a substituted C2-C6 alkenyl-O-, a substituted phenyl group, a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group, and the substitution is a C1-C6 alkyl group or a C1-C6 alkyl-O-, then the C1-C6 alkyl group in the substituent (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group).

[0817] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 or R 1-13 If the substituent is a substituted C1-C6 alkyl group, a substituted C1-C6 alkyl group-O-, a substituted C2-C6 alkenyl group, a substituted C2-C6 alkenyl group-O-, a substituted phenyl group, a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group, and the substitution is a C3-C6 cycloalkyl group, then the C3-C6 cycloalkyl group in the substituent (e.g., cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group) is a cyclopropyl group.

[0818] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R1-10 , R 1-11 , R 1-12 or R 1-13 When is a substituted C1-C6 alkyl group, a substituted C1-C6 alkyl-O- group, a substituted C2-C6 alkenyl group, a substituted C2-C6 alkenyl-O- group, a substituted phenyl group, a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group, the number of substituents is independently 1, 2, 3, or 4; preferably 1 or 2.

[0819] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , or R 1-11 and R 1-12 When each of these independently forms an unsubstituted or substituted C3-C5 heterocycloalkyl group in cooperation with nitrogen that is directly bonded to them, the C3-C5 heterocycloalkyl group either contains no heteroatoms other than nitrogen, or further contains one heteroatom selected from oxygen, sulfur, and nitrogen.

[0820] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , or R 1-11 and R 1-12 When each of these atoms independently forms an unsubstituted or substituted C3-C5 heterocycloalkenyl group in cooperation with nitrogen atoms that are directly bonded to them, the C3-C5 heterocycloalkenyl group may contain no heteroatoms other than nitrogen, or may further contain one heteroatom selected from oxygen, sulfur, and nitrogen.

[0821] A preferred embodiment of the present invention is R 1-3 and R1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , or R 1-11 and R 1-12 When each of these molecules independently forms an unsubstituted or substituted 5-6 membered heteroaryl group in cooperation with nitrogen atoms that are directly bonded to them, the 5-6 membered heteroaryl group may contain no heteroatoms other than nitrogen, or may further contain one heteroatom selected from oxygen, sulfur, and nitrogen.

[0822] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , or R 1-11 and R 1-12 Each of these groups independently forms a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group in cooperation with the nitrogen directly bonded to them, and the substitution is a halogen, the halogen is independently fluorine, chlorine, bromine, or iodine.

[0823] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , or R 1-11 and R 1-12 Each of these independently forms a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 member heteroaryl group in cooperation with the nitrogen directly bonded to them, and the substitutions are one or more R bIf the substituent is a C1-C6 alkyl group or a C1-C6 alkyl group-O-, then the C1-C6 alkyl group in the substituent (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) is independently a C1-C4 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or t-butyl group).

[0824] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , or R 1-11 and R 1-12 Each of these independently forms a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 member heteroaryl group in cooperation with the nitrogen directly bonded to them, and the substitutions are one or more R b In the case of a C3-C6 cycloalkyl group substituted with a substituent, the C3-C6 cycloalkyl group in the substituent is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0825] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , or R 1-11 and R 1-12 Each of these independently forms a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 member heteroaryl group in cooperation with the nitrogen directly bonded to them, and the substitutions are one or more R b Substituted with: C1-C6 alkyl groups, C1-C6 alkyl-O- or C3-C6 cycloalkyl groups, R bIf the halogen is a halogen, then the halogen is independently fluorine, chlorine, bromine, or iodine.

[0826] A preferred embodiment of the present invention is R 1-3 and R 1-4 , R 1-5 and R 1-6 , R 1-7 and R 1-8 , R 1-9 and R 1-10 , or R 1-11 and R 1-12 When each of these substituents independently forms a substituted C3-C5 heterocycloalkyl group, a substituted C3-C5 heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group in cooperation with the nitrogen directly bonded to them, the number of substituents is independently 1, 2, 3, or 4; preferably 1 or 2.

[0827] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 or R 1-13 If is a substituted C1-C6 alkyl group, then the substituted C1-C6 alkyl group is

[0828] [ka]

[0829] That is the case.

[0830] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9, R 1-10 , R 1-11 , R 1-12 or R 1-13 If is a substituted C2-C6 alkenyl group, then the substituted C2-C6 alkenyl group is

[0831] [ka]

[0832] That's fine.

[0833] A preferred embodiment of the present invention is R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 or R 1-13 If is a substituted C3-C6 cycloalkyl group, then the substituted C3-C6 cycloalkyl group is

[0834] [ka]

[0835] That is the case.

[0836] In a preferred embodiment of the present invention, when Q is a substituted C3-C5 heterocycloalkyl group, the substituted C3-C5 heterocycloalkyl group is

[0837] [ka]

[0838] That is the case.

[0839] In a preferred embodiment of the present invention, when Q is a substituted C3-C5 heterocycloalkenyl group, the substituted C3-C5 heterocycloalkenyl group is

[0840] [ka]

[0841] That's fine.

[0842] In a preferred embodiment of the present invention, when Q is a substituted 5-6 membered heteroaryl group, the substituted 5-6 membered heteroaryl group is

[0843] [ka]

[0844] That is the case.

[0845] In a preferred embodiment of the present invention, Q is -NH-C(=O)-R 1-1 In that case, the -NH-C(=O)-R 1-1 -NH-C(=O)-CH3, -NH-C(=O)-O-CH3,

[0846] [ka]

[0847] That is the case.

[0848] In a preferred embodiment of the present invention, Q is -S(=O)2-N(R 1-9 R 1-10 ) If the above -S(=O)2-N(R 1-9 R 1-10 ) is -S(=O)2-NH-CH3.

[0849] In preferred embodiments of the present invention, Q is H, -OH, -CF3, -CN, -NH-C(=O)-CH3, -NH-C(=O)-O-CH3,

[0850] [ka]

[0851] , -C(=O)-CH3, -C(=O)-C2H5, -C(=O)-O-CH3, -OC(=O)-NH-CH3, -C(=O)-NH-CH3, -C(=NH)-NH-CH3, -S(=O)2-NH-CH3,

[0852] [ka]

[0853] That is the case.

[0854] A preferred embodiment of the present invention is R 2 but

[0855] [ka]

[0856] If that is the case, then one of X and Y is

[0857] [ka]

[0858] The other is a single bond, methylene, or -O- (for example)

[0859] [ka]

[0860] , of which X is a single bond, methylene, or -O-; preferably X is -O-, that is

[0861] [ka]

[0862] is; more

[0863] [ka]

[0864] That is the case.

[0865] A preferred embodiment of the present invention is the heterocyclic compound shown in formula I, as shown in formula I-C':

[0866] [ka]

[0867] Among them, Q is H, halogen, -OH, -CF3, -CN, -NH2, -NH-C(=O)-R 1-1 -C(=O)-R 1-2 -OC(=O)-N(R 1-3 R 1-4 ), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), -S(=O)-N(R 1-11 R 1-12 ), -OC(=O)-R 1-13 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C1-C6 alkyl groups-O-, unsubstituted or substituted C2-C6 alkenyl groups, unsubstituted or substituted C2-C6 alkenyl groups-O-, unsubstituted or substituted C6-C 10 It is an aryl group, an unsubstituted or substituted C3-C5 heterocycloalkyl group, an unsubstituted or substituted C3-C5 heterocycloalkenyl group, or an unsubstituted or substituted 5-6 membered heteroaryl group; Preferably, the heterocyclic compound shown in formula I is as shown in formula I-C'-1:

[0868] [ka]

[0869] Among them, Q is H, halogen, -OH, -CF3, -CN, -NH2, -NH-C(=O)-R 1-1 -C(=O)-R 1-2 -OC(=O)-N(R 1-3 R 1-4 ), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), -S(=O)-N(R 1-11 R 1-12 ), -OC(=O)-R 1-13 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C1-C6 alkyl groups-O-, unsubstituted or substituted C2-C6 alkenyl groups, unsubstituted or substituted C2-C6 alkenyl groups-O-, unsubstituted or substituted C6-C 10 It is an aryl group, an unsubstituted or substituted C3-C5 heterocycloalkyl group, an unsubstituted or substituted C3-C5 heterocycloalkenyl group, or an unsubstituted or substituted 5-6 membered heteroaryl group; Preferably, the heterocyclic compound shown in formula I is as shown in formula I-C'-2:

[0870] [ka]

[0871] , eventually, R 1’ The definition is R 1 It is the same as R 1’ and R 1 X is homologous or different, X is a single bond, methylene, or -O-; Q is H, halogen, -OH, -CF3, -CN, -NH2, -NH-C(=O)-R 1-1 -C(=O)-R 1-2 -OC(=O)-N(R 1-3 R 1-4 ), -C(=NH)-N(R 1-7 R 1-8 ), -S(=O)2-N(R 1-9 R 1-10 ), -S(=O)-N(R 1-11 R1-12 ), -OC(=O)-R 1-13 , unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C1-C6 alkyl groups-O-, unsubstituted or substituted C2-C6 alkenyl groups, unsubstituted or substituted C2-C6 alkenyl groups-O-, unsubstituted or substituted C6-C 10 The group is an aryl group, an unsubstituted or substituted C3-C5 heterocycloalkyl group, an unsubstituted or substituted C3-C5 heterocycloalkenyl group, or an unsubstituted or substituted 5-6 membered heteroaryl group.

[0872] In preferred embodiments of the present invention, the heterocyclic compound represented by formula I is preferably one of the following compounds:

[0873] [ka]

[0874] [ka]

[0875] [ka]

[0876] [ka]

[0877] [ka]

[0878] [ka]

[0879] [ka]

[0880] [ka]

[0881] [ka]

[0882] [ka]

[0883] [ka]

[0884] [ka]

[0885] [ka]

[0886] [ka]

[0887] [ka]

[0888] .

[0889] In preferred embodiments of the present invention, the pharmaceutically acceptable salts of the heterocyclic compound represented by formula I are preferably the following compounds:

[0890] [ka]

[0891] .

[0892] Accordingly, throughout this specification, those skilled in the art can select the groups and substituents in the heterocyclic compounds represented by formula I, their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts, or prodrugs (including, but not limited to, the compounds in the examples of the present invention).

[0893] The present invention further includes isotope-labeled heterocyclic compounds represented by Formula I as described in the present invention, their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts, or prodrugs, in which one or more atoms are substituted with one or more atoms having a specific atomic mass or mass number. The isotopes that can be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (for example). 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S sum 36 The isotopes of the present invention, including but not limited to Cl, can be used to measure the tissue distribution of the compound and its prodrugs and metabolites; preferred isotopes used in such measurements are 3 H and 14 It contains C. Furthermore, in some cases, substitution with a heavier isotope (deuterium (2H or D)) can improve metabolic stability, resulting in therapeutic benefits such as an extended in vivo half-life and reduced dosage.

[0894] The isotope-labeled compounds of the present invention can typically be prepared using an isotope-labeled reagent instead of a non-isotopically labeled reagent by the method described herein.

[0895] The heterocyclic compounds represented by Formula I described in the present invention, their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts, or prodrugs can be synthesized by methods similar to those well known in the chemical field, with the steps and conditions relating to those of similar reactions in the art, and in particular to those synthesized herein. Starting materials are usually obtained from commercial sources such as Aldrich, or can be readily prepared by methods well known to those skilled in the art (available from SciFinder and the Reaxys online database).

[0896] In the present invention, the heterocyclic compound shown in formula I can be further modified by conventional methods in the art using a heterocyclic compound already produced and shown in formula I to obtain another heterocyclic compound shown in formula I.

[0897] Generally, the compounds of the present invention can be produced by the methods described herein, and unless otherwise specified, their substituents are defined as shown in Formula I. The present invention will be further illustrated with examples from the following reaction plans and examples.

[0898] The present invention provides a method for producing the heterocyclic compound shown in formula I, and includes the following embodiments: Form 1 comprises the following steps: In an organic solvent, in the presence of a catalyst, the compound shown in Formula II-1 and the organotin reagent shown in Formula III-1 are subjected to the following Stille coupling reaction to obtain the heterocyclic compound shown in Formula I;

[0899] [ka]

[0900] ; Eventually, X 1 It is either Br or Cl.

[0901] The method and conditions for the Stille coupling reaction described above are the usual methods and conditions for this type of reaction in this field. For example: The organic solvent is preferably a cyclic ether solvent (e.g., tetrahydrofuran and / or dioxa) and / or an aromatic hydrocarbon solvent (e.g., toluene). The amount of the organic solvent used is not particularly limited, as long as it does not affect the reaction.

[0902] The catalyst is preferably Pd(PPh3)4. The molar ratio of the catalyst to the compound shown in formula II-1 may be 1:5 to 1:20 (for example, 1:10).

[0903] The molar ratio of the compound shown in formula II-1 to the organotin reagent shown in formula III-1 is the usual molar ratio in this field, and the molar ratio of compound II-1 to the organotin reagent shown in formula III-1 in the present invention is preferably 1:3 to 1:4.

[0904] The temperature of the Stille coupling reaction may be 85°C to 110°C (for example, 95°C to 100°C).

[0905] The progress of the reaction can be monitored using conventional measurement methods in this field (e.g., TLC, GC, HNMR, or HPLC), and preferably the reaction endpoint is defined as the point at which the compound shown in formula II-1 disappears.

[0906] In a preferred embodiment of the present invention, in Embodiment 1, Q is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C2-C6 alkenyl group, or an unsubstituted or substituted C6-C6 alkyl group. 10 The group is an aryl group, an unsubstituted or substituted C3-C5 heterocycloalkyl group, an unsubstituted or substituted C3-C5 heterocycloalkenyl group, or an unsubstituted or substituted 5-6 membered heteroaryl group.

[0907] Form 2 comprises the following steps: In the presence of a catalyst and an alkaline reagent, the following Suzuki coupling reaction is carried out with the compound shown in formula II-2 and the compound shown in formula III-2 in a solvent to obtain the heterocyclic compound shown in formula I;

[0908] [ka]

[0909] ; Eventually, X 2 It is either Br or Cl.

[0910] The method and conditions for the Suzuki coupling reaction described above are standard methods and conditions for this type of reaction in this field. For example: The solvent may be a hydrated organic solvent, and the organic solvent is preferably a cyclic ether solvent (e.g., tetrahydrofuran and / or dioxa). The amount of the organic solvent used is not particularly limited, as long as it does not affect the reaction.

[0911] The catalyst is preferably Pd(PPh3)4. The molar ratio of the catalyst to the compound shown in formula II-2 may be 1:5 to 1:20 (for example, 1:20).

[0912] The alkaline reagent may be Na2CO3, and the molar ratio of the alkaline reagent to the compound shown in formula II-2 may be 1:1 to 5:1 (for example, 3:1).

[0913] The molar ratio of the compound shown in formula II-2 to the compound shown in formula III-2 is the usual molar ratio in this field, and the molar ratio of compound II-2 to the compound shown in formula III-2 in the present invention is preferably 1:1 to 1:1.2.

[0914] The temperature of the Suzuki coupling reaction may be 90°C to 100°C.

[0915] The progress of the reaction can be monitored using conventional measurement methods in this field (e.g., TLC, GC, HNMR, or HPLC), and preferably the reaction endpoint is defined as the point at which the compound shown in formula II-2 disappears.

[0916] In a preferred embodiment of the present invention, in Embodiment 2, Q is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C2-C6 alkenyl group, or an unsubstituted or substituted C6-C6 alkyl group. 10 The group is an aryl group, an unsubstituted or substituted C3-C5 heterocycloalkyl group, an unsubstituted or substituted C3-C5 heterocycloalkenyl group, or an unsubstituted or substituted 5-6 membered heteroaryl group.

[0917] Form 3 comprises the following steps: The following reaction is carried out with the organic solvent, the compound shown in Formula II-3, the compound shown in Formula III-3, and formaldehyde to obtain the heterocyclic compound shown in Formula I;

[0918] [ka]

[0919] .

[0920] The method and conditions of the reaction described above are the usual methods and conditions for this type of reaction in this field. For example: The organic solvent is preferably a carboxylic acid-based solvent (e.g., acetic acid). The amount of the organic solvent used is not particularly limited, as long as it does not affect the reaction.

[0921] The formaldehyde may be an aqueous solution of formaldehyde, preferably an aqueous solution of formaldehyde with a concentration of 37% by mass; the molar ratio of the formaldehyde to the compound shown in formula II-2 may be 1:1.

[0922] The molar ratio of the compound shown in formula II-2 to the compound shown in formula III-2 is the usual molar ratio in this field, and the molar ratio of compound II-2 to the compound shown in formula III-2 in the present invention is preferably 1.2:1 to 1:1.2.

[0923] The reaction temperature may be 40°C to 60°C.

[0924] The progress of the reaction can be monitored using conventional measurement methods in this field (e.g., TLC, GC, HNMR, or HPLC), and preferably the reaction endpoint is defined as the point at which the compound shown in formula II-3 disappears.

[0925] A preferred embodiment of the present invention is in Embodiment 3, Z 3 R is a carbon atom; 2 teeth

[0926] [ka]

[0927] Preferably

[0928] [ka]

[0929] That is the case.

[0930] Form 4 comprises the following steps: In an organic solvent, the following reaction is carried out with the compound shown in Formula II-3 and the compound shown in Formula III-4 to obtain the heterocyclic compound shown in Formula I;

[0931] [ka]

[0932] Eventually, X 3 is a leaving group (e.g., -OMs, Br, or Cl).

[0933] The method and conditions of the reaction described above are the usual methods and conditions for this type of reaction in this field. For example: The organic solvent is preferably an amide-based solvent (e.g., N,N-dimethylformamide). The amount of the organic solvent used is not particularly limited, as long as it does not affect the reaction.

[0934] The alkaline reagent is potassium tert-butoxide, and the molar ratio of the alkaline reagent to the compound shown in formula II-3 is 2:1 to 3:1 (for example, 2.2:1).

[0935] The molar ratio of the compound shown in formula II-3 to the compound shown in formula III-4 may be the usual molar ratio in this field, and in the present invention, the molar ratio of compound II-3 to the compound shown in formula III-4 is preferably 1.2:1 to 1:1.2.

[0936] The reaction temperature may be 100°C to 120°C.

[0937] The progress of the reaction can be monitored using conventional measurement methods in this field (e.g., TLC, GC, HNMR, or HPLC), and preferably the reaction endpoint is defined as the point at which the compound shown in formula II-3 disappears.

[0938] A preferred embodiment of the present invention is in form 4, R 2 teeth

[0939] [ka]

[0940] That is the case.

[0941] Form 5, comprising the following steps: The organic solvent is R in the presence of an alkaline reagent. 2 but

[0942] [ka]

[0943] Then, the following amidation reaction is carried out with the compound shown in formula I and the compound shown in formula III-5 where Y is -NH-, and Y

[0944] [ka]

[0945] The heterocyclic compound shown in formula I above is obtained;

[0946] [ka]

[0947] Eventually, X 4 These are halogens (e.g., Br or Cl).

[0948] The method and conditions for the amidation reaction described above are the usual methods and conditions for this type of reaction in this art. For example: The organic solvent is preferably a haloalkyl solvent (e.g., dichloromethane). The amount of the organic solvent used is not particularly limited, as long as it does not affect the reaction.

[0949] The alkaline reagent may be N,N-diisopropylethylamine, and the molar ratio of the alkaline reagent to the compound shown in formula II-4 may be 2:1 to 4:1 (for example, 3:1).

[0950] The molar ratio of the compound shown in formula II-4 to the compound shown in formula III-5 may be the usual molar ratio in this field, and in the present invention, the molar ratio of compound II-4 to the compound shown in formula III-5 is preferably 1.2:1 to 1:1.2.

[0951] The temperature of the amidation reaction may be -10°C to 20°C.

[0952] The progress of the amidation reaction can be monitored using conventional measurement methods in this field (e.g., TLC, GC, HNMR, or HPLC), and preferably the reaction endpoint is defined as the point at which the compound shown in formula II-4 disappears.

[0953] Form 6 comprises the following steps: In the presence of an acid in an organic solvent, the compounds shown in formula II-4 and III-5 are subjected to the following deprotection group reaction to obtain the heterocyclic compound shown in formula I;

[0954] [ka]

[0955] Of these, Y is -NH-.

[0956] The method and conditions for the aforementioned deprotection group reaction are standard methods and conditions for this type of reaction in this field. For example: The organic solvent is preferably an alcohol-based solvent (e.g., ethanol). The amount of the organic solvent used is not particularly limited, as long as it does not affect the reaction.

[0957] The acid may be hydrochloric acid, and the molar ratio of the acid to the compound shown in formula II-4 may be 1:1 to 4:1 (for example, 1.5:1).

[0958] The temperature of the deprotection reaction may be -10°C to 20°C.

[0959] The progress of the amidation reaction can be monitored using conventional measurement methods in this field (e.g., TLC, GC, HNMR, or HPLC), and preferably the reaction endpoint is defined as the point at which the compound shown in formula II-4 disappears.

[0960] Form 7 comprises the following steps: the organic solvent contains the compound shown in formula II-5 and NH(R 1-9 R 1-10 The following substitution reaction is carried out on ) to obtain the heterocyclic compound shown in formula I above; Q is -S(=O)2-N(R 1-9 R 1-10 ) and;

[0961] [ka]

[0962] ; Eventually, X 5 It is either Br or Cl.

[0963] The method and conditions of the reaction described above are the usual methods and conditions for this type of reaction in this field. For example: The organic solvent is preferably a nitrile-based solvent (e.g., acetonitrile). The amount of the organic solvent used is not particularly limited, as long as it does not affect the reaction.

[0964] The compound shown in formula II-5 and the NH(R 1-9 R 1-10 The molar ratio of ) may be 1:1 to 1:5.

[0965] Said NH(R 1-9 R 1-10 ) can be in a form common in this field, and for example, if it is NH3, it may be in the form of aqueous ammonia.

[0966] The reaction temperature may be -10°C to 20°C (for example, 0°C).

[0967] The progress of the reaction can be monitored using conventional measurement methods in this field (e.g., TLC, GC, HNMR, or HPLC), and preferably the reaction endpoint is defined as the point at which the compound shown in formula II-3 disappears.

[0968] Form 8 comprises the following steps: In the presence of an acid in an organic solvent, the compound shown in formula II-6 or formula II-6' is subjected to the following deprotection group reaction to obtain the heterocyclic compound shown in formula I;

[0969] [ka]

[0970] ; Eventually, X 6 , X 6’ and X 6’’ This is an N protecting group.

[0971] One preferred form is X 6 , X 6’ and X 6’’If the N protecting group is an N protecting group, the N protecting group may also be a 4-methoxybenzyl group (PMB).

[0972] The method and conditions of the reaction described above are the usual methods and conditions for this type of reaction in this field. For example: The organic solvent is preferably a haloparaffinic solvent (e.g., dichloromethane). The amount of the organic solvent used is not particularly limited, as long as it does not affect the reaction.

[0973] The acid may be trifluoromethanesulfonic acid, and the volume mass ratio of the acid to the compound shown in formula II-6 or formula II-6' may be 1 mL / g to 5 mL / g (for example, 3 mL / g to 4 mL / g).

[0974] The reaction temperature may be between 0°C and 100°C (for example, between 30°C and 50°C).

[0975] The progress of the reaction can be monitored using conventional measurement methods in this field (e.g., TLC, GC, HNMR, or HPLC), and preferably the reaction endpoint is defined as the point at which the compound represented by formula II-6 or formula II-6' has disappeared.

[0976] In the present invention, the reaction can be processed by conventional post-treatment methods in the art after the reaction is complete. In the present invention, after post-treatment, the crude product of the heterocyclic compound shown in formula I can be obtained and separated and purified by conventional means such as preparative HPLC, preparative TLC, or recrystallization.

[0977] The present invention further provides compounds represented by formulas II-1, II-2, II-3, II-4, II-5, II-6, or II-6':

[0978] [ka]

[0979] ; Among them, the aforementioned

[0980] [ka]

[0981] , R 3 , R 2 , R 1 W, X, Y, R 2-1 , R 2-2 n, m, X 5 , X 6 , X 6’ , X 6’’ and X 1 This is as stated above.

[0982] The present invention further provides the following compounds:

[0983] [ka]

[0984] [ka]

[0985] [ka]

[0986] [ka]

[0987] [ka]

[0988] [ka]

[0989] [ka]

[0990]

change

[0991]

change

[0992]

change

[0993]

change

[0994]

change

[0995]

change

[0996]

change

[0997] .

[0998] The present invention further provides a pharmaceutical composition comprising a heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a metabolite thereof, a stereoisomer thereof, a tautomer thereof, or a prodrug thereof, and at least one medicinal adjuvant. The pharmaceutical composition may further comprise one or more active ingredients. For example, the pharmaceutical composition may comprise one or more other heterocyclic compounds represented by formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a metabolite thereof, a stereoisomer thereof, a tautomer thereof, or a prodrug thereof. Alternatively, or otherwise, the pharmaceutical composition may further comprise one or more active ingredients other than, for example, a heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a metabolite thereof, a stereoisomer thereof, a tautomer thereof, or a prodrug thereof.

[0999] The amount of the heterocyclic compound shown in formula I, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolite, its stereoisomer, its tautomer, or its prodrug used in the pharmaceutical composition may be a therapeutically effective amount.

[1000] The effective amount of the compound, pharmaceutical composition, or drug described in the present invention can be easily measured by general experiments, and the most effective and convenient route of administration and the optimal formulation can also be determined by general experiments.

[1001] The aforementioned medicinal auxiliary material may be an auxiliary material widely used in the field of drug manufacturing. The purpose of the auxiliary material is primarily to provide a safe, stable, and functional pharmaceutical composition, and further, to provide a method for dissolving the active ingredient at a desired rate after administration to a subject, or for effectively absorbing the active ingredient after administration to a subject. The aforementioned medicinal auxiliary material may be an inert filler, or it may provide a function such as stabilizing the pH value of the entire composition or preventing the decomposition of the active ingredient of the composition. The aforementioned medicinal auxiliary material may include one or more of the following auxiliary materials: adhesives, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-sticking agents, fluidizers, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[1002] Substances that can be used as pharmaceutically acceptable auxiliary materials include ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, e.g., human serum proteins, buffers, e.g., phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars, e.g., lactose, glucose, sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., carboxymethylcellulose sodium This material includes, but is not limited to, sodium, ethylcellulose, cellulose acetate; gum powder; malt; gelatin; talc; auxiliary materials, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycol compounds, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffers, and other non-toxic and suitable lubricants, such as sodium lauryl sulfate and magnesium stearate; colorants, release agents, coating agents, sweeteners, flavoring agents, and fragrances; preservatives and antioxidants.

[1003] The pharmaceutical compositions of the present invention can be manufactured by any method known to those skilled in the art based on the published information. Examples include conventional mixing, dissolution, granulation, emulsification, grinding, encapsulation, embedding, or freeze-drying processes.

[1004] The pharmaceutical dosage forms of the compounds of the present invention can be provided in the form of immediate-release, controlled-release, sustained-release, or targeted drug delivery systems. For example, commonly used dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, sugar-coated tablets, soft or hard-shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols and lyophilized formulations. Depending on the route of administration, special equipment for using or administering the drug may be required, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. A drug dosage form typically consists of the drug, excipients, and a container / sealing system. Adding one or more excipients (also called inactive components) to the compounds of the present invention can improve or enhance the manufacture, stability, administration, and safety of the drug and provide a means to obtain a desired drug release profile. Therefore, the type of excipient added to the drug depends on various factors, such as the physical and chemical properties of the drug, the route of administration, and the preparation steps. Pharmaceutically acceptable excipients include those available in the art and listed in various pharmacopoeias (see the United States Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP); publications of the Center for Drug Evaluation and Research (CEDR) of the U.S. Food and Drug Administration (www.fda.gov), such as the Inactive Ingredient Guide (1996); the Handbook of Pharmaceutical Additives (2002) by Ash and Ash; and Synapse Information Resources, Inc., Endicott NY; etc.).

[1005] The drug dosage forms of the compounds of the present invention can be produced by any of the methods well known in the art, such as conventional mixing, sieving, dissolution, melting, granulation, sugar-coated tablet formation, tableting, suspension, extrusion, spray drying, grinding, emulsification, (nano / micron) encapsulation, encapsulation, or freeze-drying processes. As described above, the compositions of the present invention may contain one or more physiologically acceptable inactive components that facilitate the processing of the active molecules into pharmaceutical formulations.

[1006] The appropriate formulation is determined by the desired route of administration. For example, for intravenous injection, the composition can be formulated as an aqueous solution, and if necessary, physiologically compatible buffers such as phosphates, histidine or citrates, and tonic agents of sodium chloride or dextrose are used to adjust the pH of the formulation. For transmucosal or transnasal administration, semi-solid, liquid formulations or patches are preferred and may contain penetration enhancers; such penetration enhancers are generally known in the art. For oral administration, the compound can be manufactured in liquid or solid dosage forms and used as immediate-release or controlled-release / sustained-release formulations. Dosage forms suitable for oral ingestion by individuals include tablets, pills, sugar-coated tablets, hard and soft-shell capsules, liquids, gels, syrups, ointments, suspensions, and emulsions. The compound can also be incorporated into rectal compositions such as suppositories or enemas, which may contain common suppository bases such as cocoa butter or other glycerides.

[1007] Solid oral dosage forms can be obtained using excipients, which include fillers, disintegrants, adhesives (dry and wet), dissolution inhibitors, lubricants, flow promoters, anti-adhesion agents, cation exchange resins, wetting agents, antioxidants, preservatives, colorants, and flavoring agents. These excipients may be synthetic or naturally derived. Examples of excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, hydrogenated vegetable oils, and waxes. Ethanol and water can be used as granulation aids. In some cases, it may be necessary to coat the tablets with, for example, a taste-masking film, a gastric acid-resistant film, or a release-inhibiting film. Often, natural and synthetic polymers are used in combination with colorants, sugars, and organic solvents or water to coat the tablets and obtain sugar-coated tablets. If capsules are preferred over tablets, the drug powder, suspension, or solution can be delivered in the form of a suitable hard-shell or soft-shell capsule.

[1008] Depending on the embodiment, the compounds of the present invention can be administered topically, for example, via skin patches, semi-solid or liquid formulations, such as gels, (micro)emulsions, ointments, solutions, (nano / micron) suspensions, or foaming agents. The penetration of the drug into the skin and underlying tissues can be adjusted, for example, by the use of penetration enhancers; appropriate selection and combination of lipophilic, hydrophilic, and amphiphilic excipients such as water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, and emulsifiers; pH adjustment; and the use of complexing agents. Other techniques, such as iontophoresis, can be used to adjust the skin penetration of the compounds of the present invention. Transdermal or topical administration is most preferred when it is desirable to deliver the drug topically while minimizing systemic exposure.

[1009] For inhalation or nasal administration, the compounds used in the present invention can be easily delivered from a pressurized pack or nebulizer in the form of a solution, suspension, emulsion, or semi-solid aerosol, usually with the help of a propellant such as a halogenated carbon, carbon dioxide, or other suitable gas, typically derived from methane and ethane. Suitable hydrocarbons for topical aerosols include butane, isobutylene, and pentane. In the case of pressurized aerosols, the appropriate dose unit can be determined by delivering a fixed amount via a valve. Capsules and cartridges containing, for example, gelatin can be formulated for use in inhalers or sprayers. These typically contain a powder mixture of the compound and a suitable powder base (e.g., lactose or starch).

[1010] Compositions formulated for parenteral administration by injection are typically sterile and can be provided in unit-dose forms such as ampoules, syringes, injection pens, or multi-dose containers, the latter typically containing preservatives. The compositions may also be in the form of suspensions, solutions, or emulsions in oily or aqueous carriers, and may contain formulations such as buffers, tonics, thickeners, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives. Depending on the injection site, the carrier may contain water, synthetic oils, or vegetable oils, and / or organic cosolvents. In some cases, non-enteral formulations may be reconstituted or diluted before administration, for example, lyophilized products or concentrates. Depot formulations providing controlled-release or sustained-release of the compounds of the present invention may comprise injectable suspensions of nano / microparticles or nano / micro or non-microcrystalline particles. Other well-known matrices in the art, such as poly(lactic acid), poly(glycolic acid), or copolymers thereof, can be used as controlled-release / sustained-release matrices. Other depot delivery systems can be provided in the form of implants and pumps that require incision.

[1011] Suitable carriers for the compounds of the present invention for intravenous injection are well known in the art and include an aqueous solution containing a base (e.g., sodium hydroxide) for forming the ionic compound; sucrose or sodium chloride as a tonic agent; and a buffer containing, for example, phosphate or histidine. Cosolvents such as polyethylene glycol can be added. These aqueous systems effectively dissolve the compounds of the present invention and reduce toxicity upon systemic administration. The ratio of components in the solution system can be significantly altered without impairing the solubility and toxicity properties. Furthermore, the properties of the components can be modified. For example, low-toxicity surfactants such as polysorbate or poloxamer may be used, polyethylene glycol or other cosolvents may be used, biocompatible polymers such as polyvinylpyrrolidone may be added, and other sugars or polyols may be used instead of dextrose.

[1012] The therapeutically effective dose can first be estimated using various methods well known in this field. The initial dose for animal studies can be based on the effective concentration established by cell culture assays. The dose range suitable for human subjects can be determined, for example, from data obtained from animal studies and cell culture assays. Depending on the embodiment, the compound of the present invention can be prepared as an orally administered drug.

[1013] The effective amount or therapeutic effective amount or dose of a drug (for example, the compound of the present invention) means the amount of the drug or compound that produces the effect of improving the symptoms or extending the survival time of an individual. The toxicity and therapeutic effect of the molecule are expressed in cell cultures or experimental animals, for example, in LD50. 50 (Dose at which 50% of the population dies) and ED 50 It can be measured by standard pharmaceutical methods, such as (the dose that is therapeutically effective in 50% of the population). The therapeutic index is the dose-to-toxicity ratio, or LD50. 50 / ED 50 It can be expressed as follows. Drugs that show a high therapeutic index are preferred.

[1014] The effective dose or therapeutic effective dose is the amount of a compound or pharmaceutical composition that elicits a biological or medical response in the tissue, system, animal, or human being being investigated by a researcher, veterinarian, physician, or other clinician. The dose is the ED with minimal toxicity or no toxicity. 50 It is preferable that the blood concentration is within the range including [specific component]. The dose can vary within this range depending on the dosage form and / or route of administration used. The appropriate formulation, route of administration, dose, and administration interval should be selected considering the specific circumstances of the individual, using methods known in the art.

[1015] The dose and interval can be individually adjusted to provide a plasma concentration of the active portion sufficient to achieve the desired effect, i.e., the minimum effective concentration (MEC). The MEC varies depending on the compound, but can be estimated, for example, from in vitro data or animal studies. The dose required to achieve the MEC depends on individual characteristics and the route of administration. In the case of topical administration or selective ingestion, the effective local concentration of the drug may not be related to the plasma concentration.

[1016] The amount of drug or composition administered is determined by various factors, including the sex, age, and weight of the individual being treated, the severity of the disease, the method of administration, and the judgment of the prescribing physician.

[1017] If necessary, the compositions of the present invention may be provided in packs or dispenser devices containing one or more unit dosage forms containing the active ingredient. For example, the packs or dispenser devices may include metal foil or plastic foil such as blister packs, or glass and rubber stoppers such as vials. Instructions for use of the pharmaceutical product may be attached to the packs or dispenser devices. Compositions containing the compounds of the present invention prepared in a suitable pharmaceutical carrier may be prepared, placed in an appropriate container, and labeled to indicate that they treat the indicated medical condition.

[1018] The present invention further provides applications of the heterocyclic compound represented by formula I, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolite, its stereoisomer, its tautomer or prodrug, or the pharmaceutical composition thereof, in the production of P2X3 inhibitors.

[1019] The present invention further provides applications in the manufacture of drugs for heterocyclic compounds represented by formula I, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, metabolites thereof, stereoisomers thereof, tautomers thereof or prodrugs thereof, or pharmaceutical compositions thereof. The drugs are used to prevent, treat, cure or alleviate diseases in which at least a portion of animals are induced by or associated with the activity of P2X3; or the drugs are used to treat pain, urinary tract disorders, or respiratory disorders.

[1020] Depending on the embodiment, the drug may be used to treat urinary tract diseases in animals (e.g., humans); these urinary tract diseases include, but are not limited to, urinary incontinence, overactive bladder, voiding dysfunction, and cystitis.

[1021] Depending on the embodiment, the drug may be used to treat respiratory disorders in animals (e.g., humans), which include, but are not limited to, respiratory disorders including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or chronic cough.

[1022] Depending on the embodiment, the drug may be used to treat pain in animals (e.g., humans), including, but not limited to, inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, burn pain, migraine or cluster headache, and chronic pain.

[1023] The present invention further provides applications of the heterocyclic compound represented by formula I, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolite, its stereoisomer, its tautomer, or its prodrug, or the pharmaceutical composition thereof, in the treatment or prevention of disease.

[1024] The present invention further provides applications of the heterocyclic compound represented by Formula I, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolite, its stereoisomer, its tautomer, or its prodrug, or the pharmaceutical composition thereof, in the prevention, treatment, therapy, or mitigation of diseases in which at least a portion of animals (e.g., humans) are induced by or associated with the activity of P2X3. The aforementioned diseases include, but are not limited to, respiratory diseases, cough, chronic cough, idiopathic pulmonary fibrosis, chronic pulmonary obstruction, asthma, pain, urinary incontinence, autoimmune diseases, overactive bladder, voiding dysfunction, inflammation, Alzheimer's disease, Parkinson's disease, sleep disorders, epilepsy, mental disorders, arthritis, neurodegeneration, traumatic brain injury, myocardial infarction, rheumatoid arthritis, stroke, thrombosis, atherosclerosis, colon syndrome, inflammatory bowel disease, gastrointestinal diseases; gastrointestinal dysfunction, respiratory failure, sexual dysfunction, cardiovascular diseases, heart failure, hypertension, urinary incontinence, cystitis, arthritis, ectopic endometriosis, hematological disorders, musculoskeletal and connective tissue developmental disorders, and systemic disorders.

[1025] Depending on the embodiment, the disease includes, but is not limited to, inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, burn pain, migraine, or cluster headache.

[1026] Depending on the embodiment, the disease includes urinary tract diseases.

[1027] Depending on the embodiment, the disease includes, but is not limited to, respiratory disorders including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or chronic cough.

[1028] The present invention further provides a method for treating or preventing a disease, comprising administering to a patient an effective amount of the heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a metabolite thereof, a stereoisomer thereof, a tautomer thereof, or a prodrug thereof, or the pharmaceutical composition thereof.

[1029] Definitions and Common Terms Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as those understood by a person skilled in the art to which this invention pertains. All patents and published works relating to this invention are incorporated in their entirety by reference.

[1030] Unless otherwise specified, the following definitions used herein apply. For the purposes of this invention, chemical elements are consistent with the CAS version of the Periodic Table of Elements and the "Handbook of Chemistry and Physics," 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in the descriptions in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated by reference.

[1031] The term "includes" is an open expression, meaning it includes the content specified in this invention, but does not exclude other embodiments.

[1032] Stereoisomers are compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and atropisomers.

[1033] "Enantiomers" refer to two isomers of the same compound that cannot be superimposed but are mirror images of each other.

[1034] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Diastereomer mixtures can be separated by high-resolution analytical processes such as electrophoresis and chromatography, for example, HPLC.

[1035] The definitions and rules of stereochemistry used in this invention are generally based on those of SP. Parker, Ed., McGraw-Hill. Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereo chemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[1036] Any chiral atom (e.g., carbon) of the compounds disclosed in the present invention can exist in racemic or enantiomer-rich forms, for example, in (R)-, (S)-, or (R,S)- configurations. Depending on the embodiment, each chiral atom, in the case of (R)- or (S)-, has an enantiomer excess of at least 0%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% in the enantiomer excess.

[1037] The resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography and / or fractional crystallization.

[1038] The term "tautomer" or "tautomer" refers to structural isomers with different energies that can be converted to one another over a low-energy barrier. If possible (e.g., in solution), tautomers can reach chemical equilibrium. For example, proton tautomers (also called prototropic tautomers) include interconversions that occur via proton transitions, such as on-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the rearrangement of several bonding electrons. A specific example of on-enol tautomerism is the interconversion between the tautomers of pentane-2,4-dione and 4-hydroxypento-3-alkene-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-ketototherapeutic activity is the interconversion of tautomers of pyridine-4-ol and pyridine-4(1H)-one. Unless otherwise specified, all tautomer forms of the compounds of the present invention are within the scope of the present invention.

[1039] Generally speaking, the term "substitution" means that one or more hydrogen atoms in a structure are replaced by a particular substituent. Furthermore, if the group is substituted with one or more of the substituents, the substituents are independent of each other; that is, the one or more substituents may be different from each other or the same. Unless otherwise specified, one substituent can be substituted at each of the substitutable positions of the group being substituted. If multiple positions in a structural formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted in a homologous or heterologous manner at each position.

[1040] Those skilled in the art will know, by convention in the art, that the structural formula of the base described in this application is used

[1041] [ka]

[1042] This is understood to mean that the corresponding group is connected to other fragments and groups of the compound via this site.

[1043] In each part of this specification, substituents of the compounds disclosed herein are disclosed by type or range of groups. In particular, the present invention includes independent subcombinations of each member of these types and ranges of groups. For example, the terms “C1-C6 alkyl group” or “C1-6 alkyl group” may be linear or branched and are particularly independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups; “C1-4 alkyl group” are particularly independently disclosed methyl, ethyl, C3 alkyl (i.e., propyl group, including n-propyl and isopropyl groups), and C4 alkyl (i.e., butyl group, including n-butyl, isobutyl, s-butyl and t-butyl groups).

[1044] Each part of the present invention describes a linking substituent. Where a linking group is clearly required in the structure, the Markush variables listed for that group should be understood as linking groups. For example, if a structure requires a linking group and the Markush definition of that variable lists "alkyl group" or "aryl group," then it should be understood that the "alkyl group" or "aryl group" represents a bonded alkylidene group or arylene group, respectively.

[1045] As used in this invention, the term "alkyl group" refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-amyl, 2-amyl, 3-amyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-amyl, 3-methyl-2-amyl, 4-methyl-2-amyl, 3-methyl-3-amyl, 2-methyl-3-amyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, and n-octyl groups.

[1046] In some specific structures, when an alkyl group is clearly represented as a linking group, that alkyl group should be understood to represent the bonded alkylene group; for example, in "halo-C1~C6 alkyl group," the C1-C6 alkyl group should be understood to be a C1-C6 alkylidene group.

[1047] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group. Examples of alkylidene groups include the methylene group (-CH2-), the ethylene group (including -CH2CH2- or -CH(CH3)-), and the isopropylidene group (including -CH(CH3)CH2- or -C(CH3)2-).

[1048] The term "alkenyl" refers to a monovalent hydrocarbon group consisting of 2 to 12 carbon atoms, either linear or branched, and containing at least one unsaturated site, i.e., carbon-carbon sp 2 The alkenyl group contains a double bond and includes a "cis" and "tans" configuration, or an "E" and "Z" configuration. Examples of alkenyl groups include, but are not limited to, vinyl groups (-CH=CH2) and allyl groups (-CH2CH=CH2).

[1049] The terms "alkoxy group" or "alkyl-O-" mean that an alkyl group is connected to the rest of the molecule via an oxygen atom, where the alkyl group is as defined in this invention. Examples of alkoxy groups include, but are not limited to, alkoxy groups, ethoxy groups, 1-propoxy groups, 2-propoxy groups, and 1-butoxy groups.

[1050] The terms "haloalkyl group," "haloalkoxy group," or "haloalkyl group-O-" refer to an alkyl or alkoxy group substituted with one or more halogen atoms, including, but not limited to, a trifluoromethyl group and a trifluoromethoxy group.

[1051] The term "cycloalkyl group" refers to a monovalent or polyvalent saturated monocyclic or bicyclic system containing 3 to 12 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups; among these, the C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[1052] The term "cycloalkenyl group" refers to a monocyclic, unsaturated carbocycloalkenyl group containing 3 to 6 ring-forming carbon atoms ("C3-C6 cycloalkenyl group"). Examples of cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutylene, cyclopentenyl, cyclohexene, or cyclohexadienyl groups.

[1053] The term “heterocycloalkyl group” means a saturated monocyclic or bicyclic system containing 3–10 cycloatoms, including condensed, bridging, or spirocyclic systems (e.g., bicyclic systems ("bicyclic heterocycloalkyl groups"), which contain 3–9 ring-constituting carbon atoms and at least one cycloheteroatom selected from nitrogen, sulfur, and oxygen ("C3–C9 heterocycloalkyl groups"). A bicyclic heterocycloalkyl group may contain one or more heteroatoms in one or two rings) and is saturated. Unless otherwise specified, heterocycloalkyl groups may be carbon or nitrogen groups, and the -CH2- group may optionally be substituted with -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some forms, heterocycloalkyl groups are C3–C5 heterocycloalkyl groups, meaning that the heterocycloalkyl group contains 3–5 ring-constituting carbon atoms and at least one cycloheteroatom selected from O, S, and N. Examples of heterocycloalkyl groups include, but are not limited to, ethylene oxide group, thiacyclobutyl group, pyrrolidine group, pyrazoline group, pyrazolidine group, imidazoline group, imidazolidine group, oxazolidine group, tetrahydrofuran group, piperidine group, morpholinyl group, tetrahydropyrimidinyl group, oxaziridine group, thiomorpholinyl group, and piperazine group. Examples in which the -CH2- group in heterocycloalkyl groups is substituted with -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl group, 2-piperidineone group, 3-morpholinone group, 3-thiomorpholinone group, and oxotetrahydropyrimidinyl group, or their isomers and stereoisomers. Depending on the embodiment, exemplary C3-C9 heterocycloalkyl groups include, but are not limited to, the C3-C5 heterocycloalkyl groups and azepane groups, oxepan groups, thiepan groups, diazepine groups, azacyclooctatetraalkyl groups, oxacyclooctatetraalkyl groups, thiocyclooctatetraalkyl groups, quinuclidine groups, octahydroindole groups, octahydroisoindole groups, decahydroquinoline groups, decahydroisoquinoline groups, or their isomers and stereoisomers.

[1054] The term "heterocycloalkenyl group" refers to a monocyclic or bicyclic ring system containing a partially unsaturated alkenyl group, which contains 3-9 cyclo atoms, and at least one cyclo atom is selected from nitrogen, sulfur, and oxygen atoms ("C3-C9 heterocycloalkenyl group"); the heterocycloalkenyl group is non-aromatic and does not contain an aromatic ring. Unless otherwise specified, the heterocycloalkenyl group may be a carbon group or a nitrogen group, and the -CH2- group may be optionally substituted with -C(=O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide. In some embodiments, the heterocycloalkenyl group is preferably a C3-C5 heterocycloalkenyl group; examples of C3-C5 heterocycloalkenyl groups include, but are not limited to, dihydrofuran, dihydrothienyl, dihydropyrazolyl, dioxol, dihydroimidazolyl, dihydropyrazole, dihydrothiazole, dihydroisothiazole, dihydroxazole, dihydrothiadiazole, dihydrotriazol, dihydrotetrazole, tetrahydropyridinyl, 3,4-dihydro-2H-pyran, pyran, thiopyran, dihydropyridine, dihydropyrazine, dihydropyrimidine, oxazine, and dihydrotetrazole groups, or their isomers and stereoisomers. In some embodiments, the exemplary C3-C9 heterocycloalkenyl group includes, but is not limited to, the C3-C5 heterocycloalkenyl group and the octahydroisoquinoline group, 3H-indole group, dihydroisoquinoline group, dihydroquinoline group or 4H-quinolizidine group, or their isomers and stereoisomers.

[1055] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[1056] The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic systems containing 6 to 14 cycloatoms, or 6 to 10 cycloatoms. Examples of aryl groups include phenyl, naphthyl, and anthryl groups. Unless otherwise specified, "C6-C 10The term "aryl group" refers to an aryl group containing 6 to 10 ring-forming carbon atoms.

[1057] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-6 cycloatoms, 5-10 cycloatoms, or 5-12 cycloatoms, of which at least one ring contains one or more selected cycloheteroatoms from nitrogen, oxygen, and sulfur. Unless otherwise specified, heteroaryl groups can be attached to the rest of the molecule (such as the main structure of the general formula) via any reasonable site (C in CH or N in NH). Examples include, but are not limited to, furan groups, imidazolyl groups, isoxazolyl groups, oxazolyl groups, pyrazolyl groups, pyridinyl groups, pyrimidinyl groups, pyridadinyl groups, pyrazinyl groups, thienyl groups, thiazolyl groups, etc.; and also include, but are not limited to, bicyclic groups such as benzimidazolyl groups, benzofuran groups, benzothienyl groups, indole groups, oxoindole groups, imidazopyridinyl groups, pyrazolopyridinyl groups, pyrazolopyridinyl groups, quinoline groups, isoquinoline groups, and quinazoline groups.

[1058] Furthermore, unless otherwise explicitly stated, the "...independently" notation used in this invention should be understood in a broad sense, meaning that each described entity is independent of the others and may be an independently homologous or distinct concrete base. More specifically, the expression "...independently" means that, for different bases, the concrete options represented by the same symbol do not influence each other, and for the same base, the concrete options represented by the same symbol do not influence each other.

[1059] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically acceptable when administered to humans and do not typically cause allergic reactions or inappropriate responses such as gastrointestinal discomfort or dizziness.

[1060] The term "carrier" refers to a diluent, auxiliary material, excipient, or matrix administered together with a compound. These drug carriers may be sterile liquids, such as water and oil, and may be of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, or sesame oil. Water, aqueous solutions of physiological salines, aqueous glucose, and glycerol solutions are preferably used as carriers, especially injectable solutions. Suitable drug carriers are listed in E.W. Martin's "Remington's Pharmaceutical Sciences."

[1061] As used in this invention, the term "prodrug" refers to the conversion of a compound to the compound shown in formula I in vivo. Such conversion is influenced by hydrolysis of the prodrug in the blood, or by conversion to the parent structure via enzymes in the blood or tissues. The prodrug compound of this invention may be an ester, and in the prior invention, esters that can be used as prodrugs include phenyl esters and aliphatic (C1-) esters. 24 These include esters, acyloxymethyl esters, and carbonate esters, carbamates, and amino acid esters. For example, one compound of the present invention contains a hydroxyl group, i.e., it can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms contain phosphate esters, for example, these phosphate ester compounds are obtained by phosphorylation of the hydroxyl group in the parent compound. For further discussion on prodrugs, see: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriersin Drug Design, American Pharmaceutical Associationand Pergamon Press, 1987, J. Rautioetal., Prodrugs: Designand Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Heckeretal., Prodrugs of Phosphatesand Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[1062] As used in this invention, the term "metabolite" refers to a product obtained by the metabolism of a specific compound or a salt thereof in the body. Metabolites of compounds can be identified by art well known in the field, and their activity can be characterized by experimental methods described in this invention. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. of the administered compound. Accordingly, this invention includes metabolites, and metabolites produced by sufficient contact of the compounds of this invention with mammals over a certain period of time.

[1063] As used in this invention, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well known in their respective fields; for example, see: SM Bergeetal., describe pharmaceutically acceptable salts in detail. J. Pharmaceutical This is described in Sciences, 1977, 66: 1-19. Salts formed from pharmaceutically acceptable, non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobroms, phosphates, sulfates, and perchlorates; and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malons; and these salts can be obtained by other methods, such as ion exchange, as described in books and literature. Other pharmaceutically acceptable salts include adipates, alginates, ascorbic acid, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphor sulfonates, cypions, digluconates, lauryl sulfates, ethanesulfonates, formates, fumarates, glucoheptates, glycerophosphates, gluconates, hemisulfates, heptanates, capronates, hydroiodides, and 2-hydro This includes xyethanesulfonates, lactulonates, lactates, laurates, lauryl sulfates, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitic acid, pamoic acid, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propions, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valersates, etc. Salts obtained by reaction with appropriate bases include alkali metals, alkaline earth metals, ammonium, and N + This includes salts of (C1-4 alkyl)4. The present invention also devises quaternary ammonium salts formed by compounds containing an N group. Water-soluble, oil-soluble, or dispersible products can be obtained by quaternization. Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include non-toxic ammonium, quaternary ammonium salts, and amine cations formed by counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates, and aromatic sulfonates.

[1064] In this invention, "solvate" refers to an aggregate formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an aggregate formed by a solvent molecule that is water.

[1065] In the present invention, "ester" refers to an in vivo hydrolyzable ester formed by a compound containing a hydroxyl group or a carboxyl group. Such esters are, for example, pharmaceutically acceptable esters that are hydrolyzed in the body of a human or animal to produce a parent alcohol or acid. The compound of formula I of the present invention comprises a suitable group and a carboxyl group capable of forming an in vivo hydrolyzable ester, and such groups include, but are not limited to, alkyl groups and arylalkyl groups.

[1066] In this invention, "nitrogen oxide" means that if a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. For example, N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid) (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LWDeady (Syn.Comm.1977, 7,509-514), in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[1067] As used in the present invention, the term “to treat” any disease or condition means, in some embodiments, to improve the disease or condition (i.e., to delay, prevent or reduce the progression of the disease or at least one of its clinical symptoms). In other embodiments, “to treat” means to alleviate or improve at least one physical parameter, including a physical parameter that may not be perceived by the patient. In other embodiments, “to treat” means to regulate the disease or condition physically (e.g., stabilization of perceptible symptoms) or physiologically (e.g., stabilization of physical parameters) or both of the above. In other embodiments, “to treat” means to prevent or delay the onset, development, or worsening of the disease or condition.

[1068] Unless otherwise specified, abbreviations for protecting groups, amino acids, and other compounds used in this invention follow their commonly used and recognized abbreviations, or refer to the IUPAC-IUB Commissionon Biochemical Nomen clature (see Biochem. 1972, 11:942-944).

[1069] The biological activity of the compounds of the present invention can be evaluated by any conventional known method. Suitable detection methods are well known in the art. For example, the P2X3 inhibitory activity, pharmacokinetic activity, and / or liver microsomal stability of the compounds of the present invention can be measured by a suitable conventional method. The measurement methods provided by the present invention are presented as examples only and do not limit the present invention. The compounds of the present invention are active in at least one of the detection methods provided by the present invention.

[1070] In this specification, terms such as “several examples,” “examples,” or “preferred embodiments” mean that certain features, structures, materials, or properties described in relation to an example or example are included in at least one example or example of the present invention. In this specification, the descriptive expressions of the above terms do not necessarily refer to the same example or example. Furthermore, the specific features, structures, materials, or properties described may be combined in appropriate ways in any one or more examples or examples. Moreover, those skilled in the art can combine different examples or examples and features of different examples or examples described herein without contradiction.

[1071] Without contradicting common sense in this field, the above preferred conditions can be arbitrarily combined to obtain each preferred example of the present invention.

[1072] The reagents and raw materials used in this invention are commercially available.

[1073] The present invention demonstrates inventiveness in that the heterocyclic compound of the present invention possesses high P2X3 antagonistic activity, better selectivity, lower toxicity, good metabolic stability, and minimal impact on taste. The prospects for drug development were favorable. [Brief explanation of the drawing]

[1074] [Figure 1] Figure 1 shows the number of coughs induced by citrate compared to the compound and the solvent. [Figure 2] Figure 2 shows the incubation period of cough induced by citrate compared to the compound and the solvent. [Figure 3] Figure 3 shows the number of coughs induced by each compound and citrate compared to their baseline values. [Figure 4] Figure 4 shows the number of coughs, cough suppression rate, and cough incubation period obtained in the body for some compounds. [Figure 5] Figure 5 shows the number of coughs in the ATP-citric acid model for each compound. [Figure 6]Figure 6 shows the incubation period of cough in the ATP-citric acid model for each compound. [Figure 7] Figure 7 shows the quinine / tap water intake ratio in rats after compound administration. [Figure 8] Figure 8 shows the quinine / tap water drinking ratio in rats after administration of the compound in a concentration gradient. [Modes for carrying out the invention]

[1075] The present invention will be described in detail below using examples, but the present invention is not limited to the scope of these examples. In the examples below, experimental methods for which specific conditions are not specified should be followed according to usual methods and conditions, or selected according to the product description.

[1076] In this invention, the following abbreviations are used: TEMPO (2,2,6,6-tetramethyl-1-piperidine), LDA (lithium diisopropylamide), DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), DCM (dichloromethane), DME (dimethoxyethane), PE (petroleum ether), EA (ethyl acetate), DIPEA (N,N-diisopropylethylamine), THF (tetrahydrofuran), Ac (acetyl group), MeOH (methanol), Boc (t-butoxycarbonyl group), B2Pin2 (pinacol boronic acid ester), rt (room temperature), HATU (2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), refrigerator (reflux), eq is equivalent, Rf: Relative to Front, g (grams), mg (milligrams), mol (moles), mmol (millimoles), h (hours), min (minutes), mL (milliliters), μL (microliters).

[1077] Overnight is 8 to 15 hours, for example 12 hours; room temperature is 10°C to 30°C; and the solvent ratio, for example PE / EA, is a volume ratio.

[1078] In the examples described below, all temperatures are given in degrees Celsius unless otherwise specified. Unless otherwise specified, reagents were purchased from suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and were not further purified before use; common reagents were purchased from Shantou Xilonghua Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Marine Chemical Plant.

[1079] Anhydrous tetrahydrofuran, dioxane, toluene, and ethyl ether were obtained by reflux and drying over metallic sodium. Anhydrous dichloromethane and chloroform were obtained by reflux and drying over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were pre-dried over anhydrous sodium sulfate before use.

[1080] The following reactions were carried out (unless otherwise specified) under positive pressure of nitrogen or argon, or with a dry tube set in an anhydrous solvent, with the reaction flasks sealed with appropriate rubber stoppers, and the substrates injected with a syringe. All glassware was dry.

[1081] Silica gel columns were used for chromatography. Silica gel (300-400 mesh) was purchased from Qingdao Marine Chemical Plant. Nuclear magnetic resonance (NMS) spectroscopy data were measured using a BrukerAvance 400NMR spectroscopy analyzer or a BrukerAvance III HD 600NMR spectroscopy analyzer, with CDCl3, DMSO-d6, CD3OD, or Acetone-d6 as the solvent (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiple peaks appear and the multiplicity of the peaks is reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), ddd (doublet of doublets), ddt (doublet of doublets), dddd (doublet of doublets). The coupling constant is expressed in Hertz (Hz).

[1082] Low-resolution mass spectral (MS) data were measured using an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and aG1316ATCC (column temperature maintained at 30°C), with a G1329A automated sampler and G1315BDAD detector used for analysis, and the ESI source used in the LC-MS spectrometer.

[1083] The two spectrometers described above were equipped with Agilent ZorbaxSB-C18 columns with specifications of 2.1 × 30 mm and 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; and HPLC peaks were recorded and read at UV-Vis wavelengths of 210 nm and 254 nm.

[1084] (Example 1)

[1085] [ka]

[1086] Step (1) Preparation of (R)-2-formyl-morpholinyl-4-formate tert-butyl

[1087] [ka]

[1088] Compound 1-1 (10 g, 460 mmol), TEMPO (0.073 g, 0.44 mmol), aqueous solution of sodium bromide (0.5 M, 10 mL, 41 mmol), and dichloromethane (100 mL) were cooled to 0 °C-5 °C. Sodium bicarbonate (2.3 g, 23 mmol) was added to a solution of sodium hypochlorite (1.5 M, 34 ml, 58 mmol) to adjust the pH of the solution to 9.3. This solution was slowly added dropwise to the reaction system over 30 min. After the dropwise addition was complete, the mixture was stirred for half an hour, the temperature was raised to 20 °C, water (50 mL) was added, and dichloromethane was added. The aqueous phase was extracted, and after multiple extractions, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and compound 1-2 was obtained by column chromatography. It was an orange-yellow oily liquid (6 g, 60%). LC-MS: [M+H] + = 216.4.

[1089] Step (2) Preparation of (S)-2-ethynyl-morpholinyl-4-formate Tert-butyl

[1090] [ka]

[1091] Dimethyl (1-diazo-2-oxopropyl)phosphinate (6 g, 31.3 mmol) was dissolved in a mixture of (acetonitrile:methanol = 5:1), K2CO3 (59 mmol) was added, and the mixture was stirred at 20 °C for 15 min. 6 g (28 mmol) of compounds 1-2 were dissolved in 10 mL of the (acetonitrile:methanol = 5:1) mixture and then slowly added dropwise to the reaction system. After the dropwise addition was complete, the mixture was kept warm overnight. The suspension was filtered, and the filtrate was concentrated under reduced pressure to obtain an oily substance. The oily substance was added to water (approximately 100 mL), the precipitate was allowed to form, filtered, and the cake was washed with water. The residue was purified by silica gel column chromatography to obtain compounds 1-4, which were solids (3.4 g, yield 56.7%). LC-MS: [M+H] + = 212.1.

[1092] Step (3)

[1093] [ka]

[1094] Under room temperature conditions, compounds 1-4 (300 mg, 1.4 mmol), 1-5 (145 mg, 1.4 mmol), and 1-6 (145 mg, 1.4 mmol) were dissolved in toluene (3 mL). CuCl (42 mg, 0.4 mmol) and Cu(CF3SO3)2 (154 mg, 0.4 mmol) were added. The reaction mixture was heated to 85 °C under nitrogen gas protection, DME (0.1 mL) was added, and the reaction was allowed to proceed at this temperature for 5 hours. After the reaction was complete, water (15 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL × 3). The mixture was washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA, 1 / 1) to obtain 500 mg of intermediate 1-7, which was a yellow oily liquid. LC-MS: [M+H] + = 404.2.

[1095] Step (4)

[1096] [ka]

[1097] Under 0°C conditions, LiOH (936 mg, 22.3 mmol) was added to a THF (20 mL) solution of intermediates 1-7 (3 g, 7.44 mmol). The reaction mixture was stirred at room temperature for 2 hours until the reaction was complete. Then, under 0°C conditions, HCl (1 M) was added to bring the pH to 6. The mixture was extracted with DCM (10 mL x 3), washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2 g of intermediate 1-8, which was a yellow oily liquid. LC-MS: [M+H] + = 376.1.

[1098] Step (5)

[1099] [ka]

[1100] Intermediate 1-8 (375 mg) was dissolved in DCM (10 mL), and HATU (2 mmol) and DIPEA (4 mmol) were added simultaneously. The mixture was stirred at room temperature for 15 minutes, then N,O-dimethylhydroxylamine hydrochloride (1.2 mmol) was added. The mixture was then stirred at room temperature for 6-8 hours, and the reaction process was monitored by TLC. After the reaction was complete, the mixture was separated and purified by silica gel column chromatography to obtain intermediate 1-10 (275 mg, yield 65.8%). LC-MS: [M+H] + The result was 419.3.

[1101] Step (6)

[1102] [ka]

[1103] Intermediates 1-10 (418 mg, 1 mmol) were dissolved in anhydrous THF (10 mL), and methyl Grignard reagent was added dropwise to the reaction system at 0 °C. After the addition was complete, the system was stirred overnight. After the reaction was complete, the reaction system was quenched, extracted with ethyl acetate, washed, and dried. The mixture was separated and purified by silica gel column chromatography to obtain intermediate 1-11 (236 mg, yield 63.3%). LC-MS: [M+H] + = 374.1.

[1104] Step (7)

[1105] [ka]

[1106] Intermediate 1-11 (373 mg) was dissolved in DCM (5 mL), and HCl / EtOH (1 N, 1.5 mL) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred for 2 hours. The reaction mixture was added to NaHCO3 solution and adjusted to pH=8. The aqueous phase was extracted with DCM, the organic phase was washed with NaCl, and then dried with anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and separated and purified by silica gel column to obtain intermediate 1-12 (160 mg, yield 58.6%). LC-MS: [M+H] + = 274.6.

[1107] Step (8)

[1108] [ka]

[1109] Intermediate 1-12 (273 mg, 1 mmol) and DIPEA (258 mg, 2 mmol) were dissolved in DCM (5 mL), and methyl chloroformate (compound 1-13) (282 mg, 3 mmol) was added. The mixture was stirred at 0 °C for 3 hours, the reaction mixture was added to H2O, extracted with DCM, the organic phase was washed with NaCl, dried with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was separated and purified by silica gel column to obtain intermediate 1-14, which was a yellow oily substance (300 mg, yield 91%). LC-MS: [M+H] + = 332.2.

[1110] Step (9)

[1111] [ka]

[1112] Intermediate 1-14 (331 mg, 1 mmol) was dissolved in tetrahydrofuran (5 mL) and water (2 mL), N-bromosuccinimide (214 mg, 1.2 mmol) was added, and the mixture was reacted at room temperature for 1 hour under the protection of nitrogen gas. The reaction mixture was concentrated to half its volume, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the ethyl acetate layer was combined, dried over anhydrous sodium sulfate, and concentrated to obtain intermediate 1-15, which was a solid (300 mg) with a yield of 73.3%. LC-MS: [M+H] + = 410.2.

[1113] Step (10)

[1114] [ka]

[1115] Intermediate 1-15 (0.82 g, 2 mmol) was dissolved in anhydrous ethanol (10 mL), and simultaneously 1-acetylguanidine (242 mg, 2.4 mmol) and triethylamine (404 mg, 4 mmol) were added. The mixture was heated until reflux was achieved, and the reaction process was observed by TLC. After the reaction was complete, the solvent was concentrated under reduced pressure, EA was added for extraction, and the mixture was washed and separated by silica gel column chromatography to obtain compound 1 (531 mg, yield 64.4%).

[1116] LC-MS: [M+H] + = 413.2.

[1117] (Example 2)

[1118] [ka]

[1119] Step (1) Preparation of 2,6-difluoro-4-bromobenzaldehyde

[1120] [ka]

[1121] 3,5-Difluorobromobenzene (10 g, 51.8 mmol) was dissolved in anhydrous THF (80 mL), and LDA (31 mL, 62.5 mmol) was added dropwise at -78 °C under N2 protection. After the dropwise addition was complete, the mixture was stirred for 1 hour, DMF (4 mL, 51.9 mmol) was added, and the mixture was stirred for 30 minutes. The reaction mixture was then added to NH4Cl solution, extracted with ethyl acetate, washed with NaCl, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was concentrated and obtained by column chromatography, yielding compound 2-2, which was a yellow solid (8 g, yield 70%).

[1122] Step (2) Preparation of (S)-2-((2-(2,6-difluoro-4-bromophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)-methyl)morpholinyl-4-formate Tert-butyl

[1123] [ka]

[1124] Compound 2-2 (200 mg, 0.9 mmol), 2-amino-4-methylpyridine (100 mg, 0.9 mmol), compound 1-4 (191 mg, 0.9 mmol), CuCl (27 mg, 0.27 mmol), and Cu(CF3SO3)2 (100 mg, 0.27 mmol) were dissolved in toluene (3 mL), protected with N2, and heated to 85 °C. Simultaneously, DMA (0.05 mL) was added, and the reaction system was stirred for 5 hours. After cooling to room temperature and leaving overnight, the reaction mixture was placed in water (5 mL) and extracted with DCM (5 mL x 3). The organic phase was washed with saturated NaCl, dried over MgSO4, filtered, concentrated under reduced pressure, separated and purified by column (PE:EA = 1:1) to obtain intermediate 2-4, which was a yellow oily substance (100 mg, yield 21%). LC-MS: [M+H] + = 522.3.

[1125] Step (3) Preparation of (S)-2-((2-(2,6-difluoro-4-bromophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)-methyl)morpholinil

[1126] [ka]

[1127] Intermediate 2-4 (100 mg) was dissolved in DCM (1 mL), and HCl / EtOH (0.5 mL) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred for 2 hours. The reaction mixture was added to NaHCO3 solution and adjusted to pH = 8. The aqueous phase was extracted with DCM, the organic phase was washed with NaCl, and then dried with anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and separated and purified by silica gel column to obtain intermediate 2-5, which was a yellow oily substance (60 mg, yield 75%). LC-MS: [M+H] + = 422.6.

[1128] Step (4) Preparation of (S)-2-((2-(2,6-difluoro-4-bromophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)-methyl)morpholinyl-4-formate methyl

[1129] [ka]

[1130] Intermediate 2-5 (320 mg, 0.76 mmol) and DIPEA (86 mg, 0.91 mmol) were dissolved in DCM (5 mL), and methyl chloroformate (compound 2-6) (86 mg, 0.91 mmol) was added. The mixture was stirred at 0 °C for 3 hours, the reaction mixture was placed in H2O and extracted with DCM. The organic phase was washed with NaCl, dried with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The intermediate 2-7 was separated and purified by silica gel column chromatography to obtain intermediate 2-7, which was a yellow oily substance (330 mg, yield 91%). LC-MS: [M+H] + = 480.6.

[1131] Step (5) Preparation of (S)-2-((2-(2,6-difluoro-4-acetamidophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)-methyl)morpholinyl-4-formate methyl

[1132] [ka]

[1133] Under room temperature conditions, CS2CO3 (51 mg, 0.16 mmol), xant-phos (1.2 mg, 0.002 mmol), and Pd2(dba)3 (2 mg, 0.002 mmol) were added to a 1,4-dioxa (2 ml) solution of intermediate 2-7 (50 mg, 0.10 mmol) and acetamide (compound 2-8) (10 mg, 0.17 mmol). The reaction mixture was heated to 80 °C under nitrogen gas protection and allowed to react overnight. After the reaction was complete, it was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by preparative HPLC to obtain compound 2, which was a white solid (18 mg, yield 38%). LC-MS: [M + H] + = 459.7. 1 H NMR (400 MHz, MeOD): δ 8.41 (d, J = 7. 1 Hz, 1H), 7.43 (d, J = 9.7 Hz, 2H), 7.35 (s, 1H), 6.88 (dd, J = 7.1, 1.5 Hz, 1H ), 3.80 (d, J = 12.3 Hz, 3H), 3.67 (s, 3H), 3.59 (m, 1H), 3.43 - 3.34 (m, 1H), 3.15 - 3.01 (m, 2H), 2.91 (m, 1H), 2.63 (m, 1H), 2.47 (s, 3H), 2.19 (s, 3H).

[1134] (Example 3)

[1135] [ka]

[1136] Step (1) Preparation of (S)-2-((2-(2,6-difluoro-4-aminophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)-methyl)morpholinyl-4-formate methyl

[1137] [ka]

[1138] At room temperature, add hydrochloric acid (1.5 mL) to a solution of compound 2 (145 mg, 0.32 mmol) in ethanol (3 mL), and allow the reaction to proceed at 100 °C for 1 hour. After the reaction is complete, cool to room temperature, quench with 1 N NaHCO3 solution, extract with DCM (5 mL x 3), and extract with saturated sodium chloride solution (5 Washed with 2 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily liquid (90 mg). LC-MS: [M + H] + = 417.3.

[1139] Step (2) Preparation of (S)-2-((2-(2,6-difluoro-4-(methoxycarbonylamino)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)-methyl)morpholinyl-4-formate methyl

[1140] [ka]

[1141] Under 0°C conditions, methyl chloroformate (20 mg, 0.21 mmol) was added to a solution of intermediate 3-1 (70 mg, 0.17 mmol) and DIPEA (65 mg, 0.5 mmol) in DCM (5 mL), and the reaction was allowed to proceed for 3 hours at the same temperature. After the reaction was complete, water (3 mL) was added, and the mixture was extracted with DCM (3 mL x 3). The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by silica gel column (DCM / MeOH, 40 / 1) to obtain compound 3, which was a white solid (20 mg, yield 25%).

[1142] LC-MS: [M + H] + = 475.6. 1 H NMR (400 MHz, MeOD): δ 8.42 (d, J = 7.1 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J = 9.9 Hz, 2H), 6.90 (d, J = 7.1 Hz, 1H), 3.88 - 3.81 (m, 2H), 3.80 (s, 3H), 3.79 - 3.76 (m, 1H), 3.67 (s, 3H), 3.63 - 3.55 (m, 1H), 3.38 (t, J = 10.8 Hz, 1H), 3.15 - 3.00 (m, 2H), 2.90 (dt, J = 20.6, 7.7 Hz, 1H), 2.64 (t, J = 11.5 Hz, 1H), 2.47 (s, 3H).

[1143] (Example 4)

[1144] [ka]

[1145] Step (1) Preparation of (S)-2-((2-(4-(1-t-butoxycarbonylpyrrolyl-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)-methyl)morpholinyl-4-formate methyl

[1146] [ka]

[1147] Under room temperature conditions, intermediates 2-7 (50 mg, 0.1 mmol), N-butoxycarbonylpyrrolidine-2-boronic acid (compound 4-1) (26 mg, 0.12 mmol), and K2CO3 (36 mg, 0.26 mmol) were mixed in H2O (0.3 mL) and 1,4-dioxa (2 mL). Pd(dppf)Cl2 (2 mg, 0.016 mmol) was added, and the mixture was heated to 80 °C under nitrogen gas protection and reacted for 3 hours. After the reaction was complete, it was cooled to room temperature, filtered, water (3 mL) was added, and then extracted with ethyl acetate (5 mL × 3). The mixture was washed with saturated sodium chloride solution (3 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column (PE / EA, 5 / 1) to obtain a yellow oily liquid (50 mg, yield 93%). LC-MS: [M + H]+ = 567.4.

[1148] Step (2) Preparation of (S)-2-((2-(2,6-difluoro-4-(1H-pyrrolyl-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1149] [ka]

[1150] To a methanol (1 mL) solution of intermediate 4-2 (20 mg, 0.035 mmol), 1 M NaOH (4 mg, 0.1 mmol) was added, and the mixed solution was reacted at 60 °C for 2 hours. After the reaction was complete, 1 mL of water was added, and the mixture was extracted with DCM (1 mL × 3), washed with saturated sodium chloride solution (1 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC to obtain compound 4, which was a white solid (17.3 mg, yield 92.9%).

[1151] LC-MS: [M + H] + = 467.6. 1 H NMR (400 MHz, MeOD):δ 8.41 (d, J = 7.1 Hz, 1H), 7.34 (d, J = 9.2 Hz, 3H), 6.91 (dd, J = 2.6, 1.4 Hz, 1H), 6.88 (dd, J = 7.1, 1.5 Hz, 1H), 6.69 (dd, J = 3.6, 1.4 Hz, 1H), 6.24 (dd, J = 3.5, 2.7 Hz, 1H), 3.81 (d, J = 12.4 Hz, 3H), 3.66 (s, 3H), 3.63 - 3.56 (m, 1H), 3.39 (t, J = 10.6 Hz, 1H), 3.17-3.04 (m, 2H), 2.96- 2.85 (m, 1H), 2.71-2.59 (m, 1H), 2.47 (s, 3H).

[1152] (Example 5) Preparation of (S)-2-((2-(2,6-difluoro-4-(1H-imidazolyl-1-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1153] [ka]

[1154] Intermediate 2-7 (50 mg, 0.1 mmol) was dissolved in toluene (2 mL), and at the same time, imidazolyl (21 mg, 0.31 mmol), (1R,2R)-N1,N2-dimethylcyclohexyl-1,2-diamine (1.5 mg, 0.01 mmol), and K2CO3 (15 mg, 0.11 mmol) were added. CuI (2 mg, 0.01 mmol) was added under N2 protection, the reaction system was heated to 110 °C, left overnight, and then the reaction solution was filtered. The filtrate was purified by preparative chromatography to obtain compound 5, which was a yellow solid (8.4 mg, yield 17.2%).

[1155] LC-MS: [M+H] + = 468.6. 1 HNMR (400 MHz, MeOD) :δ 8.44(d, 1H), 8.42(s, 1H), 7.78(s, 1H), 7.56(d, 2H), 7.36(s, 1H), 7.22(s, 1H), 6.91(dd, 1H), 3.82(m, 3H), 3.67 (s, 3H), 3.60(m, 1H), 3.38(m, 1H), 3.12(m, 2H), 2.90(m, 2H), 2.64(s, 3H).

[1156] (Example 6)

[1157] [ka]

[1158] Step (1) Preparation of 2,6-difluoro-4-cyanobenzaldehyde

[1159] [ka]

[1160] Under nitrogen gas protection at -78 °C, LDA (8.6 mL, 17.2 mmol) was added dropwise to a solution of compound 6-1 (2 g, 14 mmol) in THF (20 mL), and the mixture was stirred for 1 hour under nitrogen gas protection at -78 °C. Within 30 minutes, DMF (1.26 g, 17.2 mmol) was added dropwise to complete the reaction. After completion, AcOH (10%) was added to quench the mixture, and the compound was extracted with ethyl acetate (50 mL x 3). The mixture was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column (PE / EA, 8 / 1) to obtain compound 6-2, which was a yellow solid (1.5 g, yield 60%).

[1161] Step (2) Preparation of (S)-2-((2-(4-cyano-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate Tert-butyl

[1162] [ka]

[1163] Under room temperature conditions, CuCl (90 mg, 0.9 mmol) and Cu(CF3SO3)2 (330 mg, 0.9 mmol) were added to toluene (15 mL) solutions of compound 6-2 (500 mg, 3 mmol), compound 1-5 (330 mg, 3 mmol), and compound 1-4 (630 mg, 3 mmol). The reaction mixture was then heated to 85 °C under nitrogen gas protection, and DME (0.1 Add (mL), react at the same temperature for 5 hours, and after the reaction is complete, add water (15 mL) to quench, extract with dichloromethane (10 mL × 3), wash with saturated sodium chloride solution (10 mL × 2), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column (PE / EA, 1 / 1) to obtain intermediate 6-3, which was a yellow oily liquid (450 mg, yield 32%).

[1164] Step (3) Preparation of (S)-3,5-difluoro-4-(7-methyl-3-(morpholinyl-2-ylmethyl)imidazo[1,2-a]pyridine-2-yl)benzonitrile

[1165] [ka]

[1166] Under 0°C conditions, TFA (2 mL) was added dropwise to a solution of intermediate 6-3 (400 mg, 1.1 mmol) in DCM (6 mL). The reaction was allowed to proceed at room temperature for 1 hour until the reaction was complete. After completion, the mixture was quenched with saturated NaHCO3 under 0°C conditions, extracted with dichloromethane (3 mL x 3), washed with saturated sodium chloride solution (3 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column (DCM / MeOH, 40 / 1) to obtain intermediate 6, which was a brown solid (280 mg, yield 79%).

[1167] Step (4) Preparation of (S)-2-((2-(4-cyano-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1168] [ka]

[1169] Under 0°C conditions, methyl chloroformate (66 mg, 0.72 mmol) was added to a solution of intermediate 6-4 (230 mg, 0.6 mmol) and DIPEA (230 mg, 1.8 mmol) in DCM (2 mL), and the reaction was allowed to proceed for 1 hour. After the reaction was complete, water (3 mL) was added, followed by extraction with dichloromethane (3 mL × 3), washing with saturated sodium chloride solution (3 mL × 2), drying over anhydrous sodium sulfate, and concentration under reduced pressure. The compound was then purified by silica gel column (PE / EA, 2 / 1) to obtain compound 6, which was a yellow solid (230 mg, yield 83%).

[1170] LC-MS: [M + H] + = 427.7. 1 H NMR (400 MHz, CDCl3):δ 8.19 (d, J = 7.1 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J = 6.2 Hz, 2H), 6.72 (d, J = 7.0 Hz, 1H), 4.03 - 3.74 (m, 3H), 3.71 (s, 3H), 3.61 - 3.51 (m, 1H), 3.38 (t, J = 11.8 Hz, 1H), 3.09 - 2.82 (m, 3H), 2.68 - 2.53 (m, 1H), 2.44 (s, 3H).

[1171] (Example 7) Preparation of (S)-2-((2-(2,6-difluoro-4-(1H-imidazolyl-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1172] [ka]

[1173] Under room temperature conditions, a solution of compound 6 (120 mg, 0.3 mmol) and NaOMe (3 mg, 0.05 mmol) in MeOH (2 mL) was stirred for 15 minutes. Then, aminoacetaldehyde diethyl acetal (49 mg, 0.4 mmol) and AcOH (34 mg, 0.6 mmol) were added, and the mixture was reacted at 50 °C for 1 hour. After cooling to room temperature, HCl (0.5 mL) and MeOH (2 mL) were added, and the mixture was reacted at 65 °C for 18 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was separated and purified by HPLC. Compound 7 was obtained by adding 1 M hydrochloric acid and then freeze-drying, which was a white solid (32 mg, yield 24%).

[1174] LC-MS: [M + H] + = 468.1. 1 H NMR (400 MHz, CDCl3): δ 16.00 (s, 2H), 15.16 (s, 1H), 8.68 (s, 3H), 8.00 (s, 1H), 7.49 (s, 2H), 7.22 (s, 1H), 3.94 (s, 3H), 3.70 (m, 3H), 3.61 (m, 1H), 3.34 (m, 1H), 2.97 (m, 4H), 2.62 (s, 3H).

[1175] (Example 8) Preparation of (S)-2-((2,(2,6-difluoro-(4-(N-methylformamidine)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1176] [ka]

[1177] Under room temperature conditions, a solution of compound 6 (50 mg, 0.12 mmol) and NaOMe (2 mg, 0.03 mmol) in MeOH (2 mL) was stirred for 30 minutes. Then, under 50 °C conditions, a solution of MeNH2 / THF (2 M, 0.1 mL, 0.15 mmol) and AcOH (14 mg, 0.24 mmol) were added and the mixture was reacted for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 8, which was a white solid (17 mg, yield 31%).

[1178] LC-MS: [M + H] + = 458.1. 1 H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 8.25 (s, 1H), 7.57 (d, J = 6.8 Hz, 2H), 7.39 (s, 1H), 6.74 (d, J = 6.8 Hz, 1H), 3.82 (m, 3H), 3.68 (s, 3H), 3.56 (m, 1H), 3.36 (m, 1H), 3.22 (s, 2H), 3.07 - 2.75 (m, 4H), 2.61 (m, 1H), 2.45 (s, 3H).

[1179] (Example 9) Preparation of (S)-2-((2-(2,6-difluoro-4-(1-methyl-1H-imidazolyl-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1180] [ka]

[1181] Intermediate 2-7 (50 mg, 0.1 mmol) was dissolved in toluene (3 mL), and simultaneously, Pd(PPh3)4 (12 mg, 0.01 mmol) and 1-methyl-2-(tributylstannyl)imidazolyl (78 mg, 0.2 mmol) were added to the reaction system. The mixture was protected with N2, heated to 85 °C and incubated for 5 hours, then filtered. The filtrate was reduced in pressure to concentrate the crude product, which was separated and purified by silica gel column chromatography to obtain compound 9, which was a white solid (24 mg, yield 49%).

[1182] LC-MS: [M+H] + = 482.2. 1 HNMR (400 MHz, MeOD): δ 8.69(s, 1H), 8.55(d, 1H), 7.99(s, 1H), 7.55(s, 1H), 7.22(d, 2H), 7.15(d, 1H), 4.06(s, 1H), 3.96(s, 3H), 3.86(m, 2H), 3.73(s, 3H), 3.68(s, 1H), 3.43(m, 1H), 3.09(d, 2H), 2.99(m, 1H), 2.73(m, 1H), 2.61(s, 3H).

[1183] (Example 10) Preparation of (S)-2-((2-(2,6-difluoro-4-(oxazole-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1184] [ka]

[1185] Under room temperature conditions, Pd(Ph3P)4 (12 mg, 0.01 mmol) and 2-(tributylstannyl)oxazole (119 mg, 0.33 mmol) were added to a solution of intermediate 2-7 (50 mg, 0.1 mmol) in 1,4-dioxa (2 mL). The reaction mixture was heated to 95 °C under nitrogen gas protection and reacted for 3 hours. After the reaction was complete, it was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by preparative HPLC to obtain compound 10, which was a white solid (12 mg, yield 25%).

[1186] LC-MS: [M+H] + = 469.7. 1 H NMR (400 MHz, MeOD):δ 8.43 (d, J = 7.1 Hz, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 0.8 Hz, 1H), 7.36 (s, 1H), 6.89 (dd, J = 7.2, 1.6 Hz, 1H), 3.93- 3.74 (m, 3H), 3.66 (s, 3H), 3.64 - 3.56 (m, 1H), 3.42 - 3.34 (m, 1H), 3.13 (d, J = 6.3 Hz, 2H), 2.97-2.85 (m, 1H), 2.73-2.60 (m, 1H), 2.48 (s, 3H).

[1187] (Example 11) Preparation of (S)-2-((2-(2,6-difluoro-4-(furan-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1188] [ka]

[1189] Intermediate 2-7 (50 mg, 0.1 mmol) was dissolved in toluene (3 mL), and simultaneously, Pd(PPh3)4 (12 mg, 0.01 mmol) and 2-(tributylstannyl)furan (37 mg, 0.1 mmol) were added to the reaction system. The mixture was protected with N2, heated to 110 °C, and incubated for 18 hours. After filtration, the filtrate was reduced in pressure to concentrate the crude product, which was then separated and purified by silica gel column chromatography to obtain compound 11, which was a white solid (12 mg, yield 24%).

[1190] LC-MS: [M+H] + = 468.1. 1 HNMR (400 MHz, CDCl3): δ 8.55 (d, 1H), 8.08 (s, 1H), 7.58(d, 1H), 7.40(d, 2H), 7.14(d, 1H), 6.86(d, 1H), 6.58(s, 1H), 3.82(m, 3H), 3. 73(s, 3H), 3.68(m, 1H),3.43(m, 1H), 3.05(m, 2H), 2.96(m, 1H), 2.71(m, 1H), 2.61 (s, 3H).

[1191] (Example 12) Preparation of (S)-2-((2-(2,6-difluoro-4-(thienyl-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1192] [ka]

[1193] Intermediate 2-7 (50 mg, 0.1 mmol) was dissolved in dioxa (3 mL), and simultaneously, Pd(PPh3)4 (12 mg, 0.01 mmol) and 2-(tributylstannyl)thienyl (117 mg, 0.31 mmol) were added to the reaction system. The mixture was protected with N2, heated to 100 °C, incubated for 8 hours, filtered, and the filtrate was reduced in pressure to concentrate the crude product. The product was separated and purified by silica gel column chromatography to obtain compound 12, which was a white solid (18 mg, yield 35%).

[1194] LC-MS: [M+H] + = 484.6. 1 HNMR (400 MHz, CDCl3): δ 8.22 (d, 1H), 7.41(m, 3H), 7.31(m, 2H), 7.14(dd, 1H), 6.71(d, 1H), 3.82(m, 3H), 3.68(s, 3H), 3.62(m, 1H), 3.41(m, 1H), 3.03(m, 2H), 2.92(m, 1H), 2.64(m, 1H), 2.46(s, 3H).

[1195] (Example 13) Preparation of (S)-2-((2-(2,6-difluoro-4-(1-methyl-1H-pyrrolyl-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1196] [ka]

[1197] Intermediate 2-7 (50 mg, 0.1 mmol) was dissolved in dioxa (3 mL), and simultaneously, Pd(PPh3)4 (12 mg, 0.01 mmol) and 2-(tributylstannyl)-methylpyrrolyl (115 mg, 0.31 mmol) were added to the reaction system. The mixture was protected with N2, heated to 100°C, incubated for 8 hours, filtered, and the filtrate was reduced in pressure to concentrate the crude product. The product was separated and purified by silica gel column chromatography to obtain compound 13, which was a white solid (28 mg, yield 54%).

[1198] LC-MS: [M+H] + = 481.4. 1 HNMR (400 MHz, CD3OD):δ 8.86 (d, 1H), 7.72(S, 1H), 7.42(dd, 1H), 7.39(d, 2H), 6.91(t, 1H), 6.49(dd, 1H),6.20(dd, 1H), 4.02(d, 1H), 3.84(s, 3H) 3.75(m, 3H), 3.69(s, 3H), 3.38(m, 1H), 3.27(m, 2H), 2.96(m, 1H), 2.79 (m, 1H), 2.66(s, 3H).

[1199] (Example 14)

[1200] [ka]

[1201] Step (1) Preparation of (S)-2-((2-(4-(1-ethoxyvinyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1202] [ka]

[1203] Intermediate 2-7 (300 mg, 0.62 mmol) was dissolved in toluene (3 mL). Simultaneously, PdCl2(PPh3)2 (44 mg, 0.062 mmol) and tri-t-butyl(1-ethoxyvinyl)tin (680 mg, 1.88 mmol) were added to the reaction system. The mixture was protected with N2, heated to 95 °C, and incubated for 3 hours. After filtration, the filtrate was reduced in pressure to concentrate the crude product, which was then separated and purified by silica gel column chromatography to obtain intermediate 14-2, a yellow oily substance (215 mg, 73% yield). LC-MS: [M+H] + = 472.7.

[1204] Step (2) Preparation of (S)-2-((2-(4-acetyl-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1205] [ka]

[1206] Intermediate 14-2 (250 mg, 0.53 mmol) was dissolved in EtOH (3 mL), then HCl (2 N, 1.7 mL) was added and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was placed in NaHCO3 solution and adjusted to pH = 8. The aqueous phase was extracted with DCM, the organic phase was washed 2-3 times with NaCl solution, and after liquid-liquid separation, the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative chromatography to obtain compound 14, which was a white solid (25 mg, yield 38%).

[1207] LC-MS: [M+H] + = 444.7. 1 HNMR (400 MHz, MeOD):δ 8.43(d, 1H), 7.76(d, 2H), 7. 36(s, 1H), 6.90(dd, 1H), 3.79(m, 3H), 3.67(s, 3H), 3.59(m, 1H), 3.36(m, 1H), 3.1 1(m, 2H), 2.86(m, 1H), 2.68(s, 3H), 2.63(m, 1H), 2.47(s, 3H).

[1208] (Example 15)

[1209] [ka]

[1210] Step (1) Preparation of (S,E)-2-((2-(4-(3-(dimethylamino)acryloyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)-methyl)morpholinyl-4-formate methyl

[1211] [ka]

[1212] Compound 14 (180 mg, 0.41 mmol) was dissolved in DMF-DMA (2 mL), protected with N2, heated to 95 °C, left overnight, and then cooled to room temperature. The mixture was concentrated under reduced pressure and purified by preparative chromatography to obtain product intermediate 15-1 (120 mg, 59.4% yield). LC-MS: [M+H] + = 499.7.

[1213] Step (2) Preparation of (S)-2-((2-(2,6-difluoro-4-(1H-pyrazole-3-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1214] [ka]

[1215] Intermediate 15-1 (80 mg, 0.12 mmol) was dissolved in ethanol (2 mL), N2H4-H2O (16 mg, 0.32 mg) was added dropwise to the reaction system, the reaction was heated to 100 °C, and after incubation for 2 hours, the reaction solution was concentrated under reduced pressure and purified by preparative chromatography to obtain compound 15, which was a white solid (49.8 mg, yield 66.4%).

[1216] LC-MS: [M+H] + = 468.6. 1H NMR (400 MHz, MeOD):δ 8.86(d, 1H), 7.81(d, 1H), 7. 76(d, 2H), 7.73(s, 1H), 7.43(dd, 1H), 6.91(d, 1H), 4.02(m, 1H), 3.79(m, 3H), 3.6 9(s, 3H), 3.37(m, 1H), 3.27(m, 2H), 2.94(m, 1H), 2.73(m, 1H), 2.66(s, 3H).

[1217] (Example 16) Preparation of (S)-2-((2-(2,6-difluoro-4-(isoxazole-3-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1218] [ka]

[1219] Intermediate 15-1 (80 mg, 0.12 mmol) was dissolved in methanol (2 mL), NH2OH-HCl (21 mg, 0.30 mmol) was added dropwise to the reaction system, the reaction was heated to 100 °C, and after incubation for 2 hours, the reaction solution was concentrated under reduced pressure and purified by preparative chromatography to obtain compound 16, which was a white solid (34.2 mg, yield 45.4%).

[1220] LC-MS: [M+H] + = 469.4. 1 H NMR (400 MHz, CDCl3):δ8.27 (d, 1H), 7.66(m, 2H), 7.35(s, 1H), 6.82(dd, 1H),3.78(m, 3H), 3.61(s, 3H),3.54(m, 1H),3.30(m, 1H), 3.10(m, 2H), 2.88(m, 1H), 2.63(m, 1H), 2.47(s, 3H).

[1221] (Example 17)

[1222] [ka]

[1223] Step (1)(S)-2-((2-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)-methyl)morpholinyl-4-formate methyl

[1224] [ka]

[1225] Intermediate 2-7 (100 mg, 0.21 mmol), borate ester (64 mg, 0.25 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol), and AcOK (6.2 mg, 0.625 mmol) were taken together, and dioxa (3 mL) was added simultaneously. The mixture was protected with N2, heated to 90 °C, left overnight, and then cooled to room temperature to obtain intermediate 17-2. LC-MS: [M+H] + = 528.2.

[1226] Step (2)(S)-2-((2-(2,6-difluoro-4-(pyridine-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl preparation

[1227] [ka]

[1228] Intermediate 17-2 (55 mg, 0.1 mmol), 2-bromopyridine (18 mg, 0.11 mmol), Na2CO3 (33 mg, 0.31 mmol), and Pd(PPh3)4 (6 mg, 0.005 mmol) were taken, dioxa (3 mL) was added, and a small amount of water was added simultaneously. The mixture was protected with N2, and the temperature was raised to 100 °C. After the reaction was complete, the mixture was filtered, the filtrate was diluted with water, and extracted with EA. The organic phase was washed with NaCl, dried, filtered, concentrated under reduced pressure, and purified by preparative chromatography to obtain compound 17, which was a white solid (25 mg, yield 50%).

[1229] LC-MS: [M+H] + = 479.7. 1 H NMR (400 MHz, CDCl3):δ 8.75 (d, 1H), 8.27 (d, 1H), 7.85(t, 1H), 7.76(dd, 3H), 7.56(m, 1H), 7.35(m, 1H), 6.76(d, 1H), 3.82(s, 3H), 3.68(s, 3H),3.62(s, 1H),3.41(s, 1H), 3.03(dd, 2H), 2.92(s, 1H), 2.64(dd, 1H), 2.47(s, 3H).

[1230] (Example 18) Preparation of (S)-2-((2-(3-fluoro-4-(methylcarbamoyl)-1H-pyrrolyl-2-yl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1231] [ka]

[1232] Intermediate 17-2 (55 mg, 0.1 mmol), 2-bromopyrimidine (19 mg, 0.11 mmol), Na2CO3 (27 mg, 0.31 mmol), and Pd(PPh3)4 (4 mg, 0.005 mmol) were taken, dioxa (3 mL) was added, and a small amount of water was added simultaneously. The mixture was protected with N2, and the temperature was raised to 90 °C. After the reaction was complete, the mixture was filtered, the filtrate was diluted with water, and extracted with EA. The organic phase was washed with NaCl, dried, filtered, concentrated under reduced pressure, and purified by preparative chromatography to obtain compound 18, which was a white solid (25 mg, yield 50%).

[1233] LC-MS: [M+H] + = 480.2. 1 HNMR (400 MHz, CDCl3):δ 8.87 (d, 2H), 8.24 (t, 1H), 8.18(d, 2H), 7.54(s, 1H), 7.30(m, 1H), 6.76(d, 1H), 3.82(s, 3H), 3.72-3.77(m, 3H), 3.68(s, 3H),3.62(s, 1H),3.41(s, 1H),3.03(t, 2H),2.92(s, 1H), 2.64(dd, 1H),2.46(s, 3H).

[1234] (Example 19)

[1235] [ka]

[1236] Step (1) Preparation of 2-(2-((2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)acetate

[1237] [ka]

[1238] 3,5-Difluoro-4-formyl-N-methylbenzamide (200 mg, 1 mmol), 2-amino-4-methylpyridine (108 mg, 1 mmol), methyl propiolate (84 mg, 1 mmol), CuCl (30 mg, 0.3 mmol), and Cu(CF3SO3)2 (109 mg, 0.3 mmol) were dissolved in toluene (3 mL), protected with N2, heated to 85 °C, and simultaneously DMA (0.05 mL) was added. The reaction system was then stirred for 5 hours, cooled to room temperature, left overnight, and the reaction mixture was placed in H2O (5 mL). Extraction was performed with DCM (5 mL × 3), the organic phase was washed with saturated NaCl, dried over MgSO4, the crude product was filtered, concentrated under reduced pressure, separated and purified by column (PE:EA = 1:1), and intermediate 19-3 was obtained, which was a yellow oily substance (172 mg, yield 25%). LC-MS: [M+H] + = 374.4.

[1239] Step (2) Preparation of 4-(3-(2-amino-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine)-3,5-difluoromethylbenzamide

[1240] [ka]

[1241] Intermediate 19-3 (82 mg, 0.22 mmol) was dissolved in methanol (2 mL), NH3·H2O (1 mL) was added to the reaction system, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative chromatography to obtain compound 19, which was a white solid (25 mg, yield 32%).

[1242] LC-MS: [M+H] + = 359.8. 1 HNMR (400 MHz, CD3OD): δ 8.36 (d, 1H), 7.63(d, 2H), 7.46(s, 1H), 7.02(d, 1H), 3.93(s, 2H), 2.97(s, 3H), 2.52(s, 3H).

[1243] (Example 20)

[1244] [ka]

[1245] Step (1) Preparation of (S)-2-((2-(3,5-difluorophenyl)carbamoyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate Tert-butyl

[1246] [ka]

[1247] Under room temperature conditions, a solution of intermediate 1-8 (400 mg, 1.07 mmol) and HATU (608 mg, 1.6 mmol) in DMF (5 mL) was stirred for 10 minutes. Then, under room temperature conditions, DIPEA (418 mg, 3.24 mmol) and compound 20-1 (168 mg, 1.3 mmol) were added and reacted for 1 hour. After the reaction was complete, water (15 mL) was added to quench the mixture, and it was extracted with dichloromethane (10 mL x 3). The mixture was washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column (DCM / MeOH, 10 / 1) to obtain intermediate 20-2, which was a yellow oily liquid (450 mg).

[1248] Step (2) Preparation of (S)-N-(3,5-difluorophenyl)-7-methyl-3-(morpholinyl-2-ylmethyl)imidazo[1,2-a]pyridine-2-formamide

[1249] [ka]

[1250] Under 0°C conditions, hydrochloric acid ethanol solution (1 mL) was added dropwise to a solution of intermediate 20-2 (330 mg, 0.7 mmol) in DCM (4 mL). The reaction was allowed to proceed at room temperature for 1 hour until the reaction was complete. After completion, the mixture was quenched with saturated NaHCO3 under 0°C conditions, extracted with dichloromethane (3 mL × 3), washed with saturated sodium chloride solution (3 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column (DCM / MeOH, 10 / 1) to obtain intermediate 20-3, which was a brown solid (80 mg, yield 31%).

[1251] Step (3) Preparation of (S)-2-((2-(3,5-difluorophenyl)carbamoyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-ethyl acetate

[1252] [ka]

[1253] Under 0°C conditions, methyl chloroformate (1 mL) was added to a solution of intermediate 20-3 (80 mg, 0.2 mmol) and DIPEA (25 mg, 0.6 mmol) in DCM (2 mL), and the reaction was allowed to proceed for 1 hour. After the reaction was complete, water (3 mL) was added, followed by extraction with dichloromethane (3 mL x 3), washing with saturated sodium chloride solution (3 mL x 2), drying over anhydrous sodium sulfate, and concentration under reduced pressure. The compound was then purified by preparative HPLC to obtain compound 20, which was a white solid (15 mg, yield 16%).

[1254] LC-MS: [M + H] + = 459.7. 1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 7.52 (s, 3H), 6.90 (s, 1H), 6.59 (t, J = 8.7 Hz, 1H), 4.23 (d, J = 9.8 Hz, 1H), 4.16 (dd, J = 14.1, 7.1 Hz, 2H), 3.96 - 3.79 (m, 3H), 3.75 (d, J = 12.2 Hz, 1H), 3.41 (dd, J = 11.9, 9.2 Hz, 1H), 3.35 - 3.19 (m, 1H), 2.99 - 2.85 (m, 1H), 2.84 - 2.73 (m, 1H), 2.50 (s, 3H), 1.35 - 1.18 (m, 3H).

[1255] (Example 21)

[1256] [ka]

[1257] Step (1) Preparation of 5-formyl-N-methylthienyl-2-formamide

[1258] [ka]

[1259] Under 0°C conditions, oxalyl chloride (447 mg, 1.1 mmol) was added to a solution of 5-formylthienyl-2-carboxylic acid (500 mg, 3.2 mmol) and DMF (12 mg), and the reaction was allowed to proceed at the same temperature for 2 hours. Within 10 minutes, aqueous methylamine solution (40% content, 746 mg, 9.6 mmol) was added, and after the reaction was complete, 3 mL of water was added to quench the mixture. The solution was extracted with dichloromethane (5 mL x 3), washed with saturated sodium chloride solution (5 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA, 1 / 1) to obtain compound 21-2, which was a white solid (300 mg, yield 56%). LC-MS: [M+H] + The result was 170.9.

[1260] Step (2)(S)-2-((7-methyl-2-(5-(methylcarbamoyl)thienyl-2-yl)imidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate Tert-butyl

[1261] [ka]

[1262] Under room temperature conditions, a solution of compound 21-2 (500 mg, 2.96 mmol), 4-methylpyridine-2-amine (320 mg, 2.96 mmol), and compound 1-4 (625 mg, 2.96 mmol) in toluene (5 mL) was prepared. Cuprous chloride (88 mg, 0.89 mmol) and copper(II) trifluoromethanesulfonate (321 mg, 0.89 mmol) were added. The reaction mixture was heated to 85 °C under nitrogen gas protection, DMA (0.05 mL) was added, and the reaction was allowed to proceed at this temperature for 5 hours. After the reaction was complete, water (5 mL) was added to quench the mixture, and it was extracted with dichloromethane (5 mL × 3). The mixture was washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column (DCM / MeOH, 40 / 1) to obtain intermediate 21-3, which was a yellow oily liquid (300 mg, yield 56%). LC-MS: [M+H]+ The result was 471.7.

[1263] Step (3)(S)-5-(7-methyl-3-(morpholinyl-2-yl-methyl)imidazo[1,2-a]pyridine-2-yl)thienyl-2-formamide preparation

[1264] [ka]

[1265] Under 0°C conditions, add 0.5 mL, 33% hydrochloric acid ethanol solution to a 4 mL solution of intermediate 21-3 (400 mg, 0.85 mmol) of DCM, and allow the reaction to proceed at room temperature for 1 hour. After the reaction is complete, quench with saturated NaHCO3 under 0°C conditions, extract with dichloromethane (5 mL x 3), wash with saturated sodium chloride solution (5 mL x 2), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to 300 ml. Intermediate 21-4 was obtained in mg, which was a yellow oily liquid, and LC-MS: [M+H] + The result was 371.8.

[1266] Step (4) Preparation of (S)-2-((7-methyl-2-(5-(methylcarbamoyl)thienyl-2-yl)imidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1267] [ka]

[1268] Under 0°C conditions, methyl chloroformate (31 mg, 0.33 mmol) was added to a solution of intermediate 21-4 (100 mg, 0.27 mmol) and DIPEA (105 mg, 0.81 mmol) in DCM (2 mL), and the reaction was allowed to proceed for 3 hours. After the reaction was complete, water (3 mL) was added, followed by extraction with dichloromethane (3 mL x 2), washing with saturated sodium chloride solution (3 mL x 2), drying over anhydrous sodium sulfate, and concentration under reduced pressure. The compound was then purified by preparative HPLC to obtain compound 21, which was a yellow solid (28.5 mg, yield 28%).

[1269] LC-MS: [M + H] + = 429.7. 1 H NMR (400 MHz, MeOD): δ 8.32 (d, J = 7.0 Hz, 1H), 7.67 (d, J = 3.9 Hz, 1H), 7.52 (d, J = 3.8 Hz, 1H), 7.31 (s, 1H), 6.88- 6.80 (m, 1H), 4.13 (d, J = 12.8 Hz, 1H), 3.92 - 3.75 (m, 3H), 3.72 (s, 3H), 3.46 - 3.28 (m, 3H), 3.01 (m, 1H), 2.94 (s, 3H), 2.91 (m, 1H), 2.44 (s, 3H).

[1270] (Examples 22-24) The product was manufactured using the method described in Example 21, with appropriate starting materials.

[1271] [Table 1]

[1272] (Example 25)

[1273] [ka]

[1274] Step (1) Preparation of (3,5-difluoro-4-formylphenyl)-benzyl carbamate

[1275] [ka]

[1276] Compound 2-2 (1 g, 4.5 mmol) was added to toluene (20 mL) at room temperature, along with cesium carbonate (2 g, 6.3 mmol), benzyl carbamate (0.8 g, 5.4 mmol), (±)-2,2'-bis-(diphenylphosphin)-1,1'-binaphthyl (0.28 g, 0.45 mmol), and tris(dibenzylideneacetone)palladium (0.2 g, 0.2 mmol). After completion, the mixture was purged three times with nitrogen gas, then heated to 100°C under nitrogen protection, stirred overnight, and reacted for 16 hours. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EA / PE=1 / 10) to obtain intermediate 25-1, which was a yellow solid (0.72 g, yield 55.2%). LC-MS: [M+H] + The result was 292.1.

[1277] Step (2) Preparation of (S)-2-((2-(4-(((benzyloxy)-carbonyl)amino)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate Tert-butyl

[1278] [ka]

[1279] Compound 25-1 (0.2 g, 0.68 mmol), compounds 1-4 (0.22 g, 1.03 mmol), and compounds 1-5 (74 mg, 0.68 mmol), cuprous chloride (20 mg, 0.2 mmol), copper trifluoromethanesulfonate (74 mg, 0.2 mmol), and toluene (6 mL) were added to a 20 mL microtube (Biotage). After completion, the tube was bubbling with nitrogen gas for 2 minutes, sealed, and reacted overnight at 120 °C for 16 hours. A new spot was observed on a thin-layer chromatography plate (PE / EA = 1 / 1) with an Rf value of approximately 0.3, and it was detected as the target product by liquid chromatography. After cooling to room temperature and concentrating under reduced pressure, the sample was mixed with silica gel and purified by silica gel column chromatography (EA / PE = 1 / 1) to obtain intermediate 25-2, which was a yellow solid (184 mg, yield 45.5%). LC-MS: [M+H] + = 593.6.

[1280] Step (3) Preparation of (S)-2-((2-(4-(((benzyloxy)carbonyl)amino)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1281] [ka]

[1282] At room temperature, intermediate 25-2 (0.8 g, 1.35 mmol) was added to ethyl acetate hydrochloric acid solution (concentration approximately 4 M, 5 mL). After completion, the mixture was stirred at room temperature for 2 hours, and liquid chromatography detected completion of the reaction. The mixture was concentrated under reduced pressure to obtain the crude product, and dichloromethane (5 mL), triethylamine (0.4 g, 4 mmol), and methyl chloroformate (0.19 g, 2 mmol) were added. After completion, the mixture was stirred at room temperature for 3 hours, and liquid chromatography detected completion of the reaction. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain (EA) intermediate 25-3, which was a brown oily substance (675 mg, yield 90.8%). LC-MS: [M+H] + = 551.2.

[1283] Step (4) Preparation of (S)-2-((2-(4-amino-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1284] [ka]

[1285] Palladium hydroxide (approximately 40 mg, 20% w / w) was added to a 10 mL methanol solution of intermediate 25-3 (200 mg, 0.363 mmol) at room temperature. After completion, the mixture was purged three times with a hydrogen balloon. The reaction system was stirred under a hydrogen gas atmosphere at room temperature for 4 hours, and completion of the reaction was detected by liquid chromatography. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain (EA) intermediate 25-4, which was a yellow solid (111 mg, 74% yield). LC-MS: [M+H] + = 417.2.

[1286] Step (5) Preparation of (S)-4-((3,5-difluoro-4-(3((4-(methoxycarbonyl)morpholinyl-2-yl)methyl)-7-methylimidazolyl[1,2-a]pyridine-2-yl)-phenyl)-amino)-4-oxobutyrate

[1287]

Chem.

[1288] At room temperature, triethylamine (24 mg, 0.24 mmol) and succinic anhydride (28.8 mg, 0.288 mmol) were added to a toluene (5 mL) solution of intermediate 25-4 (100 mg, 0.24 mmol). After completion, it was heated at 80 °C for 4 h, and it was detected by liquid chromatography that the reaction was complete. After concentration under reduced pressure, it was purified by high performance liquid preparative chromatography (ammonium bicarbonate method), freeze-dried to obtain Compound 25, which was a white solid (90 mg, yield 72.5%).

[1289] LC-MS: [M+H] + = 517.1。 1 H NMR (400 MHz, CD3OD): δ8.39 (d, J = 7.2 Hz, 1H), 7.46-7.38 (m, 2H), 7.33 (s, 1H), 6.87-6.85 (m, 1H), 3.85-3.58 (m, 3H), 3.67 (s, 3H), 3.​​​​​​​​​​​​​​​​​At room temperature, a solution of compound 25 (77.6 mg, 0.15 mmol) in acetic anhydride (2 ml) was mixed with sodium acetate (9.2 mg, 0.11 mmol), and the mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, the mixture was subjected to high-performance liquid preparative sampling. The compound 26 was purified by chromatography (trifluoroacetic acid method) and freeze-dried to obtain a white solid (30 mg, 40% yield).

[1293] LC-MS: [M+H] + = 499.1. 1 H NMR (400 MHz, CD3OD): δ8.84 (d, J = 6.8 Hz, 1H), 7.72 (s, 1H), 7.44-7.40 (m, 3H), 4.02-3.99 (m, 1H), 3.82-3.69 (m, 2H), 3.67 (s, 3H), 3.35-3.24 (m, 5H), 2.92-2.88 (m, 4H), 2.76-2.71 (m, 1H), 2.64 (s, 3H).

[1294] (Example 27) (S,E)-4-((3,5-difluoro-4-(3((4-(methoxycarbonyl)-morpholinyl-2-yl)-methyl)-7-methylimidazolyl[1,2-a]pyridine-2-yl)-phenyl)-amino)-4-oxobutyl-2-enoic acid

[1295] [ka]

[1296] At room temperature, maleic anhydride (7 mg, 0.071 mmol) was added to a solution of intermediate 25-4 (20 mg, 0.048 mmol) in tetrahydrofuran (5 mL). After completion, the mixture was heated to 60 °C and reacted overnight for 16 hours. Liquid chromatography detected completion of the reaction. The mixture was concentrated under reduced pressure, purified by high-performance liquid preparative chromatography (trifluoroacetic acid method), and lyophilized to obtain compound 27, which was a white solid (16 mg, yield 65%).

[1297] LC-MS: [M+H] + = 515.9. 1 H NMR (400 MHz, DMSO-d6): δ12.9 (br, 1H), 10.88 (s, 1H), 8.78 (d, J = 2.8 Hz, 1H), 7.68 (s, 1H), 7.56 (d, J = 10.4 Hz, 2H), 7.31-7.30 (m, 1H), 6.53 (d, J = 12 Hz, 1H), 6.37 (d, J = 12 Hz, 1H), 3.90-3.87 (m, 1H), 3.76-3.62 (m, 3H), 3.57-3.54 (m, 3H), 3.25-3.07 (m, 4H), 2.85-2.80 (m, 1H), 2.52 (overlap, 3H).

[1298] (Example 28) Preparation of (S)-2-((2-(2,6-difluoro-4-(2,5-dioxo-2,5-dihydropyrrolyl-1yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3yl)methyl)morpholinyl-4-formate methyl

[1299] [ka]

[1300] At room temperature, a solution of compound 27 (100 mg, 0.25 mmol) in acetic anhydride (3 mL) was mixed with sodium acetate (32.7 mg, 0.4 mmol) and stirred at room temperature for 4 hours. After concentration under reduced pressure, the mixture was purified by high-performance liquid preparative chromatography (trifluoroacetic acid method), lyophilized, and compound 28 was obtained, which was a white solid (40 mg, 30% yield).

[1301] LC-MS: [M+H] + = 497.1. 1H NMR (400 MHz, CD3OD): δ8.83 (d, J = 7.2 Hz, 1H), 7.71 (s, 1H), 7.56-7.52 (m, 2H), 7.43-7.39 (m, 1H), 7.68 (s, 2H), 4.02-3.99 (m, 1H), 3.83-3.69 (m, 3H), 3.67 (s, 3H), 3.36-3.33 (m, 1H), 3.30-3.22 (m, 2H), 2.92-2. 3H).

[1302] (Example 29) Preparation of (S,E)-2-((2-(2,6-difluoro-4-(4-amino-4-oxobutyl-2-enamide)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1303] [ka]

[1304] At room temperature, compound 28 (20 mg, 0.04 mmol) was dissolved in acetonitrile (3 mL) and ammonium bicarbonate aqueous solution (5%, 2 mL) was added, and the mixture was reacted at room temperature for 2 hours. After concentration under reduced pressure, the mixture was purified by high-performance liquid preparative chromatography (ammonium bicarbonate method), and then freeze-dried to obtain compound 29, which was a white solid (10 mg, 40% yield).

[1305] LC-MS: [M+H] + = 514.1. 1 H NMR (400 MHz, DMSO-d6): δ11.36 (s, 1H), 8.38 (d, J = 7.2 Hz, 1H), 7.93 (s, 1H), 7.45-7.42 (m, 3H), 7.33 (s, 1H), 6.82-6.80 (m, 1H), 6.35-6.28 (m, 2H), 3.73-3.62 (m, 3H), 3.55 (s, 3H), 3.51-3.46(m, 1H), 3.25-3.22 (m, 2H), 3.02-3.00 (m, 2H), 2.83-2.79 (m, 1H), 2.37 (s, 3H).

[1306] (Example 30)

[1307] [ka]

[1308] Step (1) Preparation of (1-acetylpiperidine-4-yl)methylacetate

[1309] [ka]

[1310] 4-Hydroxymethylpiperidine (5.2 g, 45.15 mmol) was dissolved in dichloromethane (60 mL), triethylamine (13.5 g, 133.61 mmol) was added, the temperature was reduced to 0 °C, and acetic anhydride (13.8 g, 135.4 mmol) was added to the reaction system. The reaction was carried out at room temperature for 15 hours. The reaction mixture was washed with 1 N dilute hydrochloric acid (40 mL), the organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated. Compound 30-3 was obtained, which was a yellow oily liquid (6.2 g).

[1311] Step (2) Preparation of 1-(4-(hydroxymethyl)piperidine-1-yl)ethane-1-one

[1312] [ka]

[1313] 6.2 g of compound 30-3 was dissolved in methanol (50 mL), and 25 mL of 3.75 N lithium hydroxide aqueous solution was added. The mixture was stirred at room temperature for 12 hours, and the reaction solution was concentrated and separated by column chromatography (EA / MeOH = 50 / 1) to obtain compound 30-4, which was a colorless oily liquid (7.5 g). LC-MS: [M + H] + = 158.0.

[1314] Step (3) Production of 1-acetylpiperidine-4-formaldehyde

[1315] [ka]

[1316] Compound 30-4 (3.2 g, 20.35 mmol) was dissolved in dichloromethane (40 mL), Dess-Martin oxidizing agent (12.9 g, 30.52 mmol) was added, and the reaction was carried out at room temperature for 1.5 hours. The reaction was quenched with saturated sodium thiosulfate solution (20 mL), diluted with water (40 mL), extracted with dichloromethane (40 mL x 2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (EA~EA / MeOH = 50 / 1) to obtain compound 30-5, which was a white solid (1.0 g, yield 31%). LC-MS: [M + H] + = 156.1.

[1317] Step (4) Preparation of (S)-2-((2-(1-acetylpiperidine-4-yl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate Tert-butyl

[1318] [ka]

[1319] Compound 30-5 (200 mg, 1.29 mmol) was dissolved in anhydrous toluene (40 mL), and 4-methyl-2-aminopyridine (140 mg, 1.29 mmol), t-butyl(S)-2-ethynylmorpholinyl-4-carboxylic acid ester (272 mg, 1.29 mmol), cuprous chloride (40 mg, 0.4 mmol), and copper trifluoromethanesulfonate (140 mg, 0.39 mmol) were added. Under the protection of nitrogen gas, the reaction mixture was heated to 85 °C, and then 2 drops of N,N-dimethylacetamide were added. The mixture was continued to heat, stirred for 6 hours, cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the filtrate was concentrated, and separated by column chromatography. The liquid phase was DCM / MeOH (20 / 1), and intermediate 30-6 was obtained as a yellow solid (227 mg, yield 38%). LC-MS: [M + H] + = 456.8.

[1320] Step (5) Preparation of (S)-1-(4-(7-methyl-3-(morpholinyl-2-ylmethyl)imidazo[1,2-a]pyridine-2-yl)piperidine-1-yl) acetamide

[1321] [ka]

[1322] Intermediate 30-6 (227 mg, 0.49 mmol) was dissolved in ethanol (2 mL), and a hydrogen chloride-ethanol solution (1 mL, 33%) was added. The mixture was stirred at room temperature for 1.5 hours, and the reaction mixture was concentrated to obtain 250 mg of crude intermediate 30-7, which was used directly in the next reaction. LC-MS [M + H] + = 357.8.

[1323] Step (6) Preparation of (S)-2-((2-(1-acetylpiperidine-4-yl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1324] [ka]

[1325] Intermediate 30-7 (356 mg) was dissolved in dichloromethane (5 mL), and pyridine (244 mg, 3.09 mg) was added. ( mmol) was added, followed by methyl chloroformate (62 mg, 0.65 mmol). The mixture was stirred at room temperature for 1.5 hours, and the reaction solution was concentrated to obtain product compound 30 (360 mg, yield 87%).

[1326] LC-MS: [M +H] + = 415.6. 1 HNMR (400MHz, MeOD): δ 8.42(s, 1H), 7.56(d, 1H), 6.91 (d, 1H), 3.82(m, 3H), 3.67(s, 3H), 3.60(m, 1H), 3.54(t, 4H) 3.38( dd, 1H), 3.12( m, 2H), 2.90(m, 2H), 2.83(m, 2H), 2.64(m, 2H), 2.10(s, 3H), 1.69(m, 4H).

[1327] (Example 31)

[1328] [ka]

[1329] Step (1) Preparation of methyl 4-bromo-3,5-difluorobenzoate

[1330] [ka]

[1331] 4-Bromo-3,5-difluorobenzoic acid (11.5 g, 48.5 mmol) was dissolved in methanol (100 mL), concentrated sulfuric acid (1.0 mL) was added, and the reaction was carried out under reflux for 15 hours. The reaction mixture was concentrated and diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. Separation by column chromatography (PE) yielded compound 31-2, which was a colorless oily liquid (10 g, yield 82%).

[1332] Step (2) Preparation of methyl 4-(1-ethoxyvinyl)-3,5-difluorobenzoate

[1333] [ka]

[1334] Compound 31-2 (10.0 g, 39.83 mmol) was dissolved in anhydrous toluene (90 mL), and palladium acetate (449 mg, 2 mmol), triphenylphosphine (2.0 g, 8.0 mmol), and tributyl(1-ethoxyvinyl) stannane (15.9 g, 44 mmol) were added. The mixture was refluxed overnight under nitrogen protection. The reaction mixture was concentrated and diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 3). The ethyl acetate layer was combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE) to obtain compound 31-4, which was a colorless liquid (7.4 g, yield 76%). LC-MS: [M + H] + = 214.8 / 242.8.

[1335] Step (3) Preparation of methyl 4-(2-bromoacetyl)-3,5-difluorobenzoate

[1336] [ka]

[1337] Compound 31-4 (7.4 g, 30.46 mmol) was dissolved in tetrahydrofuran (60 mL) and water (20 mL). N-bromosuccinimide (5.4 g, 30.46 mmol) was added, and the mixture was reacted at room temperature for 1 hour under the protection of nitrogen gas. The reaction solution was concentrated to half its volume, diluted with water (60 mL), extracted with ethyl acetate (30 mL x 3), the ethyl acetate layer was combined, dried over anhydrous sodium sulfate, and concentrated to obtain intermediate 31-5, which was a yellow solid (9.0 g). LC-MS: [M+H] + = 292.5.

[1338] Step (4) Preparation of methyl 3,5-difluoro-4-(7-methylimidazo[1,2-a]pyridine-2-yl)benzoate

[1339] [ka]

[1340] Intermediate 31-5 (9.0 g) was dissolved in ethanol (90 mL), 4-methyl-2-aminopyridine (3.3 g, 30.47 mmol) was added, and the mixture was refluxed for 12 hours under nitrogen protection. The reaction mixture was concentrated and diluted with water (60 mL), the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (40 mL x 3). The ethyl acetate layer was combined, dried over anhydrous sodium sulfate, concentrated, and then separated and purified by column chromatography (PE / EA = 1 / 1) to obtain intermediate 31-6, which was a yellow solid (4.2 g, yield 56%). LC-MS: [M + H] + = 303.8.

[1341] Step (5) Preparation of 3,5-difluoro-N-methyl-4-(7-methylimidazo[1,2-a]pyridine-2-yl)benzamide

[1342] [ka]

[1343] Intermediate 31-6 (1.5 g, 4.96 mmol) was dissolved in ethanol (15 mL), and an aqueous methylamine solution (6 mL, 25-30%) was added. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was concentrated and separated by column chromatography (EA~EA / MeOH = 50 / 1) to obtain intermediate 31-7, which was a yellow solid (1.1 g, yield 73%). LC-MS: [M +H] + = 302.8.

[1344] Step (6) Preparation of 3,5-difluoro-4-(7-methyl-3-((3-oxopiperazin-1-yl)methyl)imidazo[1,2-a]pyridine-2-yl)benzamide

[1345] [ka]

[1346] Intermediate 31-7 (150 mg, 0.49 mmol) and piperazine-2-one (50 mg, 0.49 mmol) were dissolved in acetic acid (1 mL), aqueous formaldehyde (40 mg, 37%) was added, the temperature was raised to 50°C and the reaction was allowed to proceed for 3 hours, then the temperature was lowered to room temperature and the mixture was stirred for 12 hours. The reaction solution was diluted with dichloromethane (10 mL), and the pH was adjusted to 8 with 2 N aqueous sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (10 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography (DCM / MeOH = 20 / 1) to obtain compound 31, which was a white solid (39.2 mg, yield 19%).

[1347] LC-MS: [M +H] + = 414.8. 1 H NMR (400 MHz, MeOD): δ 8.52 (d, J = 7.1 Hz, 1H), 7. 62 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 6.94 (dd, J = 7.1, 1.5 Hz, 1H), 3.90 (s, 2 H), 3.21 (t, J = 5.4 Hz, 2H), 3.05 (s, 2H), 2.97 (s, 3H), 2.66 - 2.54 (m, 2H), 2.48 (s, 3H).

[1348] (Example 32)

[1349] [ka]

[1350] Step (1) Preparation of methyl piperazine-1-carboxylate

[1351] [ka]

[1352] Piperazine (3 g, 34.8 mmol) was dissolved in dichloromethane (50 mL), and methyl chloroformate (658 mg, 6.96 mmol) was added in several portions. The reaction was allowed to proceed at room temperature for 30 minutes. The reaction mixture was quenched with aqueous potassium hydroxide solution (50 mL, 1 N), extracted with dichloromethane (50 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to obtain a white solid (1.8 g, yield 36%). LC-MS: [M + H] + = 145.7.

[1353] Step (2) Preparation of (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)piperazine-4-formate methyl

[1354] [ka]

[1355] Intermediate 31-7 (150 mg, 0.49 mmol) and compound 32-2 (180 mg) were dissolved in acetic acid (1 mL), aqueous formaldehyde (40 mg, 37%) was added, the temperature was raised to 50 °C and the reaction was allowed to proceed for 3 hours, then the temperature was lowered to room temperature and stirred for 12 hours. The reaction mixture was diluted with dichloromethane (10 mL), and the pH was adjusted to 8 with 2N aqueous sodium hydroxide. The aqueous layer was extracted with dichloromethane (15 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and separated by HPLC to obtain compound 32, which was a white solid (98.2 mg, yield 43%). LC-MS: [M +H] + = 458.7. 1 HNMR: 1 H NMR (400 MHz, MeOD): δ 8.55 (d, J = 7.0 Hz, 1H), 7.60 (d, J = 7.9 Hz, 2H), 7.39 (s, 1H), 6.94 (d, J = 7.1 Hz, 1H), 3.80 (s, 2H), 3.66 (s, 3H), 3.47 - 3.36 (m, 4H), 2.97 (s, 3H), 2.49 (s, 3H), 2.37 - 2.29 (m, 4H).

[1356] (Example 33) Preparation of 3,5-difluoro-4-(7-methyl-3-morpholinylmethylimidazo[1,2-a]pyridine-2-yl)benzamide

[1357] [ka]

[1358] Intermediate 31-7 (100 mg, 0.33 mmol) and morpholinil (29 mg, 0.33 mmol) were dissolved in acetic acid (0.5 mL), and aqueous formaldehyde (28 mg, 37%) was added. The mixture was heated to 50°C and reacted for 3 hours, then cooled to room temperature and stirred for 12 hours. The reaction mixture was diluted with dichloromethane (10 mL), and the pH was adjusted to 8 with 2N aqueous sodium hydroxide. The aqueous layer was extracted with dichloromethane (15 mL x 2) to combine the organic phases, dried over anhydrous sodium sulfate, concentrated, and separated by HPLC to obtain compound 33, which was a white solid (50.2 mg, yield 38%).

[1359] LC-MS: [M +H] + = 401.7. 1 HNMR (400 MHz, CDCl3): δ 8.44 (d, J = 7.0 Hz, 1H), 7. 58 - 7.37 (m, 4H), 6.80 (d, J = 6.9 Hz, 1H), 3.71 (s, 2H), 3.67 - 3.60 (m, 4H), 3.03 (d, J = 4.6 Hz, 3H), 2.48 (s, 3H), 2.39 - 2.31 (m, 4H).

[1360] (Example 34)

[1361] [ka]

[1362] Step (1) Preparation of tert-butyl 3,5-difluorobenzoate

[1363] [ka]

[1364] 3,5-Difluorobenzoic acid (10.0 g, 63.25 mmol) was dissolved in tert-butyl alcohol (100 mL), and DMAP (2.3 g, 18.98 mmol) and di-t-butyl dicarbonate (27.6 g, 126.50 mmol) were added. The reaction was allowed to proceed at room temperature for 15 hours. The reaction mixture was concentrated and diluted with water (80 mL), and extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. Separation by column chromatography (PE / EA = 20 / 1) yielded compound 34-2, which was a colorless oily liquid (12.0 g, yield 88%).

[1365] Step (2) Preparation of tert-butyl 3,5-difluoro-4-formylbenzoate

[1366] [ka]

[1367] LDA (2 N, 8.4 mL) was dissolved in tetrahydrofuran (10 mL) and cooled to -78 °C under the protection of nitrogen gas. Compound 34-2 (3.0 g, 14.0 mmol) was dissolved in tetrahydrofuran (20 mL) and added to the reaction system. The mixture was stirred at -78 °C for 1.5 hours, then DMF (1.2 g, 16.8 mmol) was added, and the mixture was stirred for another hour, during which time the temperature was maintained not to exceed -70 °C. The reaction was quenched with saturated ammonium chloride solution (60 mL) and extracted with ethyl acetate (30 mL x 3). The ethyl acetate layer was combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE / EA = 10 / 1) to obtain compound 34-3, which was a yellow solid (1.5 g, yield 44%).

[1368] Step (3)(S) Preparation of Tert-butyl (2-(4-(t-butoxycarbonyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-formate

[1369] [ka]

[1370] Compound 34-3 (480 mg, 1.98 mmol) was dissolved in anhydrous toluene (4 mL), and 4-methyl-2-aminopyridine (215 mg, 1.98 mmol), (S)-2-ethynylmorpholinyl-4-carboxylate t-butyl ester (419 mg, 1.98 mmol), cuprous chloride (62 mg, 0.63 mmol), and copper trifluoromethanesulfonate (216 mg, 0.60 mmol) were added. Under the protection of nitrogen gas, the reaction mixture was heated to 85 °C, and 2 drops of N,N-dimethylacetamide were added. The mixture was then heated and stirred for 6 hours, cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the filtrate was concentrated, and separated by column chromatography to obtain intermediate 34-4, with an eluent PE / EA = 2 / 1, which was a brown solid (340 mg, yield 31%). LC-MS: [M+H] + = 544.7.

[1371] Step (4) Preparation of (S)-3,5-difluoro-4-(7-methyl-3-(morpholinyl-2methyl)imidazo[1,2-a]pyridine-2-yl)benzoic acid

[1372] [ka]

[1373] Intermediate 34-4 (340 mg, 0.62 mmol) was dissolved in ethanol (3 mL), and hydrogen chloride-ethanol solution (1 mL, 33%) was added. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to obtain intermediate 34-5, which was a yellow oily liquid (400 mg). LC-MS: [M + H] + = 388.7.

[1374] Step (5) Preparation of (S)-3,5-difluoro-4-(3-((4-(methoxycarbonyl)morpholinyl-2-yl)methyl)-7-methylimidazo[1,2-a]pyridine-2-yl)benzoic acid

[1375] [ka]

[1376] Intermediate 34-5 (400 mg) was dissolved in dichloromethane (5 mL), and pyridine (244 mg, 3.09 mg) was added. (mol) was added, followed by methyl chloroformate (62 mg, 0.65 mmol). The mixture was stirred at room temperature for 1.5 hours, and the reaction solution was concentrated to obtain product intermediate 34-6 (190 mg). LC-MS: [M + H] + = 446.6.

[1377] Step (6)(S) Preparation of methyl morpholinyl-4 formate

[1378] [ka]

[1379] Intermediate 34-6 (445 mg, 1 mmol) was dissolved in CH3CN (10 mL), and triethylamine (1.2 mmol), DMAP (1.2 mmol), and EDCI (1.2 mmol) were added simultaneously. The mixture was stirred overnight at room temperature to complete the reaction, and intermediate 34-7 was obtained by column chromatography (362 mg, 75% yield). LC-MS: [M + H] + = 484.6.

[1380] Step (7) Preparation of (S)-2-((2-(4-(4-chloro-1H-imidazolyl-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1381] [ka]

[1382] Intermediate 34-7 (483 mg, 1 mmol) was dissolved in THF (10 mL), a fixed amount of CCl4 and PPh3 were added to the reaction system, the temperature was raised to 50 °C, the reaction process was monitored by LC-MS, and after the reaction was completed, workup was performed, and the compound was separated and purified by silica gel column to obtain compound 34 (50 mg, yield 10%). LC-MS: [M + H] + = 502.1.

[1383] (Example 35)

[1384] [ka]

[1385] Step (1) Preparation of (S)-2-((2-(2,6-difluoro-4-hydroxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate Tert-butyl

[1386] [ka]

[1387] Under nitrogen gas protection, 2,6-difluoro-4-hydroxybenzaldehyde (2.0 g, 9.05 mmol), 4-methylpyridine-2-amine (0.97 g, 9.05 mmol), compound 1-4 (1.9 g, 9.05 mmol), cuprous chloride (0.27 g, 2.70 mmol), and copper(II) trifluoromethanesulfonate (0.98 g, 2.70 mmol) were dissolved in toluene solution (20 mL), reacted at 85 °C for 10 minutes, then N,N-dimethylacetamide (0.5 mL) was added, and the mixture was reacted at 85 °C for 5 hours, before being turned back to room temperature. After letting it stand overnight and the reaction was complete, water (40 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was combined, washed with saturated brine (50 mL), dried over magnesium sulfate, and after drying, the organic phase was filtered and rotated to evaporate. The crude product was purified by elution using a 40 g silica gel column (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 35-2, which was a yellow oily substance (1.2 g, yield 29%). LC-MS: [M + H] + = 460.1.

[1388] Step (2) Preparation of (S)-3,5-difluoro-4-(7-methyl-3-(morpholinyl-2-ylmethyl)imidazo[1,2-a]pyridine-2-yl)phenol

[1389] [ka]

[1390] Intermediate 35-2 (1.0 g, 1.91 mmol) was dissolved in dichloromethane (10 mL), and hydrogen chloride-ethanol solution (2 mL, 33%) was added dropwise. After the dropwise addition was complete, the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added dropwise to bring the pH of the solution to 8, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL x 3). The organic phase was combined, washed with saturated saline solution (40 mL), dried over magnesium sulfate, and after drying, the organic phase was filtered and rotated to obtain intermediate 35-3, which was a yellow oily substance (800 mg). LC-MS [M + H] + = 360.7.

[1391] Step (3) Preparation of (S)-2-((2-(2,6-difluoro-4-hydroxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1392] [ka]

[1393] Intermediate 35-3 (350 mg, 0.97 mmol) and N,N-diisopropylethylamine (378 mg, 2.92 mmol) were dissolved in dichloromethane (10 mL), and methyl chloroformate (110 mg, 1.16 mmol) was added dropwise, controlling the temperature of the dropwise addition process to 0 °C; after the addition was complete, the mixture was reacted at 0 °C for 3 hours, and after the reaction was complete, lithium hydroxide (1.0 mL, 3 N) solution was added, and the mixture was reacted at room temperature for 2 hours, and after the reaction was complete, the pH was adjusted to 5 with dilute hydrochloric acid, diluted with water (10 mL), extracted with dichloromethane (15 mL × 3), the organic phase was combined, washed with saturated brine (20 mL), dried over magnesium sulfate, and after drying, the organic phase was filtered and rotated to evaporate, concentrated, and separated by HPLC to finally obtain compound 35, a yellow solid product (150 mg, yield 37%).

[1394] LC-MS: [M +H] + = 418.7. 1 H NMR (400 MHz, MeOD): δ 8.57 (d, J = 6.9 Hz, 1H), 7. 47 (s, 1H), 7.08 (d, J = 6.9 Hz, 1H), 6.60 (d, J = 9.6 Hz, 2H), 3.92 - 3.76 (m, 3H), 3.68 (s, 3H), 3.69 - 3.57 (m, 1H), 3.39 (dd, J = 11.9, 2.7 Hz, 1H).3.16 - 3.10 (m, 2H), 2.98 - 2.86 (m, 1H), 2.74 - 2.63 (m, 1H), 2.53 (s, 3H).

[1395] (Example 36) Preparation of (S)-2-((2-(2,6-difluoro-4-(methylaminoformyloxy)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1396] [ka]

[1397] Compound 35 (359 mg, 1 mmol) was dissolved in CH2Cl2 (10 mL), and triethylamine (2 mmol) was added simultaneously. Methylaminoformyl (186 mg, 2 mmol) was dissolved in anhydrous CH2Cl2 (2 mL) and added dropwise to the reaction system. After the reaction was complete, the reaction system was neutralized and washed, dried, filtered, separated by silica gel column, and purified to obtain compound 36 (62 mg, yield 13%). LC-MS [M + H] + = 475.1.

[1398] (Example 37)

[1399] [ka]

[1400] Step (1) Preparation of 2-(3,5-difluorophenyl)-1,3-dioxolane

[1401] [ka]

[1402] 3,5-Difluorobenzaldehyde (5.68 g, 40 mmol), p-toluenesulfonic acid (0.69 g, 4 mmol), and ethylene glycol (7.45 g, 120 mmol) were dissolved in toluene (80 mL), refluxed overnight, and water was separated. The mixture was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed with NaHCO3 solution (40 mL x 2). The organic phase was dried over Na2SO4, filtered, and the filtrate was rotated and evaporated. The filtrate was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound 37-3, which was a white solid (7.0 g, yield 94%).

[1403] 1H NMR (400 MHz, CDCl3): δ 7.03-7.00 (m, 2H), 6.82-6.76 (m, 1H), 5.79 (s, 1H), 4.09-4.05 (m, 2H), 4.07-3.99 (m, 2H).

[1404] Step (2) Preparation of 4-(1,3-dioxolan-2-yl)-2,6-difluorobenzaldehyde

[1405] [ka]

[1406] Compound 37-3 (7.0 g, 37.8 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to -78°C under nitrogen gas protection, LDA (22.4 mL, 44.8 mmol) was added dropwise, and the reaction was allowed to proceed at this temperature for 30 minutes, after which anhydrous DMF (3.3 g, 44.3 mmol) was added dropwise. After completion, the reaction was allowed to proceed at the same temperature for 2.5 hours. The reaction was quenched with saturated NH4Cl (20 mL), diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), and the organic phase was combined with saturated sodium chloride solution (50 mL The mixture was washed with (mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotated and evaporated. The resulting crude product was purified by silica gel column (PE:EA = 10:1) to obtain intermediate 37-4, which was a white solid (0.90 g, yield 12%).

[1407] 1 H NMR (300 MHz, DMSO): δ 10.18 (s, 1H), 7.28 (d, J = 9.8 Hz, 2H), 5.82 (s, 1H), 4.06-4.00 (m, 2H), 4.01-3.93 (m, 2H).

[1408] Step (3) Preparation of (S)-2-((2-(4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate Tert-butyl

[1409] [ka]

[1410] Intermediate 37-4 (100 mg, 0.47 mmol), compound 1-4 (100 mg, 0.47 mmol), 4-methylpyridine-2-amine (51 mg, 0.47 mmol), cuprous chloride (25 mg, 0.14 mmol), and copper trifluoromethanesulfonate (51 mg, 0.14 mmol) were added to a flask, and toluene (3 mL) was dissolved. The mixture was heated to 85 °C under nitrogen gas protection, then 2 drops of DMA were added, and the mixture was reacted at this temperature for 5 hours. After allowing it to return to room temperature, the mixture was stirred overnight. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated brine (20 mL), the organic phase was dried with Na2SO4, filtered, and the filtrate was rotated and evaporated to obtain the crude product, which was purified by silica gel column (PE:EA = 5:1) to obtain intermediate 37-5 (150 mg, yield 62%). LC-MS: [M +H] + = 516.7.

[1411] Step (4) Preparation of (S)-2-((2-(2,6-difluoro-4-formylphenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate Tert-butyl

[1412] [ka]

[1413] Intermediate 37-5 (150 mg, 0.29 mmol) was dissolved in acetone (10 mL) and water (1 mL), TsOH (90 mg, 0.3 mmol) was added, and the mixture was heated to 50 °C and left overnight. Dilution with water (50 mL), Na2CO3 (92 mg, 0.87 mmol) and (Boc)2O (75 mg, 0.35 mmol) were added, the mixture was stirred for 1.5 hours, extracted with ethyl acetate (15 mL × 2), the organic phase was combined, dried over anhydrous Na2SO4, filtered, and the filtrate was rotated and evaporated to obtain the crude product, which was purified by silica gel column (PE:EA = 5:1) to obtain intermediate 37-6, which was a white solid (60 mg, yield 44.8%). LC-MS: [M + H] + = 472.7.

[1414] Step (5) Preparation of (S)-2-((2-(2,6-difluoro-4-(4-trifluoromethyl-1Himidazolyl-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate Tert-butyl

[1415] [ka]

[1416] 3,3-Dibromo-1,1,1-trifluoropropan-2-one (35 mg, 0.13 mmol) was dissolved in sodium acetate (2 mL, 15% by mass) solution, stirred at 90 °C for 30 minutes, and cooled to room temperature. Intermediate 37-6 (50 mg, 0.11 mmol) was dissolved in methanol (3 mL) and concentrated aqueous ammonia (0.6 mL) and added to the reaction system. The mixture was stirred overnight at room temperature. The reaction mixture was rotated and evaporated, the remaining liquid was extracted with ethyl acetate (5 mL × 3), washed with saturated brine (10 mL), the organic phase was dried over Na₂SO₄, filtered, and the filtrate was rotated and evaporated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain intermediate 37-8, which was a white solid (45 mg, yield 72.2%). LC-MS: [M +H] + = 578.6.

[1417] Step (6) Preparation of (S)-2-((2-(2,6-difluoro-4-(4-trifluoromethyl-1Himidazolyl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinil

[1418] [ka]

[1419] Intermediate 37-8 (45 mg, 0.08 mmol) was dissolved in dichloromethane (3 mL), and a hydrochloric acid solution of ethanol (0.5 mL) was added to the system. The mixture was stirred at room temperature for 3 hours, and the reaction mixture was evaporated by rotation to obtain crude intermediate 37-9 (80 mg). LC-MS: [M + H] + = 478.7.

[1420] Step (7) Preparation of (S)-2-((2-(2,6-difluoro-4-(4-trifluoromethyl-1Himidazolyl-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1421] [ka]

[1422] Intermediate 37-9 (80 mg, crude product) and DIPEA (30 mg, 0.23 mmol) were dissolved in dichloromethane (3 mL), the mixture was cooled to 0 °C and stirred for 10 min, then a dichloromethane solution of methyl chloroformate (0.1 N, 0.8 mL) was added dropwise, the mixture was stirred for 3 hours, and then quenched with water (10 mL). Extraction was performed with ethyl acetate (10 mL x 3), the organic phase was dried with Na2SO4 and filtered, and the filtrate was rotated and evaporated to purify the crude product by silica gel column (dichloromethane:methanol = 20:1). The product was then preparatively separated and freeze-dried to obtain compound 37, which was a white solid product (7.0 mg, yield 16.3%).

[1423] LC-MS: [M +H] + = 536.7. 1 H NMR (400 MHz, CDCl3): δ 13.18 (s, 1H), 8.58 (brs, 1H), 7.97 - 7.93 (m, 3H), 7.53 (s, 1H), 7.16 (d, J = 6.0 Hz, 1H), 4.05 - 3.70 (m, 3H), 3.71 (s, 3H), 3.64 - 3.56 (m, 1H), 3.45 - 3.30 (m, 1H), 3.09 - 2.85 (m, 3H), 2.74 - 2.64 (m, 1H), 2.60 (s, 3H).

[1424] (Example 38) Preparation of (S)-2-((2-(2,6-difluoro-4-(4-cyano-1H-imidazolyl-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine-3-yl)methyl)morpholinyl-4-formate methyl

[1425] [ka]

[1426] Compound 37 (30 mg, 0.05 mmol) was dissolved in methanol (2 mL), concentrated aqueous ammonia (0.8 mL) and water (0.8 mL) were added, and the mixture was stirred at room temperature for 36 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was dried with Na2SO4, filtered, and the filtrate was rotated and evaporated to purify the crude product by thin-layer chromatography (dichloromethane:methanol = 20:1), and freeze-dried to obtain compound 38, which was a white solid product (11 mg, yield 44.6%).

[1427] LC-MS: [M +H] + = 493.6. 1 H NMR (400 MHz, CDCl3): δ 15.61 (brs, 1H), 8.31 (d, J = 7.0 Hz, 1H), 7.74 (s, 1H), 7.47 (s, 1H), 7.33 (d, J = 7.2 Hz, 2H), 6.85 (d, J = 7.0 Hz, 1H), 3.97 - 3.72 (m, 3H), 3.66 (s, 3H), 3.62 - 3.52 (m, 1H), 3.42 - 3.30 (m, 1H), 3.03 - 2.85 (m, 3H), 2.65 - 2.55 (m, 1H), 2.54 (s, 3H).

[1428] (Example 39)

[1429] [ka]

[1430] Step (1) Preparation of N-(2-bromo-5-methylphenyl)-2,2,2-trifluoroacetamide

[1431] [ka]

[1432] 2-Bromo-5-methylaniline (2.5 g, 13.44 mmol) and pyridine (3.3 ml, 40.32 mmol) were dissolved in dichloromethane (30 mL). Trifluoroacetic anhydride (3.4 g, 16.12 mmol) was added dropwise at 0 °C, and the mixture was reacted overnight at room temperature. The reaction mixture was washed with water (10 mL x 2), then with dilute hydrochloric acid (30 mL, 1 mol / L), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound 39-3, which was a gray solid (3.4 g, 90% yield). LC-MS: [M + H] + The result was 281.7.

[1433] Step (2) Production of R-(morpholinyl-2-yl)methanol

[1434] [ka]

[1435] (R)-N-Boc-2-hydroxymethylmorpholinyl (3.5 g, 16.13 mmol) was dissolved in dichloromethane (20 mL), and ethanol hydrochloric acid solution (3.5 mL, 33%) was added dropwise at 0°C. The mixture was stirred overnight at room temperature and concentrated under reduced pressure to obtain compound 39-5, which was a yellow, oily crude product (1.8 g, yield 95%). LC-MS: [M+H] + = 118.1.

[1436] Step (3) Preparation of methyl (R)-2-(hydroxymethyl)morpholinyl-4-formate

[1437] [ka]

[1438] Compound 39-5 (4.0 g, 16.13 mmol) was dissolved in dichloromethane (40 mL), DIPEA (12.5 g, 96.78 mmol) was added dropwise at 0 °C, and then methyl chloroformate (1.97 g, 20.97 mmol) was dissolved in dichloromethane (10 mL) and added dropwise to the reaction mixture at 0 °C. The mixture was stirred overnight at room temperature, dichloromethane (100 mL) was added, and the mixture was washed with brine (35 mL x 2). The mixture was concentrated under reduced pressure and separated and purified by column chromatography (20 g silica gel) (ethyl acetate:petroleum ether = 1:2) to obtain intermediate 39-6, which was a colorless oily substance (1.0 g, yield: 35%). LC-MS: [M + H] + = 176.9.

[1439] Step (4) Preparation of (R)-2-formylmorpholinyl-4-formate methyl

[1440] [ka]

[1441] Intermediate 39-6 (600 mg, 3.43 mmol) was dissolved in dichloromethane (10 ml), and Dess-Martin oxidizing agent (1.74 g, 4.11 mmol) was added. The mixture was reacted at room temperature for 2 hours. Saturated sodium thiosulfate (2 mL) was added, and the mixture was stirred for 30 minutes. The mixture was extracted with dichloromethane (30 mL x 2) and washed with brine (15 mL). Purification by silica gel column (12 g silica gel, ethyl acetate:petroleum ether = 1:1) yielded intermediate 39-A, which was a yellow oily substance (180 mg, yield 30%). LC-MS: [M + H] + = 174.5.

[1442] Step (5) Preparation of 4-ethynyl-3,5-difluoro-N-methylbenzamide

[1443] [ka]

[1444] Dimethyl (1-diazo-2-oxopropyl)phosphinate (2.2 g, 11.3 mmol) was dissolved in acetonitrile (15 mL) and methanol (3 mL), and potassium carbonate (2.3 g, 16.56 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and 3,5-difluoro-4-formyl-N-methylbenzamide (1.5 g, 7.53 mmol) was added to the reaction mixture. The mixture was stirred overnight at room temperature, filtered, concentrated, and purified by silica gel column (20 g silica gel, ethyl acetate:petroleum ether = 1:5) to obtain intermediate 39-8, which was a yellow solid (1.2 g, yield 81%). LC-MS: [M + H] + = 196.1.

[1445] Step (6) Preparation of 3,5-difluoro-4-(6-methyl-1H-indole-2-yl)benzamide

[1446] [ka]

[1447] Intermediate 39-8 (1.4 g, 7.18 mmol), intermediate 39-3 (2.43 g, 8.61 mmol), potassium carbonate (1.97 g, 15.09 mmol), copper iodide (0.14 g, 1.43 mmol), and L-proline (0.25 g, 2.87 mmol) were added to N,N-dimethylformamide (20 mL) and reacted overnight at 80°C under nitrogen gas protection. After cooling, the reaction mixture was added to water (60 mL), extracted with ethyl acetate (50 mL x 2), and washed with saturated saline (30 mL x 3). Purification by silica gel column (20 g silica gel, developing solvent: ethyl acetate:petroleum ether = 1:2) yielded intermediate 39-9, which was a yellow solid (800 mg, yield 44%). LC-MS: [M + H] + = 301.8.

[1448] Step (7) Preparation of (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylindole-3-yl)methyl)morpholinyl-4-formate methyl

[1449] [ka]

[1450] In a round-bottom flask (25 mL), trifluoroacetic acid (304 mg, 2.66 mmol) and triethylsilyl (617 mg, 5.32 mmol) were dissolved in dichloromethane (3 mL). Intermediate 39-9 (160 mg, 0.53 mmol) and intermediate 39-A (110 mg, 0.64 mmol) were then dissolved in dichloromethane (3 mL) and added dropwise to the reaction mixture at 0°C. The mixture was stirred overnight at room temperature, water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 2). Separation by reverse-phase preparative chromatography yielded compound 39, which was a white solid (18 mg, yield 7.4%).

[1451] LC-MS: [M +H] + = 458.2. 1H NMR (400 MHz, CDCl3): δ 8.18 (brs, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 7.5 Hz, 2H), 7.21 (s, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.29 (brs, 1H), 3.88 - 3.75 (m, 3H), 3.64 (s, 3H), 3.60 - 3.55 (m, 1H), 3.45-3.39 (m, 1H), 3.07 (d, J = 3.6 Hz, 3H), 3.04 - 2.98 (m, 1H), 2.90-2.88 (m, 1H), 2.78 (dd, J = 14.9, 6.6 Hz, 1H), 2.50 (s, 3H), 2.49 - 2.41 (m, 1H).

[1452] (Example 40)

[1453] [ka]

[1454] Step (1) Preparation of (R)-2-(((methylsulfonyl)oxo)methyl)morpholinyl-4-formate methyl

[1455] [ka]

[1456] Intermediate 39-6 (400 mg, 2.28 mmol) and N,N-diisopropylethylamine (737 mg, 5.71 mmol) were dissolved in dichloromethane (10 mL). Methanesulfonyl chloride (313 mg, 2.74 mmol) was added dropwise at 0°C, and after the addition was complete, the mixture was allowed to react overnight at room temperature. Dichloromethane (20 mL) was added, the mixture was washed with saturated saline (15 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 40-1, which was a 600 mg brown oily crude product. LC-MS: [M + H] += 254.9.

[1457] Step (2)(S) Preparation of methyl morpholinyl-4-formate

[1458] [ka]

[1459] Intermediate 39-9 (250 mg, 0.83 mmol) was dissolved in N,N-dimethylformamide (5 mL), and intermediate 40-1 (421 mg, 1.67 mmol) and potassium tert-butoxide (205 mg, 1.83 mmol) were added at room temperature. The mixture was stirred overnight at 120 °C under nitrogen gas protection. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was combined, washed with saturated brine (15 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by reverse-phase preparative chromatography to obtain the final compound 40, which was a white solid (35 mg, yield: 9.2%).

[1460] LC-MS: [M +H] + = 458.8. 1 H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.22 (s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.61 (s, 1H), 6.22 (brs, 1H), 4.15 - 3.99 (m, 2H), 3.85 - 3.60 (m, 3H), 3.67 (s, 3H), 3.6...

Claims

1. A heterocyclic compound represented by formula I, its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, or pharmaceutically acceptable salts, 【Chemistry 1】 Eventually, 【Chemistry 2】 teeth, 【Transformation 3】 And, m is 1, 2, 3, or 4; R 3 H, halogen, -OH, halo C 1 ~C 6 Alkyl alkyl group, -CN or C 1 ~C 6 It is an alkyl group; if m is not 1, R 3 They are independently homologous or different. W is a single bond; 【Chemistry 4】 It is a phenyl group; n is 1, 2, 3, or 4; R 1 is independently H, halogen, -OH, -CN, unsubstituted or substituted C 1 to C 6 alkyl group, or unsubstituted or substituted C 1 to C 6 alkyl group -O-; the substituted C 1 to C 6 alkyl group, or the substituted C 1 to C 6 alkyl group -O- has, for each substitution, independently, a substituent selected from halogen, -OH, -CF 3 , -CN, -COOH, -C(=O)NH 2 , C 1 to C 6 alkyl group, C 1 to C 6 alkyl group -O-, or one or more substitutions selected from =O (i.e., two geminal hydrogens on a carbon atom are substituted by the group O); when there are a plurality of substituents, the substituents are the same or different; If n is not 1, R 1 They are independently homologous or different; Q is -NH-C (=O)-R 1-1 -OC(=O)-N(R 1-3 R 1-4 ), -S (=O) 2 -N(R 1-9 R 1-10 ), -S (=O)-N (R 1-11 R 1-12 ), -N(R 1-14 R 1-15 ), -NH-S (=O) 2 -R 1-16 , unsubstituted or substituted C 3 ~C 10 Cycloalkyl groups, unsubstituted or substituted C 3 ~C 9 Heterocycloalkyl groups, unsubstituted or substituted C 3 ~C 9 A heterocycloalkenyl group, or an unsubstituted or substituted 5- to 10-membered heteroaryl group; the C 3 ~C 9 The heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C 3 ~C 9 The heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5 to 10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C 3 ~C 10 Cycloalkyl group, the substituted C 3 ~C 9 Heterocycloalkyl group, the substituted C 3 ~C 9 In the heterocycloalkenyl group, or the substituted 5- to 10-membered heteroaryl group, the substitutions are, independently of each other, a halogen, -OH, and -CF substituent. 3 -CN, -COOH, -C(=O)NH 2 ,=O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), -N (R 1-21 R 1-22 ), -C (=O)-N (R 1-23 R 1-24 ), -S (=O) 2 -N(R 1-25 R 1-26 ), -C (=O)-OR 1-27 , or unsubstituted or one or more R a Replaced with: C 1 ~C 6 Alkyl alkyl group, C 1 ~C 6 Alkyl-O- or C 3 ~C 6 One or more substitutions selected from the cycloalkyl groups, R a If there are multiple, they are either identical or different, R a Halogen, -OH, =O, -CF 3 -CN, -COOH, -C(=O)NH 2 If there are multiple substituents, the substituents are homologous or different; -OC(=O)-N(R 1-3 R 1-4 ) is -OC(=O)-NH-CH 3 And -N(R 1-14 R 1-15 )teeth, 【Transformation 5】 And, R 1-9 、R 1-10 、R 1-11 、R 1-12 、R 1-16 、R 1-21 、R 1-22 、R 1-23 、R 1-24 、R 1-25 、R 1-26 及びR 1-27 are independently H, unsubstituted or substituted C 1 ~C 6 alkyl group, unsubstituted or substituted C 1 ~C 6 alkyl group - O -, unsubstituted or substituted C 2 ~C 6 alkenyl group, unsubstituted or substituted C 2 ~C 6 alkenyl group - O -, unsubstituted or substituted C 2 ~C 6 alkynyl group, unsubstituted or substituted C 3 ~C 10 cycloalkyl group, unsubstituted or substituted C 3 ~C 9 heterocycloalkyl group, unsubstituted or substituted C 3 ~C 9 heterocycloalkenyl group, unsubstituted or substituted phenyl group, or unsubstituted or substituted 5 - 10 - member heteroaryl group; R 1-1 is H, unsubstituted or substituted C 1 ~C 6 alkyl group, unsubstituted or substituted C 1 ~C 6 alkyl group - O -, unsubstituted or substituted C 2 ~C 6 alkenyl group, unsubstituted or substituted C 2 ~C 6 alkenyl group - O -, unsubstituted or substituted C 2 ~C 6 alkynyl group, unsubstituted or substituted C 3 ~C 10 cycloalkyl group, unsubstituted or substituted C 3 ~C 9 heterocycloalkyl group, unsubstituted or substituted C 3 ~C 9 A heterocycloalkenyl group, or an unsubstituted or substituted 5- to 10-membered heteroaryl group; the C 3 ~C 9 The heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C 3 ~C 9 The heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5 to 10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C 1 ~C 6 alkyl group, the substituted C 1 ~C 6 Alkyl alkyl group -O-, the substituted C 2 ~C 6 Alkenyl group, the substituted C 2 ~C 6 Alkenyl group -O-, the aforementioned substituted C 2 ~C 6 Alkynyl group, the substituted C 3 ~C 10 Cycloalkyl group, the substituted C 3 ~C 9 Heterocycloalkyl group, the substituted C 3 ~C 9 The heterocycloalkenyl group, the substituted phenyl group, or the substituted 5- to 10-membered heteroaryl group are each independently of the substituent halogen, -OH, or -CF. 3 -CN, -COOH, -COOCH 3 , -NH 2 , =O, or unsubstituted or one or more R d Replaced with: C 1 ~C 6 Alkyl alkyl group, C 1 ~C 6 Alkyl-O- or C 3 ~C 6 One or more substitutions selected from cycloalkyl groups, R d If there are multiple, they are either identical or different, R d These are independently H, halogen, -OH, =O, and -CF. 3 -CN, -COOH, -C(=O)NH 2 If there are multiple substituents, the substituents are homologous or different; R 2 Independently 【Transformation 6】 or an unsubstituted or substituted 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substitutions are, independently of each other, a substituent halogen, -OH, -CN, unsubstituted or halogen-substituted C 1 ~C 6 C is either alkyl, unsubstituted, or substituted with a halogen. 1 ~C 6 Alkyl alkyl groups -O-, -C(=O)R 2-7 , or -C(=O)N(R 2-8 R 2-9 ) is one or more substitutions selected from; if there are multiple substituents, the substituents are homologous or different; R 2-1 and R 2-2 These are independently H, halogen, -OH, -CN, unsubstituted or substituted C 1 ~C 6 Alkyl alkyl group, unsubstituted or substituted C 1 ~C 6 Alkyl alkyl group -O- or =O; the substituted C 1 ~C 6 Alkyl alkyl group, or the substituted C. 1 ~C 6 The alkyl-O- groups are, independently of each other, substituents: halogen, -OH, and -CF. 3 ,-CN,C 1 ~C 6 Alkyl alkyl group, C 1 ~C 6 The substituents are one or more substitutions selected from alkyl-O- or =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O); if there are multiple substituents, the substituents are homologous or homologous; X and Y are independently single bonds, methylene, -O-, -N(R) 2-3 )-, or 【Transformation 7】 And; R 2-3 and R 2-4 H, unsubstituted or substituted C are independent. 1 ~C 6 Alkyl alkyl group, unsubstituted or substituted C 3 -C 8 Cycloalkyl groups, unsubstituted or substituted C 3 -C 8 Cycloalkyl group -O-, or unsubstituted or substituted C 1 -C 6 Alkyl-O-; the substituted C 1 ~C 6 alkyl group, the substituted C 3 -C 8 Cycloalkyl group, the substituted C 3 -C 8 Cycloalkyl group -O-, or the substituted C 1 -C 6 The alkyl-O- groups are, independently of each other, substituents: halogen, -OH, and -CF. 3 ,-CN,C 1 ~C 6 Alkyl alkyl group, C 1 ~C 6 The substituents are one or more substitutions selected from alkyl-O- or =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O); if there are multiple substituents, the substituents are homologous or homologous; R 2-7 These are independently H, halogen, -OH, -CN, unsubstituted or halogen-substituted C 1 ~C 6 Alkyl alkyl groups, or unsubstituted or halogenated C 1 ~C 6 It is an alkyl group -O-; R 2-8 and R 2-9 These are independently H, or unsubstituted or halogen-substituted C 1 ~C 6 A heterocyclic compound represented by formula I, which is an alkyl group; its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, or pharmaceutically acceptable salts.

2. m is either 1 or 2; and / or the R 3 If the halogen is a halogen, then the halogen is fluorine, chlorine, bromine, or iodine; and / or, R 3 C 1 ~C 6 If it is an alkyl group, then C 1 ~C 6 The alkyl group is C 1 ~C 4 It is an alkyl group; and / or, R 3 ga HaroC 1 ~C 6 When the halogen is an alkyl group, it is fluorine, chlorine, bromine, or iodine; and / or, R 3 ga HaroC 1 ~C 6 When it is an alkyl group, the number of halos is one or more; And / or, n is 1 or 2; and / or, R 1 Each of the above is independent of the above 【Transformation 8】 and Z 2 Located at the α or β position of the bond; and / or the R 1 If the halogen is a halogen, then the halogen is fluorine, chlorine, bromine, or iodine; and / or, R 1 C is either unsubstituted or substituted. 1 ~C 6 If it is an alkyl group, then C 1 ~C 6 Alkyl groups are independently C 1 ~C 4 It is an alkyl group; and / or, R 1 is the substitution C 1 ~C 6 If the alkyl group is such that each substituent is independently a halogen, then the halogen is fluorine, chlorine, bromine, or iodine; and / or, R 1 is the substitution C 1 ~C 6 In the case of an alkyl group, the C in the substituent 1 ~C 6 Alkyl groups are independently C 1 ~C 4 It is an alkyl group; and / or, R 1 is the substitution C 1 ~C 6 If it is an alkyl group, the number of substituents is independently 1, 2, or 3; and / or Q is the above 【Chemistry 9】 It is located at the β or γ position of the W bond; and / or, Q is unsubstituted or substituted C 3 ~C 9 In the case of a heterocycloalkyl group, the C 3 ~C 9 Heterocycloalkyl groups are C 3 ~C 5 The heterocycloalkyl group is the C 3 ~C 5 The heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; and / or, Q is unsubstituted or substituted C 3 ~C 9 In the case of a heterocycloalkenyl group, the C 3 ~C 9 The heterocycloalkenyl group is C 3 ~C 5 The heterocycloalkenyl group of the C 3 ~C 5 The heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; and / or, if Q is an unsubstituted or substituted 5- to 10-membered heteroaryl group, the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group, and the 5- to 6-membered heteroaryl group is an imidazolyl group, an oxazolyl group, a furan group, a thienyl group, a pyrazolyl group, an isoxazolyl group, a pyridinyl group, a triazolyl group, or a pyrimidinyl group; and / or, the above Q is a substitution of C 3 ~C 10 Cycloalkyl groups, substituted C 3 ~C 9 Heterocycloalkyl groups, substituted C 3 ~C 9 In the case of a heterocycloalkenyl group or a substituted 5- to 10-membered heteroaryl group, the number of substituents is independently 1, 2, 3, or 4; and / or, the above Q is a substitution of C 3 ~C 10 Cycloalkyl groups, substituted C 3 ~C 9 Heterocycloalkyl groups, substituted C 3 ~C 9 A heterocycloalkenyl group, or a substituted 5- to 10-membered heteroaryl group, wherein the substitution is a halogen, the halogen is independently fluorine, chlorine, bromine, or iodine; and / or the unsubstituted or one or more R a C replaced by 1 ~C 6 Alkyl alkyl group or C 1 ~C 6 C in alkyl group-O- 1 ~C 6 The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a t-butyl group; and / or the unsubstituted or one or more R a C replaced by 3 ~C 6 C in the cycloalkyl group 3 ~C 6 The cycloalkyl group is independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group; and / or, R a If the halogen is a halogen, then the halogen is independently fluorine, chlorine, bromine, or iodine; and / or, R 2-1 or R 2-2 is the substitution C 1 ~C 6 Alkyl alkyl group or substituted C 1 ~C 6 If it is an alkyl-O-, the number of substituents is independently 1, 2, 3, or 4; and / or, R 2 In the case of an unsubstituted or substituted 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group is independently a pyridinyl group; and / or, R 2 When the substituents are independently substituted 5-6 member heteroaryl groups, the halogen and halogen-substituted C in the substituents 1 ~C 6 C substituted with alkyl groups or halogens 1 ~C 6 The halogens in the alkyl-O- are independently fluorine, chlorine, bromine, or iodine; and / or, R 2 If the substituents are independently substituted 5-6 member heteroaryl groups, then the unsubstituted or halogen-substituted C in the substituents 1 ~C 6 Alkyl alkyl groups, or unsubstituted or halogenated C 1 ~C 6 C in alkyl group-O- 1 ~C 6 The heterocyclic compound represented by formula I according to claim 1, characterized in that the alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a t-butyl group, stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, or pharmaceutically acceptable salts thereof.

3. R 3 C 1 ~C 6 If it is an alkyl group, then C 1 ~C 6 The alkyl group is a methyl group; and / or R 3 ga HaroC 1 ~C 6 If it is an alkyl group, the halogen is fluorine, chlorine, bromine, or iodine; and / or R 3 ga HaroC 1 ~C 6 If it is an alkyl group, then the halo C 1 ~C 6 The alkyl group contains one, two, or three halogens; and / or, R 1 C is either unsubstituted or substituted. 1 ~C 6 If it is an alkyl group, then C 1 ~C 6 The alkyl group is a methyl group; and / or, R 1 is the substitution C 1 ~C 6 In the case of an alkyl group, the C in the substituent 1 ~C 6 Alkyl groups are independently methyl groups; and / or, Q is unsubstituted or substituted C 3 ~C 5 In the case of a heterocycloalkyl group, the C 3 ~C 5 Heterocycloalkyl groups are C 4 ~C 5 The heterocycloalkyl group is the C 4 ~C 5 The heterocycloalkyl group is either a pyrrolidinyl group or a piperazinyl group; and / or, Q is unsubstituted or substituted C 3 ~C 9 In the case of a heterocycloalkenyl group, the C 3 ~C 9 The heterocycloalkenyl group is C 4 ~C 5 It is a heterocycloalkenyl group, and the C 4 ~C 5 The heterocycloalkenyl group 【Chemistry 10】 And; And / or, if Q is an unsubstituted or substituted 5- to 10-membered heteroaryl group, the imidazolyl group 【Chemistry 11】 And; And / or, if Q is an unsubstituted or substituted 5- to 10-membered heteroaryl group, the oxazolyl group 【Chemistry 12】 And; and / or, if Q is an unsubstituted or substituted 5- to 10-membered heteroaryl group, the furan group 【Chemistry 13】 And; and / or, if Q is an unsubstituted or substituted 5- to 10-membered heteroaryl group, the thienyl group 【Chemistry 14】 And; And / or, if Q is an unsubstituted or substituted 5- to 10-membered heteroaryl group, the pyrazolyl group 【Chemistry 15】 And; And / or, if Q is an unsubstituted or substituted 5- to 10-membered heteroaryl group, the isoxazolyl group 【Chemistry 16】 And; and / or, if Q is an unsubstituted or substituted 5- to 10-membered heteroaryl group, the pyridinyl group 【Chemistry 17】 And; and / or, if Q is an unsubstituted or substituted 5- to 10-membered heteroaryl group, the pyrimidinyl group [Chemistry 18] And; And / or, if Q is an unsubstituted or substituted 5- to 10-membered heteroaryl group, the triazolyl group 【Chemistry 19】 And; and / or, Q is a substitution of C 3 ~C 9 Heterocycloalkyl groups, substituted C 3 ~C 9 In the case of a heterocycloalkenyl group or a substituted 5- to 10-membered heteroaryl group, the substituent is a halogen, and the halogen is fluorine; and / or R 2-1 or R 2-2 is the substitution C 1 ~C 6 Alkyl alkyl group or substituted C 1 ~C 6 The heterocyclic compound represented by formula I according to claim 2, characterized in that, when it is an alkyl group -O-, the number of substituents is independently 1 or 2, stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, or pharmaceutically acceptable salts thereof.

4. R 1 is the substitution C 1 ~C 6 When the alkyl group and the substituent are each independently halogens, the substituted C 1 ~C 6 C substitution in alkyl groups 1 ~C 6 Alkyl groups are independently -CF 3 And; and / or, R 3 ga HaroC 1 ~C 6 If it is an alkyl group, then the halo C 1 ~C 6 The alkyl group is -CF 3 ,-CH 2 F or -CHF 2 And; and / or at least one R 1 The above 【Chemistry 20】 and Z 2 Located at the α-position of the bond; and / or the R 1-1 , R 1-9 , R 1-10 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 is the substitution C 1 ~C 6 If it is an alkyl group, the substituted C 1 ~C 6 Alkyl groups are 【Chemistry 21】 And; and / or the R 1-1 , R 1-9 , R 1-10 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 is the substitution C 2 ~C 6 In the case of an alkenyl group, the substituted C 2 ~C 6 The alkenyl group 【Chemistry 22】 And; and / or the R 1-1 , R 1-9 , R 1-10 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 is the substitution C 2 ~C 6 In the case of an alkynyl group, the substituted C 2 ~C 6 The alkynyl group 【Chemistry 23】 And; and / or the R 1-1 , R 1-9 , R 1-10 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 is the substitution C 3 ~C 10 In the case of a cycloalkyl group, the substituted C 3 ~C 10 Cycloalkyl groups are 【Chemistry 24】 and and / or, 【Chemistry 25】 teeth 【Chemistry 26】 And; and / or -C(=O)N(R 2-8 R 2-9 ) is -C(=O)NHCH 3 A heterocyclic compound represented by formula I as described in claim 1, a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that it is a heterocyclic compound represented by formula I as described in claim 1.

5. If n is 2, then R 1 Each of them is independent 【Chemistry 27】 and Z 2 The α-position of the bond, or at least one R 1 teeth 【Chemistry 28】 Z 2 Located at the β-position of the bond; and / or, R 1-1 is the substitution C 3 ~C 10 The alkyl group is the substituted C 3 ~C 10 Alkyl groups are 【Chemistry 29】 And; and / or 【Transformation 30】 teeth 【Chemistry 31】 And; or 【Chemistry 32】 teeth 【Transformation 33】 A heterocyclic compound represented by formula I as described in claim 1, a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that it is a heterocyclic compound represented by formula I as described in claim 1.

6. The one or more R a C replaced by 1 ~C 6 Alkyl groups are 【Transformation 34】 And; and / or the one or more R a C replaced by 3 ~C 6 The cycloalkyl group is 【Chemistry 35】 And; and / or the one or more R d C replaced by 3 ~C 6 The cycloalkyl group is 【Transformation 36】 And; and / or, -N(R 1-21 R 1-22 ) is -NHCH 3 or -NH 2 And; and / or -C(=O)-N(R 1-23 R 1-24 ) is -C(=O)-NH 2 or -C(=O)-NHCH 3 And; and / or, -S (=O) 2 -N(R 1-25 R 1-26 ) is -S (=O) 2 -NH 2 And; and / or, -C (=O)-OR 1-27 -COOH, -COOC 2 H 5 or -COOCH 3 And; and / or, R 2 If the group is independently an unsubstituted or substituted 5-6 member heteroaryl group, the substituted 5-6 member heteroaryl group is independently 【Chemistry 37】 A heterocyclic compound represented by formula I as described in claim 1, a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that it is a heterocyclic compound represented by formula I as described in claim 1.

7. The aforementioned 【Transformation 38】 If it is a phenyl group, 【Chemistry 39】 teeth 【Chemistry 40】 And R 1’ The definition is R 1 It is the same as R 1’ and R 1 They are either identical or different; and / or, the above Q is NH-C(=O)-R 1-1 In that case, NH-C(=O)-R 1-1 is -NH-C(=O)-CH 3 -NH-C(=O)-O-CH 3 , 【Chemistry 41】 And; and / or, the above Q is -S (=O) 2 -N(R 1-9 R 1-10 If ), then -S (=O) 2 -N(R 1-9 R 1-10 ) is -S (=O) 2 -NH-CH 3 or -SO 2 NH 2 And; and / or, the above Q is -NH-S (=O) 2 -R 1-16 If so, -NH-S (=O) 2 -R 1-16 is -NH-S (=O) 2 -CH 3 And; and / or, the above Q is a substitution of C 3 ~C 10 In the case of a cycloalkyl group, the substituted C 3 ~C 10 Cycloalkyl groups are 【Chemistry 42】 And; and / or, the above Q is a substitution of C 3 ~C 9 In the case of a heterocycloalkyl group, the substituted C 3 ~C 9 Heterocycloalkyl groups are 【Chemistry 43】 And; and / or, the above Q is a substitution of C 3 ~C 9 In the case of a heterocycloalkenyl group, the substituted C 3 ~C 9 The heterocycloalkenyl group 【Chemistry 44】 And; and / or, if Q is a substituted 5- to 10-membered heteroaryl group, the substituted 5- to 10-membered heteroaryl group 【Chemistry 45】 And; and / or, R 2 but 【Chemistry 46】 If so, then one of X and Y is 【Chemistry 47】 The other is characterized by being a single bond, methylene, or -O-, the heterocyclic compound represented by formula I according to claim 1, stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, or pharmaceutically acceptable salts thereof. 【Request Item 8】 【Chemistry 48】 teeth 【Chemistry 49】 And; and / or, Q is a substitution of C 3 ~C 5 In the case of a heterocycloalkyl group, the substituted C 3 ~C 5 Heterocycloalkyl groups are [Transformation 50] And; and / or, Q is a substitution of C 3 ~C 5 In the case of a heterocycloalkenyl group, the substituted C 3 ~C 5 The heterocycloalkenyl group 【Chemistry 51】 And; and / or, if Q is a substituted 5- to 10-membered heteroaryl group, the 5- to 10-membered heteroaryl group 【Chemistry 52】 And; and / or, R 2 teeth 【Chemistry 53】 And; Or, R 2 but 【Chemistry 54】 If so, X or Y is -N(R 2-3 A heterocyclic compound represented by formula I as described in claim 7, characterized in that it is a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof. 【Request Item 9】 【Chemistry 55】 teeth 【Transformation 56】 And; and / or, 【Chemistry 57】 teeth 【Chemistry 58】 And; And / or Q is 【Chemistry 59】 【Transformation 60】 And; and / or, R 2 teeth 【Chemistry 61】 A heterocyclic compound represented by formula I as described in claim 1, a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that it is a heterocyclic compound represented by formula I as described in claim 1.

10. R 3 is halogen, -CHF 2 ,-CH 2 F or C 1 ~C 6 It is an alkyl group; Q is either unsubstituted or substituted C 3 ~C 9 A heterocycloalkyl group, or an unsubstituted or substituted 5- to 10-membered heteroaryl group; the C 3 ~C 9 The heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5 to 10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C 3 ~C 9 In heterocycloalkyl groups, or the substituted 5- to 10-membered heteroaryl groups, the substitutions are, each independently, substituents -N(R 1-21 R 1-22 ), -C (=O)-N (R 1-23 R 1-24 ), -S (=O) 2 -N(R 1-25 R 1-26 ), -C (=O)-OR 1-27 One or more substitutions selected from; if there are multiple substituents, the substituents are homologous or different; Or, R 3 Halogen, Halo C 1 ~C 6 Alkyl alkyl group or C 1 ~C 6 It is an alkyl group; Q is either unsubstituted or substituted C 3 ~C 10 Cycloalkyl groups, unsubstituted or substituted C 3 ~C 9 Heterocycloalkyl groups, unsubstituted or substituted C 3 ~C 9 A heterocycloalkenyl group, or an unsubstituted or substituted 5- to 10-membered heteroaryl group; the C 3 ~C 9 The heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C 3 ~C 9 The heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5 to 10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C 3 ~C 10 Cycloalkyl group, the substituted C 3 ~C 9 Heterocycloalkyl group, the substituted C 3 ~C 9 In the heterocycloalkenyl group, or the substituted 5- to 10-membered heteroaryl group, the substitutions are independently -OH and -CF substituents. 3 -CN, -N(R 1-21 R 1-22 ), -C(=O)-N(R 1-23 R 1-24 ), -S(=O) 2 -N(R 1-25 R 1-26 ), -C(=O)-OR 1-27 , =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), or unsubstituted or with one or more R a Replaced with: C 1 ~C 6 Alkyl alkyl group, C 1 ~C 6 Alkyl-O- or C 3 ~C 6 One or more substitutions selected from the cycloalkyl groups, R a If there are multiple, they are either identical or different, R a is a halogen, -OH, or -COOH; if there are multiple substituents, the substituents are homologous or different; R 2 Independently 【Transformation 62】 Alternatively, it is an unsubstituted or substituted 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substitutions are, independently of each other, a substituent halogen, -OH, -CN, unsubstituted or halogen-substituted C 1 ~C 6 C is either alkyl, unsubstituted, or substituted with a halogen. 1 ~C 6 Alkyl alkyl groups -O-, -C(=O)R 2-7 , or -C(=O)N(R 2-8 R 2-9 The heterocyclic compound represented by formula I according to claim 1, characterized in that one or more substitutions are selected from ) and, if there are multiple substituents, the substituents are homologous or homologous, stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates or pharmaceutically acceptable salts thereof.

11. It is form 1 or form 2: of which, Form 1, 【Transformation 63】 teeth 【Chemistry 64】 m is 1, 2, 3, or 4; R 3 H, halogen, -OH, halo C 1 ~C 6 Alkyl alkyl group, -CN or C 1 ~C 6 It is an alkyl group; if m is not 1, R 3 They are independently homologous or different; W is a single bond; 【Transformation 65】 It is a phenyl group; n is 1, 2, 3, or 4; R 1 These are independently H, halogen, -OH, -CN, or unsubstituted or substituted C 1 ~C 6 Alkyl alkyl group; the substituted C 1 ~C 6 The alkyl group is independently substituted with the substituent halogen, -OH, -CN, -COOH, and -C(=O)NH. 2 One or more substitutions selected from; if there are multiple substituents, the substituents are homologous or different; if n is not 1, R 1 They are independently homologous or different; Q is -NH-C (=O)-R 1-1 -OC(=O)-N(R 1-3 R 1-4 ), -S (=O) 2 -N(R 1-9 R 1-10 ), -S (=O)-N (R 1-11 R 1-12 ), -N(R 1-14 R 1-15 ), -NH-S (=O) 2 -R 1-16 , unsubstituted or substituted C 3 ~C 10 Cycloalkyl groups, unsubstituted or substituted C 3 ~C 9 Heterocycloalkyl groups, unsubstituted or substituted C 3 ~C 9 A heterocycloalkenyl group, or an unsubstituted or substituted 5- to 10-membered heteroaryl group; the C 3 ~C 9 The heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C 3 ~C 9 The heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5 to 10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C 3 ~C 10 Cycloalkyl group, the substituted C 3 ~C 9 Heterocycloalkyl group, the substituted C 3 ~C 9 In the heterocycloalkenyl group, or the substituted 5- to 10-membered heteroaryl group, the substitutions are, independently of each other, a halogen, -OH, and -CF substituent. 3 -CN, -COOH, -C(=O)NH 2 ,=O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), -N (R 1-21 R 1-22 ), -C (=O)-N (R 1-23 R 1-24 ), -S (=O) 2 -N(R 1-25 R 1-26 ), -C (=O)-OR 1-27 , or unsubstituted or one or more R a Replaced with: C 1 ~C 6 Alkyl alkyl group, C 1 ~C 6 Alkyl-O- or C 3 ~C 6 One or more substitutions selected from the cycloalkyl groups, R a If there are multiple, they are either identical or different, R a Halogen, -OH, =O, -CF 3 -CN, -COOH, -C(=O)NH 2 If there are multiple substituents, the substituents are homologous or different; -OC(=O)-N(R 1-3 R 1-4 ) is -OC(=O)-NH-CH 3 And; -N(R 1-14 R 1-15 )teeth, 【Chemical Formula 66】 And; R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 H, unsubstituted or substituted C are independent. 1 ~C 6 Alkyl alkyl group, unsubstituted or substituted C 1 ~C 6 Alkyl alkyl group -O-, unsubstituted or substituted C 2 ~C 6 Alkenyl group, unsubstituted or substituted C 2 ~C 6 Alkenyl group -O-, unsubstituted or substituted C 2 ~C 6 Alkynyl group, unsubstituted or substituted C 3 ~C 10 Cycloalkyl groups, unsubstituted or substituted C 3 ~C 9 Heterocycloalkyl groups, unsubstituted or substituted C 3 ~C 9 A heterocycloalkenyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted 5- to 10-membered heteroaryl group; R 1-1 C is either H, unsubstituted, or substituted. 1 ~C 6 Alkyl alkyl group, unsubstituted or substituted C 1 ~C 6 Alkyl alkyl group -O-, unsubstituted or substituted C 2 ~C 6 Alkenyl group, unsubstituted or substituted C 2 ~C 6 Alkenyl group -O-, unsubstituted or substituted C 2 ~C 6 Alkynyl group, unsubstituted or substituted C 3 ~C 10 Cycloalkyl groups, unsubstituted or substituted C 3 ~C 9 Heterocycloalkyl groups, unsubstituted or substituted C 3 ~C 9 A heterocycloalkenyl group, or an unsubstituted or substituted 5- to 10-membered heteroaryl group; the C 3 ~C 9 The heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C 3 ~C 9 The heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5 to 10 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C 1 ~C 6 alkyl group, the substituted C 1 ~C 6 Alkyl alkyl group -O-, the substituted C 2 ~C 6 Alkenyl group, the substituted C 2 ~C 6 Alkenyl group -O-, the aforementioned substituted C 2 ~C 6 Alkynyl group, the substituted C 3 ~C 10 Cycloalkyl group, the substituted C 3 ~C 9 Heterocycloalkyl group, the substituted C 3 ~C 9 The heterocycloalkenyl group, the substituted phenyl group, or the substituted 5- to 10-membered heteroaryl group are each independently of the substituent halogen, -OH, or -CF. 3 -CN, -COOH, -COOCH 3 , -NH 2 , =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), or unsubstituted or with one or more R d Replaced with: C 1 ~C 6 Alkyl alkyl group, C 1 ~C 6 Alkyl-O- or C 3 ~C 6 One or more substitutions selected from cycloalkyl groups, R d If there are multiple, they are either identical or different, R d These are independently H, halogen, -OH, =O, and -CF. 3 -CN, -COOH, -C(=O)NH 2 If there are multiple substituents, the substituents are homologous or different; Or, R 2 teeth 【Transformation 67】 And; R 2-1 and R 2-2 These are independently H, halogen, -OH, -CN, unsubstituted or substituted C 1 ~C 6 Alkyl alkyl group, unsubstituted or substituted C 1 ~C 6 Alkyl alkyl group -O- or =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O); the substituted C 1 ~C 6 Alkyl alkyl group, or the substituted C. 1 ~C 6 The alkyl-O- groups are, independently of each other, substituents: halogen, -OH, and -CF. 3 ,-CN,C 1 ~C 6 Alkyl alkyl group, C 1 ~C 6 The substituent is one or more substitutions selected from alkyl groups -O- or =O; if there are multiple substituents, the substituents are homologous or homologous; X and Y are independently single bonds, methylene, -O-, -N(R) 2-3 )-, or 【Transformation 68】 And; R 2-3 and R 2-4 H, unsubstituted or substituted C are independent. 1 ~C 6 Alkyl alkyl group, unsubstituted or substituted C 3 -C 8 Cycloalkyl groups, unsubstituted or substituted C 3 -C 8 Cycloalkyl group -O-, or unsubstituted or substituted C 1 -C 6 Alkyl-O-; the substituted C 1 ~C 6 alkyl group, the substituted C 3 -C 8 Cycloalkyl group, the substituted C 3 -C 8 Cycloalkyl group -O-, or the substituted C 1 -C 6 The alkyl-O- groups are, independently of each other, substituents: halogen, -OH, and -CF. 3 ,-CN,C 1 ~C 6 Alkyl alkyl group, C 1 ~C 6 The substituents are one or more substitutions selected from alkyl-O- or =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O); if there are multiple substituents, the substituents are homologous or homologous; Form 2, 【Transformation 69】 teeth 【Transformation 70】 And; m is 1, 2, 3, or 4; R 3 H, halogen, -OH, -CF 3 , -CN or C 1 ~C 6 It is an alkyl group; if m is not 1, R 3 They are either identical or different; W is a single bond; 【Chemistry 71】 It is a phenyl group; n is 1, 2, 3, or 4; R 1 These are independently H, halogen, -OH, -CN, unsubstituted or substituted C 1 ~C 6 Alkyl alkyl group; the substituted C 1 ~C 6 The alkyl group is substituted independently by the substituent halogen, -OH, and -CF. 3 -CN, -COOH, -C(=O)NH 2 , C 1 ~C 6 Alkyl alkyl group, C 1 ~C 6 One or more substitutions selected from alkyl-O- or =O; if there are multiple substituents, the substituents are homologous or homologous; if n is not 1, R 1 They are either identical or different; Q is -NH-C (=O)-R 1-1 , -S (=O) 2 -N(R 1-9 R 1-10 ), unsubstituted or substituted C 3 ~C 5 Heterocycloalkyl groups, unsubstituted or substituted C 3 ~C 5 A heterocycloalkenyl group, or an unsubstituted or substituted 5-6 membered heteroaryl group; the C 3 ~C 5 The heterocycloalkyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the C 3 ~C 5 The heterocycloalkenyl group has one or more heteroatoms selected from oxygen, sulfur, and nitrogen, and the number of heteroatoms is 1 to 3; the 5 to 6 membered heteroaryl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 3; the substituted C 1 ~C 6 alkyl group, the substituted C 1 ~C 6 Alkyl alkyl group -O-, the substituted C 2 ~C 6 Alkenyl group, the substituted C 2 ~C 6 Alkenyl group -O-, the aforementioned substituted C 6 ~C 10 Aryl group, the substituted C 3 ~C 5 Heterocycloalkyl group, the substituted C 3 ~C 5 The heterocycloalkenyl group, or the substituted 5-6 membered heteroaryl group, is independently a substituent of halogen, -OH, or -CF. 3 -CN, -COOH, -C(=O)NH 2 , =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O), or unsubstituted or with one or more R a C replaced 1 ~C 6 Alkyl alkyl group, C 1 ~C 6 Alkyl-O- or C 3 ~C 6 One or more substitutions selected from the cycloalkyl groups, R a If there are multiple, they are either identical or different, R a Halogen, -OH, =O, -CF 3 -CN, -COOH, -C(=O)NH 2 If there are multiple substituents, the substituents are homologous or different; The aforementioned -OC(=O)-N(R 1-3 R 1-4 ) is -OC(=O)-NH-CH 3 And; -N(R 1-14 R 1-15 )teeth, 【Chemistry 72】 And; R 2 teeth 【Transformation 73】 And; R 2-1 and R 2-2 These are independently H, halogen, -OH, -CN, unsubstituted or substituted C 1 ~C 6 Alkyl alkyl group, unsubstituted or substituted C 1 ~C 6 Alkyl alkyl group -O- or =O (i.e., the two geminal hydrogens on the carbon atom are substituted with the group O); the substituted C 1 ~C 6 Alkyl alkyl group, or the substituted C. 1 ~C 6 The alkyl-O- groups are, independently of each other, substituents: halogen, -OH, and -CF. 3 ,-CN,C 1 ~C 6 Alkyl alkyl group, C 1 ~C 6 The substituent is one or more substitutions selected from alkyl groups -O- or =O; if there are multiple substituents, the substituents are homologous or homologous; X and Y are independently methylene, -O-, -N(R) 2-3 )-, or 【Chemistry 74】 And; R 2-3 , R 2-4 H, unsubstituted or substituted C are independent. 1 ~C 6 Alkyl alkyl group, or unsubstituted or substituted C 1 -C 6 A heterocyclic compound represented by formula I as described in claim 1, characterized by being alkyl-O-, stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, or pharmaceutically acceptable salts thereof.

12. Q is either unsubstituted or substituted C 3 ~C 5 In the case of a heterocycloalkyl group, the C 3 ~C 5 Heterocycloalkyl groups are C 4 ~C 5 It is a heterocycloalkyl group, and the C 4 ~C 5 A heterocycloalkyl group consists of one or more heteroatoms selected from N, O, and S, with a total number of heteroatoms of 1 to 2; and / or, Q is unsubstituted or substituted C 3 ~C 5 In the case of a heterocycloalkenyl group, the C 3 ~C 5 The heterocycloalkenyl group is C 4 ~C 5 It is a heterocycloalkenyl group, and the C 4 ~C 5 A heterocycloalkenyl group has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 2; and / or, if Q is an unsubstituted or substituted 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group is an imidazolyl group, an oxazolyl group, a furan group, a thienyl group, a pyrazolyl group, an isoxazolyl group, a pyridinyl group, or a pyrimidinyl group; and / or, the above Q is a substitution of C 3 ~C 5 Heterocycloalkyl groups, substituted C 3 ~C 5 A heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group, wherein the substitution is a halogen, the halogen is independently fluorine, chlorine, bromine, or iodine; and / or, the above Q is a substitution of C 3 ~C 5 Heterocycloalkyl groups, substituted C 3 ~C 5 A heterocycloalkenyl group, or a substituted 5-6 membered heteroaryl group, wherein the substitution is one or more R a Replaced with: C 1 ~C 6 Alkyl alkyl group or C 1 ~C 6 In the case of alkyl-O-, the C in the substituent 1 ~C 6 Alkyl groups are independently C 1 ~C 4 A heterocyclic compound represented by formula I as described in claim 2, characterized by being an alkyl group, its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof.

13. Q is either unsubstituted or substituted C 4 ~C 5 In the case of a heterocycloalkyl group, the C 4 ~C 5 The heterocycloalkyl group is a pyrrolidinyl group or a piperazinyl group, and the pyrrolidinyl group is 【Chemistry 75】 The piperazinyl group is 【Transformation 76】 And; and / or, Q is unsubstituted or substituted C 3 ~C 5 In the case of a heterocycloalkenyl group, the C 3 ~C 5 The heterocycloalkenyl group 【Chemical 77】 And; And / or, if Q is an unsubstituted or substituted 5-6 member heteroaryl group, the imidazolyl group 【Transformation 78】 And; And / or, if Q is an unsubstituted or substituted 5-6 membered heteroaryl group, the oxazolyl group 【Transformation 79】 And; And / or, if Q is an unsubstituted or substituted 5-6 member heteroaryl group, the furan group is 【Chemistry 80】 And; and / or, if Q is an unsubstituted or substituted 5-6 member heteroaryl group, the thienyl group 【Chemistry 81】 And; And / or, if Q is an unsubstituted or substituted 5-6 member heteroaryl group, the pyrazolyl group 【Chemistry 82】 And; And / or, if Q is an unsubstituted or substituted 5-6 member heteroaryl group, the isoxazolyl group 【Chemistry 83】 And; And / or, if Q is an unsubstituted or substituted 5-6 member heteroaryl group, the pyridinyl group 【Chemical 84】 And; And / or, if Q is an unsubstituted or substituted 5-6 membered heteroaryl group, the pyrimidinyl group 【Chemical 85】 And; and / or, when Q is a substituted C 3 -C 5 heterocycloalkyl group, substituted C 3 -C 5 heterocycloalkenyl group or, when it is a substituted 5- to 6-membered heteroaryl group, the substituent is fluorine; and / or, Q is a substituted C 3 -C 5 heterocycloalkyl group, substituted C 3 -C 5 heterocycloalkenyl group or, when it is a substituted 5- to 6-membered heteroaryl group, the substituent is one or more R a substituted C 1 -C 6 alkyl group or C 1 -C 6 alkyl group -O-, and the C 1 -C 6 alkyl group is a methyl group, the heterocyclic compound represented by Formula I according to Claim 1, its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate or pharmaceutically acceptable salt.

14. The aforementioned Q is a substitution of C 3 ~C 5 In the case of a heterocycloalkyl group, the substituted C 3 ~C 5 Heterocycloalkyl groups are 【Chemical 86】 And; and / or, the above Q is a substitution of C 3 ~C 5 In the case of a heterocycloalkenyl group, the substituted C 3 ~C 5 The heterocycloalkenyl group 【Chemistry 87】 Even if that is fine; and / or, if Q is a substituted 5-6 membered heteroaryl group, the substituted 5-6 membered heteroaryl group is 【Chemical 88】 And; and / or, the above Q is -NH-C(=O)-R 1-1 In that case, the -NH-C(=O)-R 1-1 teeth 【Chemical 89】 And; and / or, the above Q is -S (=O) 2 -N(R 1-9 R 1-10 ) If the above -S (=O) 2 -N(R 1-9 R 1-10 ) is -S (=O) 2 -NH-CH 3 And; and / or, R 2 but [Chemical 90] If R 2 teeth 【Chemistry 91】 A heterocyclic compound represented by formula I as described in claim 13, characterized by being a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof.

15. The heterocyclic compound shown in formula I is as shown in formula IC-1: 【Chemistry 92】 And; Alternatively, the heterocyclic compound shown in formula I is as shown in formula IE: 【Chemistry 93】 And; R 2 Independently 【Chemical 94】 Alternatively, the heterocyclic compound represented by formula I according to claim 1, characterized by being an unsubstituted or substituted 5-6 membered heteroaryl group, its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, and pharmaceutically acceptable salts.

16. The heterocyclic compound shown in formula I is as shown in formula IC-2: 【Chemical 95】 , eventually, R 1’ The definition is R 1 It is the same as R 1’ and R 1 are homologous or different, and X is a single bond, methylene, or -O-; Alternatively, the heterocyclic compound shown in formula I is as shown in formula IE-1: 【Chemistry 96】 A heterocyclic compound represented by formula I as described in claim 15, characterized in that it is a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof.

17. The heterocyclic compound shown in formula I above is as shown in formula IE-2: 【Chemistry 97】 A heterocyclic compound represented by formula I as described in claim 15, characterized in that it is a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof.

18. m is either 1 or 2; and / or, R 3 H, halogen, -OH, halo C 1 ~C 6 Alkyl alkyl group or C 1 ~C 6 It is an alkyl group; And / or, W is a single bond; And / or, n is 1 or 2; and / or, R 1 These are independently H, halogen, -OH, -CN, or unsubstituted or substituted C 1 ~C 6 It is an alkyl group; and / or, R 1 The substituents in each of these are independently halogen, -OH, -CN, or -C(=O)NH 2 One or more substitutions selected from the substituents of; And / or, Q is -NH-C(=O)-R 1-1 , -S (=O) 2 -N(R 1-9 R 1-10 ), -NH-S (=O) 2 -R 1-16 , or an unsubstituted or substituted 5- to 10-membered heteroaryl group, an unsubstituted or substituted C 3 ~C 9 Heterocycloalkyl groups, unsubstituted or substituted C 3 ~C 9 A heterocycloalkenyl group, or an unsubstituted or substituted 5- to 10-membered heteroaryl group; and / or, R 2 Independently 【Chem.98】 A heterocyclic compound represented by formula I as described in claim 1, characterized by being a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof.

19. Heterocyclic compounds, their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, or solvates, The aforementioned heterocyclic compound is one of the following compounds: 【Chem.99】 【Chemistry 100】 【Chemistry 101】 【Chemical Engineering 102】 【Chemistry 103】 【Chemical 104】 【Chemistry 105】 【Chemistry 106】 【Chemistry 107】 【Chemistry 108】 【Chemistry 109】 And; Alternatively, the heterocyclic compound may be: 【Chemical 110】 It is a compound having the formula:

20. The manufacturing method is of form 1, form 2, form 3, form 4, form 5, form 6, form 7, or form 8: of which, Form 1 comprises the following steps: In an organic solvent, in the presence of a catalyst, the compound shown in Formula II-1 and the organotin reagent shown in Formula III-1 are subjected to the following Stille coupling reaction to obtain the heterocyclic compound shown in Formula I; 【Chemistry 111】 Eventually, X 1 is either Br or Cl; Form 2 comprises the following steps: In the presence of a catalyst and an alkaline reagent, the following Suzuki coupling reaction is carried out with the compound shown in formula II-2 and the compound shown in formula III-2 in a solvent to obtain the heterocyclic compound shown in formula I; 【Chemistry 112】 Eventually, X 2 is either Br or Cl; Form 3 comprises the following steps: The following reaction is carried out with the organic solvent, the compound shown in Formula II-3, the compound shown in Formula III-3, and formaldehyde to obtain the heterocyclic compound shown in Formula I; 【Chemistry 113】 Form 4 comprises the following steps: In an organic solvent, the following reaction is carried out with the compound shown in formula II-3 and the compound shown in formula III-4 to obtain the heterocyclic compound shown in formula I; 【Chemical 114】 Eventually, X 3 is a leaving group; Form 5 comprises the following steps: The organic solvent is R in the presence of an alkaline reagent. 2 but 【Chemical 115】 Then, the following amidation reaction is carried out with the compound shown in formula I and the compound shown in formula III-5 where Y is -NH-, and Y 【Chemistry 116】 The heterocyclic compound shown in formula I above is obtained; 【Chemistry 117】 Eventually, X 4 It is a halogen; Form 6 comprises the following steps: In the presence of an acid in an organic solvent, the compounds shown in formula II-4 and III-5 are subjected to the following deprotection group reaction to obtain the heterocyclic compound shown in formula I; 【Chemistry 118】 Form 7, including the following steps: In an organic solvent, a substitution reaction shown below is carried out for the compound shown in Formula II-5 and NH(R 1-9 R 1-10 ), to obtain the heterocyclic compound shown in Formula I; Q is -S(=O) 2 -N(R 1-9 R 1-10 ); 【Chemical 119】 Eventually, X 5 is either Br or Cl; Form 8 comprises the following steps: In the presence of an acid in an organic solvent, the compound shown in formula II-6 or formula II-6' is subjected to the following deprotection group reaction to obtain the heterocyclic compound shown in formula I; 【Chemical 120】 Eventually, X 6 , X 6’ and X 6’’ is an N protecting group; The aforementioned 【Chemistry 121】 R 3 , R 2 , R 1 W, Q, X, R 1-9 , R 1-10 , R 2-1 , R 2-2 , R 2-4 A method for producing a heterocyclic compound represented by formula I according to claim 1, characterized in that n and m are as described in any one of claims 1 to 14.

21. The compound in question: 【Chemistry 122】 Among them, the aforementioned 【Chemical 123】 R 3 、R 2 、R 1 、W, Q, X, R 1-9 、R 1-10 、R 2-1 、R 2-2 、n and m The terms are as described in any one of claims 1 to 14; X 5, X 6 , X 6’ and X 6’’ The compound is represented by formula II-2, II-4, II-5, II-6, or II-6', as described in claim 20.

22. The compound to be selected from the following: 【Chemistry 124】 【Chemistry 125】 【Chemistry 126】 【Chemistry 127】 【Chemistry 128】 【Chemistry 129】 【Chemistry 130】 【Chemistry 131】 。

23. A pharmaceutical composition characterized by comprising a heterocyclic compound represented by formula I as described in claim 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a stereoisomer or tautomer thereof, and at least one medicinal auxiliary material.

24. The heterocyclic compound represented by formula I as described in claim 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a stereoisomer thereof or a tautomer thereof, or the pharmaceutical composition as described in claim 23, is for use in the manufacture of a P2X3 inhibitor or drug.

25. The aforementioned drugs are used to prevent, treat, cure or alleviate diseases in which at least a portion of animals are induced by or associated with the activity of P2X3; The use according to claim 24, characterized in that the drug is a drug used to treat pain, urinary tract disease, or respiratory disease.

26. The use according to claim 25, characterized in that the disease includes pain, urinary tract disease, or respiratory disease.

27. The use according to claim 26, characterized in that the pain includes inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, burn pain, migraine or cluster headache; the urinary tract disorders include urinary incontinence, overactive bladder, dysuria, and cystitis; and the respiratory disorders include respiratory disorders including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or chronic cough.

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