Tricyclic compounds as ATR kinase inhibitors

Abstract

This application relates to a compound represented by formula I, its isomers, isotope-labeled compounds or pharmaceutically acceptable salts thereof, and their uses as an ATR kinase inhibitor and for treating cancer, where each group is as defined herein. [C1] JPEG2026515658000287.jpg48170

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical technology and relates to a tricyclic compound represented by formula I, a method for preparing the same, a pharmaceutical composition containing the compound, and the use thereof as a therapeutic agent, in particular, the use thereof as an ATR kinase inhibitor, and the use thereof in the manufacture of a medicament for treating and / or preventing hyperproliferative diseases. [Background technology]

[0002] Human cells are constantly subjected to thousands of events, including DNA damage, every day. Cellular repair of DNA damage is crucial for maintaining genomic stability and cell survival. In normal cells, multiple DNA damage repair mechanisms exist simultaneously. These mechanisms complement each other during the DNA repair process, working in a highly coordinated manner to repair damage, acting as checkpoints within the cell, and preventing the replication of cells with damaged DNA. Tumor cells have more endogenous cell damage than normal cells, have defects in one or more DNA damage repair pathways, and rely more heavily on intact repair pathways.

[0003] Ataxia telangiectasia mutation and Rad3-related kinase (ATR kinase) belong to the PIKK family and are important protein kinases in the homologous recombination repair pathway. Once activated, ATR regulates cellular biological processes through various signals, including cell cycle arrest, inhibition of replication origin, and initiation of replication forks, thereby promoting DNA damage repair. ATR kinase works in conjunction with Ataxia telangiectasia mutation kinase (ATM kinase) and numerous other proteins to regulate the cell's response to DNA damage. Cancer cells, due to oncogenic mutations, dysfunctional G1 / S checkpoint regulation, and defects in other DNA repair pathways, rely more strongly than normal cells on the remaining intact repair pathways, including ATR, to regulate cellular DNA damage repair and maintain cell survival, making ATR an important target for cancer therapies.

[0004] To treat cancer, ATR kinase inhibitors can be used alone or in combination with other targeted agents that affect DNA damage or DNA damage repair pathways. Currently, five small molecule entities—AZD-6738, RP-3500, VX-970, ART-0380, and ATRN-119—are in Phase II or Phase III clinical trials, but the corresponding drugs have not yet been launched. [Overview of the project]

[0005] Therefore, there is still an urgent need for ATR kinase inhibitors with higher efficacy and improved pharmacokinetic parameters for the treatment of cancer.

[0006] Contents of the present invention This application provides a tricyclic compound represented by formula I that has excellent ATR kinase inhibitory activity and can be used as an ATR kinase inhibitor to treat and / or prevent proliferative or hyperproliferative diseases such as cancer.

[0007] In one embodiment, this application relates to a compound represented by formula I, its isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof:

[0008] [ka]

[0009] (In the formula,

[0010] [ka]

[0011] This indicates that the ring to which it belongs is an aromatic ring system. X1 is N or C(R X1 Selected from the group consisting of, X2 is selected from the group consisting of C or N. X3 is N, C(RX2 ) or N(R X3 ) selected from the group consisting of, X4 is selected from the group consisting of N or C(R X4 ) selected from the group consisting of, X5 is selected from the group consisting of C or N, X6 is N, N(R X5 ) or C(R X6 ) selected from the group consisting of, R X1 , R X2 , R X3 , R X4 , R X5 and R X6 are each independently selected from the group consisting of H, halogen, C 6~10 aryl, C 3~10 cycloalkyl, C 3~10 cycloalkenyl, 3- to 10-membered heterocyclyl or 5- to of 10-membered heteroaryl, respectively, and C 6~10 aryl, C 3~10 cycloalkyl, C 3~10 cycloalkenyl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl may each be substituted with one, two or three R X groups, R X are each independently selected from the group consisting of halogen, cyano, hydroxyl, C 1~6 alkyl, C 1~6 heteroalkyl, C 3~10 cycloalkyl, 3- to of 10-membered heterocyclyl or -NR c R d selected independently from the group consisting of, and C 1~6 alkyl, C 1~6 heteroalkyl, C 3~10 cycloalkyl and 3- to 10-membered heterocyclyl may each be substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano, hydroxyl or C 1~6 alkyl, A is selected from the group consisting of 4- to 10-membered heterocyclyl, and 4- to 10-membered heterocyclyl may be substituted with one, two or three R a groups, R a These are C 1~10 Alkyl, C 1~10 Heteroalkyl, amino, or -S(=O)2-C 1~10 Independently selected from the group consisting of alkyls, Ring B is selected from the group consisting of a 5-7 membered heterocyclic ring, a 5-7 membered carbocyclic ring, a benzene ring, or a 5-7 membered heteroaromatic ring. R b These are halogen, hydroxyl, cyano, amino, oxo, and C, respectively. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR e R f -C(O)OC 1~10 Alkyl, -SO2NR g R h , -SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl or

[0012] [ka]

[0013] Independently selected from the group consisting of C 1~10 Alkyl, C 1~10 Heteroalkyl, C3~10 Cycloalkyl, 3- to 10-membered heterocyclyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR e R f 、-C(O)OC 1~10 Alkyl, -SO2NR g R h 、-SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkynyl, -SO2-C 3~10 Cycloalkyl, -SO2-3- to 10-membered heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3- to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Aryl, -C 1~6 Alkyl-5- to 10-membered heteroaryl and

[0014]

Chemical formula

[0015] is each independently selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, C 1~10 Alkyl, halogenated C 1~10 Alkyl, hydroxy-C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3- to 10-membered heterocyclyl or -CONR i R j and may each be substituted with one, two, three or four substituents independently selected from the group consisting of R’ is selected from the group consisting of H, C 1~10 Alkyl, C 3~10 Cycloalkyl or CN, R c 、Rd , R e , R f , R g , R h , R i and R j are each independently selected from the group consisting of H or C 1~10 alkyl, and optionally, two R groups are linked to each other to form a C b cycloalkyl or a 3- to 10-member heterocyclyl, and the C 3~10 cycloalkyl and the 3- to 10-member heterocyclyl may each be substituted with one, two, three or four substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, C 3~10 alkyl, halogenated C 1~10 alkyl, C 1~10 heteroalkyl, C 1~10 cycloalkyl or a 3- to 10-member heterocyclyl) 3~10 n is selected from the group consisting of 0, 1, 2, 3 or 4) to provide.

[0016] In some embodiments, the compound has the structural formula II:

[0017]

Chemical formula

[0018] (wherein

[0019]

Chemical formula

[0020] represents that the ring to which it belongs is an aromatic ring system,

[0021]

Chemical formula

[0022] ​This represents either a single bond or a double bond. R1 and R2 are hydrogen or C 1~6 Each is independently selected from the group consisting of alkyls, or R1 and R2, together with the carbon atom to which they are bonded and the adjacent nitrogen atom, form a 4- to 8-membered aza-cyclic ring. X2 is selected from the group consisting of C or N. X3 is selected from the group consisting of C(R3) or N(R3), X4 is selected from the group consisting of N or CH. X5 is selected from the group consisting of C or N, and if X5 is N, then X3 is C(R3). R3 is C 6~10 Ariel, C 3~10 Selected from the group consisting of cycloalkyl or 5-10 member heteroaryls, C 6~10 Ariel, C 3~10 Cycloalkyl and 5-10 membered heteroaryls have one, two or three R 3a Each of these may be substituted by the base, R 3a These are halogen, cyano, hydroxyl, and C, respectively. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 A cycloalkyl group is independently selected from the group consisting of 3-10 member heterocyclines or -NR4R5, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl and 3- to 10-membered heterocyclyls are halogen, cyano, hydroxyl, or C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups, R4 and R5 are hydrogen or C 1~10 Each is independently selected from the group consisting of alkyl groups, The Z1 is CR6R7, The Z2 is CR8R9, N, NR 10 Selected from the group consisting of O, S, -C(O)- or -SO2-, The Z3 is CR 11 CR 12 R 13 , N, NR 14 , O, -C(O)-, -SO2- or -S(O)(NR 15 Selected from the group consisting of )-, The Z4 is CR 16 CR 17 R 18 , N, NR 19 , O, S, -C(O)-, -SO2- or -S(O)(NR 20 Selected from the group consisting of )-, One or two of Z1, Z2, Z3, and Z4 may be absent, and a ring containing X5, Z1, Z2, Z3, and Z4 is a stable ring structure. R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 These are hydrogen, halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2-C1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl or

[0023] [ka]

[0024] Each of the groups consisting of C is independently selected. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl and

[0025] [ka]

[0026] These are deuterium, halogen, hydroxyl, cyano, amino, and C. 1~10Alkyl, halogenated C 1~10 Alkyl, hydroxy-C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, -CONR 25 R 26 They may each be substituted by one, two, three, or four substituents independently selected from the group consisting of the above, R' is H, C 1~10 Alkyl, C 3~10 Selected from the group consisting of cycloalkyl or CN, R 21 , R 22 , R 23 , R 24 , R 25 and R 26 is H or C 1~10 Each is independently selected from the group consisting of alkyl groups, Alternatively, R6 and R7, R8 and R9, R 12 and R 13 or R 17 and R 18 They are connected to each other, C 3~10 Forming a cycloalkyl or 3-10 membered heterocycline, C 3~10 Cycloalkyl or 3-10 membered heterocyclyls are deuterium, halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, halogenated C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 (May be substituted with one, two, three, or four substituents independently selected from the group consisting of cycloalkyls and 3- to 10-membered heterocyclines.) It has.

[0027] In some embodiments, the compound has structural formula IIA, IIB, or IIC:

[0028] [ka]

[0029] (In the formula, R3 is C 6~10 Ariel, C 3~10 It is a cycloalkyl or a 5-10 member heteroaryl, C 6~10 Ariel, C 3~10 Cycloalkyl and 5-10 membered heteroaryls have one, two or three R 3a Each of these may be substituted by the base, R 3a These are halogen, cyano, hydroxyl, and C, respectively. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 A cycloalkyl group is independently selected from the group consisting of 3-10 member heterocyclines or -NR4R5, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl and 3- to 10-membered heterocyclyls are halogen, cyano, hydroxyl, or C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups, R4 and R5 are independently hydrogen or C 1~10 It is alkyl, Z1, Z2, Z3, and Z4 are as defined in Equation II above.) It has.

[0030] In another embodiment, the present application provides a pharmaceutical composition comprising the compound of the present application, its isomers, isotope-labeled compounds or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0031] In another embodiment, the present application provides the compounds of the present application, their isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof, which are used as ATR kinase inhibitors.

[0032] In another embodiment, the present application provides the use of the compounds of the present application, their isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof in the production of ATR kinase inhibitors.

[0033] In another embodiment, the present application provides the use of the compounds of the present application, their isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for treating cancer.

[0034] In another embodiment, the present application provides the compounds of the present application, their isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof, for use in treating cancer.

[0035] In another embodiment, the present application provides a method for treating cancer in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of the compound of the present application, its isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof.

[0036] In some embodiments, the cancer is colon cancer. [Modes for carrying out the invention]

[0037] Specific methods for carrying out the present invention definition Unless otherwise defined, technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the claimed subject matter belongs.

[0038] It should be understood that the brief description above and the detailed description below are illustrative and descriptive only and are not intended to limit the subject matter of the present invention.

[0039] All or some of the references cited in this application, including but not limited to patents, patent applications, articles, books, instruction manuals, and papers, are incorporated herein by reference in their entirety.

[0040] It should be noted that, unless otherwise specified, the terms “or” and “alternatively” mean “and / or” when used herein. Furthermore, the term “comprise,” as well as other forms such as “contain,” “include,” and “have,” are intended to be non-restrictive.

[0041] Certain chemical groups as defined herein are preceded by a convenient notation indicating the total number of carbon atoms present in the group. For example, C 1~10 Alkyl refers to an alkyl group having a total of 1 to 10 carbon atoms, as defined below: C 3~10 A cycloalkyl group is a group having a total of 3 to 10 carbon atoms, as defined below: 6~10 The term "aryl" refers to an aryl group defined below, which has a total of 6 to 10 carbon atoms. In simplified notation, the total number of carbon atoms does not include carbon atoms that may be present in substituents of the group.

[0042] In addition to the foregoing, where used in the description and claims of this application, unless otherwise specifically indicated, the following terms have the meanings set forth below.

[0043] The term "amino" refers to the -NH2 group.

[0044] The term "cyano" refers to the -CN group.

[0045] The term "hydroxyl" refers to the -OH group.

[0046] The term "oxo" refers to an =O substituent.

[0047] As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0048] The term "alkyl," as used herein, refers to a linear or branched group consisting only of carbon and hydrogen atoms, either alone or as part of another group, without unsaturated bonds, and bonded to the rest of the molecule by single bonds. Alkyl groups may have, for example, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, and decyl. Hydrogen atoms on an alkyl group may be optionally replaced by any suitable group, such as halogens, hydroxyls, alkyls, haloalkyls, alkoxys, cycloalkyls, and heterocyclyls.

[0049] As used herein, the term "heteroalkyl" refers to the alkyl group defined above, which contains one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur in its alkyl chain. As used herein, heteroalkyl mainly includes alkyl groups containing oxygen in their alkyl chain, including, but not limited to, alkoxy, alkoxyalkyl, and alkoxyalkoxyalkyl groups. Examples of alkoxy include, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Examples of alkoxyalkyl include, but not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, and propoxyethyl. Hydrogen atoms on the heteroalkyl group may be optionally replaced by any preferred group, such as halogens, hydroxyls, alkyls, haloalkyls, cycloalkyls, and heterocyclyls.

[0050] As used herein, the term "hydroxyalkyl" refers to an alkyl group having a hydroxyl substituent at a preferred position on the alkyl chain, as defined above. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 2-hydroxyethyl, 2-hydroxypropyl, and 2-hydroxybutyl.

[0051] As used herein, the term “haloalkyl” refers to an alkyl group defined above, which is substituted with one or more halogen atoms. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, chloromethyl, chloroethyl, dichloromethyl, and 1,2-dichloroethyl.

[0052] As used herein, the term “alkenyl” refers to a linear or branched hydrocarbon group consisting only of carbon and hydrogen atoms, containing at least one double bond, and having, for example, 2 to 10, 2 to 8, 2 to 6, 2 to 5, or 2 to 4 carbon atoms, which are bonded to the rest of the molecule by single bonds. Examples include, but are not limited to, ethenyl, propenyl, allyl, buta-1-enyl, buta-2-enyl, penta-1-enyl, penta-2-enyl, penta-1,4-dienyl, etc. The hydrogen atoms on the alkenyl may be substituted with any preferred group such as halogen, hydroxyl, amino, monosubstituted amino, disubstituted amino, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, etc.

[0053] As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon group consisting only of carbon and hydrogen atoms, comprising at least one triple bond and optionally one or more double bonds, having, for example, 2 to 10, 2 to 8, 2 to 6, 2 to 5, or 2 to 4 carbon atoms, and bonded to the rest of the molecule by single bonds. Examples of alkynyls include, but are not limited to, ethynyl, propa-1-inyl, and penta-1-en-4-inyl. The hydrogen atoms on the alkynyl may be substituted with any preferred group, such as halogens, hydroxyl, amino, alkyl, haloalkyl, alkoxy, cycloalkyl, or heterocyclyl.

[0054] In this application, the term "cycloalkyl" refers to a stable, saturated, non-aromatic monocyclic or polycyclic hydrocarbon group (which may include spiro, condensed, or bridging ring systems) consisting only of carbon and hydrogen atoms, for example, having 3 to 12, 3 to 10, 3 to 8, or 3 to 6 carbon atoms, and linked to the rest of the molecule by single bonds via any suitable carbon atom on the ring. Cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiro[2.3]hexyl, spiro[3.3]heptyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, and adamantyl. The hydrogen atoms on the cycloalkyl group may be substituted with any suitable group such as halogen, hydroxyl, cyano, alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, or heterocyclyl.

[0055] As used herein, the term "cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group (which may include spiro, condensed, or bridging ring systems) consisting only of carbon and hydrogen atoms, containing double bonds, and having, for example, 3 to 12, 3 to 10, 3 to 8, or 3 to 6 carbon atoms, and being bonded to the rest of the molecule by single bonds via any suitable carbon atom in the ring. Examples of cycloalkenyls include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1H-indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro These include -5-hydro-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, octahydro-4,7-methylene-1-hydro-indenyl, and octahydro-2,5-methylene-pentalenyl. The hydrogen atoms on the cycloalkenyl may be substituted with any suitable group such as halogens, hydroxyls, aminos, monosubstituted aminos, disubstituted aminos, alkyls, alkoxys, and heterocyclyls.

[0056] As used herein, the terms “heterocyclic ring” or “heterocyclyl” refer to a stable 3- to 12-membered non-aromatic cyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, either as independent groups or as part of another group. Heterocyclic rings or heterocyclyls may be monocyclic, bicyclic, tricyclic, or polycyclic ring systems, which may include spiro, condensed, or bridging ring systems. For example, the heterocyclic ring or heterocyclyl may be a stable 3-10 member non-aromatic monocyclic ring group, bicyclic ring group, spirocyclic ring group, fused ring group or bridging ring group containing one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; for example, a stable 3-8 member non-aromatic monocyclic ring group, bicyclic ring group, spirocyclic ring group, fused ring group or bridging ring group containing one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; for example, a stable 4-8 member non-aromatic monocyclic ring group, bicyclic ring group, spirocyclic ring group, fused ring group or bridging ring group containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In the heterocyclic ring or heterocyclyl, the nitrogen atom, carbon atom, or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, and the heterocyclic ring or heterocyclyl may be partially saturated or fully saturated. A heterocyclic ring or heterocyclyl can be bonded to the rest of the molecule by single bonds via carbon atoms or heteroatoms. In a heterocyclic ring or heterocyclyl-containing fused ring, one or more rings may be aryl or heteroaryl, provided that the bonding sites to the rest of the molecule are non-aromatic ring atoms.Examples of heterocyclic rings or heterocyclyls include, but are not limited to, oxetanyl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperadinyl, piperidinyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolidinyl, thiazolidinyl, isothiazolidinyl, isoxox Examples include zolidinyl, indlinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, 8-oxabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 3,6-dihydro-2H-pyranyl, 3-oxabicyclo[4.1.0]heptyl, and 2-oxa-5-azabicyclo[2.2.1]heptyl. The heterocyclic ring or heterocyclyl may be substituted with any suitable substituent, including but not limited to halogens, hydroxyl, amino, alkyl, alkoxy, and alkylcarbonyl.

[0057] In this application, "azacyclic ring" or "azacyclyl" refers to the heterocyclic or heterocyclyl defined above, which contains at least one nitrogen atom within the ring.

[0058] As used herein, the term “aryl” refers to a ring system having 6 to 18, preferably 6 to 12, more preferably 6 to 10 carbon atoms and at least one aromatic ring, either as an independent group or as part of another group. Aryls can be monocyclic, bicyclic, tricyclic, or polycyclic systems, which may include fused or bridging ring systems. The aryl is bonded to the rest of the molecule by a single bond via the aromatic ring atoms. Examples of aryls include, but are not limited to, phenyl, naphthyl, anthracenyl, phenantrenyl, and fluorenyl.

[0059] As used herein, the terms “heteroaromatic ring” or “heteroaryl” refer to a 5- to 16-membered cyclic group having 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring, either as an independent group or as part of another group. Heteroaryls can be monocyclic, bicyclic, tricyclic, or polycyclic cyclic systems, which may include fused or bridging cyclic systems, provided that the bonding sites are mediated by aromatic ring atoms. In heteroaromatic rings or heteroaryls, the nitrogen, carbon, or sulfur atoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. For example, the heteroaromatic ring or heteroaryl can be a stable 5-10 member aromatic monocyclic or bicyclic group containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; for example, a stable 5-8 member aromatic monocyclic or bicyclic group containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; for example, a stable 5-6 member aromatic monocyclic group containing 1-2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heteroaromatic rings or heteroaryls include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, benzopyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, triazinyl, pyrimidinyl, pyridadinyl, indolidine, indolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, fenopiazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, and ka. This includes porinyl, phenanthidinyl, phenanthrolinyl, acridinyl, phenazinyl, thiazolyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, sinnolinyl, quinazolinyl, phenylthio, indolidinyl, orthophenanthrenyl, phenoxadinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, imidazo[1,2-a]pyridinyl, and others.The heteroaromatic ring or heteroaryl may be substituted with any preferred substituent, including but not limited to halogens, hydroxyl, amino, alkyl, haloalkyl, alkoxy, and alkylcarbonyl.

[0060] The term "isomer" refers to an isomer resulting from differences in the spatial arrangement of atoms within a molecule. Unless otherwise specified, the compounds described herein include all such isomers, including stereoisomers, geometric isomers, tautomers, and stable conformational isomers, and may exist as mixtures of isomers or as isolated isomers. For example, if a compound has a chiral carbon atom, enantiomers and diastereomers may arise, and if a compound has a carbon-carbon double bond, a carbon-nitrogen double bond, or a ring structure, cis-trans isomers may arise. Methods for preparing optically active products from optically inert starting materials, such as by the resolution of racemic mixtures or stereoselective synthesis, are known in the art.

[0061] The compounds described herein may have one or more chiral carbon atoms (optical centers), and some compounds may also have double bonds or ring structures. All resulting isomers, such as racemates, enantiomers, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., individual enantiomers) and mixtures thereof, are intended to fall within the scope of the invention. Where stereochemical descriptions are given, a compound is described in which one isomer is present and substantially no other isomers are present. "Substantially no other isomers" means that the ratio of the two isomers is at least 80 / 20, for example 90 / 10 or 95 / 5, or even higher. In some embodiments, one of the isomers is present in an amount of at least 99%.

[0062] The compounds of the present invention may contain atomic isotopes in unnatural ratios in one or more atoms constituting the compound. For example, this compound contains deuterium ( 2 H), tritium ( 3 H), Iodine-125(125 I) or C-14 ( 14 The compounds may be labeled with radioactive isotopes such as C). All isotopic variants of the compounds of the present invention are encompassed by the present invention, whether or not they are radioactive. In some embodiments of the present invention, when H is mentioned, it includes deuterium or tritium. In some embodiments, the isotope-labeled compounds of the present invention refer to deuterated compounds.

[0063] As used herein, the term "optionally" means that the event or situation described thereafter may or may not occur, and that this statement includes both the cases in which the event or situation occurs and the cases in which it does not occur. For example, "optionally substituted alkyl" means that the alkyl is either unsubstituted or substituted with one or more halogens, and that this statement includes both substituted and unsubstituted alkyls.

[0064] As used herein, the term "pharmaceutically acceptable salt" refers to a salt in which the basic group in the parent compound is converted into a salt form that retains the biological potency of the free base compound and has no biological or other harmful effects.

[0065] As used herein, the term “pharmaceutical composition” refers to a formulation comprising the compound of the present invention and a generally accepted medium in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes pharmaceutically acceptable excipients. The pharmaceutical composition of the present invention may be a single preparation or a combination of several preparations.

[0066] As used herein, the term “pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, pigments / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are approved by the relevant government regulatory authority as acceptable for use in humans or animals.

[0067] As used herein, the terms “subject” or “patient” refer to an individual, including mammals and non-mammals, that is suffering from a disease, disorder or condition. In one embodiment, the mammal is a human.

[0068] As used herein, the term “treatment” includes reducing, alleviating, or improving the symptoms of a disease or condition; inhibiting a disease or condition, such as halting its progression; alleviating a disease or condition; causing improvement of a disease or condition; reducing symptoms caused by a disease or condition; stopping symptoms of a disease or condition; preventing other symptoms; and improving or preventing the underlying metabolic cause of symptoms. Furthermore, the term encompasses preventive purposes. The term also encompasses achieving therapeutic and / or preventive effects. A therapeutic effect refers to curing or improving the underlying disease being treated. Furthermore, curing or improving one or more physiological symptoms associated with an underlying disease is also a therapeutic effect, for example, when an improvement in the patient's condition is observed even if the patient is still suffering from the underlying disease. In the case of a preventive effect, the composition may be administered to patients at risk of a particular disease, or to patients suffering from one or more physiological symptoms of a disease, even if the disease has not yet been diagnosed.

[0069] As used herein, the term “administer” means a method by which a compound or composition is delivered to a site where a biological effect is desired. Such methods include, but are not limited to, oral administration, intraduodenal administration, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with preferred techniques for administering compounds and the methods described herein, such as those discussed by Goodman and Gilman, The Pharmacological Basis of Therapeutics (current edition), Pergamon and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0070] As used herein, the terms “effective dose” or “therapeutic effective dose” mean an amount of at least one active substance (e.g., a compound of the present invention) that, when administered, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. This can result in the reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired change in the biological system. For example, a therapeutic effective dose is the amount of a composition containing the compounds disclosed herein that is necessary to achieve clinically significant relief of the symptoms. Techniques such as dose escalation studies may be used to determine an appropriate effective dose for any individual case.

[0071] Compounds and pharmaceutical compositions of this application In one embodiment, the present invention relates to a compound represented by formula I, its isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof:

[0072] [ka]

[0073] (In the formula,

[0074] [ka]

[0075] This indicates that the ring to which it belongs is an aromatic ring system. X1 is N or C(R X1 Selected from the group consisting of, X2 is selected from the group consisting of C or N. X3 is N, C(R X2 ) or N(R X3 Selected from the group consisting of, X4 is N or C(R X4 Selected from the group consisting of, X5 is selected from the group consisting of C or N. X6 is N, N(R X5 ) or C(R X6 Selected from the group consisting of, R X1 , R X2 , R X3 , R X4 , R X5 and R X6 H, halogen, C 6~10 Ariel, C 3~10 Cycloalkyl, C 3~10 A cycloalkenyl, a 3-10 membered heterocyclyl, or a 5-10 membered heteroaryl is independently selected from the group, C 6~10 Ariel, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyls, 3-10 membered heterocyclyls, and 5-10 membered heteroaryls have one, two, or three R groups. X Each of these may be substituted by the base, R X These are halogen, cyano, hydroxyl, and C, respectively. 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, or -NR c R d Independently selected from the group consisting of C 1~6 Alkyl, C 1~6 Heteroalkyl, C3~10 Cycloalkyl and 3- to 10-membered heterocyclyls are halogen, cyano, hydroxyl, or C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups, A is selected from a group consisting of 4-10 member heterocyclils, and each 4-10 member heterocyclil has one, two, or three R a It may be substituted by the base, R a These are C 1~10 Alkyl, C 1~10 Heteroalkyl, amino, or -S(=O)2-C 1~10 Independently selected from the group consisting of alkyls, Ring B is selected from the group consisting of a 5-7 membered heterocyclic ring, a 5-7 membered carbocyclic ring, a benzene ring, or a 5-7 membered heteroaromatic ring. R b These are halogen, hydroxyl, cyano, amino, oxo, and C, respectively. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR e R f -C(O)OC 1~10 Alkyl, -SO2NR g R h , -SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C1~6 Alkyl-5 to 10-membered heteroaryl or

[0076] [ka]

[0077] Independently selected from the group consisting of C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR e R f -C(O)OC 1~10 Alkyl, -SO2NR g R h , -SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryls and

[0078] [ka]

[0079] These are deuterium, halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, halogenated C 1~10 Alkyl, hydroxy-C 1~10 Alkyl, C 1~10 Heteroalkyl, C3~10 Cycloalkyl, 3-10 membered heterocyclyl or -CONR i R j They may each be substituted by one, two, three, or four substituents independently selected from the group consisting of the above, R' is H, C 1~10 Alkyl, C 3~10 Selected from the group consisting of cycloalkyl or CN, R c , R d , R e , R f , R g , R h , R i and R j is H or C 1~10 Each is independently selected from the group consisting of alkyl groups, Alternatively, two R b The bases are connected to each other, C 3~10 Forming a cycloalkyl or 3-10 membered heterocycline, C 3~10 Cycloalkyl and 3-10 membered heterocyclyls are deuterium, halogen, hydroxyl, cyano, amino, and C 1~10 Alkyl, halogenated C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 They may be substituted with one, two, three, or four substituents independently selected from the group consisting of cycloalkyls or 3- to 10-membered heterocyclines, respectively. n is selected from the group consisting of 0, 1, 2, 3, or 4. To provide.

[0080] In one embodiment of the compound represented by formula I, X1 is N. In one embodiment of the compound represented by formula I, X1 is CH. In one embodiment of the compound represented by formula I, X1 is C(R X1 ) and R X1 is halogen, C 6~10 Ariel, C 3~10 Cycloalkyl, C 3~10Selected from the group consisting of cycloalkenyls, 3-10 membered heterocyclyls, or 5-10 membered heteroaryls, C 6~10 Ariel, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyls, 3-10 membered heterocyclyls, or 5-10 membered heteroaryls have one, two, or three R groups. X Each of them may be substituted by the group, R X These are halogen, cyano, hydroxyl, and C, respectively. 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, or -NR c R d Independently selected from the group consisting of C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl and -NR c R d These are halogens, cyano, hydroxyl, or C 1~6 Each of the substituents may be independently selected from the group consisting of alkyl groups, R c and R d Each of them is independently of hydrogen or C 1~6 It is alkyl.

[0081] In one embodiment of the compound represented by formula I, X2 is C. In one embodiment of the compound represented by formula I, X2 is N.

[0082] In one embodiment of the compound represented by formula I, X3 is N. In one embodiment of the compound represented by formula I, X3 is C(R X2 ) or N(R X3 ) and R X2 and R X3 H, halogen, C 6~10 Ariel, C 3~10 Cycloalkyl, C 3~10A cycloalkenyl is independently selected from the group consisting of a 3-10 member heterocyclyl or a 5-10 member heteroaryl, and a halogen, C 6~10 Ariel, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyls, 3-10 membered heterocyclyls, or 5-10 membered heteroaryls have one, two, or three R groups. X It may be substituted with a group, R X These are halogen, cyano, hydroxyl, and C, respectively. 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, or -NR c R d Independently selected from the group consisting of C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl and 3- to 10-membered heterocyclyls are halogen, cyano, hydroxyl, or C 1~6 Each of the substituents may be independently selected from the group consisting of alkyl groups, R c and R d Each of them is independently of hydrogen or C 1~6 It is alkyl.

[0083] In one embodiment of the compound represented by formula I, X3 is C(R X2 ) or N(R X3 Selected from the group consisting of ), R X2 and R X3 The group is independently selected from a group consisting of 5-10 member heteroaryls, and each 5-10 member heteroaryl has one, two, or three R X It may be substituted with a group, R X These are as defined above. In one embodiment of the compound represented by formula I, X3 is C(R X2 ) or N(R X3 Selected from the group consisting of ), R X2 and R X3The group is independently selected from a group consisting of 5-6 member heteroaryls, and each 5-6 member heteroaryl has one or two R X It may be substituted with a group, R X These are as defined above. In one embodiment of the compound represented by formula I, X3 is C(R X2 ) or N(R X3 Selected from the group consisting of ), R X2 and R X3 It is independently selected from the group consisting of 5-membered heteroaryls, and each 5-membered heteroaryl has one or two R X It may be substituted with a group, R X These are C 1~6 It is independently selected from the group consisting of alkyls. In one embodiment of the compound represented by formula I, X3 is C(R X2 ) or N(R X3 Selected from the group consisting of ), R X2 and R X3 It is independently pyrazolyl, and pyrazolyl is C such as methyl. 1~4 C such as alkyl 1~6 It may be substituted with one substituent selected from the group consisting of alkyl groups. In one embodiment of the compound represented by formula I, X3 is C(R X2 ) or N(R X3 Selected from the group consisting of ), R X2 and R X3 It is independently pyrazolyl.

[0084] In one embodiment of the compound represented by formula I, X4 is N. In one embodiment of the compound represented by formula I, X4 is CH. In one embodiment of the compound represented by formula I, X4 is C(R X4 ) and R X4 is halogen, C 6~10 Ariel, C 3~10 Cycloalkyl, C 3~10 Selected from the group consisting of cycloalkenyls, 3-10 membered heterocyclyls, or 5-10 membered heteroaryls, C 6~10 Ariel, C 3~10Cycloalkyl, C 3~10 Cycloalkenyls, 3-10 membered heterocyclyls, and 5-10 membered heteroaryls have one, two, or three R groups. X Each of them may be substituted by the group, R X These are halogen, cyano, hydroxyl, and C, respectively. 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, or -NR c R d Independently selected from the group consisting of C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl and 3- to 10-membered heterocyclyls are halogen, cyano, hydroxyl, or C 1~6 Each of the substituents may be independently selected from the group consisting of alkyl groups, R c and R d Each of them is independently of hydrogen or C 1~6 It is alkyl.

[0085] In one embodiment of the compound represented by formula I, X5 is C. In one embodiment of the compound represented by formula I, X5 is N.

[0086] In one embodiment of the compound represented by formula I, X6 is CH. In one embodiment of the compound represented by formula I, X6 is N. In one embodiment of the compound represented by formula I, X6 is N(R X5 ) or C(R X6 Selected from the group consisting of ), R X5 and R X6 is halogen, C 6~10 Ariel, C 3~10 Cycloalkyl, C 3~10 A cycloalkenyl, a 3-10 membered heterocyclyl, or a 5-10 membered heteroaryl is independently selected from the group, C 6~10 Ariel, C 3~10 Cycloalkyl, C 3~10Cycloalkenyls, 3-10 membered heterocyclyls, and 5-10 membered heteroaryls have one, two, or three R groups. X Each of them may be substituted by the group, R X These are halogen, cyano, hydroxyl, and C, respectively. 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, or -NR c R d Independently selected from the group consisting of C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl and 3- to 10-membered heterocyclyls are halogen, cyano, hydroxyl, or C 1~6 Each of the substituents may be independently selected from the group consisting of alkyl groups, R c and R d Each of them is independently of hydrogen or C 1~6 It is alkyl.

[0087] In one embodiment of the compound represented by formula I, A is a 4- to 10-membered heterocycline, and the 4- to 10-membered heterocycline has one, two or three R a It may be substituted with a group, R a These are C 1~10 Alkyl, C 1~10 Heteroalkyl, amino, or -S(=O)2-C 1~10 Independently selected from the group consisting of alkyl groups. In one embodiment of the compound represented by formula I, A is a 5- to 8-membered heterocycline, and the 5- to 8-membered heterocycline has one, two or three R groups. a It may be substituted with a group, R a These are C 1~10 Alkyl, C 1~10 Heteroalkyl, amino, or -S(=O)2-C 1~10Independently selected from the group consisting of alkyls. In one embodiment of the compound represented by formula I, A is a 5- to 8-membered heterocycline containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen, and the 5- to 8-membered heterocycline contains one or two R a It may be substituted with a group, R a These are C 1~6 Alkyl, C 1~6 Heteroalkyl, amino, or -S(=O)2-C 1~6 Independently selected from the group consisting of alkyl groups. In one embodiment of the compound represented by formula I, A is a 6-membered heterocycline, and the 6-membered heterocycline has one or two R a It may also be substituted by R a These are C 1~10 Alkyl, C 1~10 Heteroalkyl, amino, or -S(=O)2-C 1~10 Independently selected from the group consisting of alkyl groups. In one embodiment of the compound represented by formula I, A is a 6-membered azacyclic ring group, and the azacyclic ring has one or two R a It may be substituted with a group, R a These are C, such as methyl. 1~6 C such as alkyl 1~10 It is independently selected from the group consisting of alkyl groups.

[0088] In one embodiment of the compound represented by formula I, A is

[0089] [ka]

[0090] It is selected from the group consisting of the following.

[0091] In one embodiment of the compound represented by formula I, A is

[0092] [ka]

[0093] R1 and R2 are, independently, hydrogen or C such as methyl. 1~4 C such as alkyl 1~6 It is alkyl. In one embodiment of the compound represented by formula I, A is

[0094] [ka]

[0095] And R1 and R2, together with the carbon atom and adjacent nitrogen atom to which they are bonded,

[0096] [ka]

[0097] They form azathal rings with 4 to 8 members.

[0098] In one embodiment of the compound represented by formula I, A is

[0099] [ka]

[0100] In one embodiment of the compound represented by formula I, A is

[0101] [ka]

[0102] That is the case.

[0103] In one embodiment of the compound represented by formula I, ring B is selected from the group consisting of a 5- to 7-membered heterocyclic ring, a 5- to 7-membered carbocyclic ring, a benzene ring, or a 5- to 7-membered heteroaromatic ring. In one embodiment of the compound represented by formula I, ring B is a 5-membered ring. In another embodiment, ring B is a 6-membered ring. In another embodiment, ring B is a 7-membered ring. In one embodiment of the compound represented by formula I, ring B is selected from the group consisting of a 7-membered heterocyclic ring, a 7-membered carbocyclic ring, a benzene ring, or a 7-membered heteroaromatic ring. In one embodiment of the compound represented by formula I, ring B is selected from the group consisting of a 7-membered heterocyclic ring, a 7-membered carbocyclic ring, or a benzene ring. In one embodiment of the compound represented by formula I, ring B is selected from the group consisting of a 7-membered heterocyclic ring or a 7-membered carbocyclic ring.

[0104] In one embodiment of the compound represented by formula I, ring B has the following structure:

[0105] [ka]

[0106] (In the formula,

[0107] [ka]

[0108] This represents a single bond or a double bond. X5 is selected from the group consisting of C or N. The Z1 is CR6R7, The Z2 is CR8R9, N, NR 10 Selected from the group consisting of O, S, -C(O)- or -SO2-, The Z3 is CR 11 CR 12 R 13 , N, NR 14 , O, -C(O)-, -SO2- or -S(O)(NR 15 Selected from the group consisting of )-, The Z4 is CR 16 CR 17 R 18 , N, NR 19 , O, S, -C(O)-, -SO2- or -S(O)(NR 20 Selected from the group consisting of )-, One or both of Z1, Z2, Z3, and Z4 may be absent, and a ring containing X5, Z1, Z2, Z3, and Z4 is a stable ring structure. R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 These are hydrogen, halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl or

[0109] [ka]

[0110] Each of the groups consisting of C is independently selected. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl and

[0111] [ka]

[0112] These are deuterium, halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, halogenated C 1~10 Alkyl, hydroxy-C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl or -CONR25 R 26 They may each be substituted by one, two, three, or four substituents independently selected from the group consisting of the above, R' is H, C 1~10 Alkyl, C 3~10 Selected from the group consisting of cycloalkyl or CN, R 21 , R 22 , R 23 , R 24 , R 25 and R 26 is H or C 1~10 Each is independently selected from the group consisting of alkyl groups, Alternatively, R6 and R7, R8 and R9, R 12 and R 13 or R 17 and R 18 They are connected to each other, C 3~10 Forming a cycloalkyl or 3-10 membered heterocycline, C 3~10 Cycloalkyl or 3-10 membered heterocyclines are halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 It has one, two, three or four substituents independently selected from the group consisting of cycloalkyl or 3- to 10-membered heterocyclyls. In one embodiment of the above-described ring B, R6, R7, R8, R9, R 11 , R 12 , R 13 , R 16 , R 17 and R 18 These are, independently, hydrogen, halogen, hydroxyl, cyano, and C. 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 1~10 Alkoxy, C 2~5 Alkenil, C 2~5 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -COC 1~10 Alkyl, -CONR 21 R 22 -C(O)OC1~10 Alkyl, -SO2NR 23 R 24 or -SO2C 1~10 It is alkyl, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 1~10 Alkoxy, C 2~5 Alkenil, C 2~5 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 and -SO2C 1~10 Alkyl compounds include halogen, hydroxyl, cyano, amino, and C. 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CONR 25 R 26 They may each be substituted with one, two, three, or four substituents independently selected from the group consisting of, or R6 and R7, R8 and R9, R 12 and R 13 or R 17 and R 18 They are connected to each other, C 3~10 Forms a cycloalkyl group, C 3~10 Cycloalkyls include halogen, hydroxyl, cyano, amino, and C. 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 R may be substituted with one or two substituents independently selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl groups. 10 , R 14 , R 15 , R 19 and R 20 These are, independently, hydrogen and C 1~10 Alkyl, C 3~10Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, C 1~10 Alkyloxy, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl or

[0113] [ka]

[0114] C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~5 Alkenil, C 2~5 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, C 1~10 Alkoxy, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2C 1~10 Alkyl, -SO2-C 2~6Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryls and

[0115] [ka]

[0116] These are deuterium, halogen, hydroxyl, cyano, amino, and C. 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, or -CONR 25 R 26 Each of the substituents may be independently selected from the group consisting of H, C, and R' may be substituted with one, two, three, or four substituents, where R' is H, C 1~10 Alkyl, C 3~10 Selected from the group consisting of cycloalkyl or CN, R 21 , R 22 , R 23 , R 24 , R 25 and R 26 is H or C 1~6 Each is independently selected from the group consisting of alkyl groups.

[0117] In one embodiment of ring B described above, one of Z1, Z2, Z3, and Z4 may be absent; for example, Z3 may be absent, and in another example, Z4 may be absent, in which case ring B becomes a 6-membered ring. In one embodiment of ring B described above, two of Z1, Z2, Z3, and Z4 may be absent; for example, both Z3 and Z4 may be absent, in which case ring B becomes a 5-membered ring.

[0118] In one embodiment of ring B described above, Z1 is CR6R7, Z2 is selected from the group consisting of CR8R9 or -C(O)-, and Z3 is absent, CR 11 CR 12 R 13 , N, NR 14 Selected from the group consisting of , O or -C(O)-, Z4 is absent, CR 16 CR 17 R 18 , N, NR 19 Or selected from the group consisting of -C(O)-, R6, R7, R8, R9, R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 18 and R 19 These are as defined above. In a particular embodiment, R6, R7, R8, R9, R 11 , R 12 , R 13 , R 16 , R 17 and R 18 is hydrogen, hydroxyl, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Each is independently selected from the group consisting of aryls or 5-10 member heteroaryls, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Aryls and 5-10 member heteroaryls are halogens, C 1~6 Alkyl or halogenated C 1~6Each of them may be substituted with one or two substituents independently selected from the group consisting of alkyl groups, or R6 and R7, R8 and R9, R 12 and R 13 or R 17 and R 18 They are connected to each other, C 3~8 Forming a cycloalkyl or 3-8 membered heterocycline, C 3~8 Cycloalkyl or 3- to 8-membered heterocyclyls are halogen, hydroxyl, cyano, amino, and C. 1~4 Alkyl, halogenated C 1~4 Alkyl, C 1~4 Heteroalkyl, C 3~6 R may be substituted with one or two substituents independently selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl groups. 14 and R 19 is hydrogen, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclyl, -C 1~4 Alkyl-C 6~10 Ariel, -C 1~4 Alkyl-5 to 10-membered heteroaryl or

[0119] [ka]

[0120] Each of the groups consisting of C is independently selected. 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -C(O)OC 1~10 Alkyl, -SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclyl, -C 1~4 Alkyl-C 6~10 Ariel, -C 1~4 Alkyl-5 to 10-membered heteroaryls and

[0121] [ka]

[0122] Deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CONR 25 R 26 Each of the substituents may be independently selected from the group consisting of H, C, and R' may be substituted with one, two, or three substituents, where R' is H, C 1~10 Alkyl, C 3~10 Selected from the group consisting of cycloalkyl or CN, R 23 , R 24 , R 25 and R 26 is hydrogen or C 1~6Each is independently selected from the group consisting of alkyl groups.

[0123] In one embodiment of ring B described above, Z1 is CR6R7, Z2 is selected from the group consisting of CR8R9 or -C(O)-, and Z3 is CR 11 CR 12 R 13 , N, NR 14 Selected from the group consisting of , O or -C(O)-, Z4 is absent, CR 16 CR 17 R 18 , N, NR 19 Or selected from the group consisting of -C(O)-, R6, R7, R8, R9, R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 18 and R 19 These are as defined above. In certain embodiments, R6, R7, R8, R9, R 11 , R 12 , R 13 , R 16 , R 17 and R 18 is hydrogen, hydroxyl, C 1~6 Alkyl, C 3~8 Each is independently selected from the group consisting of cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, C 1~6 Alkyl, C 3~8 Cycloalkyls, 3-8 membered heterocyclyls, phenyls, and 5-6 membered heteroaryls are halogens, C 1~6 Alkyl or halogenated C 1~6 Each of the substituents may be independently selected from the group consisting of alkyl groups, R 14 and R 19 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkynyl, phenyl, 5-6 member heteroaryl, -CO-C1~6 Alkyl, -CO-C 3~8 Cycloalkyl, -C(O)OC 1~6 Alkyl, -SO2NR 23 R 24 , -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~8 Cycloalkyl, -SO2-3~8 member heterocyclyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-3 to 8-membered heterocyclyl, -C 1~4 Alkylphenyl, -C 1~4 Alkyl-5 to 6-membered heteroaryl or

[0124] [ka]

[0125] Each of the groups consisting of C is independently selected. 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkynyl, phenyl, 5-6 member heteroaryl, -CO-C 1~6 Alkyl, -CO-C 3~8 Cycloalkyl, -C(O)OC 1~6 Alkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~8 Cycloalkyl, -SO2-3~8 member heterocyclyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-3 to 8-membered heterocyclyl, -C 1~4 Alkylphenyl, -C 1~4 Alkyl-5~6 member heteroaryl and

[0126] [ka]

[0127] Deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CONR 25 R 26 Each of the substituents may be independently selected from the group consisting of H, C, and R' may be substituted with one, two, or three substituents, where R' is H, C 1~6 Alkyl, C 3~6 Selected from the group consisting of cycloalkyl or CN, R 23 , R 24 , R 25 and R 26 is hydrogen or C 1~6 Each is independently selected from the group consisting of alkyl groups.

[0128] In one embodiment of ring B described above, Z1 is CR6R7, and R6 and R7 are as defined above. In one embodiment, R6 and R7 are hydrogen, or C such as methyl 1~4 C such as alkyl 1~6 C such as alkyl 1~10 Each is independently selected from the group consisting of alkyl groups. In one embodiment of ring B described above, Z1 is CH2.

[0129] In one embodiment of ring B described above, Z2 is selected from the group consisting of -C(O)- or CR8R9, and R8 and R9 are as defined above. In one embodiment, R8 and R9 are hydrogen, or C such as methyl 1~4 C such as alkyl 1~6 C such as alkyl 1~10 Each is independently selected from the group consisting of alkyl groups. In one embodiment of ring B described above, Z2 is selected from the group consisting of CR8R9, and R8 and R9 are hydrogen or C such as methyl. 1~4 C such as alkyl 1~6It is independently selected from the group consisting of alkyl. In one embodiment of the above-mentioned ring B, Z2 is CH2.

[0130] In one embodiment of the above-mentioned ring B, Z3 is CR 11 , CR 12 R 13 , N, NR 14 , O or -C(O)-, and R 11 , R 12 , R 13 and R 14 are as defined above. In one embodiment, R 11 , R 12 and R 13 are independently selected from the group consisting of hydrogen, hydroxyl, C 1~10 alkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, and C 1~10 alkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl may each be substituted by one or two substituents independently selected from the group consisting of C 1~6 alkyl or halogenated C 1~6 alkyl, and R 14 is hydrogen, C 1~10 alkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 2~6 alkenyl, C 2~6 alkynyl, C 6~10 aryl, 5- to 10-membered heteroaryl, -CO-C 1~10 alkyl, -CO-C 3~10 cycloalkyl, -C(O)OC 1~10 alkyl, -SO2NR 23 R 24 , -SO2-C 1~10 alkyl, -SO2-C 2~6 alkenyl, -SO2-C 3~10 cycloalkyl, -SO2-3- to 10-membered heterocyclyl, -C 1~4 alkyl-C 3~10 cycloalkyl, -C 1~4Alkyl-3 to 10-membered heterocyclines or

[0131] [ka]

[0132] Selected from the group consisting of C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -C(O)OC 1~10 Alkyl, -SO2-C 1~10 Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-C 2~6 Alkenyl, -SO2-3~10-membered heterocyclyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclyl and

[0133] [ka]

[0134] Deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl or halogenated C 1~6 Each atom may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups, where R' is H, C 1~10 Alkyl, C 3~10 Selected from the group consisting of cycloalkyl or CN, R 23 and R 24 is hydrogen or C 1~6 Each is independently selected from the group consisting of alkyl groups.

[0135] In one embodiment of ring B described above, Z3 is CR 12R 13 , N, NR 14 Selected from the group consisting of , O or -C(O)-, R 12 , R 13 and R 14 This is as defined above. In one embodiment, R 12 and R 13 is hydrogen, hydroxyl, C 1~6 Alkyl, C 3~7 A cycloalkyl group is independently selected from the group consisting of a 3- to 7-membered heterocyclyl group or a 5- to 6-membered heteroaryl group, C 1~6 Alkyl, C 3~7 Cycloalkyls, 3-7 membered heterocyclyls, or 5-6 membered heteroaryls are halogens, C 1~6 Alkyl or halogenated C 1~6 Each of the substituents may be independently selected from the group consisting of alkyl groups, R 14 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkynyl, phenyl, 5-6 member heteroaryl, -CO-C 1~6 Alkyl, -CO-C 3~8 Cycloalkyl, -C(O)OC 1~6 Alkyl, -SO2NR 23 R 24 , -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~8 Cycloalkyl, -SO2-3~8 member heterocyclyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-3 to 8-membered heterocyclyl or

[0136] [ka]

[0137] Selected from the group consisting of C 1~6 Alkyl, C3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 2~6 Alkenyl, C 2~6 Alkynyl, phenyl, 5- to 6-membered heteroaryl, -CO-C 1~6 Alkyl, -CO-C 3~8 Cycloalkyl, -C(O)OC 1~6 Alkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~8 Cycloalkyl, -SO2-3- to 8-membered heterocyclyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-3- to 8-membered heterocyclyl and

[0138]

Chemical Structure

[0139] is each independently optionally substituted with one, two or three substituents selected from the group consisting of deuterium, halogen, hydroxyl, cyano, C 1~6 alkyl or halogenated C 1~6 alkyl, and R' is H, C 1~6 alkyl or C 3~6 cycloalkyl, R 23 and R 24 are each independently selected from the group consisting of hydrogen or C 1~6 alkyl.

[0140] In one embodiment of the above ring B, Z3 is selected from the group consisting of CR 12 R 13 , N, NR 14 , O or -C(O)-, and R 12 , R 13 and R 14 are as defined above. In one embodiment, R 12 and R 13 are each independently selected from the group consisting of hydrogen or C 1~6 alkyl.1~6 Alkyl compounds are halogens and C, respectively. 1~4 Alkyl or halogenated C 1~4 R may be substituted with one or two substituents independently selected from the group consisting of alkyl groups, 14 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkynyl, phenyl, 5-6 member heteroaryl, -CO-C 1~6 Alkyl, -CO-C 3~8 Cycloalkyl, -C(O)OC 1~6 Alkyl, -SO2NR 23 R 24 , -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~8 Cycloalkyl, -SO2-3~8 member heterocyclyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-3 to 8-membered heterocyclyl or

[0141] [ka]

[0142] Selected from the group consisting of C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkynyl, phenyl, 5-6 member heteroaryl, -CO-C 1~6 Alkyl, -CO-C 3~8 Cycloalkyl, -C(O)OC 1~6 Alkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~8 Cycloalkyl, -SO2-3~8 member heterocyclyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4Alkyl-3 to 8-membered heterocyclyl and

[0143] [ka]

[0144] Deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl or halogenated C 1~6 Each atom may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups, where R' is H, C 1~6 Alkyl or C 3~6 Selected from the group consisting of cycloalkyl, R 23 and R 24 is hydrogen or C 1~6 Each is independently selected from the group consisting of alkyl groups.

[0145] In one embodiment of ring B described above, Z3 is CR 12 R 13 , N, NR 14 Selected from the group consisting of , O or -C(O)-, R 12 and R 13 is hydrogen or C 1~4 Each is independently selected from the group consisting of alkyls, C 1~4 Alkyls are halogens, C 1~4 Alkyl or halogenated C 1~4 Each of the substituents may be independently selected from the group consisting of alkyl groups, R 14 C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -CO-C 1~6 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~6 Cycloalkyl, -C 1~4 Alkyl-C 3~6Cycloalkyl or

[0146] [ka]

[0147] Selected from the group consisting of C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -CO-C 1~6 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~6 Cycloalkyl, -C 1~4 Alkyl-C 3~6 Cycloalkyl or

[0148] [ka]

[0149] Deuterium, halogen, hydroxyl, cyano, C 1~4 Alkyl and halogenated C 1~4 Each atom may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups, where R' is H, C 1~6 Alkyl or C 3~6 Selected from the group consisting of cycloalkyl groups.

[0150] In one embodiment of ring B described above, Z3 is CR 12 R 13 , NR 14 Selected from the group consisting of , O or -C(O)-, R 12 , R 13 and R 14 This is as defined above. In one embodiment, R 12 and R 13 These are H and R respectively. 14 C 1~4Alkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~4 Alkyl, -SO2-C 2~4 Alkenyl, -SO2-C 3~6 Cycloalkyl or

[0151] [ka]

[0152] Selected from the group consisting of C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~4 Alkyl, -SO2-C 2~4 Alkenyl, -SO2-C 3~6 Cycloalkyl or

[0153] [ka]

[0154] Deuterium, halogen, hydroxyl, cyano, C 1~4 Alkyl and halogenated C 1~4 Each atom may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups, where R' is H or C 1~4 Selected from the group consisting of alkyl groups.

[0155] In one embodiment of the B ring described above, Z4 is absent, CR 16 CR 17 R 18 , N, NR 19 Or selected from the group consisting of -C(O)-, R 16 , R 17 , R 18 and R 19This is as defined above. In one embodiment, R 16 , R 17 and R 18 is hydrogen, C 1~10 Alkyl or C 3~10 Each is independently selected from the group consisting of cycloalkyls, C 1~10 Alkyl and C 3~10 Cycloalkyls are halogens, C 1~6 Alkyl or halogenated C 1~6 They may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups, or R 17 and R 18 They are connected to each other, C 3~8 Forming a cycloalkyl or 3-8 membered heterocycline, C 3~8 Cycloalkyl or 3- to 8-membered heterocyclyls are halogen, hydroxyl, cyano, amino, and C. 1~4 Alkyl, halogenated C 1~4 Alkyl, C 1~4 Heteroalkyl, C 3~6 R may be substituted with one or two substituents independently selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl groups. 19 is hydrogen, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -SO2-C 1~10 Alkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclyl, -C 1~4 Alkyl-C 6~10 aryl or -C 1~4 Selected from the group consisting of alkyl-5 to 10-membered heteroaryls, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C6~10 Aryl, 5-10 member heteroaryl, -SO2C 1~10 Alkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclyl, -C 1~4 Alkyl-C 6~10 Aryl and -C 1~4 Alkyl-5 to 10-membered heteroaryls include halogens, hydroxyls, cyanos, and C. 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl or -CONR 25 R 26 Each of the substituents may be independently selected from the group consisting of R 25 and R 26 is hydrogen or C 1~6 Each is independently selected from the group consisting of alkyl groups.

[0156] In one embodiment of the ring B described above, Z4 is CR 16 CR 17 R 18 , NR 19 Or selected from the group consisting of -C(O)-, R 16 , R 17 , R 18 and R 19 This is as defined above. In one embodiment, R 16 , R 17 and R 18 is hydrogen, C 1~6 Alkyl or C 3~6 Each is independently selected from the group consisting of cycloalkyls, C 1~6 Alkyl and C 3~6 Cycloalkyls are halogens, C 1~6 Alkyl or halogenated C 1~6 They may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups, or R 17 and R18 They are connected to each other, C 3~6 Forming a cycloalkyl or 3-6 membered heterocycline, C 3~6 Cycloalkyl or 3-6 membered heterocyclyls are halogens, C 1~4 Alkyl, halogenated C 1~4 Alkyl, C 1~4 Heteroalkyl or C 3~6 R may be substituted with one or two substituents independently selected from the group consisting of cycloalkyl groups, 19 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkynyl, phenyl, 5-6 member heteroaryl, -SO2-C 1~6 Alkyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl or -C 1~4 Selected from the group consisting of alkyl-5~6 member heteroaryls, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkynyl, phenyl, 5-6 member heteroaryl, -SO2-C 1~6 Alkyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl or -C 1~4 Alkyl-5 to 6-membered heteroaryls include halogens, hydroxyls, cyanos, and C. 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl, -CONR 25 R 26 Each of the substituents may be independently selected from the group consisting of R 25 and R 26 is hydrogen or C 1~6 Each is independently selected from the group consisting of alkyl groups.

[0157] In one embodiment of the ring B described above, Z4 is CR 16 CR 17 R 18 , NR 19 Or selected from the group consisting of -C(O)-, R 16 , R 17 and R 18 is hydrogen, C 1~6 Alkyl or C 3~6 Each is independently selected from the group consisting of cycloalkyls, C 1~6 Alkyl or C 3~6 Cycloalkyls are halogens, C 1~6 Alkyl or halogenated C 1~6 They may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups, or R 17 and R 18 They are connected to each other, C 3~6 Forms a cycloalkyl group, C 3~6 Cycloalkyls are halogens, C 1~4 Alkyl or halogenated C 1~4 R may be substituted with one or two substituents independently selected from the group consisting of alkyl groups, 19 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkylalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -SO2-C 1~6 Alkyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl or -C 1~4 Selected from the group consisting of alkyl-5~6 member heteroaryls, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -SO2-C 1~6 Alkyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl or -C 1~4 Alkyl-5 to 6-membered heteroaryls include halogens, hydroxyls, cyanos, and C.1~4 Alkyl, halogenated C 1~4 Alkyl, hydroxy-C 1~4 Alkyl, C 1~4 Heteroalkyl and C 3~6 Each molecule may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl molecules.

[0158] In one embodiment of the ring B described above, Z4 is CR 17 R 18 , NR 19 Or selected from the group consisting of -C(O)-, R 17 , R 18 and R 19 This is as defined above. In one embodiment, R 17 and R 18 is hydrogen, C 1~4 Alkyl or C 3~6 Each is independently selected from the group consisting of cycloalkyls, C 1~4 Alkyl or C 3~6 Cycloalkyls are halogens and C 1~4 Each of them may be substituted with one or two substituents independently selected from the group consisting of alkyl groups, or R 17 and R 18 They are connected to each other, C 3~6 Forming a cycloalkyl group, R 19 C 1~4 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, -SO2-C 1~4 Alkyl or -C 1~4 Alkyl-C 3~6 Selected from the group consisting of cycloalkyls, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, -SO2-C 1~4 Alkyl or -C 1~4 Alkyl-C 3~6 Cycloalkyls are halogens, hydroxyls, cyanos, and C 1~4 Alkyl, halogenated C 1~4 Alkyl, hydroxy-C 1~4Alkyl, C 1~4 Heteroalkyl and C 3~6 Each molecule may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl molecules.

[0159] To one embodiment of the above-mentioned ring B: The Z1 is CR6R7, Z2 is selected from the group consisting of CR8R9 or -C(O)-, Z3 is absent, CR 11 CR 12 R 13 , N, NR 14 Selected from the group consisting of O or -C(O)-, Z4 is absent, CR 16 CR 17 R 18 , N, NR 19 Or selected from the group consisting of -C(O)-, R6, R7, R8, R9, R 11 , R 12 , R 13 , R 16 , R 17 and R 18 is hydrogen, hydroxyl, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Each is independently selected from the group consisting of aryls or 5-10 member heteroaryls, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Aryls and 5-10 member heteroaryls are halogens, C 1~6 Alkyl or halogenated C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups. Alternatively, R6 and R7, R8 and R9, R 12 and R 13 or R 17 and R 18 They are connected to each other, C 3~8 Forming a cycloalkyl or 3-8 membered heterocycline, C3~8 Cycloalkyl or 3- to 8-membered heterocyclyls are halogen, hydroxyl, cyano, amino, and C. 1~4 Alkyl, halogenated C 1~4 Alkyl, C 1~4 Heteroalkyl, C 3~6 It may be substituted with one or two substituents independently selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines. R 14 and R 19 is hydrogen, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2-C 1~10 Alkyl, deuterium-SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclyl, -C 1~4 Alkyl-C 6~10 Ariel, -C 1~4 Alkyl-5 to 10-membered heteroaryl or

[0160] [ka]

[0161] Each of the groups consisting of C is independently selected. 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~10Alkyl, -CO-C 3~10 Cycloalkyl, -C(O)OC 1~10 Alkyl, -SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclyl, -C 1~4 Alkyl-C 6~10 Ariel, -C 1~4 Alkyl-5 to 10-membered heteroaryls and

[0162] [ka]

[0163] Deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, or -CONR 25 R 26 Each of these may be substituted by one, two, or three substituents independently selected from the group consisting of the following: R' is H, C 1~10 Alkyl, C 3~10 Selected from the group consisting of cycloalkyl or CN, R 23 , R 24 , R 25 and R 26 is hydrogen or C 1~6 Each is independently selected from the group consisting of alkyl groups.

[0164] In one embodiment of ring B described above, Z1 is CR6R7, Z2 is CR8R9 or -C(O)-, and Z3 is CR 11 CR 12 R 13, N, NR 14 , O or -C(O)-, and Z4 is either absent or CR 16 CR 17 R 18 , N, NR 19 Alternatively, it is -C(O)-, and R6, R7, R8, R9, R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 18 and R 19 This is as defined above.

[0165] In one embodiment of ring B described above, Z1 is CR6R7, Z2 is CR8R9, and Z3 is CR 12 R 13 , N, NR 14 , O or -C(O)-, and Z4 is CR 16 CR 17 R 18 , NR 19 or -C(O)-, R6, R7, R8, R9, R 12 , R 13 , R 14 , R 16 , R 17 , R 18 and R 19 This is as defined above.

[0166] To one embodiment of the above-mentioned ring B: The Z1 is CR6R7, The Z2 is the CR8R9, The Z3 is CR 12 R 13 , N, NR 14 , O or -C(O)-, The Z4 is CR 16 CR 17 R 18 , NR 19 Or -C(O)-, R6, R7, R8, R9, R 12 and R 13 is hydrogen and C 1~4Each is independently selected from the group consisting of alkyls, C 1~4 Alkyl compounds are halogens and C, respectively. 1~4 Alkyl or halogenated C 1~4 It may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. R 14 C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -CO-C 1~6 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~6 Cycloalkyl, -C 1~4 Alkyl-C 3~6 Cycloalkyl or

[0167] [ka]

[0168] Selected from the group consisting of C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -CO-C 1~6 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~6 Cycloalkyl, -C 1~4 Alkyl-C 3~6 Cycloalkyl or

[0169] [ka]

[0170] Deuterium, halogen, hydroxyl, cyano, C1~4 Alkyl and halogenated C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups, R' is H, C 1~6 Alkyl or C 3~6 Selected from the group consisting of cycloalkyl groups, R 16 , R 17 and R 18 is hydrogen, C 1~6 Alkyl or C 3~6 Each is independently selected from the group consisting of cycloalkyls, C 1~6 Alkyl or C 3~6 Cycloalkyls are halogens, C 1~6 Alkyl or halogenated C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups, Alternatively, R 17 and R 18 They are connected to each other, C 3~6 Forms a cycloalkyl group, C 3~6 Cycloalkyls are halogens, C 1~4 Alkyl or halogenated C 1~4 It may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. R 19 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -SO2-C 1~6 Alkyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl or -C 1~4 Selected from the group consisting of alkyl-5~6 member heteroaryls, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -SO2-C 1~6 Alkyl, -C 1~4Alkyl-C 3~8 Cycloalkyl or -C 1~4 Alkyl-5 to 6-membered heteroaryls include halogens, hydroxyls, cyanos, and C. 1~4 Alkyl, halogenated C 1~4 Alkyl, hydroxy-C 1~4 Alkyl, C 1~4 Heteroalkyl and C 3~6 Each molecule may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl molecules.

[0171] In one embodiment of ring B described above, Z1 is CR6R7, Z2 is CR8R9, and Z3 is CR 12 R 13 , NR 14 , O or -C(O)-, and Z4 is CR 17 R 18 , NR 19 or -C(O)-, R6, R7, R8, R9, R 12 , R 13 , R 14 , R 17 , R 18 and R 19 This is as defined above.

[0172] To one embodiment of the above-mentioned ring B: The Z1 is CR6R7, The Z2 is the CR8R9, The Z3 is CR 12 R 13 , NR 14 , O or -C(O)-, The Z4 is CR 17 R 18 , NR 19 Or -C(O)-, R6, R7, R8, R9, R 12 and R 13 These are H, R 14 C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CO-C 1~4Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~4 Alkyl, -SO2-C 2~4 Alkenyl, -SO2-C 3~6 Cycloalkyl or

[0173] [ka]

[0174] Selected from a group consisting of a group consisting of C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~4 Alkyl, -SO2-C 2~4 Alkenyl, -SO2-C 3~6 Cycloalkyl or

[0175] [ka]

[0176] Deuterium, halogen, hydroxyl, cyano, C 1~4 Alkyl and halogenated C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups, R' is H or C 1~4 Selected from the group consisting of alkyl groups, R 17 and R 18 is hydrogen, C 1~4 Alkyl or C 3~6 Each is independently selected from the group consisting of cycloalkyls, C 1~4 Alkyl or C 3~6 Cycloalkyls are halogens and C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups. Alternatively, R 17 and R18 They are connected to each other, C 3~6 Forming a cycloalkyl group, R 19 C 1~4 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, -SO2-C 1~4 Alkyl or -C 1~4 Alkyl-C 3~6 Selected from the group consisting of cycloalkyls, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, -SO2-C 1~4 Alkyl or -C 1~4 Alkyl-C 3~6 Cycloalkyls are halogens, hydroxyls, cyanos, and C 1~4 Alkyl, halogenated C 1~4 Alkyl, hydroxy-C 1~4 Alkyl, C 1~4 Heteroalkyl and C 3~6 Each molecule may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl molecules.

[0177] In one embodiment of the compound represented by formula I, R b These are halogen, hydroxyl, cyano, amino, oxo, and C, respectively. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR e R f -C(O)OC 1~10 Alkyl, -SO2NR g R h , -SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl or

[0178] [ka]

[0179] Independently selected from the group consisting of C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR e R f -C(O)OC 1~10 Alkyl, -SO2NR g R h , -SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryls and

[0180] [ka]

[0181] These are deuterium, halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, halogenated C 1~10 Alkyl, hydroxy-C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl or -CONR i R j Each of the substituents may be independently selected from the group consisting of H, C, and R' may be substituted with one, two, three, or four substituents, where R' is H, C 1~10 Alkyl, C 3~10 Selected from the group consisting of cycloalkyl or CN, R e , R f , R g , R h , R i and R j is H or C 1~10 Each is independently selected from the group consisting of alkyl groups.

[0182] In one embodiment of the compound represented by formula I, R b These are hydroxyl, oxo, and C, respectively. 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -C(O)OC 1~10 Alkyl, -SO2NR g R h , -SO2-C 1~10 Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-3~10-membered heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C1~6 Alkyl-5 to 10-membered heteroaryl or

[0183] [ka]

[0184] Independently selected from the group consisting of C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -C(O)OC 1~10 Alkyl, -SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-5 to 10-membered heteroaryls and

[0185] [ka]

[0186] Deuterium, halogen, hydroxyl, cyano, C 1~10 Alkyl, Halo C 1~10 Alkyl, hydroxy C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl or -CONR i R j Each of the substituents may be independently selected from the group consisting of H, C, and R' may be substituted with one, two, or three substituents, where R' is H, C 1~10 Alkyl, C3~10 Selected from the group consisting of cycloalkyl or CN, R g , R h , R i and R j is H or C 1~10 Each is independently selected from the group consisting of alkyl groups.

[0187] In one embodiment of the compound represented by formula I, R b These are hydroxyl, oxo, and C, respectively. 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkynyl, phenyl, 5-6 member heteroaryl, -CO-C 1~6 Alkyl, -CO-C 3~8 Cycloalkyl, -C(O)OC 1~6 Alkyl, -SO2NR g R h , -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~8 Cycloalkyl, -SO2-3~8 member heterocyclyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-3 to 8-membered heterocyclyl, -C 1~4 Alkyl-5 to 6-membered heteroaryl or

[0188] [ka]

[0189] Independently selected from the group consisting of C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkynyl, phenyl, 5-6 member heteroaryl, -CO-C 1~6 Alkyl, -CO-C 3~8 Cycloalkyl, -C(O)OC1~6 Alkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~8 Cycloalkyl, -SO2-3~8 member heterocyclyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-3 to 8-membered heterocyclyl, -C 1~4 Alkyl-5~6 member heteroaryl and

[0190] [ka]

[0191] Deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, or -CONR i R j Each of the substituents may be independently selected from the group consisting of H, C, and R' may be substituted with one, two, or three substituents, where R' is H, C 1~6 Alkyl or C 3~6 Selected from the group consisting of cycloalkyl, R g , R h , R i and R j is H or C 1~6 Each is independently selected from the group consisting of alkyl groups.

[0192] In one embodiment of the compound represented by formula I, R b These are oxo and C, respectively. 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -CO-C 1~6 Alkyl, -CO-C 3~8Cycloalkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~8 Cycloalkyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-3 to 8-membered heterocyclyl, -C 1~4 Alkyl-5 to 6-membered heteroaryl or

[0193] [ka]

[0194] Independently selected from the group consisting of C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -CO-C 1~6 Alkyl, -CO-C 3~8 Cycloalkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~8 Cycloalkyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-3 to 8-membered heterocyclyl, -C 1~4 Alkyl-5~6 member heteroaryl and

[0195] [ka]

[0196] Deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl and C 3~6Each of the substituents may be independently selected from the group consisting of cycloalkyl groups, where R' is H, C 1~6 Alkyl or C 3~6 Selected from the group consisting of cycloalkyl groups.

[0197] In one embodiment of the compound represented by formula I, R b These are oxo and C, respectively. 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 2~6 Alkenyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~4 Alkyl, -SO2-C 2~4 Alkenyl, -SO2-C 3~6 Cycloalkyl, -C 1~4 Alkyl-C 3~6 Cycloalkyl or

[0198] [ka]

[0199] Independently selected from the group consisting of C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 2~6 Alkenyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~4 Alkyl, -SO2-C 2~4 Alkenyl, -SO2-C 3~6 Cycloalkyl, -C 1~4 Alkyl-C 3~6 Cycloalkyl or

[0200] [ka]

[0201] Deuterium, halogen, hydroxyl, cyano, C1~4 Alkyl, halogenated C 1~4 Alkyl, hydroxy-C 1~4 Alkyl, C 1~4 Heteroalkyl and C 3~6 Each of the substituents may be independently selected from the group consisting of cycloalkyl groups, where R' is H or C 1~4 Selected from the group consisting of alkyl groups.

[0202] In one embodiment of the compound represented by formula I, n is selected from the group consisting of 0, 1, 2, or 3.

[0203] In one embodiment, the present invention relates to a compound represented by formula II, its isomers, isotopically labeled compounds thereof, or pharmaceutically acceptable salts thereof:

[0204] [ka]

[0205] (In the formula,

[0206] [ka]

[0207] This indicates that the ring to which it belongs is an aromatic ring system.

[0208] [ka]

[0209] This represents either a single bond or a double bond. R1 and R2 are hydrogen or C 1~6 Each is independently selected from the group consisting of alkyls, or R1 and R2, together with the carbon atom to which they are bonded and the adjacent nitrogen atom, form a 4- to 8-membered aza-cyclic ring. X2 is selected from the group consisting of C or N. X3 is selected from the group consisting of C(R3) or N(R3), X4 is selected from the group consisting of N or CH. X5 is selected from the group consisting of C or N, and if X5 is N, then X3 is C(R3). R3 is C 6~10 Ariel, C 3~10 Selected from the group consisting of cycloalkyl or 5-10 member heteroaryls, C 6~10 Ariel, C 3~10 Cycloalkyl and 5-10 membered heteroaryls have one, two or three R 3a Each of these may be substituted by the base, R 3a These are halogen, cyano, hydroxyl, and C, respectively. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 A cycloalkyl group is independently selected from the group consisting of 3-10 member heterocyclines or -NR4R5, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl and 3- to 10-membered heterocyclyls are halogen, cyano, hydroxyl, or C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups, R4 and R5 are hydrogen or C 1~10 Each is independently selected from the group consisting of alkyl groups, The Z1 is CR6R7, The Z2 is CR8R9, N, NR 10 Selected from the group consisting of O, S, -C(O)- or -SO2-, The Z3 is CR 11 CR 12 R 13 , N, NR 14 , O, -C(O)-, -SO2- or -S(O)(NR 15 Selected from the group consisting of )-, The Z4 is CR 16 CR 17 R18 , N, NR 19 , O, S, -C(O)-, -SO2- or -S(O)(NR 20 Selected from the group consisting of )-, One or two of Z1, Z2, Z3, and Z4 may be absent, and a ring containing X5, Z1, Z2, Z3, and Z4 is a stable ring structure. R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 These are hydrogen, halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2-C 1~10 Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl or

[0210] [ka]

[0211] Each of the groups consisting of C is independently selected. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl and

[0212] [ka]

[0213] These are deuterium, halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, halogenated C 1~10 Alkyl, hydroxy-C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, -CONR 25 R 26 They may each be substituted by one, two, three, or four substituents independently selected from the group consisting of the above, R' is H, C1~10 Alkyl, C 3~10 Selected from the group consisting of cycloalkyl or CN, R 21 , R 22 , R 23 , R 24 , R 25 and R 26 is H or C 1~10 Each is independently selected from the group consisting of alkyl groups, Alternatively, R6 and R7, R8 and R9, R 12 and R 13 or R 17 and R 18 They are connected to each other, C 3~10 Forming a cycloalkyl or 3-10 membered heterocycline, C 3~10 Cycloalkyl or 3-10 membered heterocyclyls are deuterium, halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, halogenated C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 (May be substituted with one, two, three, or four substituents independently selected from the group consisting of cycloalkyls and 3- to 10-membered heterocyclines.) To provide.

[0214] In one embodiment of the compound represented by formula II, R1 is hydrogen or C 1~6 It is alkyl. In one embodiment of the compound represented by formula II, R1 is hydrogen. In one embodiment of the compound represented by formula II, R1 is C such as methyl. 1~4 C such as alkyl 1~6 It is alkyl.

[0215] In one embodiment of the compound represented by formula II, R2 is hydrogen or C 1~6 It is alkyl. In one embodiment of the compound represented by formula II, R2 is hydrogen. In one embodiment of the compound represented by formula II, R2 is C such as methyl. 1~4 C such as alkyl 1~6 It is alkyl.

[0216] In one embodiment of the compound represented by formula II, R1 and R2, together with the carbon atom to which they are bonded and the adjacent nitrogen atom, form a 4- to 8-membered aza ring.

[0217] In one embodiment of the compound represented by formula II,

[0218] [ka]

[0219] teeth,

[0220] [ka]

[0221] Selected from the group consisting of: In one embodiment of the compound represented by formula II,

[0222] [ka]

[0223] teeth,

[0224] [ka]

[0225] In one embodiment of the compound represented by formula II,

[0226] [ka]

[0227] teeth,

[0228] [ka]

[0229] In this case, the compound represented by formula II has the following structural formula:

[0230] [ka]

[0231] It has.

[0232] In one embodiment of the compound represented by formula II, X2 is C. In one embodiment of the compound represented by formula II, X2 is N.

[0233] In one embodiment of the compound represented by formula II, X3 is selected from the group consisting of C(R3) or N(R3), and R3 is C 6~10 Ariel, C 3~10 Selected from the group consisting of cycloalkyl or 5-10 member heteroaryls, C 6~10 Ariel, C 3~10 Cycloalkyl and 5-10 membered heteroaryls have one, two or three R 3a Each of them may be substituted by the group, R 3a These are halogen, cyano, hydroxyl, and C, respectively. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 A substituent independently selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, or -NR4R5, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl and 3- to 10-membered heterocyclyls are halogen, cyano, hydroxyl, or C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups, R4 and R5 are hydrogen or C 1~10 Each is independently selected from the group consisting of alkyl groups.

[0234] In one embodiment of the compound represented by formula II, X3 is selected from the group consisting of C(R3) or N(R3), R3 is a 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl has one, two or three R 3a It may be substituted with a group, R 3a These are halogen, cyano, hydroxyl, and C, respectively. 1~6 Alkyl, halogenated C 1~6 Alkyl, C 1~6 Alkoxy, C halogenated 1~6 Alkoxy, C 3~10 A cycloalkyl group is independently selected from the group consisting of cycloalkyl groups, 3-10 member heterocyclines, or -NR4R5 groups, where R4 and R5 are independently hydrogen or C6. 1~6 It is alkyl.

[0235] In one embodiment of the compound represented by formula II, X3 is selected from the group consisting of C(R3) or N(R3), R3 is a 5-6 member heteroaryl, and the 5-6 member heteroaryl has one or two R 3a It may be substituted with a group, R 3a These are halogen, cyano, hydroxyl, and C, respectively. 1~6 Alkyl, halogenated C 1~6 Alkyl, C 1~6 Alkoxy, C halogenated 1~6 Alkoxy, C 3~8 A cycloalkyl group is independently selected from the group consisting of cycloalkyl groups, 3- to 8-membered heterocyclines, or -NR4R5 groups, where R4 and R5 are independently hydrogen or C6. 1~6 It is alkyl. In one embodiment of the compound represented by formula II, X3 is selected from the group consisting of C(R3) or N(R3), R3 is a 5-6 member heteroaryl, and the 5-6 member heteroaryl is C 1~6 They may be substituted with one or two substituents independently selected from the group consisting of alkyl groups.

[0236] In one embodiment of the compound represented by formula II, X3 is selected from the group consisting of C(R3) or N(R3), R3 is a 5-membered heteroaryl, and the 5-membered heteroaryl is C such as methyl. 1~4 C such as alkyl 1~6 It may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. In one embodiment of the compound represented by formula II, X3 is selected from the group consisting of C(R3) or N(R3), where R3 is pyrazolyl, and pyrazolyl is C such as methyl. 1~4 C such as alkyl 1~6 It may be substituted with one substituent selected from the group consisting of alkyl groups. In one embodiment of the compound represented by formula II, X3 is selected from the group consisting of C(R3) or N(R3), where R3 is pyrazolyl.

[0237] In one embodiment of the compound represented by formula II, X4 is N. In one embodiment of the compound represented by formula II, X4 is CH.

[0238] In one embodiment of the compound represented by formula II, X5 is C. In one embodiment of the compound represented by formula II, X5 is N.

[0239] In one embodiment of the compound represented by formula II, if X5 is N, then X3 is C(R3), and R3 is as defined above.

[0240] In one embodiment of the compound represented by formula II, Z1, Z2, Z3, and Z4 and their combinations are as defined above with respect to Z1, Z2, Z3, and Z4 and their combinations in ring B of formula I.

[0241] In one embodiment, the present invention relates to compounds represented by formulas IIA, IIB, or IIC, their isomers, their isotope-labeled compounds, or pharmaceutically acceptable salts thereof:

[0242] [ka]

[0243] (In the formula, R3 is C 6~10 Ariel, C 3~10 It is a cycloalkyl or a 5-10 member heteroaryl, C 6~10 Ariel, C 3~10 Cycloalkyl and 5-10 membered heteroaryls have one, two or three R 3a Each of these may be substituted by the base, R 3a These are halogen, cyano, hydroxyl, and C, respectively. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 A cycloalkyl group is independently selected from the group consisting of 3-10 member heterocyclines or -NR4R5, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl and 3- to 10-membered heterocyclyls are halogen, cyano, hydroxyl, or C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups, R4 and R5 are independently hydrogen or C 1~10 It is alkyl, The Z1 is CR6R7, The Z2 is CR8R9, N, NR 10 Selected from the group consisting of O, S, -C(O)- or -SO2-, The Z3 is CR 11 CR 12 R 13 , N, NR 14 , O, -C(O)-, -SO2- or -S(O)(NR 15 Selected from the group consisting of )-, The Z4 is CR 16 CR 17 R 18 , N, NR 19 , O, S, -C(O)-, -SO2- or -S(O)(NR20 Selected from the group consisting of )-, One or two of Z1, Z2, Z3, and Z4 may be absent, and a ring containing X5, Z1, Z2, Z3, and Z4 is a stable ring structure. R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 These are hydrogen, halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2-C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl or

[0244] [ka]

[0245] Each of the groups consisting of C is independently selected. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2C 1~10 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 2~6 Alkinyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl and

[0246] [ka]

[0247] These are deuterium, halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, halogenated C 1~10 Alkyl, hydroxy-C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl or -CONR 25 R 26 They may each be substituted by one, two, three, or four substituents independently selected from the group consisting of the above, R' is H, C1~10 Alkyl, C 3~10 Selected from the group consisting of cycloalkyl or CN, R 21 , R 22 , R 23 , R 24 , R 25 and R 26 is H or C 1~10 Each is independently selected from the group consisting of alkyl groups, Alternatively, R6 and R7, R8 and R9, R 12 and R 13 or R 17 and R 18 They are connected to each other, C 3~10 Forming a cycloalkyl or 3-10 membered heterocycline, C 3~10 Cycloalkyl or 3-10 membered heterocyclines are halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, halogenated C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 (May be substituted with one, two, three, or four substituents independently selected from the group consisting of cycloalkyl or 3- to 10-membered heterocyclines.) To provide.

[0248] In one embodiment, a compound represented by formula IIA, IIB, or IIC is defined by the following formula:

[0249] [ka]

[0250] It has a structure represented by [this].

[0251] In one embodiment of a compound represented by formula IIA, IIB, or IIC, R3 is a 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl has one, two, or three R3s. 3a It may be substituted with a group, R 3a These are halogen, cyano, hydroxyl, and C, respectively. 1~6Alkyl, C 1~6 Heteroalkyl, C 3~8 Independently selected from the group consisting of cycloalkyl, 3- to 8-membered heterocyclyl, or -NR4R5, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, or -NR4R5 may be halogen, cyano, hydroxyl, or C 1~6 Each of the alkyl groups may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups, and R4 and R5 may each be independently hydrogen or C 1~6 It is alkyl. In one embodiment of the compound represented by formula IIA, IIB, or IIC, R3 is a 5-6 member heteroaryl, and the 5-6 member heteroaryl is one or two R 3a It may also be substituted by R 3a These are halogen, cyano, hydroxyl, and C, respectively. 1~6 Alkyl, halogenated C 1~6 Alkyl, C 1~6 Alkoxy, C 3~8 A cycloalkyl group is independently selected from the group consisting of cycloalkyl groups, 3- to 8-membered heterocyclines, or -NR4R5 groups, where R4 and R5 are independently hydrogen or C6. 1~6 It is alkyl. In one embodiment of the compound represented by formula IIA, IIB, or IIC, R3 is a 5-6 member heteroaryl, and the 5-10 member heteroaryl is one or two R 3a It may also be substituted by R 3a These are C, such as methyl. 1~4 C such as alkyl 1~6 Independently selected from the group consisting of alkyl groups. In one embodiment of the compound represented by formula IIA, IIB, or IIC, R3 is a 5-membered heteroaryl, and the 5-membered heteroaryl has one or two R 3a It may be substituted with a group, R 3a These are C, such as methyl. 1~4 C such as alkyl 1~6It is independently selected from the group consisting of alkyl groups. In one embodiment of the compound represented by formula IIA, IIB, or IIC, R3 is pyrazolyl, and pyrazolyl is C such as methyl. 1~4 C such as alkyl 1~6 It may be substituted with one substituent selected from the group consisting of alkyl groups. In one embodiment of the compound represented by formula IA, IIB, or IIC, R3 is pyrazolyl.

[0252] In one embodiment of a compound represented by formula IIA, IIB, or IIC, Z1, Z2, Z3, and Z4 and their combinations are as defined above with respect to ring B of formula I, or Z1, Z2, Z3, and Z4 in formula II, and their combinations.

[0253] In one embodiment of a compound represented by formula IIA, IIB, or IIC, R3 is a 5-6 member heteroaryl, and a 5-6 member heteroaryl can have one or two R3s. 3a It may be substituted with a group, R 3a These are C 1~6 Independently selected from the group consisting of alkyls, The Z1 is CR6R7, The Z2 is the CR8R9, Z3 is absent, CR 12 R 13 , N, NR 14 Selected from the group consisting of O or -C(O)-, Z4 is absent, CR 16 CR 17 R 18 , NR 19 Or selected from the group consisting of -C(O)-, R6, R7, R8, R9, R 12 , R 13 , R 14 , R 16 , R 17 , R 18 and R 19 These are defined above. In a particular embodiment, R6, R7, R8, R9, R12 and R 13 is hydrogen and C 1~4 Independently selected from the group consisting of alkyls, C 1~4 Alkyl compounds are halogens and C, respectively. 1~4 Alkyl or halogenated C 1~4 R may be substituted with one or two substituents independently selected from the group consisting of alkyl groups, 14 C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -CO-C 1~6 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~6 Cycloalkyl, -C 1~4 Alkyl-C 3~6 Cycloalkyl or

[0254] [ka]

[0255] Selected from the group consisting of C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -CO-C 1~6 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~6 Cycloalkyl, -C 1~4 Alkyl-C 3~6 Cycloalkyl or

[0256] [ka]

[0257] Deuterium, halogen, hydroxyl, cyano, C 1~4 Alkyl and halogenated C 1~4 Each atom may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups, where R' is H, C 1~6 Alkyl or C 3~6 Selected from the group consisting of cycloalkyl, R 16 , R 17 and R 18 is hydrogen, C 1~6 Alkyl or C 3~6 Each is independently selected from the group consisting of cycloalkyls, C 1~6 Alkyl or C 3~6 Cycloalkyls are halogens, C 1~6 Alkyl or halogenated C 1~6 They may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups, or R 17 and R 18 They are connected to each other, C 3~6 Forms a cycloalkyl group, C 3~6 Cycloalkyls are halogens, C 1~4 Alkyl or halogenated C 1~4 R may be substituted with one or two substituents independently selected from the group consisting of alkyl groups, 19 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -SO2-C 1~6 Alkyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl or -C 1~4 Selected from the group consisting of alkyl-5~6 member heteroaryls, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -SO2-C 1~6 Alkyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl or -C1~4 Alkyl-5 to 6-membered heteroaryls include halogens, hydroxyls, cyanos, and C. 1~4 Alkyl, halogenated C 1~4 Alkyl, hydroxy-C 1~4 Alkyl, C 1~4 Heteroalkyl and C 3~6 Each molecule may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl molecules.

[0258] In one embodiment of a compound represented by formula IIA, IIB, or IIC, R3 is a 5-membered heteroaryl, and a 5-membered heteroaryl is one R 3a It may also be substituted by R 3a C 1~4 Selected from the group consisting of alkyl groups, The Z1 is CR6R7, The Z2 is the CR8R9, The Z3 is CR 12 R 13 , NR 14 Selected from the group consisting of O or -C(O)-, The Z4 is CR 17 R 18 , NR 19 Or selected from the group consisting of -C(O)-, R6, R7, R8, R9, R 12 and R 13 These are H, R 14 C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~4 Alkyl, -SO2-C 2~4 Alkenyl, -SO2-C 3~6 Cycloalkyl or

[0259] [ka]

[0260] Selected from the group consisting of C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~4 Alkyl, -SO2-C 2~4 Alkenyl, -SO2-C 3~6 Cycloalkyl or

[0261] [ka]

[0262] Deuterium, halogen, hydroxyl, cyano, C 1~4 Alkyl and halogenated C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups, R' is H or C 1~4 Selected from the group consisting of alkyl groups, R 17 and R 18 is hydrogen, C 1~4 Alkyl or C 3~6 Each is independently selected from the group consisting of cycloalkyls, C 1~4 Alkyl or C 3~6 Cycloalkyls are halogens and C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups. Alternatively, R 17 and R 18 They are connected to each other, C 3~6 Forming a cycloalkyl group, R 19 C 1~4 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, -SO2-C 1~4 Alkyl or -C 1~4 Alkyl-C 3~6Selected from the group consisting of cycloalkyls, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 2~6 Alkenyl, -SO2-C 1~4 Alkyl or -C 1~4 Alkyl-C 3~6 Cycloalkyls are halogens, hydroxyls, cyanos, and C 1~4 Alkyl, halogenated C 1~4 Alkyl, hydroxy-C 1~4 Alkyl, C 1~4 Heteroalkyl and C 3~6 Each molecule may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl molecules.

[0263] In one embodiment of the compound represented by formula IIA: R3 is a 5-6 member heteroaryl, and a 5-6 member heteroaryl can have one or two R3s. 3a It may be substituted with a group, R 3a These are C 1~6 Independently selected from the group consisting of alkyls, The Z1 is CR6R7, The Z2 is the CR8R9, The Z3 is NR 14 , O or -C(O)-, The Z4 is CR 17 R 18 , NR 19 Or -C(O)-, R6, R7, R8, and R9 are hydrogen and C 1~4 Each is independently selected from the group consisting of alkyls, C 1~4 Alkyl compounds are halogens and C, respectively. 1~4 Alkyl or halogenated C 1~4 It may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. R 14 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~6 Alkyl, -CO-C 3~8 Cycloalkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~8 Cycloalkyl, -SO2-3~8 member heterocyclyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~6 Alkyl-3 to 8-membered heterocyclyl or

[0264] [ka]

[0265] Selected from the group consisting of C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~6 Alkyl, -CO-C 3~8 Cycloalkyl, -SO2-C 1~6 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~8 Cycloalkyl, -SO2-3~8 member heterocyclyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~6 Alkyl-3 to 8-membered heterocyclyl or

[0266] [ka]

[0267] Deuterium, halogen, hydroxyl, cyano, C 1~4 Alkyl and halogenated C 1~4Each of these substituents may be independently selected from the group consisting of alkyl groups, R' is H, C 1~6 Alkyl or C 3~6 Selected from the group consisting of cycloalkyl groups, R 17 and R 18 is hydrogen, C 1~6 Alkyl or C 3~6 Each is independently selected from the group consisting of cycloalkyls, C 1~6 Alkyl or C 3~6 Cycloalkyls are halogens, C 1~4 Alkyl or halogenated C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups, Alternatively, R 17 and R 18 They are connected to each other, C 3~6 Forms a cycloalkyl group, C 3~6 Cycloalkyls are halogens, C 1~4 Alkyl or halogenated C 1~4 It may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. R 19 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl or -C 1~4 Alkyl-C 3~8 Selected from the group consisting of cycloalkyls, C 1~6 Alkyl, C 3~8 Cycloalkyl or -C 1~4 Alkyl-C 3~8 Cycloalkyls are halogens, C 1~4 Alkyl and halogenated C 1~4 Each atom may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups.

[0268] In one embodiment of the compound represented by formula IIA: R3 is a 5-membered heteroaryl, and a 5-membered heteroaryl is one C1~4 It may also be substituted with alkyl, The Z1 is CR6R7, The Z2 is the CR8R9, The Z3 is NR 14 , O or -C(O)-, The Z4 is CR 17 R 18 , NR 19 Or -C(O)-, R6, R7, R8, and R9 are each independently hydrogen. R 14 C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 2~6 Alkinyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~4 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~6 Cycloalkyl, -SO2-3~6 member heterocyclyl, -C 1~4 Alkyl-3 to 6-membered heterocyclyl or

[0269] [ka]

[0270] Selected from a group consisting of a group consisting of C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 2~6 Alkinyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~4 Alkyl, -SO2-C 2~6 Alkenyl, -SO2-C 3~6 Cycloalkyl, -SO2-3~6 member heterocyclyl, -C 1~4 Alkyl-3 to 6-membered heterocyclyl or

[0271] [ka]

[0272] Deuterium, halogen, hydroxyl, cyano, C 1~4 Alkyl and halogenated C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups, R' is H, C 1~4 Alkyl or C 3~6 Selected from the group consisting of cycloalkyl groups, R 17 and R 18 is hydrogen, C 1~4 Alkyl or C 3~6 Each is independently selected from the group consisting of cycloalkyls, C 1~4 Alkyl or C 3~6 Cycloalkyls are halogens, C 1~4 Alkyl or halogenated C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups, Alternatively, R 17 and R 18 They are connected to each other, C 3~6 Forms a cycloalkyl group, C 3~6 Cycloalkyls are halogens, C 1~4 Alkyl or halogenated C 1~4 It may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. R 19 is hydrogen, C 1~4 Alkyl, C 3~6 Cycloalkyl or -C 1~4 Alkyl-C 3~6 Selected from the group consisting of cycloalkyls, C 1~4 Alkyl, C 3~6 Cycloalkyl or -C 1~4 Alkyl-C 3~6 Cycloalkyls are halogens, C 1~4 Alkyl and halogenated C 1~4Each atom may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups.

[0273] In one embodiment of the compound represented by formula IIA: R3 is a 5-membered heteroaryl compound. The Z1 is CR6R7, The Z2 is the CR8R9, The Z3 is NR 14 , O or -C(O)-, The Z4 is CR 17 R 18 , NR 19 Or -C(O)-, R6, R7, R8, and R9 are each independently hydrogen. R 14 C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~4 Alkyl, -SO2-C 2~4 Alkenyl, -SO2-C 3~6 Cycloalkyl or

[0274] [ka]

[0275] Selected from a group consisting of a group consisting of C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl, -SO2-C 1~4 Alkyl, -SO2-C 2~4 Alkenyl, -SO2-C 3~6 Cycloalkyl or

[0276] [ka]

[0277] Deuterium, halogen, hydroxyl, cyano, C 1~4 Alkyl and halogenated C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups, R' is H or C 1~4 Selected from the group consisting of alkyl groups, R 17 and R 18 is hydrogen, C 1~4 Alkyl or C 3~6 Each is independently selected from the group consisting of cycloalkyls, C 1~4 Alkyl or C 3~6 Cycloalkyls are halogens or C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups. Alternatively, R 17 and R 18 They are connected to each other, C 3~6 Forming a cycloalkyl group, R 19 C 1~4 Alkyl, C 3~6 Cycloalkyl or -C 1~4 Alkyl-C 3~6 Selected from the group consisting of cycloalkyls, C 1~4 Alkyl, C 3~6 Cycloalkyl or -C 1~4 Alkyl-C 3~6 Cycloalkyls are halogens, C 1~4 Alkyl and halogenated C 1~4 Each atom may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups.

[0278] In one embodiment of the compound represented by formula IIB: R3 is a 5-6 member heteroaryl, which is one or two R3s. 3a It may be substituted with a group, R 3a These are C 1~6Independently selected from the group consisting of alkyls, The Z1 is CR6R7, Z2 is CR8R9 or -C(O)-, The Z3 is CR 12 R 13 , N, NR 14 Or -C(O)-, The Z4 is CR 16 CR 17 R 18 or NR 19 And, R6, R7, R8, and R9 are hydrogen and C 1~4 Each is independently selected from the group consisting of alkyls, C 1~4 Alkyl compounds are halogens and C, respectively. 1~4 Alkyl or halogenated C 1~4 It may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. R 12 and R 13 is hydrogen, hydroxyl, C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 They are independently selected from the group consisting of aryls or 5-membered or 6-membered heteroaryls, C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl or 5-membered or 6-membered heteroaryls are halogens, C 1~4 Alkyl or halogenated C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups. R 14 is hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl or 5-membered or 6-membered heteroaryl, -CO-C 1~6 Alkyl, -CO-C 3~6 Cycloalkyl, -C(O)OC 1~6 Alkyl or -SO2-C 1~6Selected from the group consisting of alkyl groups, C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl or 5-membered or 6-membered heteroaryl, -CO-C 1~6 Alkyl, -CO-C 3~6 Cycloalkyl, -C(O)OC 1~6 Alkyl or -SO2-C 1~6 Alkyls are halogens, C 1~4 Alkyl and halogenated C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups, R 16 C 1~6 Selected from the group consisting of alkyl groups, R 17 and R 18 is hydrogen or C 1~6 Each is independently selected from the group consisting of alkyls, C 1~6 Alkyl compounds are halogens and C, respectively. 1~4 Alkyl or halogenated C 1~4 It may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups. R 19 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -SO2-C 1~6 Alkyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl or -C 1~4 Selected from the group consisting of alkyl-5~6 member heteroaryls, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -SO2-C 1~6 Alkyl, -C 1~4 Alkyl-C 3~8 Cycloalkyl or -C 1~4Alkyl-5 to 6-membered heteroaryls include halogens, hydroxyls, cyanos, and C. 1~4 Alkyl, halogenated C 1~4 Alkyl, hydroxy-C 1~4 Alkyl, C 1~4 Heteroalkyl, C 3~6 Cycloalkyl and -CONR 25 R 26 Each of these may be substituted by one, two, or three substituents independently selected from the group consisting of the following: R 25 and R 26 is hydrogen or C 1~4 Each is independently selected from the group consisting of alkyl groups.

[0279] In one embodiment of the compound represented by formula IIB: R3 is a 5-membered heteroaryl, and a 5-membered heteroaryl is one C 1~4 It may also be substituted with alkyl, The Z1 is CR6R7, The Z2 is the CR8R9, The Z3 is CR 12 R 13 , N, NR 14 Or -C(O)-, The Z4 is CR 16 CR 17 R 18 or NR 19 And, R6 and R7 are independently selected from the group consisting of hydrogen. R8 and R9 are hydrogen or C 1~4 Each is independently selected from the group consisting of alkyls, C 1~4 Alkyl compounds are halogens and C, respectively. 1~4 Alkyl or halogenated C 1~4 It may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. R 12 and R 13 is hydrogen or C 1~4 Each is independently selected from the group consisting of alkyls, C 1~4Alkyl compounds are halogens and C, respectively. 1~4 Alkyl or halogenated C 1~4 It may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. R 14 C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl or -SO2-C 1~4 Selected from the group consisting of alkyl groups, C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CO-C 1~4 Alkyl, -CO-C 3~6 Cycloalkyl and -SO2-C 1~4 Alkyls are halogens, C 1~4 Alkyl and halogenated C 1~4 Each of these substituents may be independently selected from the group consisting of alkyl groups, R 16 C 1~4 Selected from the group consisting of alkyl groups, R 17 and R 18 is hydrogen or C 1~4 Each is independently selected from the group consisting of alkyls, C 1~4 Alkyl compounds are halogens and C, respectively. 1~4 Alkyl or halogenated C 1~4 It may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups. R 19 is hydrogen, C 1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -SO2-C 1~4 Alkyl, -C 1~4 Alkyl-C 3~6 Cycloalkyl or -C 1~4 Selected from the group consisting of alkyl-5~6 member heteroaryls, C1~4 Alkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -SO2-C 1~4 Alkyl, -C 1~4 Alkyl-C 3~6 Cycloalkyl or -C 1~4 Alkyl-5 to 6-membered heteroaryls include halogens, hydroxyls, cyanos, and C. 1~4 Alkyl, halogenated C 1~4 Alkyl, hydroxy-C 1~4 Alkyl, C 1~4 Heteroalkyl and C 3~6 Each molecule may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl molecules.

[0280] In one embodiment of the compound represented by formula IIB: R3 is a 5-membered heteroaryl, and a 5-membered heteroaryl is one C 1~4 It may also be substituted with alkyl, The Z1 is CR6R7, The Z2 is the CR8R9, The Z3 is CR 12 R 13 Or -C(O)-, The Z4 is CR 17 R 18 or NR 19 And, R6, R7, R8, R9, R 12 , R 13 , R 17 and R 18 Each of them is independently hydrogen, R 19 C 1~4 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenyl, -SO2-C 1~4 Alkyl or -C 1~4 Alkyl-C 3~6 Selected from the group consisting of cycloalkyls, C 1~4 Alkyl, C 3~6Cycloalkyl, C 2~6 Alkenyl, -SO2-C 1~4 Alkyl or -C 1~4 Alkyl-C 3~6 Cycloalkyls are halogens, hydroxyls, cyanos, and C 1~4 Alkyl, halogenated C 1~4 Alkyl, hydroxy-C 1~4 Alkyl, C 1~4 Heteroalkyl and C 3~6 Each molecule may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl molecules.

[0281] Other Embodiments Embodiment 1: Compounds represented by formula I, their isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof:

[0282] [ka]

[0283] (In the formula,

[0284] [ka]

[0285] This indicates that the ring to which it belongs is an aromatic ring system. X1 is N or C(R X1 Selected from the group consisting of, X2 is selected from the group consisting of C or N. X3 is N, C(R X2 ) or N(R X3 Selected from the group consisting of, X4 is N or C(R X4 Selected from the group consisting of, X5 is selected from the group consisting of C or N. X6 is N, N(R X5 ) or C(R X6 Selected from the group consisting of, RX1 , R X2 , R X3 , R X4 , R X5 and R X6 H, halogen, C 6~10 Ariel, C 3~10 Cycloalkyl, C 3~10 A cycloalkenyl, a 3-10 membered heterocyclyl, or a 5-10 membered heteroaryl is independently selected from the group, C 6~10 Ariel, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyls, 3-10 membered heterocyclyls, and 5-10 membered heteroaryls have one, two, or three R groups. X Each of these may be substituted by the base, R X These are halogen, cyano, hydroxyl, and C, respectively. 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, or -NR c R d Independently selected from the group consisting of C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl and 3- to 10-membered heterocyclyls are halogen, cyano, hydroxyl, or C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups, A is selected from a group consisting of 4-10 member heterocyclils, and each 4-10 member heterocyclil has one, two, or three R a It may be substituted by the base, R a These are C 1~10 Alkyl, C 1~10 Heteroalkyl, amino, or -S(=O)2-C 1~10 Independently selected from the group consisting of alkyls, Ring B is selected from the group consisting of a 5- to 7-membered heterocyclic ring, a 5- to 7-membered carbocyclic ring, a benzene ring, or a 5- to 7-membered heteroaromatic ring. R bThese are halogen, hydroxyl, cyano, amino, oxo, and C, respectively. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR e R f -C(O)OC 1~10 Alkyl, -SO2NR g R h , -SO2-C 1~10 Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl or

[0286] [ka]

[0287] Independently selected from the group consisting of C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR e R f -C(O)OC 1~10 Alkyl, -SO2NR g R h , -SO2-C 1~10Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryls and

[0288] [ka]

[0289] These are halogen, hydroxyl, cyano, amino, and C 1~10 Alkyl, halogenated C 1~10 Alkyl, hydroxy-C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl or -CONR i R j They may each be substituted by one, two, three, or four substituents independently selected from the group consisting of the above, R' is H, C 1~10 Selected from the group consisting of alkyl or CN, R c , R d , R e , R f , R g , R h , R i and R j is H or C 1~10 Each is independently selected from the group consisting of alkyl groups, Alternatively, two R b The bases are connected to each other, C 3~10 Forming a cycloalkyl or 3-10 membered heterocycline, C 3~10 Cycloalkyl and 3-10 membered heterocyclyls are halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10They may be substituted with one, two, three, or four substituents independently selected from the group consisting of cycloalkyls or 3- to 10-membered heterocyclines, respectively. n is selected from the group consisting of 0, 1, 2, 3, or 4.

[0290] Embodiment 2: The compound is structural formula II

[0291] [ka]

[0292] Compounds according to Embodiment 1, their isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof, having the above characteristics. (In the formula,

[0293] [ka]

[0294] This indicates that the ring to which it belongs is an aromatic ring system.

[0295] [ka]

[0296] This represents either a single bond or a double bond. R1 and R2 are hydrogen or C 1~6 Each is independently selected from the group consisting of alkyls, or R1 and R2, together with the carbon atom to which they are bonded and the adjacent nitrogen atom, form a 4- to 8-membered aza-cyclic ring. X2 is selected from the group consisting of C or N. X3 is selected from the group consisting of C(R3) or N(R3), X4 is selected from the group consisting of N or CH. X5 is selected from the group consisting of C or N, and if X5 is N, then X3 is C(R3). R3 is C 6~10 Ariel, C 3~10 Selected from the group consisting of cycloalkyl or 5-10 member heteroaryls, C 6~10 Ariel, C 3~10 Cycloalkyl and 5-10 membered heteroaryls have one, two or three R 3a Each of these may be substituted by the base, R 3a These are halogen, cyano, hydroxyl, and C, respectively. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 A cycloalkyl group is independently selected from the group consisting of 3-10 member heterocyclines or -NR4R5, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl and 3- to 10-membered heterocyclyls are halogen, cyano, hydroxyl, or C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups, R4 and R5 are hydrogen or C 1~10 Each is independently selected from the group consisting of alkyl groups, The Z1 is CR6R7, The Z2 is CR8R9, N, NR 10 Selected from the group consisting of O, S, -C(O)- or -SO2-, The Z3 is CR 11 CR 12 R 13 , N, NR 14 , O, -C(O)-, -SO2- or -S(O)(NR 15 Selected from the group consisting of )-, The Z4 is CR 16 CR 17 R 18 , N, NR 19 , O, S, -C(O)-, -SO2- or -S(O)(NR 20 Selected from the group consisting of )-, However, one or two of Z1, Z2, Z3, and Z4 may be absent, and the ring containing X5, Z1, Z2, Z3, and Z4 is provided that it has a stable ring structure. R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 These are halogen, hydroxyl, cyano, amino, and C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2-C 1~10 Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl or

[0297] [ka]

[0298] Each of the groups consisting of C is independently selected. 1~10 Alkyl, C 1~10 Heteroalkyl, C3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryl, -CO-C 3~10 Cycloalkyl, -CO-C 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2C 1~10 Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl and

[0299] [ka]

[0300] These are halogen, hydroxyl, cyano, amino, and C 1~10 Alkyl, halogenated C 1~10 Alkyl, hydroxy-C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl or -CONR 25 R 26 They may each be substituted by one, two, three, or four substituents independently selected from the group consisting of the above, R' is H, C 1~10 Selected from the group consisting of alkyl or CN, R 21 , R 22 , R 23 , R 24 , R 25 and R 26 is H or C1~10 Each is independently selected from the group consisting of alkyl groups, Alternatively, R6 and R7, R8 and R9, R 12 and R 13 or R 17 and R 18 They are connected to each other, C 3~10 Forming a cycloalkyl or 3-10 membered heterocycline, C 3~10 Cycloalkyl and 3-10 membered heterocyclyls are halogen, hydroxyl, cyano, amino, and C. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 (They may be substituted with one, two, three, or four substituents independently selected from the group consisting of cycloalkyls or 3- to 10-membered heterocyclines.)

[0301] Embodiment 3: R6, R7, R8, R9, R 11 , R 12 , R 13 , R 16 , R 17 and R 18 However, each is independent of hydrogen, halogen, hydroxyl, cyano, and C. 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 1~10 Alkoxy, C 2~5 Alkenil, C 2~5 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -COC 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 or -SO2C 1~10 It is alkyl, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 1~10 Alkoxy, C 2~5 Alkenil, C 2~5 Alkinyl, C 6~10Aryl, 5-10 member heteroaryl, -CO-C 1~10 Alkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 and -SO2C 1~10 Alkyl, halogen, hydroxyl, cyano, amino, C 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl and -CONR 25 R 26 They may each be substituted by one, two, three, or four substituents independently selected from the group consisting of the above, R 10 , R 14 , R 15 , R 19 and R 20 However, each is independent of hydrogen and C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, C 1~10 Alkoxy, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2-C 1~10 Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6Alkyl-5 to 10-membered heteroaryl or

[0302] [ka]

[0303] C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~5 Alkenil, C 2~5 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, C 1~10 Alkoxy, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -CONR 21 R 22 -C(O)OC 1~10 Alkyl, -SO2NR 23 R 24 , -SO2C 1~10 Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~6 Alkyl-C 3~10 Cycloalkyl, -C 1~6 Alkyl-3 to 10-membered heterocyclyl, -C 1~6 Alkyl-C 6~10 Ariel, -C 1~6 Alkyl-5 to 10-membered heteroaryls and

[0304] [ka]

[0305] However, halogen, hydroxyl, cyano, amino, C 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, -CONR 25 R 26They may each be substituted by one, two, three, or four substituents independently selected from the group consisting of the above, R' is H, C 1~10 Selected from the group consisting of alkyl or CN, R 21 , R 22 , R 23 , R 24 , R 25 and R 26 However, H or C 1~6 Each is independently selected from the group consisting of alkyl groups. A compound, its isomer, isotope-labeled compound, or pharmaceutically acceptable salt thereof, according to Embodiment 2.

[0306] Embodiment 4: The compound has structural formula IIA, IIB, or IIC:

[0307] [ka]

[0308] (In the formula, R3 is C 6~10 Ariel, C 3~10 Selected from the group consisting of cycloalkyl or 5-10 member heteroaryls, C 6~10 Ariel, C 3~10 Cycloalkyl and 5-10 membered heteroaryls have one, two or three R 3a Each of these may be substituted by the base, R 3a These are halogen, cyano, hydroxyl, and C, respectively. 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 A cycloalkyl group is independently selected from the group consisting of 3-10 member heterocyclines or -NR4R5, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl and 3-10 membered heterocyclyl and -NR4R5 are halogen, cyano, hydroxyl or C 1~6Each of these substituents may be independently selected from the group consisting of alkyl groups, R4 and R5 are independently hydrogen or C 1~10 (It is alkyl.) Compounds according to Embodiment 2 or 3, isomers thereof, isotope-labeled compounds, or pharmaceutically acceptable salts thereof, having the above characteristics.

[0309] Embodiment 5: R3 is a 5-6 member heteroaryl, and the 5-6 member heteroaryl is C 1~6 Compounds according to Embodiment 4, their isomers, or pharmaceutically acceptable salts thereof, which may be substituted with one or two substituents independently selected from the group consisting of alkyl groups.

[0310] Embodiment 6: The Z1 is the CR6R7, Z2 is selected from the group consisting of CR8R9 or -C(O)-, Z3, CR 11 CR 12 R 13 , N, NR 14 Or selected from the group consisting of -C(O)-, The Z4 is CR 16 CR 17 R 18 , N, NR 19 Or selected from the group consisting of -C(O)-, R6, R7, R8, R9, R 11 , R 12 , R 13 , R 16 , R 17 and R 18 However, hydrogen, hydroxyl, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Each is independently selected from the group consisting of aryls or 5-10 member heteroaryls, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Aryls and 5-10 member heteroaryls are C1~6 Alkyl or halogenated C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups. R 14 and R 19 However, hydrogen, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -C(O)OC 1~10 Alkyl, -SO2-C 1~10 Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclyl, -C 1~4 Alkyl-C 6~10 Ariel, -C 1~4 Alkyl-5 to 10-membered heteroaryl or

[0311] [ka]

[0312] Each of the groups consisting of C is independently selected. 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -C(O)OC 1~10 Alkyl, -SO2-C 1~10 Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~4Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclyl, -C 1~4 Alkyl-C 6~10 Ariel, -C 1~4 Alkyl-5 to 10-membered heteroaryls and

[0313] [ka]

[0314] However, halogen, hydroxyl, cyano, C 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl, 3-6 member heterocyclyl, or -CONR 25 R 26 Each of these may be substituted by one, two, or three substituents independently selected from the group consisting of the following: R' is H, C 1~10 Selected from the group consisting of alkyl or CN, R 25 and R 26 However, hydrogen or C 1~6 Each is independently selected from the group consisting of alkyl groups. A compound, its isomer, an isotope-labeled compound, or a pharmaceutically acceptable salt thereof, according to any one of Embodiments 2 to 5.

[0315] Embodiment 7: The Z1 is the CR6R7, R6 and R7 are hydrogen or C 1~10 Each is independently selected from the group consisting of alkyl groups. A compound according to any one of Embodiments 2 to 6, an isomer thereof, an isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

[0316] Embodiment 8: Z2 is selected from the group consisting of CR8R9 or -C(O)-, R8 and R9 are hydrogen or C 1~10 Compounds according to any one of Embodiments 2 to 7, isomers thereof, isotope-labeled compounds, or pharmaceutically acceptable salts thereof, each independently selected from the group consisting of alkyl groups.

[0317] Embodiment 9: Z3, CR 11 CR 12 R 13 , N, NR 14 Or selected from the group consisting of -C(O)-, R 11 , R 12 and R 13 However, hydrogen, hydroxyl, C 1~10 Alkyl, C 3~10 A cycloalkyl group is independently selected from the group consisting of a 3-10 member heterocyclyl group or a 5-10 member heteroaryl group, C 1~10 Alkyl, C 3~10 Cycloalkyls, 3-10 membered heterocyclyls, and 5-10 membered heteroaryls are C 1~6 Alkyl or halogenated C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups. R 14 However, hydrogen, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkyl, -C(O)OC 1~10 Alkyl, -SO2-C 1~10 Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclines or

[0318] [ka]

[0319] Selected from the group consisting of C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, -CO-C 1~10 Alkyl, -CO-C 3~10 Cycloalkylalkyl, -C(O)OC 1~10 Alkyl, -SO2-C 1~10 Alkyl, -SO2-C 3~10 Cycloalkyl, -SO2-3~10 member heterocyclyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclyl and

[0320] [ka]

[0321] However, halogen, hydroxyl, cyano, C 1~6 Alkyl or halogenated C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups, R' is H, C 1~10 Selected from the group consisting of alkyl or CN, A compound according to any one of Embodiments 2 to 8, an isomer thereof, an isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

[0322] Embodiment 10: The Z4 is CR 16 CR 17 R 18 , N, NR 19 Or selected from the group consisting of -C(O)-, R 16 , R17 and R 18 However, hydrogen, C 1~10 Alkyl or C 3~10 Each is independently selected from the group consisting of cycloalkyls, C 1~10 Alkyl and C 3~10 Cycloalkyl is C 1~6 Alkyl or halogenated C 1~6 Each of these substituents may be independently selected from the group consisting of alkyl groups. R 19 However, hydrogen, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, -SO2-C 1~10 Alkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclyl, -C 1~4 Alkyl-C 6~10 aryl or -C 1~4 Selected from the group consisting of alkyl-5 to 10-membered heteroaryls, C 1~10 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 2~5 Alkenil, C 2~5 Alkinyl, -SO2C 1~10 Alkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 1~4 Alkyl-3 to 10-membered heterocyclyl, -C 1~4 Alkyl-C 6~10 Aryl and -C 1~4 Alkyl-5 to 10-membered heteroaryls, halogens, hydroxyls, cyanos, C 1~6 Alkyl, halogenated C 1~6 Alkyl, hydroxy-C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl or -CONR 25 R 26Each of these may be substituted by one, two, or three substituents independently selected from the group consisting of the following: R 25 and R 26 However, hydrogen or C 1~6 Each is independently selected from the group consisting of alkyl groups. A compound according to any one of Embodiments 2 to 9, its isomer, isotope-labeled compound, or pharmaceutically acceptable salt thereof.

[0323] Those skilled in the art will understand that, in the above description of this application, substituent combinations are permissible only if such combinations result in a stable compound. Therefore, when describing compounds of the general formula, substituent combinations that do not result in a stable compound are not included within the scope of this application. Those skilled in the art will be able to easily exclude such unacceptable substituent combinations.

[0324] In one embodiment, the compound of this application is

[0325] [ka] [ka] [ka] [ka] [ka]

[0326] Alternatively, the group consists of isomers of the above compounds, isotope-labeled compounds, or pharmaceutically acceptable salts thereof.

[0327] In one embodiment, the compound of this application is

[0328] [ka] [ka] [ka] [ka] [ka] [ka]

[0329] Alternatively, the group consists of isomers of the above compounds, isotope-labeled compounds, or pharmaceutically acceptable salts thereof.

[0330] In another embodiment, the present invention provides a pharmaceutical composition comprising the compound of this application, its isomers, isotope-labeled compounds or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0331] Method or use of the compound in this application In another embodiment, the present application provides the compounds of the present application, their isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof, which are used as ATR kinase inhibitors.

[0332] In another embodiment, the present application provides the use of the compounds of the present application, their isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof in the production of ATR kinase inhibitors.

[0333] In another embodiment, the present application provides the use of the compounds of the present application, their isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for treating cancer.

[0334] In another embodiment, the present application provides the compounds of the present application, their isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof, for use in treating cancer.

[0335] In another embodiment, the present application provides a method for treating cancer in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of the compound of the present application, its isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof.

[0336] In some embodiments, the cancer is colon cancer.

[0337] In another embodiment, the present application provides the use of the compounds of the present application, their isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for treating diseases mediated by ATR kinases.

[0338] In another embodiment, the present application provides the compounds of the present application, their isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof, for use in treating diseases mediated by ATR kinases.

[0339] In another embodiment, the present application provides a method for treating an ATR kinase-mediated disease in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of the compound of the present application, its isomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof.

[0340] In some embodiments, ATR kinase-mediated diseases are proliferative or hyperproliferative disorders caused by excessive or abnormal cell proliferation, particularly proliferative or hyperproliferative disorders caused by excessive or abnormal cell proliferation mediated by ATR kinase. In some embodiments, examples of ATR kinase-mediated diseases include, but are not limited to, cancer and myeloproliferative disorders. [Examples]

[0341] Preparation of the compound in this application The following reaction scheme illustrates a method for preparing the compound of the present invention.

[0342] Preparation of intermediate INT-1

[0343] [ka]

[0344] Step 1: 2,6-difluoro-4-iodopyridine (50 g, 207 mmol) was dissolved in dimethyl sulfoxide (500 mL). (R)-3-methylmorpholine (19.9 g, 197 mmol) and N,N-diisopropylethylamine (68.6 mL, 415 mmol) were added sequentially. The reaction mixture was stirred overnight at 100°C. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and successively washed with water and saturated brine. The mixture was dehydrated with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by silica gel chromatography to obtain the intermediate INT-1-2 (47 g, 70.3%). LCMS(ESI)[M+H] + :323.0.

[0345] Step 2: Intermediate INT-1-2 (48 g, 149 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL), and lithium diisopropylamide (149 mL, 2 M) was slowly added dropwise at -70°C. The reaction mixture was stirred at -70°C for 1 hour. Next, 3-benzyloxypropanal (29.3 g, 179 mmol) was slowly added dropwise to the reaction mixture at -70°C, and the reaction mixture was stirred at -70°C for 1 hour. After the reaction was complete, formic acid (12.5 mL) was slowly added dropwise to the reaction mixture at -60°C, and then diluted with ethyl acetate. Once the reaction mixture reached room temperature, it was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by silica gel chromatography to obtain intermediate INT-1-3 (22.7 g, 31.3%). LCMS(ESI)[M+H] + :487.1.

[0346] Step 3: Intermediate INT-1-3 (23 g, 47.3 mmol) was dissolved in dichloromethane (200 mL). Dess-Martin periodinane (30.1 g, 70.9 mmol) was slowly added in small amounts at 0°C. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. After the reaction was complete, sodium bicarbonate was added to the reaction mixture to adjust the pH to 8, and then the reaction mixture was filtered. The filtrate was washed with water, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel chromatography to obtain intermediate INT-1-4 (20 g, 87.3%). LCMS(ESI)[M+H] + :485.1.

[0347] Step 4: Intermediate INT-1-4 (20 g, 41.3 mmol) was dissolved in ethanol (200 mL), and hydrazine hydrate (20.4 mL, 413 mmol, 98.0 wt%) was added at room temperature. The reaction mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove most of the ethanol, and then diluted with ethyl acetate. The organic phase was washed with water, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel chromatography to obtain intermediate INT-1-5 (7 g, 35.4%). LCMS(ESI)[M+H] + :479.1.

[0348] Step 5: Intermediate INT-1-5 (4.9 g, 10.2 mmol) and potassium N-Boc-aminomethyltrifluoroborate (3.64 g, 15.3 mmol) were dissolved in a mixed solvent of dioxane (90 mL) and water (10 mL). n-butyl-di(1-adamantyl)phosphine (0.73 g, 2.05 mmol), palladium acetate (0.46 g, 2.05 mmol), and cesium carbonate (10 g, 30.7 mmol) were added in sequence. The reaction mixture was stirred at 100 °C for 6 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel chromatography to obtain intermediate INT-1-6 (4.8 g, 97.3%). LCMS(ESI)[M+H] + :482.3.

[0349] [ka]

[0350] Step 6: 3-iodo-1-hydrogen-pyrazole (14.5 g, 74.7 mmol) was dissolved in dichloromethane (150 mL), and p-toluenesulfonic acid monohydrate (1.29 g, 7.47 mmol) and 3,4-dihydro-2H-pyran (12.6 g, 149 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the dichloromethane was removed under reduced pressure to obtain a residue, which was separated and purified by silica gel chromatography to obtain the intermediate INT-1-7 (14 g, 67.4%). LCMS(ESI)[M+H] + :279.0.

[0351] Step 7: Intermediate INT-1-6 (4.60 g, 9.55 mmol) and intermediate INT-1-7 (3.19 g, 11.46 mmol) were dissolved in toluene (50 mL), and cuprous iodide (1.82 g, 9.55 mmol), anhydrous potassium phosphate (8.11 g, 38.2 mmol), and N,N-dimethylethylenediamine (1.68 g, 19.1 mmol) were added in sequence. Next, this reaction mixture was heated to 110°C and stirred overnight under a nitrogen atmosphere at 110°C. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by silica gel chromatography to obtain intermediate INT-1-8 (3 g, 49.7%). LCMS(ESI)[M+H] + :632.3.

[0352] Step 8: Intermediate INT-1-8 (3 g, 4.75 mmol) was dissolved in methanol (30 mL), and carbon-supported palladium hydroxide (6.67 g, 4.75 mmol, 10.0 wt%) was added. This reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere (50 psi). After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to obtain the crude intermediate INT-1-9 (1.50 g, 2.77 mmol). LCMS(ESI)[M+H] + :542.3.

[0353] Step 9: Intermediate INT-1-9 (400 mg, 0.74 mmol) was dissolved in dioxane (20 mL), and cyanomethylenetributylphosphoran (891 mg, 3.69 mmol) was added. This reaction mixture was stirred at 150°C for 1 hour under microwave irradiation. After cooling, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by silica gel chromatography to obtain intermediate INT-1 (320 mg, 82.7%). LCMS(ESI)[M+H] + :524.3.

[0354] Preparation of intermediate INT-2

[0355] [ka]

[0356] Step 1: INT-2-1 (20 g, 128.1 mmol) was dissolved in N-methylpyrrolidone (80 mL), and (R)-3-methylmorpholine (19.44 g, 192.2 mmol) and diisopropylethylamine (33.12 g, 256.2 mmol) were added. This reaction mixture was heated under nitrogen to 110°C and stirred for 1 hour. The reaction mixture was cooled to 25°C and quenched with ice water (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with water, then with saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain crude INT-2-3 (25 g, 82.3%). LCMS(ESI)[M+H] + :238.2.

[0357] Step 2: INT-2-3 (25 g, 105.4 mmol) was dissolved in anhydrous ethanol (250 mL). 10% carbon-supported palladium (2.24 g, 21.1 mmol) was added, and the reaction mixture was stirred at 25°C for 24 hours under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with anhydrous methanol. The filtrate was concentrated to obtain INT-2-4 (21.50 g, 98.4%). LCMS(ESI)[M+H] +:208.4.

[0358] Step 3: INT-2-4 (7.5 g, 36.18 mmol) was dissolved in trifluoroacetic acid (75 mL). At 25°C, N-bromosuccinimide (10.3 g, 57.9 mmol) was added in small portions to this reaction system. The reaction system was stirred for 30 minutes, and then the reaction solution was diluted with dichloromethane (70 mL). The reactants were quenched with saturated sodium carbonate solution at 0°C to adjust the pH to 8. The aqueous phase was extracted with dichloromethane (60 mL x 3), and the combined organic phase was washed with saturated brine (50 mL x 3). The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain INT-2-5 (4.2 g, 40.6%). LCMS(ESI)[M+H] + :286.2, 288.2.

[0359] Step 4: INT-2-5 (4.2 g, 14.7 mmol) was dissolved in toluene (15 mL). Potassium acetate (2.88 g, 29.4 mmol) and acetic acid (2 mL) were added under a nitrogen atmosphere at 0°C. The reaction system was thoroughly stirred, and then isoamyl nitrite (2.58 g, 22 mmol) was slowly added. The reaction mixture was heated to 30°C and reacted for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (50 mL x 3), dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain INT-2 (2.5 g, 57.79%). LCMS(ESI)[M+H] + :296.8 and 299.0.

[0360] Preparation of intermediate INT-3

[0361] [ka]

[0362] Step 1: INT-2 was dissolved in N,N-dimethylformamide (25 mL), and N-iodosuccinimide (2.5 g, 10.94 mmol) was added in small portions. This reaction mixture was stirred at 25°C for 1 hour. Next, this reaction mixture was quenched at 25°C with ice water (50 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and centrifuged to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain INT-3-1 (1.9 g, 53.4%). LCMS(ESI)[M+H] + :423.0, 425.0.

[0363] Step 2: INT-3-1 (0.63 g, 1.49 mmol) was dissolved in dioxane / water (10 / 1) (9 mL), and INT-3-2 (1.65 g, 5.96 mmol), tetrakis(triphenylphosphine palladium) (0.34 g, 0.3 mmol), and potassium carbonate (0.62 g, 4.47 mmol) were added in sequence. This mixture was stirred under a nitrogen atmosphere at 80°C for 6 hours. The reaction product was quenched with water at 25°C. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water (20 mL) and saturated brine (20 mL), dehydrated with anhydrous sodium sulfate, filtered, and centrifuged to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain INT-3-3 (440 mg, 66%). LCMS(ESI)[M+H] + :447.0, 449.0.

[0364] Step 3: INT-3-3 (0.44 g, 0.98 mmol) was dissolved in N,N-dimethylformamide (5 mL), and INT-3-4 (0.27 g, 1.48 mmol), potassium carbonate (0.41 g, 2.95 mmol), and sodium iodide (44.2 mg, 0.3 mmol) were added in sequence. The reaction mixture was stirred at 120 °C for 1 hour. The reaction mixture was quenched with ice water at 25 °C. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water (20 mL) and saturated brine (20 mL), dehydrated with anhydrous sodium sulfate, filtered, and centrifuged to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain INT-3-5 (0.52 g, 89.5%). LCMS(ESI)[M+H] + : 590.5, 592.5.

[0365] Step 4: INT-3-5 (0.57 g, 0.97 mmol) was dissolved in dioxane (8 mL), and BrettPhos Pd G3 (87.5 mg, 0.097 mmol) and cesium carbonate (0.95 g, 2.9 mmol) were added sequentially. The reaction mixture was stirred under nitrogen at 100°C for 2 hours. Next, the reaction mixture was cooled to room temperature, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain INT-3 (0.3 g, 61%). LCMS(ESI)[M+H] + :510.2.

[0366] Preparation of intermediate INT-4

[0367] [ka]

[0368] Step 1: INT-3-3 (1.50 g, 3.35 mmol) was dissolved in N,N-dimethylformamide (15 mL), and (2-bromoethoxy)-tert-butyldimethylsilane (2.00 g, 8.38 mmol), potassium carbonate (1.40 g, 10.1 mmol), and sodium iodide (0.10 g, 0.671 mmol) were added in sequence. The reaction mixture was stirred at 120 °C for 1 hour. The reaction mixture was cooled to room temperature, quenched with ice water, and then extracted with ethyl acetate (10 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified by silica gel column chromatography to obtain the intermediate INT-4-1 (1.72 g, 84.7%). LCMS(ESI)[M+H] + :606.4.

[0369] Step 2: Intermediate INT-4-1 (1.5 g, 2.48 mmol) was dissolved in dioxane / water (10 mL, 1 / 4), and potassium [(tert-butoxycarbonylamino)methyl]trifluoroborate (1.17 g, 4.95 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (362 mg, 0.495 mmol), and cesium carbonate (2.42 g, 7.43 mmol) were added in sequence. The reaction mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, quenched with ice water, and extracted with ethyl acetate (10 mL x 3). The combined organic phase was successively washed with water and saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain intermediate INT-4-2 (1 g, 55.2%). LCMS(ESI)[M+H] + :656.2.

[0370] Step 3: Intermediate INT-4-2 (110 mg, 0.168 mmol) was dissolved in tetrahydrofuran, and tetrabutylammonium fluoride-tetrahydrofuran solution (0.25 mL, 1 M) was added sequentially. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was centrifuged to obtain the crude product, which was purified by silica gel column chromatography to obtain intermediate INT-4-3 (70 mg, 77.1%). LCMS(ESI)[M+H] + :542.0.

[0371] Step 4: Intermediate INT-4-3 (50 mg, 0.092 mmol) was dissolved in toluene (3 mL), and cyanomethylenetributylphosphoran (159 mg, 0.462 mmol) was added. This reaction mixture was stirred under a nitrogen atmosphere at 120°C for 2 hours. The solvent was centrifuged to obtain the crude product, which was purified by silica gel column chromatography to obtain intermediate INT-4 (48 mg, 99.3%). LCMS(ESI)[M+H] + :524.2.

[0372] Preparation of intermediate INT-5

[0373] [ka]

[0374] Step 1: Intermediate INT-1-5 (30 g, 62.7 mmol) and tetrakis(triphenylphosphine)palladium (7.2 g, 6.27 mmol) were dissolved in anhydrous dioxane (400 mL), and tributyl(1-ethoxyethylene)tin (49.8 g, 138 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred overnight at 120 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and slowly poured into 10% potassium fluoride solution (500 mL). After stirring and filtration, the filtrate was extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with saturated brine (500 mL), dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate INT-5-2 (28 g, crude product). LCMS(ESI)[M+H] + :423.4.

[0375] Step 2: Intermediate INT-5-2 (28 g, crude) was dissolved in tetrahydrofuran (300 mL), and aqueous hydrochloric acid (49.7 mL, 2 M) was added. The reaction mixture was cooled at room temperature for 1 hour. After the reaction was complete, the reaction solution was neutralized with aqueous sodium bicarbonate (200 mL). This reaction mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by silica gel column chromatography to obtain intermediate INT-5-3 (17 g, 65.0%). LCMS(ESI)[M+H] + :395.4.

[0376] Step 3: Intermediate INT-5-3 (17 g, 43.1 mmol) and intermediate INT-1-7 (14.4 g, 51.7 mmol) were dissolved in toluene (300 mL), and cuprous iodide (8.2 g, 43.1 mmol), anhydrous potassium phosphate (36.6 g, 172.4 mmol), and N,N-dimethylethylenediamine (7.6 g, 86.2 mmol) were added in sequence. This reaction solution was stirred overnight at 110°C under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, poured into ice water, and then extracted with ethyl acetate (300 mL x 3). The organic phase was washed sequentially with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the product, which was separated and purified by silica gel column chromatography to obtain intermediate INT-5-4 (21 g, 89.5%). LCMS(ESI)[M+H] + :545.4.

[0377] Step 4: Intermediate INT-5-4 (10 g, 18.4 mmol) and ammonium acetate (14.2 g, 183.6 mmol) were dissolved in methanol (200 mL) at room temperature. This reaction mixture was stirred at room temperature for 1 hour, and then sodium borohydride cyanohydride (5.8 g, 91.8 mmol) was added in small amounts. This reaction mixture was stirred at 70°C overnight. After the reaction was complete, the reaction mixture was cooled to room temperature, poured into ice water, and extracted with dichloromethane (200 mL x 3). The organic phase was washed with water, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel column chromatography to obtain intermediate INT-5-5 (4.3 g, 42.7%). LCMS(ESI)[M+H] + :546.4.

[0378] Step 5: Intermediate INT-5-5 (9.0 g, 16.5 mmol) was dissolved in dichloromethane (100 mL), and N,N-diisopropylethylamine (5.46 mL, 33.1 mmol) and di-tert-butyl dicarbonate (4.0 g, 18.1 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into ice water and extracted with dichloromethane (200 mL x 3). The organic phase was washed with water, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate INT-5-6 (12 g, crude product). LCMS(ESI)[M+H] + :646.5.

[0379] Step 6: Intermediate INT-5-6 (12 g, crude) was dissolved in methanol (100 mL), and wet carbon-supported palladium (4.0 g, 3.72 mmol) and carbon-supported palladium hydroxide (5.2 g, 10.0 wt%) were added. This reaction mixture was stirred under a hydrogen atmosphere (15 psi) at 50°C for 72 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to obtain intermediate INT-5-7 (10 g, crude). LCMS(ESI)[M+H] + :556.5.

[0380] Step 7: Intermediate INT-5-7 (10 g, 18.0 mmol) was dissolved in dioxane (200 mL) at room temperature, and cyanomethylenetributylphosphoran (21.7 g, 90.0 mmol) was added. The reaction mixture was stirred at 120 °C for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure to remove the dioxane and obtain the crude product. Next, the crude product was separated and purified by silica gel column chromatography to obtain intermediate INT-5-8 (9 g, 93.0%). LCMS(ESI)[M+H] + :538.4.

[0381] Step 8: Intermediate INT-5-8 (9.0 g, 16.7 mmol) was dissolved in methanol (100 mL), and a solution of hydrochloric acid and dioxane (41.8 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure to obtain intermediate INT-5 (8 g, crude product). LC-MS(ESI)[M+H] + :354.2.

[0382] Preparation of intermediate INT-6

[0383] [ka]

[0384] Step 1: Intermediate INT-5-5 (7.5 g, 13.7 mmol) was dissolved in methanol (100 mL), and wet carbon-supported palladium (2.9 g, 2.75 mmol) and carbon-supported palladium hydroxide (3.9 g, 2.75 mmol) were added. This reaction mixture was stirred under a hydrogen atmosphere (15 psi) at 50°C for 48 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. This was purified by silica gel column chromatography to obtain intermediate INT-6-2 (6.0 g, 95.8%). LCMS(ESI)[M+H] + :456.3.

[0385] Step 2: Intermediate INT-6-2 (4.0 g, 8.8 mmol) was dissolved in dioxane (100 mL) at room temperature, and cyanomethylenetributylphosphoran (10.6 g, 43.9 mmol) was added. The reaction mixture was stirred at 120 °C for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure to obtain the crude product. This crude product was then separated and purified by silica gel column chromatography to obtain intermediate INT-6 (2.5 g, 65.1%). LCMS(ESI)[M+H] + :438.2.

[0386] Preparation of intermediate INT-7

[0387] [ka]

[0388] Step 1: 4-(tert-butyldimethylsilyl)oxo-1-butanol (25 g, 122.30 mmol) was dissolved in dichloromethane (200 mL). Dess-Martin periodinane (57.1 g, 134.54 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with sodium bicarbonate and sodium thiosulfate (500 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (100 mL x 3). The organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the intermediate INT-7-2 (23.0 g, 92.9%). 1 H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 3.85 - 3.48 (m, 2H), 2.50 (m, 2H), 2.03 - 1.74 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H).

[0389] Step 2: Under a nitrogen atmosphere, intermediate INT-1-2 (20 g, 62.09 mmol) was dissolved in tetrahydrofuran (200 mL) and cooled to -70°C. Lithium diisopropylamide (62.09 mL, 2 M in THF) was added dropwise, and the mixture was stirred at -70°C for 1 hour. To this reaction mixture, a solution of intermediate INT-7-2 (15.1 g, 74.51 mmol) in tetrahydrofuran (50 mL) was added dropwise. After the addition was complete, the reaction mixture was continuously stirred for 1 hour. The reaction product was quenched with ammonium chloride solution (500 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate INT-7-3 (22.0 g, 67.6%). LCMS(ESI)[M+Na] +:546.9.

[0390] Step 3: Under a nitrogen atmosphere, intermediate INT-7-3 (20 g, 38.12 mmol) was dissolved in dichloromethane (200 mL), and des-martin periodinane (26.0 g, 57.18 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding water. The reaction mixture was quenched with sodium bicarbonate and sodium thiosulfate (500 mL, 1:1). The resulting organic phase was separated, and the aqueous phase was extracted with dichloromethane (100 mL x 3). The organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate INT-7-4 (14.0 g, 70.3%). LCMS(ESI)[M+H] + :523.2.

[0391] Step 4: Under a nitrogen atmosphere, intermediate INT-7-4 (6.0 g, 11.48 mmol) was dissolved in ethanol (60 mL), and hydrazine hydrate (5.8 g, 114.8 mmol) was added. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was quenched by adding water. The resulting organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate INT-7-5 (900 mg, 15.6%). LCMS(ESI)[M+H] + :517.4.

[0392] Step 5: Under a nitrogen atmosphere, intermediate INT-7-5 (670 mg, 1.30 mmol) was dissolved in tetrahydrofuran (10 mL), and methanol solution of hydrochloric acid (6 M, 5 mL) was added. The reaction mixture was stirred at 50°C for 1 hour. The reaction product was quenched by adding water at room temperature. The resulting organic phase was separated, and the aqueous phase was extracted with dichloromethane (20 mL x 3). The organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation and purification of the crude product by silica gel column chromatography yielded intermediate INT-7-6 (400 mg, 73.7%). LCMS(ESI)[M+H] + :403.2.

[0393] Step 6: Under a nitrogen atmosphere, intermediate INT-7-6 (500 mg, 1.24 mmol) was dissolved in dichloromethane (10 mL), and di-tert-butyl dicarbonate (0.43 mL, 1.87 mmol) and triethylamine (0.52 mL, 3.73 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water. The resulting organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation and purification of the crude product by silica gel column chromatography yielded intermediate INT-7-7 (500 mg, 80.1%). LCMS(ESI)[M+H] + :503.2.

[0394] Step 7: Under a nitrogen atmosphere, intermediate INT-7-7 (500 mg, 1.00 mmol) was dissolved in dichloromethane (10 mL), and des-martin periodinane (506.4 mg, 1.19 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched by adding water. The resulting organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation and purification of the crude product by silica gel column chromatography yielded intermediate INT-7-8 (390 mg, 78.3%). LCMS(ESI)[M+Na] + :523.1.

[0395] Step 8: Under a nitrogen atmosphere, intermediate INT-7-8 (390 mg, 0.78 mmol) was dissolved in acetonitrile (10 mL), and 2,2,6,6-tetramethylpiperidine-1-oxyl (243.2 mg, 1.56 mmol) and iodophenyldiacetic acid (505.3 mg, 1.56 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water. The resulting organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate INT-7 (360 mg, 89.4%). LCMS(ESI)[M+H] + :517.2.

[0396] Example 1: Preparation of (R)-4-(2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (Compound 1)

[0397] [ka]

[0398] Intermediate INT-1 (300 mg, 0.57 mmol) was dissolved in methanol (2 mL), and a solution of dioxane in hydrochloric acid (2 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain the crude product. Separation and purification of the crude product by preparative reverse-phase high-performance liquid chromatography yielded (R)-4-(2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 1) (80.0 mg, 41.2%). LCMS (ESI) [M+H] + : 340.1. 1 H NMR (400 MHz, CD3OD) δ 7.76 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.69 (s, 1H), 4.52 (s, 3H), 4.12 (dd, J = 2.1, 13.2 Hz, 1H), 4.05 (dd, J = 3.8, 11.4 Hz, 1H), 3.89 - 3.82 (m, 1H), 3.82 - 3.75 (m, 1H), 3.65 - 3.56 (m, 3H), 3.36 (d, J = 3.9 Hz, 1H), 3.30 (s, 2H), 1.32 (d, J = 6.6 Hz, 3H).

[0399] Example 2: Preparation of (R)-4-(7-isopropyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine carboxylate (Compound 2)

[0400] [ka]

[0401] Compound 1 (200 mg, 0.589 mmol) was dissolved in methanol (3 mL). N,N-diisopropylethylamine (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 20 minutes. Next, acetone (0.217 mL, 2.95 mmol) and sodium triacetoxyborohydride (624 mg, 2.95 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 2 hours. The crude product was concentrated under reduced pressure and purified by preparative reverse-phase high-performance liquid chromatography to obtain (R)-4-(7-isopropyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine carboxylate (Compound 2) (55.0 mg, 24.4%). LCMS (ESI) [M+H] + : 382.1. 1 H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.73 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.66 (s, 1H), 4.54 - 4.42 (m, 3H), 4.14 - 3.98 (m, 2H), 3.86 - 3.73 (m, 2H), 3.62 (dt, J = 2.9, 11.8 Hz, 1H), 3.57 - 3.44 (m, 3H), 3.26 - 3.18 (m, 2H), 1.33 (d, J = 6.6 Hz, 6H), 1.30 (d, J = 6.6 Hz, 4H).

[0402] Example 3: Preparation of (R)-4-(2-(1H-pyrazole-3-yl)-7-(tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (Compound 3)

[0403] [ka]

[0404] Title compound 3 was prepared using tetrahydropyran-4-one instead of acetone, in the same manner as in Example 2. (R)-4-(2-(1H-pyrazole-3-yl)-7-(tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 3) (6.20 mg, 24.8%) was obtained. LCMS (ESI) [M+H] + : 424.1. 1 H NMR (400 MHz, CD3OD) δ 7.74 (d, J = 1.5 Hz, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 4.52 (d, J = 4.8 Hz, 1H), 4.28 (s, 2H), 4.15 - 3.94 (m, 4H), 3.87 - 3.74 (m, 2H), 3.63 (dt, J = 2.6, 11.8 Hz, 1H), 3.45 - 3.35 (m, 4H), 3.29 - 3.20 (m, 1H), 3.13 (s, 2H), 3.00 (t, J = 11.0 Hz, 1H), 1.87 (d, J = 12.8 Hz, 2H), 1.77 - 1.60 (m, 2H), 1.30 (d, J = 6.6 Hz, 3H).

[0405] Example 4: Preparation of a diastereomer mixture of (3R)-4-(2-(1H-pyrazole-3-yl)-7-(tetrahydrofuran-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 4)

[0406] [ka]

[0407] Title compound 4 was prepared using 3-tetrahydrofuranone instead of acetone, in the same manner as in Example 2. A diastereomer mixture (23.2 mg, 63.2%) of (3R)-4-(2-(1H-pyrazole-3-yl)-7-(tetrahydrofuran-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 4) was obtained. LCMS (ESI) [M+H] + : 410.2. 1 H NMR (400 MHz, CD3OD) δ 7.73 (br s, 1H), 6.93 (s, 1H), 6.59 (s, 1H), 4.52 (br d, J = 5.4 Hz, 1H), 4.18 (s, 2H), 4.10 (br d, J = 12.5 Hz, 1H), 4.06 - 3.98 (m, 2H), 3.95 - 3.89 (m, 1H), 3.87 - 3.81 (m, 1H), 3.81 - 3.73 (m, 3H), 3.70 - 3.59 (m, 2H), 3.32 - 3.30 (m, 2H), 3.28 (br d, J = 5.4 Hz, 1H), 3.16 (br d, J = 5.5 Hz, 2H), 2.20 (dtd, J = 3.9, 7.8, 11.9 Hz, 1H), 2.06 - 1.93 (m, 1H), 1.31 (d, J = 6.6 Hz, 3H).

[0408] Example 5: Preparation of (R)-1-(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)ethane-1-one (Compound 5)

[0409] [ka]

[0410] Step 1: Intermediate INT-1 (300 mg, 0.573 mmol) was dissolved in trifluoroethanol (2 mL), and trimethylsilyl chloride (0.073 mL, 0.573 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to obtain the crude product. This was separated and purified by preparative reverse-phase high-performance liquid chromatography to obtain intermediate 5-1 (100 mg, 41.2%). LCMS(ESI)[M+H] + :424.2.

[0411] Step 2: Intermediate 5-1 (50 mg, 0.118 mmol) and triethylamine (49 μL, 0.354 mmol) were dissolved in dichloromethane (1 mL), and acetyl chloride (17 μL, 0.236 mmol) was added dropwise in an ice bath under a nitrogen atmosphere. The reaction mixture was stirred in an ice bath for 1 hour and concentrated under reduced pressure to obtain the crude product of intermediate 5-2, which was used directly in the next reaction. LCMS(ESI)[M+H] + :466.2.

[0412] Step 3: Intermediate 5-2 (50 mg, 0.107 mmol) was dissolved in methanol (2 mL), and a solution of hydrochloric acid and dioxane (2 mL, 1 M) was added. The reaction solution was stirred at room temperature for 4 hours, and then concentrated under reduced pressure to obtain the crude product. This was separated and purified by preparative reverse-phase high-performance liquid chromatography to obtain (R)-1-(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)ethane-1-one (compound 5) (14.7 mg, 33.2%). LCMS (ESI) [M+H] + : 382.2. 1H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 6.91 (s, 1H), 6.73 - 6.63 (m, 1H), 4.99 (d, J = 4.8 Hz, 1H), 4.93 (d, J = 4.5 Hz, 2H), 4.61 - 4.45 (m, 1H), 4.16 - 3.93 (m, 4H), 3.87 - 3.72 (m, 2H), 3.62 (t, J = 11.6 Hz, 1H), 3.26 (d, J = 5.5 Hz, 3H), 2.26 (d, J = 1.9 Hz, 1H), 2.12 (d, J = 1.3 Hz, 2H), 1.34 - 1.26 (m, 3H).

[0413] Example 6: Preparation of a diastereomer mixture of (3R)-4-(7-(8-oxabicyclo[3.2.1]octan-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 6)

[0414] [ka]

[0415] Title compound 6 was prepared using 8-oxabicyclo[3.2.1]octan-3-one instead of acetone, in the same manner as the preparation method of Example 2. (3R)-4-(7-(8-oxabicyclo[3.2.1]octan-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 6) (4.47 mg, 10.9%) was obtained. LCMS (ESI) [M+H] + : 450.2. 1H NMR (400 MHz, CD3OD) δ 7.73 (d, J = 1.5 Hz, 1H), 6.93 (d, J = 1.6 Hz, 1H), 6.59 (s, 1H), 4.56 - 4.49 (m, 1H), 4.47 (s, 2H), 4.22 (s, 2H), 4.14 - 4.00 (m, 2H), 3.88 - 3.75 (m, 2H), 3.63 (dt, J = 3.0, 11.8 Hz, 1H), 3.32 - 3.30 (m, 1H), 3.30 - 3.22 (m, 3H), 3.13 - 3.06 (m, 2H), 1.98 - 1.88 (m, 2H), 1.84 - 1.71 (m, 6H), 1.30 (d, J = 6.6 Hz, 3H).

[0416] Example 7: Preparation of (R)-4-(7-(3,3-difluorocyclobutyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (Compound 7)

[0417] [ka]

[0418] Title compound 7 was prepared using 3,3-difluorocyclobutyl-1-one instead of acetone, in the same manner as in Example 2. (R)-4-(7-(3,3-difluorocyclobutyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 7) (6.26 mg, 22.9%) was obtained. LCMS (ESI) [M+H] + : 430.1. 1H NMR (400 MHz, CD3OD) δ 7.61 (s, 1H), 6.81 (s, 1H), 6.46 (s, 1H), 4.51 - 4.35 (m, 2H), 4.01 - 3.88 (m, 4H), 3.77 - 3.62 (m, 2H), 3.51 (dt, J = 3.0, 11.8 Hz, 1H), 3.19 - 3.15 (m, 1H), 3.14 - 3.07 (m, 2H), 3.05 - 2.98 (m, 2H), 2.67 (ddt, J = 3.1, 7.3, 13.8 Hz, 2H), 2.49 - 2.32 (m, 2H), 1.19 (d, J = 6.8 Hz, 3H).

[0419] Example 8: Preparation of (R)-3-methyl-4-(7-(oxetan-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (Compound 8)

[0420] [ka]

[0421] Title compound 8 was prepared using 3-oxetanone instead of acetone, in the same manner as in Example 2. (R)-3-methyl-4-(7-(oxetan-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 8) (46.5 mg, 39.9%) was obtained. LCMS (ESI) [M+H] + : 396.2. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 2.1 Hz, 1H), 6.85 (s, 1H), 6.30 (s, 1H), 4.69 (dt, J = 16.3, 6.3 Hz, 4H), 4.38 (d, J = 6.8 Hz, 1H), 4.14 (d, J = 6.6 Hz, 1H), 4.09 - 3.95 (m, 4H), 3.80 (dt, J = 11.4, 7.1 Hz, 2H), 3.64 (td, J = 11.9, 3.0 Hz, 1H), 3.34 (td, J = 12.7, 3.9 Hz, 1H), 3.17 (dd, J = 10.0, 3.5 Hz, 4H), 1.32 (d, J = 6.8 Hz, 3H).

[0422] Example 9: Preparation of (R)-(3,3-difluorocyclobutyl)(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)methanone (compound 9)

[0423] [ka]

[0424] Step 1: 3,3-difluorocyclobutanecarboxylic acid (6 mg, 0.047 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (18 mg, 0.141 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.071 mmol), and intermediate 5-1 (20 mg, 0.047 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 16 hours, diluted by adding ice water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate 9-2 (10 mg, 39.1%). LCMS(ESI)[M+H] + :542.3.

[0425] Step 2: Intermediate 9-2 (10 mg) was dissolved in methanol (2 mL), and a 4 M hydrochloric acid solution in 1,4-dioxane (0.5 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated and purified by preparative reverse-phase high-performance liquid chromatography to obtain (R)-(3,3-difluorocyclobutyl)(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)methanone (compound 9) (4 mg, 47.3%). LCMS (ESI) [M+H] + : 458.3. 1H NMR (400 MHz, DMSO-d6) δ 12.7 (s, 1H), 7.82 (s, 1H), 6.81 - 6.76 (m, 2H), 4.95 - 4. 87 (m, 2H), 4.53 - 4.49 (m, 1H), 4.01 - 3.98 (m, 4H), 3.92 - 3.77 (m, 2H), 3.56 - 3.45 (m, 1H), 3.18 - 3.12 (m, 4H), 2.78 - 2.50 (m, 4H), 1.24 - 1.17 (m, 3H).

[0426] Example 10: Preparation of (R)-3,3,3-trifluoro-1-(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)propan-1-one (Compound 10)

[0427] [ka]

[0428] Title compound 10 was prepared using 3,3,3-trifluoropropionic acid instead of 3,3-difluorocyclobutancarboxylic acid, in the same manner as the preparation method of Example 9. (R)-3,3,3-trifluoro-1-(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)propan-1-one (compound 10) (6.9 mg, 32.8%) was obtained. LCMS (ESI) [M+H] + : 450.4. 1H NMR (400 MHz, CD3OD) δ 7.74 (br s, 1H), 6.93 (br d, J = 4.3 Hz, 1H), 6.71 (d, J = 4.1 Hz, 1H), 5.08 - 4.95 (m, 2H), 4.61 - 4.47 (m, 1H), 4.23 - 3.99 (m, 4H), 3.87 - 3.49 (m, 5H), 3.32 - 3.25 (m, 3H), 1.38 - 1.23 (m, 3H).

[0429] Example 11: Preparation of (R)-4-(2-(1H-pyrazole-3-yl)-7-(spiro[2,3]hexane-5-yl)-6,7,8,9-tetrahydro-2H-benzo[cd]azulene-4-yl)-3-methylmorpholine (Compound 11)

[0430] [ka]

[0431] Title compound 11 was prepared using spiro[2.3]hexane-5-one instead of acetone, in the same manner as in Example 2. (R)-4-(2-(1H-pyrazole-3-yl)-7-(spiro[2.3]hexane-5-yl)-6,7,8,9-tetrahydro-2H-benzo[cd]azulene-4-yl)-3-methylmorpholine (compound 11) (26.5 mg, 21.4%) was obtained. LCMS (ESI) [M+H] + : 420.3. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.1 Hz, 1H), 6.83 (s, 1H), 6.31 (s, 1H), 4.38 (d, J = 6.3 Hz, 1H), 4.13 - 3.95 (m, 4H), 3.81 (dt, J = 11.5, 7.2 Hz, 2H), 3.64 (td, J = 11.9, 3.0 Hz, 2H), 3.40 - 3.14 (m, 5H), 2.29 (d, J = 54.0 Hz, 2H), 2.05 (dd, J = 11.6, 7.6 Hz, 3H), 1.31 (d, J = 6.7 Hz, 4H), 0.54 - 0.36 (m, 4H).

[0432] Example 12: Preparation of a diastereomer mixture of (3R)-3-methyl-4-(7-(4-methyltetrahydrofuran-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 12)

[0433] [ka]

[0434] Step 1: 3-Tetrahydrofuranone (11.4 g, 132 mmol) and tert-butoxybis(dimethylamino)methane (23.1 g, 132 mmol) were dissolved in toluene (130 mL). The reaction mixture was stirred at room temperature for 12 hours. When this reaction mixture was concentrated, intermediate 12-2 (17.0 g, 90.9%) was obtained. LCMS(ESI)[M+H] + :141.9.

[0435] Step 2: Intermediate 12-2 (17.0 g, 120 mmol) was dissolved in acetone (170 mL), and wet carbon-supported palladium (1.70 g, 15.9 mmol) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was then distilled to obtain intermediate 12-3 (200 mg, 1.70%). 1 H NMR (400 MHz, CDCl3) δ 4.45 (t, J = 8.88 Hz, 1 H), 4.04 (d, J = 17.13 Hz, 1 H), 3.80 (d, J = 17.13 Hz, 1 H), 3.68 (t, J = 9.26 Hz, 1 H), 2.57 - 2.45 (m, 1 H), 1.12 (d, J = 7.13 Hz, 3 H).

[0436] Step 3: Intermediate 12-3 was used in place of acetone, and title compound 12 was prepared in the same manner as in Example 2. (3R)-3-methyl-4-(7-(4-methyltetrahydrofuran-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 12) (3.6 mg, 5.6%) was obtained. LCMS (ESI) [M+H] + : 424.3. 1 H NMR (400 MHz, CD3OD) δ 7.72 (s, 1 H), 6.91 (s, 1 H), 6.55 (s, 1 H), 4.51 (d, J = 6.38 Hz, 1 H), 4.18 - 3.89 (m, 6 H), 3.86 - 3.73 (m, 3 H), 3.67 - 3.48 (m, 3 H), 3.36 - 3.33 (m, 1 H), 3.30 - 3.22 (m, 2 H), 3.21 - 3.12 (m, 2 H), 2.50 - 2.36 (m, 1 H), 1.29 (d, J = 6.63 Hz, 3 H), 1.07 (d, J = 6.88 Hz, 3 H).

[0437] Examples 13A and 13B: Preparation of (R)-4-(2-(1H-pyrazole-3-yl)-7-(3-(trifluoromethyl)cyclobutyl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 13A, isomer 1) and (R)-4-(2-(1H-pyrazole-3-yl)-7-(3-(trifluoromethyl)cyclobutyl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 13B, isomer 2)

[0438] [ka]

[0439] Step 1: Title compound 13 was prepared using 3-(trifluoromethyl)cyclobutan-1-one instead of acetone, in the same manner as the preparation method of Example 2. A diastereomer mixture (20.0 mg, 14.7%) of (R)-4-(2-(1H-pyrazole-3-yl)-7-(3-(trifluoromethyl)cyclobutyl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 13) was obtained. LCMS(ESI)[M+H] + :462.4.

[0440] Step 2: A diastereomer mixture (20.0 mg) of (R)-4-(2-(1H-pyrazole-3-yl)-7-(3-(trifluoromethyl)cyclobutyl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 13) was further purified by chiral SFC. SFC analysis: Daicel Chiral PAK IB column (100 × 3.0 mm, 3 μm), mobile phase: 20% methanol in CO2 (containing 0.05% ammonia), temperature: 35°C, flow rate: 2.0 mL / min, detection wavelength: 210 nm.

[0441] The first peak was (R)-4-(2-(1H-pyrazole-3-yl)-7-(3-(trifluoromethyl)cyclobutyl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 13A, isomer 1) (1.6 mg). LCMS (ESI) [M+H] + : 462.4. HPLC-SFC: Rt = 2.812 min. 1 H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 6.95 (d, J = 40.0 Hz, 1H), 6.28 (s, 1H), 4.38 (d, J = 5.4 Hz, 1H), 4.02 (dd, J = 25.8, 11.8 Hz, 4H), 3.81 (dd, J = 22.8, 11.0 Hz, 2H), 3.63 (t, J = 11.2 Hz, 1H), 3.39 - 3.22 (m, 2H), 3.04 (d, J = 55.5 Hz, 4H), 2.52 (dt, J = 17.2, 8.6 Hz, 1H), 2.34 - 2.05 (m, 4H), 1.44 - 1.26 (m, 4H).

[0442] The second peak was (R)-4-(2-(1H-pyrazole-3-yl)-7-(3-(trifluoromethyl)cyclobutyl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 13B, isomer 2) (2.6 mg). LCMS (ESI) [M+H] + : 462.4. HPLC-SFC: Rt = 3.253 min. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 1.8 Hz, 1H), 6.87 (s, 1H), 6.29 (s, 1H), 4.38 (d, J = 6.0 Hz, 1H), 4.12 - 3.94 (m, 4H), 3.84 - 3.75 (m, 2H), 3.64 (m, 1H), 3.31 (dd, J = 15.2, 6.4 Hz, 2H), 3.17 - 3.02 (m, 3H), 2.55 (td, J = 17.6, 8.8 Hz, 1H), 2.32 - 2.21 (m, 2H), 2.14 - 1.96 (m, 2H), 1.45 - 1.25 (m, 4H).

[0443] Example 14: Preparation of (R)-4-(2-(1H-pyrazole-3-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (Compound 14)

[0444] [ka]

[0445] Step 1: Intermediate 5-1 (50.0 mg, 0.118 mmol) was dissolved in toluene (2.0 mL), and N,N-diisopropylethylamine (31.0 mg, 0.236 mmol) and trifluoroethyl trifluoromethanesulfonate (55.0 mg, 0.236 mmol) were added sequentially. The reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature, quenched by adding ice water, and extracted with ethyl acetate (20 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified by silica gel column chromatography to obtain intermediate 14-2 (30.0 mg, 50.3%). LCMS(ESI)[M+H] + :506.4.

[0446] Step 2: Dissolve 14-2 (30.0 mg, 0.059 mmol) in methanol (3.0 mL) and add a 1,4-dioxane solution in hydrochloric acid (1.0 mL, 4 M). The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by preparative reverse-phase high-performance liquid chromatography to obtain (R)-4-(2-(1H-pyrazole-3-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 14) (8.9 mg, 35.8%). LCMS (ESI) [M+H] + : 422.4. 1 H NMR (400 MHz, CD3OD) δ 7.73 (d, J = 1.9 Hz, 1H), 6.92 (d, J = 1.9 Hz, 1H), 6.53 (, 1H), 4.58 - 4.43 (m, 1H), 4.34 (s, 2H), 4.13 - 3.96 (m, 2H), 3.86 - 3.70 (m, 2H), 3.61 (dt, J = 3.0, 11.8 Hz, 1H), 3.49 - 3.37 (m, 4H), 3.30 - 3.24 (m, 2H), 3.18 (t, J = 5.6 Hz, 2H), 1.28 (d, J = 6.8 Hz, 3H).

[0447] Example 15: Preparation of (R)-(3-methylcyclobutyl)(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)methanone (Compound 15)

[0448] [ka]

[0449] Title compound 15 was prepared using 3-methylcyclobutanecarboxylic acid instead of 3,3-difluorocyclobutanecarboxylic acid, in the same manner as the preparation method of Example 9. (R)-(3-methylcyclobutyl)(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)methanone (compound 15) (4.2 mg, 23.5%) was obtained. LCMS (ESI) [M+H] + : 436.5. 1 H NMR (400 MHz, CD3OD) δ 7.71 (s, 1H), 6.90 (s, 1H), 6.67 - 6.63 (m, 1H), 4.97 - 4.90 (m, 2H), 4.51 (d, J = 6.3 Hz, 1H), 4.11 (d, J = 13.5 Hz, 1H), 4.07 - 3.93 (m, 3H), 3.87 - 3.71 (m, 2H), 3.71 - 3.56 (m, 1H), 3.50 - 3.33 (m, 2H), 3.29 - 3.16 (m, 3H), 2.43 - 2.16 (m, 3H), 1.97 - 1.58 (m, 1H), 1.37 - 1.24 (m, 3H), 1.05 (d, J = 6.1 Hz, 1H), 0.95 (d, J = 6.0 Hz, 2H).

[0450] Example 16: Preparation of 3,3,3-trifluoro-2-methyl-1-(4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)propan-1-one (Compound 16)

[0451] [ka]

[0452] Title compound 16 was prepared using 3,3,3-trifluoro-2-methylpropionic acid instead of 3,3-difluorocyclobutanic acid, in the same manner as in Example 9. 3,3,3-trifluoro-2-methyl-1-(4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)propan-1-one (compound 16) (25 mg, 36.9%) was obtained. LCMS (ESI) [M+H] + : 464.2. 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 1.5 Hz, 1H), 6.97 - 6.87 (m, 1H), 6.49 - 6.34 (m, 1H), 5.34 - 4.87 (m, 1H), 4.83 - 4.66 (m, 1H), 4.48 - 4.37 (m, 1H), 4.35 - 4.17 (m, 1H), 4.13 - 3.97 (m, 2H), 3.95 - 3.53 (m, 5H), 3.50 - 3.18 (m, 4H), 1.52 - 1.27 (m, 6H).

[0453] Example 17: Preparation of (R)-3-methyl-4-(7-phenyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (Compound 17)

[0454] [ka]

[0455] Step 1: Intermediate 5-1 (20.0 mg, 0.047 mmol) and iodobenzene (28.9 mg, 0.142 mmol) were dissolved in toluene (1 mL). 2-Dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (2.20 mg, 0.005 mmol), tris(dibenzylideneacetone)dipalladium (4.30 mg, 0.005 mmol), and cesium carbonate (30.8 mg, 0.094 mmol) were added. The reaction mixture was stirred under a nitrogen atmosphere at 90°C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by preparative thin-layer chromatography to obtain intermediate 17-2 (20.0 mg, 84.8%). LCMS(ESI)[M+H] + :500.7.

[0456] Step 2: Intermediate 17-2 (20.0 mg, 0.040 mmol) was dissolved in methanol (2 mL), and a solution of dioxane in hydrochloric acid (2 mL, 4 M) was added. The reaction solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure to remove dioxane and methanol, yielding the crude product. This was then separated and purified by preparative reverse-phase high-performance liquid chromatography to obtain (R)-3-methyl-4-(7-phenyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 17) (4.31 mg, 25.9%). LCMS (ESI) [M+H] + : 416.3. 1H NMR (400 MHz, CD3OD) δ 7.71 (s, 1H), 7.15 (t, J = 7.6 Hz, 2H), 6.94 - 6.76 (m, 4H), 6.67 - 6.60 (m, 1H), 4.86 (s, 2H), 4.63 - 4.53 (m, 1H), 4.25 - 4.12 (m, 3H), 4.06 (dd, J = 2.8, 11.1 Hz, 1H), 3.90 - 3.78 (m, 2H), 3.71 - 3.61 (m, 1H), 3.43 - 3.36 (m, 2H), 3.30 - 3.26 (m, 1H), 1.35 (d, J = 6.6 Hz, 3H).

[0457] Example 18: Preparation of (R)-(4-(3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)(1-(trifluoromethyl)cyclopropyl)methanone (compound 18)

[0458] [ka]

[0459] Title compound 18 was prepared using 1-trifluoromethylcyclopropane-1-carboxylic acid instead of 3,3-difluorocyclobutanecarboxylic acid, in the same manner as the preparation method of Example 9. (R)-(4-(3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)(1-(trifluoromethyl)cyclopropyl)methanone (compound 18) (22.4 mg, 37.7%) was obtained. LCMS (ESI) [M+H] + : 476.2. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 1.6 Hz, 1H), 6.39 (s, 1H), 5.09 (s, 2H), 4.40 (d, J = 6.7 Hz, 1H), 4.15 - 3.96 (m, 4H), 3.89 - 3.77 (m, 2H), 3.71 - 3.61 (m, 1H), 3.46 - 3.27 (m, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.29 (t, J = 5.6 Hz, 2H), 1.03 (s, 2H).

[0460] Example 19: Preparation of (2,2-difluorocyclopropyl)(4-((R)-3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)methanone (compound 19)

[0461] [ka]

[0462] Title compound 19 was prepared using 2,2-difluorocyclopropylcarboxylic acid instead of 3,3-difluorocyclobutanecarboxylic acid, in the same manner as in Example 9. (2,2-difluorocyclopropyl)(4-((R)-3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)methanone (compound 19) (43.1 mg, 42.7%) was obtained. LCMS (ESI) [M+H] + : 444.2. 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.82 (s, 1H), 6.77 (s, 2H), 5.25 - 4.75 (m, 2H), 4.54 - 3.87 (m, 5H), 3.81 - 3.72 (m, 1H), 3.69 - 3.60 (m, 1H), 3.55 - 3.44 (m, 1H), 3.32 - 3.25 (m, 1H), 3.23 - 3.03 (m, 3H), 2.05 - 1.78 (m, 2H), 1.24 - 1.15 (m, 3H).

[0463] Examples 20A and 20B: Preparation of (R)-(1,1-difluorospiro[2.3]hexane-5-yl)(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)methane (compound 20A, isomer 1) and preparation of (R)-(1,1-difluorospiro[2.3]hexane-5-yl)(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)methane (compound 20B, isomer 2)

[0464] [ka]

[0465] Title compounds 20A and 20B were prepared using 1,1-difluorospiro[2.3]hexane-5-carboxylic acid instead of 3,3-difluorocyclobutanecarboxylic acid, in the same manner as the preparation method of Example 9. Reverse-phase high-performance liquid chromatography was used for preparative separation and purification.

[0466] The first peak was (R)-(1,1-difluorospiro[2.3]hexane-5-yl)(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)methanone (compound 20A, isomer 1) (4.9 mg). LCMS (ESI) [M+H] + : 484.2. 1 H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 6.94 - 6.87 (m, 1H), 6.73 - 6.66 (m, 1H), 5.07 - 4.90 (m, 3H), 4.63 - 4.45 (m, 1H), 4.11 - 3.90 (m, 4H), 3.88 - 3.76 (m, 3H), 3.73 - 3.53 (m, 2H), 3.29 - 3.20 (m, 2H), 2.68 - 2.20 (m, 4H), 1.36 - 1.21 (m, 5H).

[0467] The second peak was (R)-(1,1-difluorospiro[2,3]hexane-5-yl)(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)methanone (compound 20B, isomer 2) (3.3 mg). LCMS (ESI) [M+H] + : 484.2. 1 H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 6.90 - 6.89 (m, 1H), 6.78 - 6.60 (m, 1H), 5.07 - 4.90 (m, 3H), 4.63 - 4.44 (m, 1H), 4.18 - 3.94 (m, 4H), 3.88 - 3.71 (m, 3H), 3.68 - 3.53 (m, 2H), 3.28 - 3.11 (m, 2H), 2.58 - 2.20 (m, 4H), 1.40 - 1.22 (m, 3H), 1.14 (t, J = 8.6 Hz, 2H).

[0468] Example 21: Preparation of (3R)-4-(7-(buta-3-in-2-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (Compound 21)

[0469] [ka]

[0470] Step 1: 3-Butyn-2-ol (500 mg, 7.1 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Triethylamine (1.48 mL, 10.7 mmol) was added, and methanesulfonyl chloride (980 mg, 8.6 mmol) was slowly added dropwise. The reaction mixture was stirred overnight at 25°C. The reaction product was quenched with ice water (10 mL). The aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine (20 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain crude intermediate 21-2 (900 mg, 85.1%).

[0471] Step 2: Intermediate 21-2 was used in place of trifluoroethyl trifluoromethanesulfonate, and title compound 21 was prepared in the same manner as in Example 14. (3R)-4-(7-(buta-3-in-2-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 21) (43.1 mg, 42.7%) was obtained. LCMS (ESI) [M+H] + : 392.4. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 2.2 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 6.33 (s, 1H), 4.44 - 4.30 (m, 1H), 4.27 - 4.15 (m, 1H), 4.11 - 3.95 (m, 3H), 3.88 - 3.75 (m, 3H), 3.69 - 3.60 (m, 1H), 3.39 - 3.28 (m, 2H), 3.25 - 2.93 (m, 3H), 2.33 (d, J = 2.1 Hz, 1H), 1.47 (d, J = 7.0 Hz, 3H), 1.30 (dd, J = 6.7, 2.2 Hz, 3H).

[0472] Example 22: Preparation of (R)-3-methyl-4-(7-(methylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (Compound 22)

[0473] [ka]

[0474] Step 1: Intermediate 5-1 (100 mg, 0.236 mmol) was dissolved in dichloromethane (5 mL) at room temperature. Triethylamine (0.07 mL, 0.472 mmol) was added, and methanesulfonyl chloride (40.6 mg, 0.354 mmol) was added under stirring. The reaction mixture was stirred at room temperature for 1 hour, and then quenched with ice water (5 mL). The aqueous phase was extracted with dichloromethane (5 mL x 3). The organic phase was washed with saturated brine (20 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 22-2 (100 mg, 84.4%). LCMS(ESI)[M+H] + :502.2.

[0475] Step 2: Intermediate 22-2 (100 mg, 0.199 mmol) was dissolved in methanol (5 mL) at room temperature, and then aqueous hydrochloric acid (1 mL, 2 M) was added. The reaction mixture was stirred at 50°C for 4 hours. After the reaction was complete, methanol was removed by concentration, the reaction mixture was diluted with dichloromethane (10 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This crude product was then separated and purified by preparative reverse-phase high-performance liquid chromatography to obtain (R)-3-methyl-4-(7-(methylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 22) (36.5 mg, 43.9%). LCMS (ESI) [M+H] + : 418.2. 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 7.83 (s, 1H), 6.75 (d, J = 28.1 Hz, 2H), 4.76 (s, 2H), 4.45 (d, J = 4.9 Hz, 1H), 4.08 - 3.93 (m, 2H), 3.86 - 3.74 (m, 3H), 3.69 - 3.61 (m, 1H), 3.56 - 3.44 (m, 1H), 3.16 (d, J = 5.5 Hz, 3H), 2.98 (s, 3H), 1.19 (d, J = 6.6 Hz, 3H).

[0476] Example 23: Preparation of (R)-4-(7-(cyclopropylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (Compound 23)

[0477] [ka]

[0478] Title compound 23 was prepared using cyclopropanesulfonyl chloride instead of methanesulfonyl chloride, in the same manner as in Example 22. (R)-4-(7-(cyclopropylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 23) (7.8 mg, 37.4%) was obtained. LCMS (ESI) [M+H] + : 444.4. 1 H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 6.92 (s, 1H), 6.64 (s, 1H), 4.83 (s, 2H), 4.50 (d, J = 5.1 Hz, 1H), 4.11 - 3.94 (m, 3H), 3.85 - 3.73 (m, 2H), 3.67 - 3.57 (m, 1H), 3.35 - 3.32 (m, 2H), 3.29 - 3.25 (m, 2H), 2.53 - 2.34 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H), 1.21 (t, J = 7.1 Hz, 1H), 1.09 - 1.04 (m, 2H), 0.89 - 0.85 (m, 1H).

[0479] Example 24: Preparation of (R)-4-(7-(isopropylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (Compound 24)

[0480] [ka]

[0481] Title compound 24 was prepared using isopropanesulfonyl chloride instead of methanesulfonyl chloride, in the same manner as in Example 22. (R)-4-(7-(isopropylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 24) (8.4 mg, 50.2%) was obtained. LCMS (ESI) [M+H] + : 446.4. 1 H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 6.92 (s, 1H), 6.61 (s, 1H), 4.82 (s, 2H), 4.57 - 4.44 (m, 1H), 4.05 - 4.13 (m, 1H), 4.01 (dd, J = 3.5, 11.5 Hz, 1H), 3.91 (t, J = 5.4 Hz, 2H), 3.84 - 3.73 (m, 2H), 3.66 - 3.56 (m, 1H), 3.47 (td, J = 6.8, 13.5 Hz, 1H), 3.34 - 3.33 (m, 1H), 3.30 - 3.25 (m, 2H), 1.35 (d, J = 6.8 Hz, 6H), 1.29 (d, J = 6.8 Hz, 3H).

[0482] Example 25: Preparation of (R)-4-(2-(1H-pyrazole-3-yl)-7-((trifluoromethyl)sulfonyl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (Compound 25)

[0483] [ka]

[0484] Title compound 25 was prepared using trifluoromethanesulfonyl chloride instead of methanesulfonyl chloride, in the same manner as in Example 22. (R)-4-(2-(1H-pyrazole-3-yl)-7-((trifluoromethyl)sulfonyl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 25) (1.1 mg, 16.3%) was obtained. LCMS (ESI) [M+H] + : 472.2. 1 H NMR (400 MHz, CD3OD) δ 7.75 (s, 1H), 7.03 - 6.89 (m, 1H), 6.70 (s, 1H), 5.06 - 4.96 (m, 3H), 4.60 - 4.49 (m, 1H), 4.31 - 4.00 (m, 4H), 3.89 - 3.74 (m, 2H), 3.69 - 3.58 (m, 1H), 3.55 - 3.41 (m, 2H), 1.32 (d, J = 6.9 Hz, 3H).

[0485] Example 26: Preparation of (R)-3-methyl-4-(7-(oxetan-3-ylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (Compound 26)

[0486] [ka]

[0487] Step 1: Toluene-4-sulfonic acid oxetane-3-yl (10.0 g, 43.8 mmol) and potassium thioacetate (15.1 g, 131 mmol) were dissolved in N,N-dimethylformamide (50.0 mL). This reaction mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature and quenched with aqueous lithium chloride (200 mL, 5 wt%). This mixture was extracted with dichloromethane (100 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain intermediate 26-2 (2.0 g, 34.5%). 1 H NMR (400 MHz, CDCl3) δ 5.06 (t, J = 7.2 Hz, 2H), 4.71 - 4.62 (m, 1H), 4.60 - 4.55 (m, 2H), 2.33 (s, 3H).

[0488] Step 2: N-chlorosuccinimide (808 mg, 6.05 mmol) was dissolved in acetonitrile (10 mL). Aqueous hydrochloric acid (1.13 mL, 2 M) was added at 0°C, and then a solution of intermediate 26-2 (200 mg, 1.51 mmol) in acetonitrile (10 mL) was slowly added dropwise. The reaction mixture was stirred at 0°C for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution (10 mL) was added, and the reaction mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was successively washed with saturated sodium thiosulfate solution and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 26-3 (100 mg, 42.2%) (36.5 mg, 43.9%). 1 H NMR (400 MHz, CDCl3) δ 5.13 - 4.93 (m, 5H).

[0489] Step 3: Intermediate 26-3 was used in place of methanesulfonyl chloride, and title compound 26 was prepared in the same manner as in Example 22. (R)-3-methyl-4-(7-(oxetan-3-ylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 26) (1.5 mg, 11.6%) was obtained. LCMS (ESI) [M+H] + : 460.4. 1 H NMR (400 MHz, CD3OD) δ 7.73 (d, J = 1.5 Hz, 1H), 6.93 (s, 1H), 6.64 (s, 1H), 4.84 - 4.83 (m, 3H), 4.71 (dt, J = 3.8, 7.4 Hz, 3H), 4.67 - 4.60 (m, 1H), 4.56 - 4.47 (m, 1H), 4.13 - 4.07 (m, 1H), 4.06 - 3.99 (m, 1H), 3.93 (t, J = 5.8 Hz, 2H), 3.86 - 3.74 (m, 3H), 3.62 (dt, J = 2.9, 11.7 Hz, 2H), 3.29 - 3.26 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H).

[0490] Example 27: Preparation of (R)-4-(7-((difluoromethyl)sulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (Compound 27)

[0491] [ka]

[0492] Step 1: Title compound 27 was prepared using difluoromethanesulfonyl chloride instead of methanesulfonyl chloride, in the same manner as the preparation method in Example 22. (R)-4-(7-((difluoromethyl)sulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 27) (3.0 mg, 7.1%) was obtained. LCMS (ESI) [M+H] + : 454.2. 1 H NMR (400 MHz, CD3OD) δ 12.85 (s, 1H), 7.89 (s, 1H), 7.27 (t, J = 52.4 Hz, 1H), 6.84 (s, 2H), 4.99 (s, 2H), 4.53 - 4.51 (m, 1H), 4.06 - 4.04 (m, 4H), 3.84 - 3.82 (m, 1H), 3.73 - 3.69 (m, 1H), 3.57 - 3.55 (m, 1H), 3.29 - 3.22 (m, 3H), 1.26 (d, J = 6.8 Hz, 3H).

[0493] Example 28: Preparation of (3R)-3-methyl-4-(7-(S-methylsulfonylimino)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (Compound 28)

[0494] [ka]

[0495] Step 1: Methylsulfonamide (5.0 g, 52.5 mmol) was dissolved in chloroform (60 mL) at 0°C, and triethylamine (10.6 g, 105.1 mmol) and tert-butyldimethylsilyl chloride (11.9 g, 78.8 mmol) were added. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched by adding ice water, and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain intermediate 28-2 (10.0 g, 90.8%). 1 H NMR (400 MHz, DMSO-d6) δ 7.07 (s, 1H), 2.93 (s, 3H), 0.91 (s, 9H), 0.18 (s, 6H).

[0496] Step 2: Hexachloroethane (6.8 g, 28.7 mmol) and triphenylphosphine (7.5 g, 28.7 mmol) were dissolved in chloroform (100 mL) at room temperature. This reaction mixture was stirred at 70°C for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature. Triethylamine (4.8 g, 47.8 mmol) and intermediate 28-2 (5 g, 23.9 mmol) were added, and the reaction mixture was stirred continuously at room temperature for 1 hour. To this reaction mixture, a solution of imidazole (2.0 g, 28.7 mmol) and triethylamine (4.8 g, 47.8 mmol) in tetrahydrofuran was added dropwise. This mixture was stirred at room temperature for 18 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated and extracted with n-hexane (150 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was then purified by silica gel column chromatography to obtain intermediate 28-3 (3.0 g, 48.4%). 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.28 (dd, J = 2.5, 1.2 Hz, 1H), 7.15 - 7.09 (m, 1H), 3.22 (s, 3H), 0.92 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H).

[0497] Step 3: Intermediate 28-3 (1.2 g, 4.63 mmol) was dissolved in diethyl ether (30 mL) at 0°C, and methyl trifluoromethanesulfonate (0.8 g, 4.62 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and filtered. The filter cake was washed with diethyl ether to obtain the crude product as intermediate 28-4 (1.6 g). 1 H NMR (400 MHz, CDCl3) δ 9.07 (d, J = 0.5 Hz, 1H), 7.54 (t, J = 1.9 Hz, 1H), 7.50 (t, J = 1.8 Hz, 1H), 4.08 (s, 3H), 3.57 (s, 3H), 0.91 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H).

[0498] Step 4: Under a nitrogen atmosphere, intermediate 5-1 (130 mg, 0.31 mmol) was dissolved in anhydrous acetonitrile (2.0 mL) at room temperature, and triethylamine (62 mg, 0.61 mmol) was added. Intermediate 28-4 (195 mg, 0.46 mmol) was dissolved in anhydrous acetonitrile (2.0 mL) and added dropwise to this reaction system. The reaction mixture was stirred at 50°C for 16 hours. The reaction products were quenched by adding ice water, and the aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified by silica gel column chromatography to obtain intermediate 28-5 (60 mg, 31.8%). LCMS(ESI)[M+H] + :615.6.

[0499] Step 5: Intermediate 28-5 (40 mg, 0.055 mmol) was dissolved in tetrahydrofuran (3.0 mL) at room temperature, and aqueous hydrochloric acid (3.0 mL, 6 M) was added. The reaction mixture was stirred at 40°C for 1 hour. The reaction mixture was quenched by adding ice water, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phases were sequentially washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was then separated and purified by preparative reverse-phase high-performance liquid chromatography to obtain (3R)-3-methyl-4-(7-(S-methylsulfonylimino)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 28) (4.0 mg, 14.8%). LCMS (ESI) [M+H] + : 417.2. 1 H NMR (400 MHz, CD3OD) δ 7.75 (s, 1H), 6.94 (s, 1H), 6.65 (s, 1H), 4.58 - 4.47 (m, 1H), 4.11 (d, J = 12.0 Hz, 1H), 4.06 - 4.02 (m, 1H), 3.99 - 3.86 (m, 2H), 3.84 (d, J = 11.4 Hz, 1H), 3.80 - 3.75 (m, 1H), 3.66 - 3.59 (m, 1H), 3.37 - 3.32 (m, 2H), 3.30 - 3.27 (m, 3H), 2.94 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H).

[0500] Examples 31A and 31B: Preparation of (3R)-4-(7-cyclopropyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 31A, isomer 1) and preparation of (3R)-4-(7-cyclopropyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 31B, isomer 2)

[0501] [ka]

[0502] Step 1: Intermediate INT-5 (100 mg, 0.23 mmol) and 1-ethoxy-1-trimethylsilyloxycyclopropane (172.6 mg, 0.99 mmol) were dissolved in methanol (5 mL), and acetic acid (0.16 mL, 2.83 mmol) and sodium borohydride cyanohydride (80.0 mg, 1.27 mmol) were added sequentially under ice water bath. The reaction mixture was allowed to rise naturally to room temperature and stirred for 2 hours. Saturated aqueous ammonium chloride (10 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was sequentially washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and centrifuged to obtain the crude product. Purification of the crude product by silica gel column chromatography yielded a diastereomer mixture (70.0 mg, 63.6%) of (3R)-4-(7-cyclopropyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 31). LCMS(ESI)[M+H] + :394.4.

[0503] Step 2: A diastereomer mixture (70.0 mg) of (3R)-4-(7-cyclopropyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 31) was further purified by chiral SFC. SFC analysis: Daicel Chiral PAK® OD column (100 × 3.0 mm, 3 μm), mobile phase: 20% methanol in CO2 (containing 0.1% diethylamine), temperature: 35°C, flow rate: 1.5 mL / min, detection wavelength: 214 nm.

[0504] The first peak was (3R)-4-(7-cyclopropyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 31A, isomer 1) (10 mg). LCMS (ESI) [M+H] + : 394.4. HPLC-SFC: Rt = 3.106 min. 1 H NMR (400 MHz, CD3OD) δ 7.70 (s, 1H), 6.90 (s, 1H), 6.54 (s, 1H), 4.51 (d, J = 6.8 Hz, 1H), 4.46 (q, J = 7.2 Hz, 1H), 4.07 (d, J = 10.8 Hz, 1H), 4.01 (dd, J = 11.4, 3.6 Hz, 1H), 3.81 (d, J = 11.4 Hz, 1H), 3.76 (dd, J = 11.4, 2.9 Hz, 1H), 3.66 - 3.55 (m, 2H), 3.46 - 3.35 (m, 1H), 3.33 (d, J = 3.8 Hz, 1H), 3.26 (d, J = 3.8 Hz, 1H), 3.20 (d, J = 14.6 Hz, 1H), 3.07 (d, J = 17.4 Hz, 1H), 2.29 - 2.20 (m, 1H), 1.49 (d, J = 7.2 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H), 0.61 - 0.48 (m, 4H).

[0505] The second peak was (3R)-4-(7-cyclopropyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 31B, isomer 2) (10 mg). LCMS (ESI) [M+H] + : 394.4. HPLC-SFC: Rt = 3.755 min. 1 H NMR (400 MHz, CD3OD) δ 7.70 (s, 1H), 6.90 (s, 1H), 6.54 (s, 1H), 4.51 (d, J = 6.4 Hz, 1H), 4.46 (q, J = 7.2 Hz, 1H), 4.07 (d, J = 10.8 Hz, 1H), 4.01 (dd, J = 11.4, 3.7 Hz, 1H), 3.82 (d, J = 11.4 Hz, 1H), 3.76 (dd, J = 11.4, 2.8 Hz, 1H), 3.66 - 3.54 (m, 2H), 3.46 - 3.36 (m, 1H), 3.35 - 3.31 (m, 1H), 3.29 - 3.24 (m, 1H), 3.20 (dd, J = 10.8, 3.6 Hz, 1H), 3.07 (d, J = 17.2 Hz, 1H), 2.29 - 2.19 (m, 1H), 1.49 (d, J = 7.2 Hz, 3H), 1.28 (d, J = 6.7 Hz, 3H), 0.62 - 0.46 (m, 4H).

[0506] Examples 32A and 32B: Preparation of (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 32A, isomer 1) and (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 32B, isomer 2)

[0507] [ka]

[0508] Step 1: Intermediate INT-5 (4.0 g, 11.3 mmol) was dissolved in methanol (100 mL). Diisopropylethylamine (5.62 mL, 34.0 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes, and then 3-oxetanone (4.1 g, 56.6 mmol) was added. After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (11.9 g, 56.6 mmol) was added in small amounts. The reaction mixture was stirred at room temperature overnight. After the reaction was complete, the reaction mixture was poured into ice water, extracted with dichloromethane (100 mL x 3), dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by silica gel column chromatography to obtain a diastereomer mixture of (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 32) (2.5 g, 53.9%). LCMS(ESI)[M+H] + :410.2.

[0509] Step 2: A diastereomer mixture (2.5 g, 6.1 mmol) of (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 32) was further purified by chiral SFC. SFC analysis: Daicel ChiralPAK IG column (100 × 3.0 mm, 3 μm), mobile phase: 20% methanol in CO2 (containing 0.05% diethylamine), temperature: 35°C, flow rate: 2.0 mL / min, detection wavelength: 210 nm.

[0510] The first peak was (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 32A, isomer 1) (865.8 mg). LCMS (ESI) [M+H] + : 410.2. HPLC-SFC: Rt = 1.839 min. 1 H NMR (400 MHz, CD3OD) δ 7.71 (s, 1H), 6.91 (s, 1H), 6.53 (s, 1H), 4.74 (d, J = 7.2 Hz, 2H), 4.65 (d, J = 6.8 Hz, 2H), 4.49 (d, J = 5.2 Hz, 1H), 4.36 - 4.23 (m, 2H), 4.11 - 3.97 (m, 2H), 3.89 - 3.72 (m, 2H), 3.67 - 3.49 (m, 2H), 3.30 - 3.13 (m, 2H), 3.08 - 2.97 (m, 2H), 1.48 (d, J = 7.2 Hz, 3H), 1.28 (d, J = 6.8 Hz, 3H).

[0511] The second peak was (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 32B, isomer 2) (6.2 mg). LCMS (ESI) [M+H] + : 410.2. HPLC-SFC: Rt = 2.368 min. 1 H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 6.91 (s, 1H), 6.53 (s, 1H), 4.74 (d, J = 7.2 Hz, 2H), 4.66 (d, J = 6.8 Hz, 2H), 4.51 (d, J = 5.2 Hz, 1H), 4.38 - 4.26 (m, 2H), 4.11 - 3.98 (m, 2H), 3.85 - 3.73 (m, 2H), 3.66 - 3.51 (m, 2H), 3.30 - 3.13 (m, 2H), 3.08 - 3.01 (m, 2H), 1.48 (d, J = 7.2 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H).

[0512] Examples 33A and 33B: Preparation of (R)-(4-(3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)(1-(trifluoromethyl)cyclopropyl)methane (compound 33A, isomer 1) and preparation of (R)-(4-(3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)(1-(trifluoromethyl)cyclopropyl)methane (compound 33B, isomer 2)

[0513] [ka]

[0514] Step 1: 1-Trifluoromethylcyclopropane-1-carboxylic acid (54.9 mg, 0.36 mmol), N,N-diisopropylethylamine (0.12 mL, 0.71 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (135 mg, 0.357 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was stirred at room temperature for 10 minutes. Intermediate INT-6 (78.0 mg, 0.178 mmol) was added to the reaction system, and stirring was continued for 18 hours. The reaction product was quenched with ice water (10 mL), and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and centrifuged to obtain the crude product. Purification of the crude product by silica gel column chromatography yielded intermediate 33-2 (11.0 mg, 10.8%). LCMS(ESI)[M+H] + :574.6.

[0515] Step 2: Intermediate 33-2 (11.0 mg, 0.02 mmol) was dissolved in a solution of hydrochloric acid in dioxane (5 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was separated and purified by preparative reverse-phase high-performance liquid chromatography to obtain a diastereomer mixture (11 mg, crude) of (R)-(4-(3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)(1-(trifluoromethyl)cyclopropyl)methanone (compound 33). LCMS(ESI)[M+H] + :490.3.

[0516] Step 3: A diastereomer mixture (11 mg) of (R)-(4-(3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)(1-(trifluoromethyl)cyclopropyl)methanone (compound 33) was further purified by chiral SFC. SFC analysis: Daicel ChiralPAK IC-3 column (50 × 3.0 mm, 3 μm), mobile phase: 40% methanol in CO2 (containing 0.05% diethylamine), temperature: 35°C, flow rate: 3.0 mL / min, detection wavelength: 220 nm.

[0517] The first peak was (R)-(4-(3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)(1-(trifluoromethyl)cyclopropyl)methanone (compound 33A, isomer 1) (4.0 mg). LCMS (ESI) [M+H] + : 490.3. HPLC-SFC: Rt = 1.276 min. 1 H NMR (400 MHz, CD3OD) δ 7.72 (br d, J = 1.6 Hz, 1H), 6.90 (br d, J = 4.3 Hz, 1H), 6.75 (s, 1H), 6.08 - 5.95 (m, 1H), 4.61 - 4.46 (m, 2H), 4.40 - 4.28 (m, 1H), 4.11 (br dd, J = 1.4, 14.0 Hz, 1H), 4.03 (dd, J = 3.4, 11.0 Hz, 1H), 3.87 - 3.74 (m, 2H), 3.74 - 3.58 (m, 2H), 3.42 - 3.34 (m, 1H), 3.16 - 3.02 (m, 1H), 1.73 (d, J = 6.9 Hz, 3H), 1.45 - 1.33 (m, 3H), 1.32 - 1.20 (m, 5H).

[0518] The second peak was (R)-(4-(3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)(1-(trifluoromethyl)cyclopropyl)methanone (compound 33B, isomer 2) (4.0 mg). LCMS (ESI) [M+H] + : 490.3. HPLC-SFC: Rt = 2.760 min. 1 H NMR (400 MHz, CD3OD) δ 7.72 (br s, 1H), 6.91 (br s, 1H), 6.79 - 6.68 (m, 1H), 6.08 - 5.94 (m, 1H), 4.62 - 4.46 (m, 2H), 4.40 - 4.27 (m, 1H), 4.17 - 4.08 (m, 1H), 4.03 (br dd, J = 2.9, 10.8 Hz, 1H), 3.88 - 3.58 (m, 4H), 3.41 - 3.34 (m, 1H), 3.16 - 3.02 (m, 1H), 1.73 (br d, J = 6.9 Hz, 3H), 1.43 - 1.34 (m, 3H), 1.33 - 1.23 (m, 7H).

[0519] Example 34: Preparation of (R)-2-((4-(3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)sulfonyl)ethane-1-ol (Compound 34)

[0520] [ka]

[0521] Step 1: Intermediate INT-6 (170 mg, 0.389 mmol) was dissolved in pyridine (5 mL), and 2-(benzyloxy)ethane-1-sulfonyl chloride (274 mg, 1.17 mmol) was added. The reaction mixture was stirred at 25°C for 30 minutes. The reaction product was quenched with ice water (20 mL), and the resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was successively washed with water and saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by C-18 column chromatography using an acetonitrile / water system to obtain intermediate 34-2 (120 mg, 48.6%). LCMS(ESI)[M+H] + :636.6.

[0522] Step 2: Intermediate 34-2 (120 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at 25°C for 18 hours. The reaction was quenched with ice water (20 mL), the pH of the resulting mixture was adjusted to 8 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane (30 mL x 3). The organic phase was successively washed with water and saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation and purification of the crude product by silica gel chromatography yielded intermediate 34-3 (52 mg, 50.5%). LCMS(ESI)[M+H] + :552.4.

[0523] Step 3: Intermediate 34-3 (40 mg, 0.073 mmol) was dissolved in tetrahydrofuran (10 mL). Carbon-supported palladium (15 mg, 0.145 mmol) and palladium hydroxide (15 mg, 0.145 mmol) were added sequentially, and the reaction mixture was stirred at 60°C for 18 hours under a hydrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, and concentrated to obtain the crude product. Separation and purification of the crude product by preparative reverse-phase high-performance liquid chromatography yielded (R)-2-((4-(3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)sulfonyl)ethane-1-ol (compound 34) (2.9 mg, 8.7%). LCMS (ESI) [M+H] + : 462.4. 1 H NMR (400 MHz, CD3OD) δ 7.71 (s, 1H), 6.90 (s, 1H), 6.61 (s, 1H), 5.46 (q, J = 8.0 Hz, 1H), 4.51 (d, J = 6.2 Hz, 1H), 4.08 (d, J = 13.6 Hz, 2H), 4.04 - 3.99 (m, 1H), 3.91 (t, J = 6.2 Hz, 2H), 3.84 - 3.73 (m, 3H), 3.65 - 3.57 (m, 1H), 3.46 - 3.32 (m, 3H), 3.27 (d, J = 5.6 Hz, 1H), 3.17 (d, J = 17.2 Hz, 1H), 1.65 (d, J = 7.2 Hz, 3H), 1.29 (t, J = 6.8 Hz, 3H).

[0524] Examples 35A and 35B: Preparation of (3R)-4-(6,7-dimethyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 35A, isomer 1) and preparation of (3R)-4-(6,7-dimethyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 35B, isomer 2)

[0525] [ka]

[0526] Step 1: Intermediate INT-5-5 (10 g, 18.4 mmol) and ammonium acetate (14.2 g, 183.6 mmol) were dissolved in methanol (200 mL). This reaction mixture was stirred at room temperature for 1 hour. Sodium borohydride cyanohydride (5.8 g, 91.8 mmol) was added in small portions. This reaction mixture was stirred at 70°C overnight. This reaction mixture was cooled to room temperature, poured into ice water, and extracted with dichloromethane (200 mL x 3). The organic phase was successively washed with water and saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation and purification of the crude product by silica gel chromatography yielded a mixture of intermediates 35-2A and 35-2B (9 g).

[0527] Step 2: A mixture of intermediates 36-2A and 36-2B (9 g) was dissolved in dioxane (40 mL) at room temperature, and cyanomethylenetributylphosphoran (5.3 g, 21.9 mmol) was added. The reaction mixture was stirred at 120°C for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure to remove the dioxane and obtain the crude product, which was purified by silica gel chromatography to obtain intermediate 35-3 (0.5 g, 25.2%).

[0528] Step 3: Intermediate 35-3 (0.5 g, 1.1 mmol) was dissolved in methanol (10 mL) at room temperature, and then a solution of dioxane in hydrochloric acid (2.8 mL, 4 M) was added. The reaction mixture was stirred at 60°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated, diluted with dichloromethane (20 mL), and the pH was adjusted to approximately 7 with saturated sodium bicarbonate solution. This reaction mixture was extracted with dichloromethane (10 mL x 3), and the organic phase was successively washed with water and saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation and purification of the crude product by preparative reverse-phase high-performance liquid chromatography yielded a mixture of enantiomers (200 mg, 49.0%) of (3R)-4-(6,7-dimethyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 35). LCMS(ESI)[M+H] + :368.2.

[0529] Step 4: The enantiomer mixture of (3R)-4-(6,7-dimethyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 35) (200 mg) was further purified by chiral SFC. SFC analysis: Daicel CHIRALPAK® OD column (100 × 3.0 mm, 3 μm), mobile phase: 20% methanol in CO2 (containing 0.1% diethylamine), temperature: 35°C, flow rate: 1.5 mL / min, detection wavelength: 214 nm.

[0530] The first peak was (3R)-4-(6,7-dimethyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 35A, isomer 1) (70.0 mg). LCMS (ESI) [M+H] + : 368.2. HPLC-SFC: Rt = 2.445 min. 1H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 6.92 (s, 1H), 6.55 (s, 1H), 4.51 (d, J = 5.2 Hz, 1H), 4.35 - 4.24 (m, 1H), 4.14 - 3.95 (m, 2H), 3.87 - 3.73 (m, 2H), 3.70 - 3.55 (m, 2H), 3.31 - 3.26 (m, 2H), 3.16 - 3.06 (m, 2H), 2.56 (s, 3H), 1.53 (d, J = 7.2 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H).

[0531] The second peak was (3R)-4-(6,7-dimethyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 35B, isomer 2) (59.8 mg). LCMS (ESI) [M+H] + : 368.2. HPLC-SFC: Rt = 2.968 min. 1 H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 6.91 (s, 1H), 6.54 (s, 1H), 4.51 (d, J = 4.8 Hz, 1H), 4.31 - 4.22 (m, 1H), 4.14 - 3.98 (m, 2H), 3.89 - 3.74 (m, 2H), 3.72 - 3.57 (m, 2H), 3.31 - 3.24 (m, 2H), 3.16 - 3.05 (m, 2H), 2.56 (s, 3H), 1.54 (d, J = 7.2 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H).

[0532] Examples 36A and 36B: Preparation of (3R)-4-(7-isopropyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 36A, isomer 1) and preparation of (3R)-4-(7-isopropyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 36B, isomer 2)

[0533] [ka]

[0534] Step 1: Intermediate INT-6 (190 mg, 0.434 mmol) was dissolved in methanol (5 mL), and acetone (252 mg, 4.34 mmol), zinc cyanide (204 mg, 1.74 mmol), and sodium borohydride cyanohydride (111 mg, 1.74 mmol) were added in sequence. The reaction mixture was stirred at 60°C for 18 hours. The reaction was quenched by adding ice water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was successively washed with water and saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation and purification of the crude product by silica gel chromatography yielded intermediate 36-2 (110 mg, 52.8%). LCMS(ESI)[M+H] + :480.1.

[0535] Step 2: Intermediate 36-2 (110 mg, 0.229 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was centrifuged to dry the crude product, which was then diluted with dichloromethane (20 mL). The pH of this mixture was adjusted to approximately 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (20 mL x 3). The organic phase was successively washed with water and saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation and purification of the crude product by preparative reverse-phase high-performance liquid chromatography yielded a diastereomer mixture of (3R)-4-(7-isopropyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 36) (25.0 mg, 27.6%). LCMS(ESI)[M+H] + :396.4.

[0536] Step 3: The enantiomer mixture of (3R)-4-(7-isopropyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 36) (25.0 mg) was further purified by chiral SFC. SFC analysis: Daicel CHIRALPAK® IC column (100 × 3.0 mm, 3 μm), mobile phase: 20% methanol in CO2 (containing 0.1% diethylamine), temperature: 35°C, flow rate: 1.5 mL / min, detection wavelength: 214 nm.

[0537] The first peak was (3R)-4-(7-isopropyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 36A, isomer 1) (4.9 mg). LCMS (ESI) [M+H] + : 396.4. HPLC-SFC: Rt = 2.474 min.1 H NMR (400 MHz, CD3OD) δ 7.75 (s, 1H), 6.94 (s, 1H), 6.57 (s, 1H), 4.59 (d, J = 6.8 Hz, 1H), 4.55 (s, 1H), 4.11 (d, J = 13.2 Hz, 1H), 4.05 (d, J = 8.0 Hz, 1H), 3.85 (d, J = 11.6 Hz, 1H), 3.80 (d, J = 11.2 Hz, 1H), 3.64 (d, J = 11.6 Hz, 2H), 3.33 - 3.23 (m, 3H), 3.19 (d, J = 6.8 Hz, 1H), 3.05 (d, J = 17.6 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H).

[0538] The second peak was (3R)-4-(7-isopropyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 36B, isomer 2) (3.5 mg). LCMS (ESI) [M+H] + : 396.4. HPLC-SFC: Rt = 2.859 min. 1H NMR (400 MHz, CD3OD) δ 7.74 (s, 1H), 6.94 (s, 1H), 6.58 (s, 1H), 4.62 - 4.57 (m, 1H), 4.53 (d, J = 6.0 Hz, 1H), 4.12 (d, J = 13.6 Hz, 1H), 4.05 (d, J = 11.2 Hz, 1H), 3.85 (d, J = 11.2 Hz, 1H), 3.80 (d, J = 11.2 Hz, 1H), 3.67 (d, J = 9.2 Hz, 1H), 3.61 (d, J = 11.2 Hz, 1H), 3.33 - 3.25 (m, 3H), 3.22 - 3.17 (m, 1H), 3.06 (d, J = 17.6 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H).

[0539] Examples 37A and 37B: Preparation of (3R)-4-(7-(cyclopropylsulfonyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 37A, isomer 1) and (3R)-4-(7-(cyclopropylsulfonyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 37B, isomer 2)

[0540] [ka]

[0541] Step 1: Intermediate INT-6 (100 mg, 0.23 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium diisopropylamide (0.23 mL, 2 M) was added dropwise at -78°C. After the addition was complete, the mixture was stirred at -78°C for 30 minutes, and then cyclopropanesulfonyl chloride (96.4 mg, 0.69 mmol) was added. The mixture was stirred overnight at room temperature. The reaction was quenched by adding ice water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was successively washed with water and saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation and purification of the crude product by silica gel chromatography yielded intermediate 37-2 (40 mg, 32.3%). LCMS(ESI)[M+H] + :541.9.

[0542] Step 2: Intermediate 37-2 (30 mg, 0.055 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (1.5 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, ice water (20 mL) was added to the reaction mixture to quench it, and the pH of the resulting mixture was adjusted to approximately 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was successively washed with water and saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation and purification of the crude product by silica gel chromatography yielded a diastereomer mixture (18 mg, 71.5%) of (3R)-4-(7-(cyclopropylsulfonyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 37). LCMS(ESI)[M+H] + :458.4.

[0543] Step 3: A diastereomer mixture (18 mg) of (3R)-4-(7-(cyclopropylsulfonyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 37) was further purified by chiral SFC. SFC analysis: Daicel CHIRALPAK-ADHS column (150 × 4.6 mm, 5 μm), mobile phase: 50% ethanol in n-hexane, temperature: 35°C, flow rate: 1.0 mL / min, detection wavelength: 254 nm.

[0544] The first peak was (3R)-4-(7-(cyclopropylsulfonyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 37A, isomer 1) (2.5 mg). LCMS (ESI) [M+H] + : 458.4. HPLC-SFC: Rt = 4.710 min. 1 H NMR (400 MHz, CD3OD) δ 7.71 (s, 1H), 6.91 (s, 1H), 6.63 (s, 1H), 5.49 - 5.38 (m, 1H), 4.54 - 4.44 (m, 1H), 4.14 - 4.05 (m, 2H), 4.04 - 3.98 (m, 1H), 3.90 - 3.71 (m, 3H), 3.66 - 3.57 (m, 1H), 3.46 - 3.35 (m, 1H), 3.23 - 3.14 (m, 1H), 2.48 - 2.39 (m, 1H), 1.67 (d, J = 7.2 Hz, 3H), 1.29 (d, J = 6.4 Hz, 4H), 1.13 - 1.03 (m, 2H), 0.94 - 0.84 (m, 2H).

[0545] The second peak was (3R)-4-(7-(cyclopropylsulfonyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 37B, isomer 2) (2.3 mg). LCMS (ESI) [M+H] + : 458.4. HPLC-SFC: Rt = 7.152 min. 1 H NMR (400 MHz, CD3OD) δ 7.71 (s, 1H), 6.91 (s, 1H), 6.62 (s, 1H), 5.52 - 5.38 (m, 1H), 4.49 (d, J = 6.8 Hz, 1H), 4.20 - 3.94 (m, 3H), 3.91 - 3.70 (m, 3H), 3.67 - 3.56 (m, 1H), 3.46 - 3.34 (m, 1H), 3.22 - 3.14 (m, 1H), 2.50 - 2.41 (m, 1H), 1.68 (d, J = 7.2 Hz, 3H), 1.27 (d,J = 7.8 Hz, 4H), 1.13 - 1.04 (m, 2H), 0.93 - 0.87 (m, 2H).

[0546] Example 38: Preparation of 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)ethane-1-one (Compound 38)

[0547] [ka]

[0548] Step 1: Intermediate INT-6 (100 mg, 0.23 mmol) was dissolved in tetrahydrofuran (5 mL). Acetic anhydride (0.11 mL, 1.14 mmol) and triethylamine (0.16 mL, 1.14 mmol) were added at room temperature, and the reaction mixture was continuously stirred for 1 hour. The reaction mixture was concentrated to obtain crude intermediate 38-2 (80 mg, 73.0%). LC-MS(ESI)[M+H] + :480.0.

[0549] Step 2: Intermediate 38-2 (80 mg, 0.167 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched by adding ice water (10 mL), and the pH of the resulting mixture was adjusted to approximately 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was successively washed with water and saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification of the crude product by preparative high-performance liquid chromatography yielded 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[cd]azulene-7-yl)ethane-1-one (compound 38) (50 mg, 75.8%). LCMS (ESI) [M+H] + : 396.4. 1H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 6.91 (d, J = 5.5 Hz, 1H), 6.66 (d, J = 10.2 Hz, 1H), 6.37 - 5.47 (m, 1H), 4.57 - 4.31 (m, 2H), 4.16 - 3.90 (m, 3H), 3.86 - 3.72 (m, 2H), 3.67 - 3.57 (m, 2H), 3.44 - 3.32 (m, 1H), 3.30 - 3.18 (m, 1H), 3.30 - 3.02 (m, 2H), 3.10 - 3.01 (m, 1H), 2.33 - 2.14 (m, 3H), 1.74 - 1.55 (m, 3H), 1.33 - 1.26 (m, 3H).

[0550] Examples 39A and 39B: Preparation of (3R)-3-methyl-4-(6-methyl-7-(methylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 39A, isomer 1) and (3R)-3-methyl-4-(6-methyl-7-(methylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 39B, isomer 2)

[0551] [ka]

[0552] Step 1: Title compound 39 was prepared using methanesulfonyl chloride instead of cyclopropanesulfonyl chloride, in the same manner as the preparation method in Example 37. A diastereomer mixture of (3R)-3-methyl-4-(6-methyl-7-(methylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 39) (960 mg, 88.3%) was obtained. LCMS(ESI)[M+H]+ :432.4.

[0553] Step 2: A diastereomer mixture (960 mg) of (3R)-3-methyl-4-(6-methyl-7-(methylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 39) was further purified by chiral SFC. SFC analysis: Daicel ChiralPAK OD column (150 × 4.6 mm, 5 μm), mobile phase: 50% methanol in CO2 (containing 0.05% ammonia), temperature: 35°C, flow rate: 1.0 mL / min, detection wavelength: 210 nm.

[0554] The first peak was (3R)-3-methyl-4-(6-methyl-7-(methylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 39A, isomer 1) (364.5 mg). LCMS (ESI) [M+H] + : 432.4. HPLC-SFC: Rt = 4.710 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 7.82 (s, 1H), 6.74 (d, J = 17.8 Hz, 1H), 5.50 - 5.21 (m, 1H), 4.46 (d, J = 5.2 Hz, 1H), 4.07 - 3.90 (m, 1H), 3.83 - 3.61 (m, 1H), 3.56 - 3.45 (m, 1H), 3.26 - 3.08 (m, 1H), 2.99 (s, 1H), 1.59 (d, J = 10.4 Hz, 1H), 1.18 (d, J = 6.6 Hz, 1H).

[0555] The second peak was (3R)-3-methyl-4-(6-methyl-7-(methylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 39B, isomer 2) (304.1 mg). LCMS (ESI) [M+H] + : 432.4. HPLC-SFC: Rt = 7.152 min. 1 H NMR (400 MHz, CD3OD) δ 12.75 (s, 1H), 7.81 (s, 1H), 6.74 (d, J = 16.2 Hz, 1H), 5.40 (m, 1H), 4.11 - 3.88 (m, 1H), 3.81 - 3.61 (m, 1H), 3.49 (m, 1H), 3.23 - 3.08 (m, 1H), 2.98 (s, 1H), 1.57 (d, J = 7.2 Hz, 1H), 1.20 (d, J = 6.6 Hz, 1H).

[0556] Examples 40A and 40B: Preparation of 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-7-carbonyl)cyclopropane-1-carbonyl (compound 40A, isomer 1) and 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-7-carbonyl)cyclopropane-1-carbonyl (compound 40B, isomer 2)

[0557] [ka]

[0558] Step 1: Compound 40 was prepared using 1-cyano-1-cyclopropanecarboxylic acid instead of 1-trifluoromethylcyclopropane-1-carboxylic acid, similar to the preparation method in Example 33. A diastereomer mixture of 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-7-carbonyl)cyclopropane-1-carbonyl (compound 40) (40 mg, 39.6%) was obtained. LCMS(ESI)[M+H] + :447.2.

[0559] Step 2: A diastereomer mixture (40 mg) of 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-7-carbonyl)cyclopropane-1-carbonitrile (compound 40) was further purified by chiral SFC. SFC analysis: Daicel ChiralPAK AD column (150 × 4.6 mm, 5 μm), mobile phase: 20% methanol in n-hexane, temperature: 35°C, flow rate: 1.0 mL / min, detection wavelength: 254 nm.

[0560] The first peak was 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-7-carbonyl)cyclopropane-1-carbonyl (compound 40A, isomer 1) (7.0 mg). LCMS (ESI) [M+H] + : 447.2. HPLC-SFC: Rt = 2.578 min. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.51 - 6.36 (m, 1H), 5.99 - 5.90 (m, 1H), 4.52 - 4.29 (m, 2H), 4.25 - 4.03 (m, 2H), 3.93 - 3.80 (m, 2H), 3.71 - 3.30 (m, 4H), 3.18 - 3.10 (m, 1H), 1.81 (d, J = 6.8 Hz, 3H), 1.62 - 1.47 (m, 3H), 1.33 (d, J = 8.8 Hz, 3H), 1.30 - 1.19 (m, 2H).

[0561] The second peak was 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-7-carbonyl)cyclopropane-1-carbonyl (compound 40B, isomer 2) (8.7 mg). LCMS (ESI) [M+H] + : 447.2. HPLC-SFC: Rt = 3.484 min. 1 H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.49 - 6.3 (m, 1H), 5.97 - 5.90 (m, 1H), 4.46 - 4.29 (m, 2H), 4.17 - 3.98 (m, 3H), 3.84 - 3.78 (m, 2H), 3.75 - 3.55 (m, 2H), 3.37 - 3.30 (m, 2H), 3.22 - 3.05 (m, 1H), 1.80 (d, J = 6.0 Hz, 3H), 1.67 - 1.51 (m, 3H), 1.35 (d, J = 6.4 Hz, 3H), 0.94 - 0.79 (m, 1H).

[0562] Examples 41A and 41B: Preparation of (3R)-4-(7-ethyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 41A, isomer 1) and preparation of (3R)-4-(7-ethyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 41B, isomer 2)

[0563] [ka]

[0564] Step 1: Intermediate INT-5-5 (5.0 g, 9.16 mmol) was dissolved in ethanol (50 mL), and wet carbon-supported palladium (1.9 g, 1.83 mmol) and carbon-supported palladium hydroxide (2.6 g, 1.83 mmol) were added. This mixture was stirred under a hydrogen atmosphere (15 psi) at room temperature for 48 hours, filtered, and concentrated to obtain the crude product. Separation and purification of the crude product by silica gel chromatography yielded intermediate 41-2 (0.4 g, 9.0%). LC-MS(ESI)[M+H] + :484.2.

[0565] Step 2: Using intermediate 41-2 instead of intermediate 35-2A, title compound 41 was prepared in the same manner as in Example 35. A diastereomer mixture of (3R)-4-(7-ethyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 41) (95 mg, 77.3%) was obtained. LCMS(ESI)[M+H] + :382.2.

[0566] Step 3: A diastereomer mixture (95 mg) of (3R)-4-(7-ethyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 41) was further purified by chiral SFC. SFC analysis: Daicel ChiralPAK® OD column (100 × 3.0 mm, 3 μm), mobile phase: 20% methanol in CO2, temperature: 35°C, flow rate: 1.5 mL / min, detection wavelength: 210 nm.

[0567] The first peak was (3R)-4-(7-ethyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 41A, isomer 1) (15 mg). LCMS (ESI) [M+H] + : 382.2. HPLC-SFC: Rt = 2.713 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 7.80 (s, 1H), 6.76 (s, 1H), 6.56 (s, 1H), 4.49 - 4.37 (m, 1H), 4.37 - 4.21 (m, 1H), 4.02 (d, J = 13.3 Hz, 1H), 3.96 (dd, J = 11.5, 3.2 Hz, 2H), 3.75 (d, J = 11.3 Hz, 1H), 3.65 (dd, J = 11.3, 3.0 Hz, 1H), 3.57 - 3.41 (m, 2H), 3.17 (dd, J = 12.6, 3.2 Hz, 1H), 3.13 - 3.03 (m, 2H), 3.01 - 2.87 (m, 1H), 2.86 - 2.72 (m, 1H), 2.68 - 2.58 (m, 1H), 1.43 (d, J = 6.9 Hz, 3H), 1.19 (d, J = 6.7 Hz, 3H), 1.09 (t, J = 6.9 Hz, 3H).

[0568] The second peak was (3R)-4-(7-ethyl-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 41B, isomer 2) (15 mg). LCMS (ESI) [M+H] + : 382.2. HPLC-SFC: Rt = 3.488 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 7.79 (s, 1H), 6.76 (s, 1H), 6.56 (s, 1H), 4.50 - 4.39 (m, 1H), 4.37 - 4.25 (m, 1H), 4.09 - 3.91 (m, 2H), 3.76 (d, J = 10.5 Hz, 1H), 3.64 (d, J = 9.5 Hz, 1H), 3.57 - 3.44 (m, 2H), 3.23 - 3.03 (m, 3H), 2.95 (d, J = 17.9 Hz, 1H), 2.84 - 2.72 (m, 1H), 2.70 - 2.59 (m, 1H), 1.44 (brs, 3H), 1.18 (d, J = 5.9 Hz, 3H), 1.09 (brs, 3H).

[0569] Examples 42A and 42B: Preparation of 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[[cd]azulene-7-yl)cyclopropane-1-carbonitrile (compound 42A, isomer 1) and preparation of 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[[cd]azulene-7-yl)cyclopropane-1-carbonitrile (compound 42B, isomer 2)

[0570] [ka]

[0571] Step 1: INT-6 (200 mg, 0.46 mmol) was dissolved in isopropanol (2.0 mL), and 1-ethoxy-1-trimethylsilyloxycyclopropane (79.7 mg, 0.46 mmol), trimethylsilyl cyanide (90.7 mg, 0.92 mmol), and acetic acid (0.2 mL) were added in sequence. The reaction mixture was stirred at 60°C for 18 hours. The reaction was quenched by adding ice water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel chromatography to obtain intermediate 42-2 (100 mg, 43.5%). LCMS(ESI)[M+H] + :503.2.

[0572] Step 2: Intermediate 42-2 (100 mg, 0.20 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (2 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. Ice water (10 mL) was added to the residue, and then the residue was extracted with ethyl acetate (20 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification of the crude product by silica gel column chromatography yielded a diastereomer mixture (30 mg, 36.0%) of 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[[cd]azulene-7-yl)cyclopropane-1-carbonitrile (compound 42). LCMS(ESI)[M+H] + :419.2.

[0573] Step 3: A diastereomer mixture (30 mg) of 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[[cd]azulene-7-yl)cyclopropane-1-carbonitrile (compound 42) was further purified by chiral SFC. SFC analysis: WHELK-O® column (150 × 4.6 mm, 5 μm), mobile phase: 40% methanol in CO2, temperature: 35°C, flow rate: 2.0 mL / min, detection wavelength: 210 nm.

[0574] The first peak was 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[[cd]azulene-7-yl)cyclopropane-1-carbonitrile (compound 42A, isomer 1) (8.0 mg). LCMS (ESI) [M+H] + : 419.2. HPLC-SFC: Rt = 5.205 min. 1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 6.86 (s, 1H), 6.27 (s, 1H), 4.58 - 4.49 (m, 1H), 4.44 - 4.35 (m, 1H), 4.11 - 3.96 (m, 2H), 3.88 - 3.77 (m, 2H), 3.69 - 3.58 (m, 2H), 3.38 - 3.13 (m, 4H), 1.61 (d, J = 6.8 Hz, 3H), 1.32 (d, J = 6.6 Hz, 3H), 1.29 - 1.23 (m, 3H), 1.19 - 1.13 (m, 1H).

[0575] The second peak was 1-(6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-2,6,8,9-tetrahydro-7H-1,2,3,7-tetraazabenzo[[cd]azulene-7-yl)cyclopropane-1-carbonitrile (compound 42B, isomer 2) (4.7 mg). LCMS (ESI) [M+H]+ : 419.2. HPLC-SFC: Rt = 5.951 min. 1 H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 6.91 (s, 1H), 6.28 (s, 1H), 4.58 - 4.50 (m, 1H), 4.42 - 4.34 (m, 1H), 4.12 - 3.98 (m, 2H), 3.88 - 3.76 (m, 2H), 3.70 - 3.59 (m, 2H), 3.38 - 3.14 (m, 4H), 1.62 (d, J = 6.8 Hz, 3H), 1.34 (d, J = 6.6 Hz, 3H), 1.33 - 1.25 (m, 3H), 1.20 - 1.15 (m, 1H).

[0576] Example 43: Preparation of (3R)-3-methyl-4-(6-methyl-7-(1-methyl-1H-pyrazole-4-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (Compound 43)

[0577] [ka]

[0578] Step 1: Intermediate INT-5-5 (500 mg, 0.92 mmol) and 1-methyl-1H-pyrazole-4-amine hydrochloride (367.9 mg, 2.75 mmol) were dissolved in methanol (10 mL) at room temperature, and tetraethyl titanate (521.8 mg, 1.84 mmol) was added. This reaction mixture was stirred at room temperature for 1 hour. Next, sodium triacetoxyborohydride (387.2 mg, 1.84 mmol) was added to this reaction mixture in small amounts, and the reaction mixture was continuously stirred overnight. The reaction product was quenched by adding ice water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate 43-2 (200 mg, 34.8%). LCMS(ESI)[M+H] + :626.4.

[0579] Step 2: Intermediate 43-2 (200 mg, 0.32 mmol) was dissolved in ethanol (10 mL) at room temperature, and wet carbon-supported palladium (68.0 mg, 0.064 mmol) and carbon-supported palladium hydroxide (89.7 mg, 0.064 mmol) were added. This reaction mixture was stirred overnight at 50°C under a hydrogen atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate 43-3 (60 mg, 35.0%). LCMS(ESI)[M+H] + :536.4.

[0580] Step 3: Intermediate 43-3 (30 mg, 0.056 mmol) was dissolved in dichloromethane (2 mL) at room temperature, and triethylamine (0.04 mL, 0.28 mmol) and methanesulfonyl chloride (9.6 mg, 0.084 mmol) were added. This mixture was stirred overnight at room temperature. The reaction was quenched by adding ice water (5 mL) and extracted with dichloromethane (5 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification of the crude product by silica gel column chromatography yielded intermediate 43-4 (10 mg, 34.5%). LCMS(ESI)[M+H] + :518.3.

[0581] Step 4: Intermediate 43-4 (10 mg, 0.019 mmol) was dissolved in methanol (1 mL) at room temperature, and hydrochloric acid / ethyl acetate (0.05 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the crude product was concentrated and the pH was adjusted to 7 by adding saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (5 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The crude product was obtained by concentrating the filtrate under reduced pressure. Separation and purification of the crude product by silica gel column chromatography yielded (3R)-3-methyl-4-(6-methyl-7-(1-methyl-1H-pyrazole-4-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 43) (4.1 mg, 48.9%). LCMS (ESI) [M+H] + : 434.4. 1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 7.78 (s, 1H), 7.06 (d, J = 1.4 Hz, 2H), 6.73 (s, 2H), 4.77 (d, J = 6.8 Hz, 1H), 4.43 (s, 1H), 4.15 - 3.86 (m, 3H), 3.82 - 3.72 (m, 1H), 3.72 - 3.58 (m, 5H), 3.57 - 3.46 (m, 1H), 3.45 - 3.35 (m, 1H), 3.17 (t, J = 12.8 Hz, 1H), 2.90 (d, J = 16.8 Hz, 1H), 1.56 (d, J = 7.2 Hz, 3H), 1.20 (d, J = 7.8 Hz, 3H).

[0582] Examples 44A and 44B: Preparation of (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-ylmethyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 44A, isomer 1) and (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-ylmethyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 44B, isomer 2)

[0583] [ka]

[0584] Step 1: Title compound 44 was prepared using oxetane-3-carboxyaldehyde instead of 3-oxetanone, in the same manner as the preparation method in Example 32A. A diastereomer mixture of (3R)-3-methyl-4-(6-methyl-7-(oxetane-3-ylmethyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 44) ​​(100 mg, 41.7%) was obtained. LCMS(ESI)[M+H] + :424.2.

[0585] Step 2: A diastereomer mixture (100 mg) of (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-ylmethyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 44) ​​was further purified by chiral SFC. SFC analysis: Daicel ChiralPAK® AS column (100 × 3.0 mm, 3 μm), mobile phase: 10% methanol in CO2 (containing 0.1% ammonia), temperature: 35°C, flow rate: 1.5 mL / min, detection wavelength: 210 nm.

[0586] The first peak was (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-ylmethyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 44A, isomer 1) (865.8 mg). LCMS (ESI) [M+H] + : 424.2. HPLC-SFC: Rt = 3.156 min. 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 7.80 (s, 1H), 6.75 (s, 1H), 6.54 (s, 1H), 4.71 - 4.55 (m, 2H), 4.42 (d, J = 4.8 Hz, 1H), 4.21 - 4.18 (m, 3H), 4.09 - 3.89 (m, 2H), 3.75 (d, J = 11.2 Hz, 1H), 3.68 - 3.61 (m, 1H), 3.49 (t, J = 10.8 Hz, 2H), 3.24 - 3.06 (m, 3H), 3.04 - 2.81 (m, 4H), 1.44 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H).

[0587] The second peak was (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-ylmethyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 44B, isomer 2) (6.2 mg). LCMS (ESI) [M+H] + : 424.2. HPLC-SFC: Rt = 4.043 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 7.79 (s, 1H), 6.75 (s, 1H), 6.53 (s, 1H), 4.66 - 4.56 (m, 2H), 4.42 (d, J = 5.6 Hz, 1H), 4.25 - 4.13 (m, 3H), 3.98 - 3.88 (m, 2H), 3.75 (d, J = 11.2 Hz, 1H), 3.69 - 3.59 (m, 1H), 3.49 (t, J = 11.6 Hz, 2H), 3.27 - 3.07 (m, 3H), 3.03 - 2.79 (m, 4H), 1.43 (d, J = 7.2 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H).

[0588] Examples 45A and 45B: Preparation of (3R)-4-(7-(2,2-difluoroethyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 45A, isomer 1) and preparation of (3R)-4-(7-(2,2-difluoroethyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 45B, isomer 2)

[0589] [ka]

[0590] Step 1: Title compound 45 was prepared using difluoroacetaldehyde ethylhemiaacetal instead of acetone, in the same manner as the preparation method in Example 36A. A diastereomer mixture of (3R)-4-(7-(2,2-difluoroethyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 45) (95 mg, 63.8%) was obtained. LCMS(ESI)[M+H] + :418.2.

[0591] Step 2: A diastereomer mixture (100 mg) of (3R)-4-(7-(2,2-difluoroethyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 45) was further purified by chiral SFC. SFC analysis: Daicel ChiralPAK® OD column (150 × 4.6 mm, 5 μm), mobile phase: 20% methanol in n-hexane, temperature: 35°C, flow rate: 1.0 mL / min, detection wavelength: 210 nm.

[0592] The first peak was (3R)-4-(7-(2,2-difluoroethyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 45A, isomer 1) (40 mg). LCMS (ESI) [M+H] + : 418.2. HPLC-SFC: Rt = 2.484 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 7.76 (s, 1H), 6.73 (s, 1H), 6.48 (s, 1H), 6.05 (tt, J = 56.4, 4.2 Hz, 1H), 4.42 - 4.35 (m, 1H), 4.35 - 4.26 (m, 1H), 3.98 (d, J = 12.7 Hz, 1H), 3.95 - 3.89 (m, 1H), 3.71 (d, J = 11.3 Hz, 1H), 3.64 - 3.37 (m, 3H), 3.21 - 3.04 (m, 4H), 3.00 - 2.82 (m, 2H), 1.43 (d, J = 7.0 Hz, 3H), 1.15 (d, J = 6.6 Hz, 3H).

[0593] The second peak was (3R)-4-(7-(2,2-difluoroethyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 45B, isomer 2) (40 mg). LCMS (ESI) [M+H] + : 418.2. HPLC-SFC: Rt = 2.900 min. 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 7.76 (s, 1H), 6.73 (s, 1H), 6.48 (s, 1H), 6.05 (tt, J = 56.4, 4.2 Hz, 1H), 4.44 - 4.36 (m, 1H), 4.34 - 4.25 (m, 1H), 4.02 - 3.88 (m, 2H), 3.72 (d, J = 11.2 Hz, 1H), 3.65 - 3.40 (m, 3H), 3.22 - 3.02 (m, 4H), 3.00 - 2.81 (m, 2H), 1.43 (d, J = 7.0 Hz, 3H), 1.13 (d, J = 6.6 Hz, 3H).

[0594] Example 46: Preparation of (3R)-3-methyl-4-(6-methyl-7-(S-methylsulfonylimino)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 46)

[0595] [ka]

[0596] Step 1: Title compound 46 was prepared using intermediate INT-6 instead of intermediate INT-5-1, in the same manner as the preparation method of Example 28. An isomer mixture of (3R)-3-methyl-4-(6-methyl-7-(S-methylsulfonylimino)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 46) (150 mg, crude) was obtained. LCMS(ESI)[M+H] + :431.2.

[0597] Step 2: The isomer mixture of (3R)-3-methyl-4-(6-methyl-7-(S-methylsulfonylimino)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 46) (150 mg) was further purified by chiral SFC.

[0598] SFC analysis: Daicel ChiralPAK® OJ column (100 × 3.0 mm, 3 μm), mobile phase: 20% methanol in CO2 (containing 0.1% diethylamine), temperature: 35°C, flow rate: 1.5 mL / min, detection wavelength: 214 nm.

[0599] The first peak was (3R)-3-methyl-4-(6-methyl-7-(S-methylsulfonylimino)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 46A, isomer 1) (12.0 mg). LCMS (ESI) [M+H] + : 431.2. HPLC-SFC: Rt = 2.781 min. 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 6.75 (d, J = 1.8 Hz, 1H), 6.69 (s, 1H), 5.55 (d, J = 7.1 Hz, 1H), 4.47 (d, J = 6.2 Hz, 1H), 4.05 - 3.92 (m, 3H), 3.80 (s, 1H), 3.76 (d, J = 11.4 Hz, 1H), 3.64 (d, J = 11.8 Hz, 2H), 3.50 (s,1H), 3.19 (d, J = 3.8 Hz, 1H), 3.16 (s, 1H), 3.04 (d, J = 16.9 Hz, 1H), 2.83 (s, 3H), 1.54 (d, J = 7.1 Hz, 3H), 1.17 (d, J = 6.6 Hz, 3H).

[0600] The second peak was (3R)-3-methyl-4-(6-methyl-7-(S-methylsulfonylimino)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 46B, isomer 2) (12.0 mg). LCMS (ESI) [M+H] + : 431.2. HPLC-SFC: Rt = 3.237 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 7.79 (s, 1H), 6.76 (d, J = 1.6 Hz, 1H), 6.69 (s, 1H), 5.50 (q, J = 6.9 Hz, 1H), 4.45 (d, J = 5.4 Hz, 1H), 4.07 - 3.90 (m, 3H), 3.85 (s, 1H), 3.76 (d, J = 11.3 Hz, 1H), 3.69 - 3.56 (m, 2H), 3.49 (dd, J = 11.6, 9.4 Hz, 1H), 4.32 - 3.22 (m, 1H), 3.14 (td, J = 12.7, 3.3 Hz, 1H), 3.03 (d, J = 17.0 Hz, 1H), 2.80 (3, 3H), 1.54 (d, J = 7.1 Hz, 3H), 1.17 (d, J = 6.6 Hz, 3H).

[0601] SFC analysis: Daicel ChiralPAK® OD column (100 × 3.0 mm, 3 μm), mobile phase: 20% methanol in CO2 (containing 0.1% diethylamine), temperature: 35°C, flow rate: 1.5 mL / min, detection wavelength: 214 nm.

[0602] The third peak was (3R)-3-methyl-4-(6-methyl-7-(S-methylsulfonylimino)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 46C, isomer 3) (10.0 mg). LCMS (ESI) [M+H] +: 431.4. HPLC-SFC: Rt = 4.059 min. 1 H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 6.86 (s, 1H), 6.28 (s, 1H), 5.65 (t, J = 6.8 Hz, 1H), 4.38 (t, J = 5.8 Hz, 1H), 4.19 - 3.94 (m, 3H), 23.83 (dd, J = 24.4, 11.3 Hz, 2H), 3.65 (t, J = 12.5 Hz, 2H), 3.50 (d, J = 3.9 Hz, 1H), 3.37 (dd, J = 12.8,3.5 Hz, 1H), 3.25 (d, J = 17.1 Hz, 1H), 2.91 (s, 3H), 1.61 (d, J = 7.1 Hz, 3H), 1.34 (d, J = 6.7 Hz, 3H).

[0603] The fourth peak was (3R)-3-methyl-4-(6-methyl-7-(S-methylsulfonylimino)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 46D, isomer 4) (8.0 mg). LCMS (ESI) [M+H] + : 431.4. HPLC-SFC: Rt = 4.970 min. 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 6.76 (s, 1H), 6.69 (s, 1H), 5.51 (d, J = 7.1 Hz, 1H), 4.44 (d, J = 4.8 Hz, 1H), 4.14 - 3.89 (m, 3H), 3.84 (s, 1H), 3.75 (d, J = 11.3 Hz, 1H), 3.64 -3.56 (m, 2H), 3.49 (t, J = 10.6 Hz, 1H), 3.28 (d, J = 13.3 Hz, 1H), 3.20 - 3.10 (m,1H), 3.02 (d, J = 16.9 Hz, 1H), 2.79(3, 3H), 1.54 (d, J = 7.1 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H).

[0604] Examples 47A and 47B: Preparation of (3R)-3-methyl-4-(6-methyl-7-(methyl-d3)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 47A, isomer 1) and (3R)-3-methyl-4-(6-methyl-7-(methyl-d3)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 47B, isomer 2)

[0605] [ka]

[0606] Step 1: Title compound 47 was prepared in the same manner as in Example 43, by using deuterated methylamine hydrochloride instead of 1-methyl-1H-pyrazole-4-amine hydrochloride. A diastereomer mixture of (3R)-3-methyl-4-(6-methyl-7-(methyl-d3)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 47) (200 mg, 76.8%) was obtained. LCMS(ESI)[M+H] + :370.8.

[0607] Step 2: A diastereomer mixture (100 mg) of (3R)-3-methyl-4-(6-methyl-7-(methyl-d3)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 47) was further purified by chiral SFC. SFC analysis: Daicel ChiralCel OD column (150 × 4.6 mm, 5 μm), mobile phase: 20% methanol in CO2 (containing 0.1% ammonia), flow rate: 1.0 mL / min, detection wavelength: 210 nm.

[0608] The first peak was (3R)-3-methyl-4-(6-methyl-7-(methyl-d3)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 47A, isomer 1) (42 mg). LCMS (ESI) [M+H] + : 370.8. HPLC-SFC: Rt = 2.571 min. 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.81 (s, 1H), 6.77 (s, 1H), 6.55 (s, 1H), 4.43 (d, J = 5.2 Hz, 1H), 4.20 (s, 1H), 4.08 - 3.91 (m, 2H), 3.75 (d, J = 11.3 Hz, 1H), 3.68 - 3.61 (m, 1H), 3.59 - 3.44 (m, 2H), 3.24 - 2.93 (m, 4H), 1.46 (d, J = 5.9 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H).

[0609] The second peak was (3R)-3-methyl-4-(6-methyl-7-(methyl-d3)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 47B, isomer 2) (40 mg). LCMS (ESI) [M+H] + : 370.8. HPLC-SFC: Rt = 3.217 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.81 (s, 1H), 6.77 (s, 1H), 6.55 (s, 1H), 4.44 (d, J = 4.6 Hz, 1H), 4.19 (s, 1H), 4.07 - 3.92 (m, 2H), 3.76 (d, J = 11.3 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.59 - 3.45 (m, 2H), 3.25 - 2.93 (m, 4H), 1.46 (d, J = 5.8 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H).

[0610] Examples 48A and 48B: Preparation of (3R)-4-(7-(ethylsulfonyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 48A, isomer 1) and (3R)-4-(7-(ethylsulfonyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 48B, isomer 2)

[0611] [ka]

[0612] Step 1: Title compound 48 was prepared using ethanesulfonyl chloride instead of cyclopropanesulfonyl chloride, in the same manner as the preparation method in Example 37. A diastereomer mixture of (3R)-4-(7-(ethylsulfonyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 48) (80 mg, 54.4%) was obtained. LCMS(ESI)[M+H] + :446.2.

[0613] Step 2: A diastereomer mixture (80 mg) of (3R)-4-(7-(ethylsulfonyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 48) was further purified by chiral SFC. SFC analysis: Daicel ChiralPAK IH column (150 × 4.6 mm, 5 μm), mobile phase: 15% methanol in n-hexane, temperature: 35°C, flow rate: 2.0 mL / min, detection wavelength: 254 nm.

[0614] The first peak was (3R)-4-(7-(ethylsulfonyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 48A, isomer 1) (10.3 mg). LCMS (ESI) [M+H] + : 446.2. HPLC-SFC: Rt = 1.783 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.82 (s, 1H), 6.75 - 6.73 (m, 2H), 5.38 - 5.36 (m, 1H), 4.44 - 4.42 (m, 1H), 4.05 - 4.03 (m, 1H), 3.97 - 3.95 (m, 2H), 3.76 - 3.74 (m, 2H), 3.66 - 3.64 (m, 1H), 3.50 - 3.48 (m, 1H), 3.15 - 3.13 (m, 5H), 1.58 (d, J = 7.2 Hz, 3H), 1.19 - 1.17 (m, 6H).

[0615] The second peak was (3R)-4-(7-(ethylsulfonyl)-6-methyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 48B, isomer 2) (12.8 mg). LCMS (ESI) [M+H] + : 446.3. HPLC-SFC: Rt = 2.790 min. 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.81 (s, 1H), 6.74 - 6.72 (m, 2H), 5.35 - 5.33 (m, 1H), 4.46 - 4.44 (m, 1H), 3.98 - 3.96 (m, 3H), 3.78 - 3.76 (m, 2H), 3.66 - 3.64 (m, 1H), 3.51 - 3.49 (m, 1H), 3.22 - 3.07 (m, 5H), 1.58 (d, J = 7.2 Hz, 3H), 1.22 - 1.15 (m, 6H).

[0616] Examples 49A and 49B: Preparation of (3R)-3-methyl-4-(6-methyl-7-((1-methylcyclopropyl)sulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 49A, isomer 1) and (3R)-3-methyl-4-(6-methyl-7-((1-methylcyclopropyl)sulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 49B, isomer 2)

[0617] [ka]

[0618] Step 1: Title compound 49 was prepared using 1-methylcyclopropanesulfonyl chloride instead of cyclopropanesulfonyl chloride, in the same manner as the preparation method in Example 37. A diastereomer mixture of (3R)-3-methyl-4-(6-methyl-7-((1-methylcyclopropyl)sulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 49) (50 mg, 65.5%) was obtained. LCMS(ESI)[M+H] + :472.4.

[0619] Step 2: A diastereomer mixture (50 mg) of (3R)-3-methyl-4-(6-methyl-7-((1-methylcyclopropyl)sulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 49) was further purified by chiral SFC. SFC analysis method: Daicel ChiralPAK OJ column (150 × 4.6 mm, 5 μm), mobile phase: 10% methanol in n-hexane, flow rate: 1.0 mL / min, detection wavelength: 210 nm.

[0620] The first peak was (3R)-3-methyl-4-(6-methyl-7-((1-methylcyclopropyl)sulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 49A, isomer 1) (15 mg). LCMS (ESI) [M+H] + : 472.4. HPLC-SFC: Rt = 2.428 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.82 (s, 1H), 6.78 (s,1H), 6.77 (s,1H), 5.35 (t, J = 7.0 Hz, 1H), 4.51 - 4.36 (m, 1H), 4.09 - 3.94 (m, 3H), 3.89 - 3.74 (m, 2H), 3.71 - 3.61 (m, 1H), 3.59 - 3.46 (m, 1H), 3.22 - 3.07 (m, 3H), 1.63 (d, J = 7.0 Hz, 3H), 1.37 (s, 3H), 1.35 - 1.31 (m, 1H), 1.26 - 1.23 (m, 1H), 1.18 (d, J = 6.6 Hz, 3H), 0.99 - 0.92 (m, 1H), 0.90 - 0.82 (m, 1H).

[0621] The second peak was (3R)-3-methyl-4-(6-methyl-7-((1-methylcyclopropyl)sulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 49B, isomer 2) (15 mg). LCMS (ESI) [M+H] + : 472.4. HPLC-SFC: Rt = 3.462 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.82 (s, 1H), 6.78 (s, 1H), 6.77 (s, 1H), 5.45 - 5.28 (m, 1H), 4.55 - 4.35 (m, 1H), 4.15 - 3.89 (m, 3H), 3.89 - 3.71 (m, 2H), 3.70 - 3.61 (m, 1H), 3.54 - 3.46 (m, 1H), 3.22 - 3.07 (m, 3H), 1.62 (d, J = 6.7 Hz, 3H), 1.40 - 1.35 (m, 1H), 1.34 (s, 3H), 1.27 - 1.23 (m, 1H), 1.20 (d, J = 6.3 Hz, 3H), 0.98 - 0.90 (m, 1H), 0.88 - 0.81 (m, 1H).

[0622] Example 50: Preparation of a diastereomer mixture of (3R)-3-methyl-4-(6-methyl-2-(1H-pyrazole-3-yl)-7-(vinylsulfonyl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 50)

[0623] [ka]

[0624] Step 1: Intermediate INT-6 (1.0 g, 2.29 mmol) was dissolved in acetonitrile (50 mL), and triethylamine (0.32 mL, 2.29 mmol) and 2-chloroethanesulfonyl chloride (373 mg, 2.29 mmol) were added sequentially. This mixture was reacted at room temperature for 2 hours, and then saturated ammonium chloride (50 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified by silica gel column chromatography to obtain intermediate 50-2 (500 mg, 41.5%). LCMS(ESI)[M+H] + :528.2.

[0625] Step 2: Intermediate 50-2 (50 mg, 0.09 mmol) was dissolved in methanol (1 mL), and hydrochloric acid (1 mL, 1 M) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to obtain the crude product, which was then separated and purified by silica gel column chromatography to obtain a diastereomer mixture of (3R)-3-methyl-4-(6-methyl-2-(1H-pyrazole-3-yl)-7-(vinylsulfonyl)-6,7,8,9-tetrahydro-2H-1,2,3,7-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 50) (15 mg, 35.7%). LCMS (ESI) [M+H] + : 444.4. 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 7.80 (s, 1H), 6.85 (ddd, J = 16.3, 9.9, 5.6 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.74 (s, 1H), 6.14 (dd, J = 16.4, 1.9 Hz, 1H), 6.01 (dd, J = 9.9, 5.8 Hz, 1H), 5.38 - 5.28 (m, 1H), 4.50 - 4.39 (m, 1H), 4.08 - 3.94 (m, 2H), 3.90 - 3.82 (m, 1H), 3.80 - 3.68 (m, 2H), 3.65 (dd, J = 11.4, 2.8 Hz, 1H), 3.56 - 3.45 (m, 1H), 3.22 - 3.07 (m, 3H), 1.55 (d, J = 7.1 Hz, 3H), 1.22 - 1.17 (m, 3H).

[0626] Example 51: Preparation of (R)-4-(2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (Compound 51)

[0627] [ka]

[0628] Step 1: Intermediate INT-4 (48 mg, 0.092 mmol) was dissolved in tetrahydrofuran (1 mL), and dilute hydrochloric acid (1 mL, 1 M) was added. The reaction mixture was stirred at room temperature for 30 minutes, and the solvent was removed by centrifugation to obtain intermediate 51-2 (32.0 mg, 79.1%). LC-MS(ESI)[M+H] + :440.2.

[0629] Step 2: Intermediate 51-2 (32 mg, 0.073 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (83.0 mg, 0.728 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and the solvent was removed by centrifugal drying to obtain the crude product. This was purified by reverse-phase high-performance liquid chromatography to obtain (R)-4-(2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 51) (13 mg, 52.6%). LCMS (ESI) [M+H] + : 340.2. 1 H NMR (400 MHz, DMSO-d6) δ 13.05 (d, J = 117.2 Hz, 1H), 7.60 (s, 1H), 7.04 (s, 1H), 6.89 (s, 1H), 4.44 - 4.34 (m, 3H), 4.18 (s, 2H), 4.02 - 3.94 (m, 2H), 3.76 (d, J = 11.2 Hz, 1H), 3.71 - 3.66 (m, 1H), 3.56 - 3.49 (m, 1H), 3.32 - 3.24 (m, 3H), 3.17 - 3.09 (m, 1H), 1.14 (d, J = 6.6 Hz, 3H).

[0630] Example 52: Preparation of (R)-4-(7-(3,3-difluorocyclobutyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (Compound 52)

[0631] [ka]

[0632] Step 1: Intermediate INT-4 (200 mg, 0.382 mmol) was dissolved in dichloromethane. Hexamethyldisilazane (185 mg, 1.146 mmol) and trimethylsilyl trifluoromethanesulfonate (127.4 mg, 0.573 mmol) were added sequentially, and the reaction mixture was stirred at 0°C for 0.5 hours. This reaction mixture was quenched with water at 25°C. The resulting mixture was separated, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was successively washed with water (10 mL) and saturated brine (10 mL). The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography to obtain intermediate 52-2 (115 mg, 71.1%). LCMS(ESI)[M+H] + :424.2.

[0633] Step 2: Intermediate 52-2 (100 mg, 0.236 mmol) was dissolved in isopropyl acetate (10 mL), and 3,3-difluorocyclobutyl-1-one (50.1 mg, 0.472 mmol), trifluoroacetic acid (26.9 mg, 0.236 mmol), and sodium triacetoxyborohydride (60.0 mg, 0.283 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed by centrifugation to obtain the crude product. The crude product was purified by column chromatography to obtain intermediate 52-3 (50 mg, 41.2%). LCMS(ESI)[M+H] + :514.0.

[0634] Step 3: Intermediate 52-3 (45 mg, 0.088 mmol) was dissolved in dichloromethane (4.5 mL). Trifluoroacetic acid (1.125 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, and then centrifuged to remove the solvent and obtain the crude product. The crude product was purified by preparative reverse-phase high-performance liquid chromatography to obtain (R)-4-(7-(3,3-difluorocyclobutyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 52) (14 mg, 37.2%). LCMS (ESI) [M+H] + : 429.9. 1 H NMR (400 MHz, CD3OD) δ 7.73 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.99 (s, 1H), 4.51 - 4.45 (m, 2H), 4.44 - 4.36 (m, 1H), 4.14 (s, 2H), 4.09 - 4.02 (m, 1H), 4.00 - 3.92 (m, 1H), 3.89 - 3.79 (m, 2H), 3.72 - 3.63 (m, 1H), 3.44 - 3.37 (m, 1H), 3.37 - 3.32 (m, 3H), 2.89 - 2.77 (m, 2H), 2.65 - 2.50 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H).

[0635] Example 53: Preparation of (R)-(3,3-difluorocyclobutyl)(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-8,9-dihydro-1,3,7,9a-tetraazabenzo[cd]azulene-7(6H)-yl)methanone (compound 53)

[0636] [ka]

[0637] Step 1: Intermediate 52-2 (98.8 mg, 0.260 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 3,3-difluorocyclobutanecarboxylic acid (50.0 mg, 0.118 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (98.8 mg, 0.260 mmol), and diisopropylethylamine (45.8 mg, 0.354 mmol) were added in sequence. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water at 25°C. The resulting mixture was separated, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phase was successively washed with water (10 mL) and saturated brine (10 mL). The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was then purified by silica gel column chromatography to obtain intermediate 53-2 (35.0 mg, 54.7%). LCMS(ESI)[M+H] + :542.2.

[0638] Step 2: Intermediate 53-2 (35.0 mg, 0.065 mmol) was dissolved in methanol (1.5 mL), and dilute hydrochloric acid (3.0 mL, 1 M) was added. The mixture was stirred overnight at 30°C and centrifuged to remove the solvent, yielding the crude product. This was then purified by preparative reverse-phase high-performance liquid chromatography to obtain (R)-(3,3-difluorocyclobutyl)(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-8,9-dihydro-1,3,7,9a-tetraazabenzo[cd]azulene-7(6H)-yl)methanone (compound 53) (13.8 mg, 46.7%). LCMS (ESI) [M+H] + : 458.2. 1H NMR (400 MHz, DMSO-d6) δ 13.11 (d, J = 119.5 Hz, 1H), 7.70 (d, J = 75.7 Hz, 1H), 7.27 - 6.91 (m, 2H), 5.07 - 4.89 (m, 2H), 4.52 - 4.41 (m, 3H), 4.22 - 4.10 (m, 2H), 4.08 - 3.95 (m, 2H), 3.86 - 3.66 (m, 2H), 3.61 - 3.50 (m, 1H), 3.36 - 3.27 (m, 1H), 3.24 - 3.10 (m, 1H), 2.92 - 2.62 (m, 4H), 1.23 - 1.13 (m, 3H).

[0639] Example 54: Preparation of (R)-cyclopropyl(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-8,9-dihydro-1,3,7,9a-tetraazabenzo[cd]azulene-7(6H)-yl)methanone (compound 54)

[0640] [ka]

[0641] Title compound 54 was prepared using cyclopropanecarboxylic acid instead of 3,3-difluorocyclobutanecarboxylic acid, in the same manner as the preparation method of Example 53. (R)-Cyclopropyl(4-(3-methylmorpholino)-2-(1H-pyrazole-3-yl)-8,9-dihydro-1,3,7,9a-tetraazabenzo[cd]azulene-7(6H)-yl)methanone (compound 54) (5.0 mg, 20.1%) was obtained. LCMS (ESI) [M+H] + : 408.0. 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 6.84 (s, 1H), 6.65 (d, J = 12.3 Hz, 1H), 5.04 - 4.89 (m, 2H), 4.66 - 4.48 (m, 2H), 4.28 (s, 2H), 4.13 - 3.98 (m, 2H), 3.90 - 3.73 (m, 3H), 3.64 - 3.55 (m, 1H), 3.34 - 3.25 (m, 1H), 1.77 - 1.67 (m, 1H), 1.25 - 1.20 (m, 3H), 1.01 - 0.92 (m, 2H), 0.83 - 0.73 (m, 2H).

[0642] Example 55: Preparation of (R)-3-methyl-4-(7-(methylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)morpholine (Compound 55)

[0643] [ka]

[0644] Title compound 55 was prepared using intermediate 52-2 instead of intermediate 5-1, in the same manner as the preparation method of Example 22. (R)-3-methyl-4-(7-(methylsulfonyl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 55) (22.5 mg, 60.1%) was obtained. LCMS (ESI) [M+H] + : 418.3. 1H NMR (400 MHz, DMSO-d6) δ 13.25 - 12.95 (m, 1H), 7.79 - 7.62 (m, 1H), 7.06 (s, 2H), 4.82 (s, 2H), 4.52 (s, 2H), 4.43 (d, J = 5.4 Hz, 1H), 4.10 - 3.93 (m, 4H), 3.78 (d, J = 11.2 Hz, 1H), 3.73 - 3.65 (m, 1H), 3.58 - 3.50 (m, 1H), 3.21 - 3.11 (m, 1H), 3.05 (s, 3H), 1.17 (d, J = 6.6 Hz, 3H).

[0645] Example 56: Preparation of 6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-6,7-dihydro-1,3,7,9a-tetraazabenzo[cd]azulene-8(9H)-one (compound 56)

[0646] [ka]

[0647] Step 1: Under a nitrogen atmosphere, INT-3-3 (2.60 g, 5.81 mmol) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (2.41 g, 17.44 mmol) and ethyl bromoacetate (0.64 g, 2.80 mmol) were added sequentially. The reaction mixture was stirred at 50°C for 12 hours. The mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure to remove most of the N,N-dimethylformamide, and then diluted with dichloromethane (20 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate 56-2 (2.45 g, 79.0%). LCMS(ESI)[M+H] + :534.8.

[0648] Step 2: Under a nitrogen atmosphere, intermediate 56-2 (2.45 g, 4.59 mmol) was dissolved in 1,4-dioxane (20 mL), and tributyl(1-ethoxyethylene)tin (3.3 g, 9.18 mmol) and tetrakis(triphenylphosphine)palladium (0.50 g, 0.459 mmol) were added in sequence. The reaction mixture was stirred at 110°C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and 10% aqueous potassium fluoride (20 mL) was added. The mixture was stirred for 30 minutes and filtered, and the filter cake was washed with dichloromethane. The filtrate was extracted with dichloromethane (20 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate 56-3 (2.4 g, 99.6%). LCMS(ESI)[M+H] + :525.0.

[0649] Step 3: Intermediate 56-3 (2.40 g, 4.58 mmol) was dissolved in tetrahydrofuran (5 mL), and then dilute hydrochloric acid (1 mL, 2 M) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, saturated sodium bicarbonate solution (20 mL) was added to quench the reaction product, and the aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification of the crude product by silica gel column chromatography yielded intermediate 56-4 (1.05 g, 55.7%). LCMS(ESI)[M+H] + :412.9.

[0650] Step 4: Intermediate 56-4 (1.30 g, 3.15 mmol) was dissolved in acetonitrile (20 mL), and triethylamine (1.30 mL, 9.45 mmol), di-tert-butyl dicarbonate (1.45 mL, 6.30 mmol), and 4-dimethylaminopyridine (269.6 mg, 2.21 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated to obtain the crude product. Separation and purification of the crude product by silica gel column chromatography yielded intermediate 56-5 (1.00 g, 61.9%). LCMS(ESI)[M+H] + :512.9.

[0651] Step 5: Under a nitrogen atmosphere, intermediate 56-5 (0.87 mg, 1.70 mmol) was dissolved in ethanol (15 mL), and then ammonium acetate (1.31 g, 17.0 mmol) was added. This reaction mixture was stirred at 80°C for 2 hours, and then sodium borohydride cyanohydride (532.9 mg, 8.49 mmol) was added to the reaction mixture in small amounts, and this reaction mixture was continuously stirred at 80°C for 22 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, saturated sodium bicarbonate solution was added to quench the reaction products, and the aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The crude product was obtained by concentrating the filtrate under reduced pressure. Separation and purification of the crude product by silica gel column chromatography yielded 6-methyl-4-((R)-3-methylmorpholinyl)-2-(1H-pyrazole-3-yl)-6,7-dihydro-1,3,7,9a-tetraazabenzo[cd]azulene-8(9H)-one (compound 56) (410.0 mg, 51.7%). LCMS (ESI) [M+H] + : 368.4. 1H NMR (400 MHz, DMSO-d6) δ 13.19 - 12.87 (m, 1H), 8.40 (d, J = 5.2 Hz, 1H), 7.66 (s, 1H), 7.00 (s, 1H), 6.82 (s, 1H), 5.65 (d, J = 15.2 Hz, 1H), 5.34 - 5.19 (m, 1H), 4.86 (d, J = 14.8 Hz, 1H), 4.88 - 4.79 (m, 1H), 4.06 - 3.91 (m, 2H), 3.76 (d, J = 11.4 Hz, 1H), 3.68 (dd, J = 11.4, 2.4 Hz, 1H), 3.53 (td, J = 11.4, 2.4 Hz, 1H), 3.16 (td, J = 12.8, 3.6 Hz, 1H), 1.63 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H).

[0652] Example 57: Preparation of (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)morpholine (Compound 57)

[0653] [ka]

[0654] Step 1: Under a nitrogen atmosphere, compound 56 (440.0 mg, 1.20 mmol) was dissolved in tetrahydrofuran (2 mL), and a 1 M borane solution (5 mL) in tetrahydrofuran was added. The reaction mixture was stirred at 30°C for 1 hour. Methanol (10 mL) was added to the reaction mixture, and the mixture was refluxed and stirred for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography and reversed-phase high-performance liquid chromatography to obtain intermediate 57-2 (70.0 mg, 16.5%). LCMS(ESI)[M+H] + :354.0.

[0655] Step 2: Under a nitrogen atmosphere, intermediate 57-2 (40.0 mg, 0.11 mmol) was dissolved in methanol (5 mL), and 3-oxetanone (24.5 mg, 0.34 mmol) was added. The reaction mixture was stirred at 30°C for 1 hour. Next, under a nitrogen atmosphere, sodium triacetoxyborohydride (238.7 mg, 1.13 mmol) was added to the reaction mixture in small amounts, and the mixture was continuously stirred at 30°C for 2 hours. After the reaction was complete, saturated sodium chloride solution was added to quench the reaction product, and the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The crude product was obtained by concentrating the filtrate under reduced pressure. Separation and purification of the crude product by preparative reverse-phase high-performance liquid chromatography yielded (3R)-3-methyl-4-(6-methyl-7-(oxetan-3-yl)-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 57) (10.0 mg, 21.6%). LCMS (ESI) [M+H] + : 410.4. 1 H NMR (400 MHz, DMSO-d6) δ 13.16 - 12.94 (m, 1H), 7.62 (s, 1H), 7.04 (s, 1H), 6.83 (s, 1H), 4.49 - 4.36 (m, 2H), 4.37 - 4.27 (m, 1H), 4.27 - 4.17 (m, 1H), 4.03 - 3.90 (m, 2H), 3.81 - 3.63 (m, 2H), 3.60 - 3.42 (m, 2H), 3.19 - 3.01 (m, 2H), 1.53 (d, J = 6.7 Hz, 3H), 1.14 (d, J = 6.6 Hz, 3H).

[0656] Example 58: Preparation of (R)-3-methyl-4-(6-methyl-2-(1H-pyrazole-3-yl)-8,9-dihydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)morpholine (Compound 58)

[0657] [ka]

[0658] Step 1: Intermediate 58-4 was prepared using N-Boc-bromoethylamine instead of ethyl bromoethyl, in the same manner as the preparation method of Example 56. tert-butyl(R)-(2-(7-acetyl-5-(3-methylmorpholinyl)-3-(1H-pyrazole-5-yl)-1H-pyrazolo[4,3-b]pyridine-1-yl)ethyl)carbamate (intermediate 58-4) (180.0 mg, 89.2%) was obtained. LCMS(ESI)[M+H] + :470.4.

[0659] Step 2: Under a nitrogen atmosphere, intermediate 58-4 (180.0 mg, 0.38 mmol) was dissolved in dichloromethane (4 mL), and p-toluenesulfonic acid (6.60 mg, 0.038 mmol) and 3,4-dihydro-2H-pyran (20.0 mg, 0.24 mmol) were added sequentially. The reaction mixture was stirred at 40°C for 18 hours. The reaction mixture was concentrated to obtain the crude product. Separation and purification of the crude product by silica gel column chromatography yielded intermediate 58-5 (150.0 mg, 70.7%). LCMS(ESI)[M+H] + :554.5.

[0660] Step 3: Under a nitrogen atmosphere, intermediate 58-5 (150.0 mg, 0.27 mmol) was dissolved in dichloromethane (2 mL), and 2,6-dimethylpyridine (203.3 mg, 1.90 mmol) and trimethylsilyl trifluoromethanesulfonate (150.6 mg, 0.68 mmol) were added. The reaction mixture was stirred at 40°C for 3 hours. The reaction product was quenched by adding saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phase was successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification of the crude product by silica gel column chromatography yielded intermediate 58-6 (60.0 mg, 48.8%). LCMS(ESI)[M+H] + :454.2.

[0661] Step 4: Intermediate 58-6 (60.0 mg, 0.13 mmol) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1 mL, 2 M) was added. The reaction mixture was stirred at 40°C for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, and the reaction products were quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative reverse-phase high-performance liquid chromatography to obtain (R)-3-methyl-4-(6-methyl-2-(1H-pyrazole-3-yl)-8,9-dihydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)morpholine (compound 58) (10.0 mg, 21.5%). LCMS (ESI) [M+H] + : 352.3. 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.67 (s, 1H), 7.24 (s, 1H), 7.02 (d, J = 1.2 Hz, 1H), 4.59 - 4.47 (m, 3H), 4.16 - 3.94 (m, 4H), 3.78 (d, J = 11.2 Hz, 1H), 3.71 (dd, J = 11.2, 2.4 Hz, 1H), 3.56 (td, J = 11.6, 2.4 Hz, 1H), 3.20 (td, J = 12.6, 2.4 Hz, 1H), 2.54 (s, 3H), 1.18 (d, J = 6.6 Hz, 3H).

[0662] Examples 59A and 59B: Preparation of (3R)-4-(6,7-dimethyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 59A, isomer 1) and preparation of (3R)-4-(6,7-dimethyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 59B, isomer 2)

[0663] [ka]

[0664] Step 1: Under a nitrogen atmosphere, compound 58 (150 mg, 0.42 mmol) was dissolved in methanol (3 mL), and paraformaldehyde (382.0 mg, 4.24 mmol) was added. The reaction mixture was stirred at 50°C for 1 hour. Sodium borohydride cyanohydride (131.6 mg, 2.122 mmol) was added in small amounts, and the reaction solution was continuously stirred at 50°C for 2 hours. The mixture was cooled to room temperature, and the reaction products were quenched with ice water (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were successively washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and filtered. The crude product was obtained by concentrating the filtrate under reduced pressure. Separation and purification of the crude product by silica gel chromatography yielded a diastereomer mixture (90.0 mg, 57.7%) of (3R)-4-(6,7-dimethyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 59). LCMS(ESI)[M+H] + :368.4.

[0665] Step 2: The enantiomer mixture of (3R)-4-(6,7-dimethyl-2-(1H-pyrazole-3-yl)-6,7,8,9-tetrahydro-1,3,7,9a-tetraazabenzo[cd]azulene-4-yl)-3-methylmorpholine (compound 59) (90.0 mg) was further purified by chiral SF...

Claims

1. Compounds represented by formula I, their isomers, isotopically labeled compounds, or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula, 【Chemistry 2】 This indicates that the ring to which it belongs is an aromatic ring system. X １ is N or C (R Ｘ１ Selected from the group consisting of, X ２ It is selected from the group consisting of C or N, X ３ N, C(R Ｘ２ ) or N(R Ｘ３ Selected from the group consisting of, X ４ is N or C (R Ｘ４ Selected from the group consisting of, X ５ is selected from the group consisting of C or N, X ６ is N, N(R Ｘ５ ) or C (R Ｘ６ Selected from the group consisting of, R Ｘ１ , R Ｘ２ , R Ｘ３ , R Ｘ４ , R Ｘ５ and R Ｘ６ H, halogen, C ６～１０ Ariel, C ３～１０ Cycloalkyl, C ３～１０ A cycloalkenyl, a 3- to 10-membered heterocyclyl, or a 5- to 10-membered heteroaryl is independently selected from the group, C ６～１０ Ariel, C ３～１０ Cycloalkyl, C ３～１０ Cycloalkenyls, 3- to 10-membered heterocyclyls, and 5- to 10-membered heteroaryls have one, two, or three R Ｘ Each of these may be substituted by the base, R Ｘ These are halogen, cyano, hydroxyl, and C, respectively. １～６ Alkyl, C １～６ Heteroalkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl or -NR ｃ R ｄ Independently selected from the group consisting of C １～６ Alkyl, C １～６ Heteroalkyl, C ３～１０ Cycloalkyls and 3- to 10-membered heterocyclines are halogens, cyano, hydroxyl, or C １～６ Each of these substituents may be independently selected from the group consisting of alkyl groups, A is selected from a group consisting of 4- to 10-membered heterocyclils, and each 4- to 10-membered heterocyclil has one, two, or three R ａ It may be substituted by the base, R ａ These are C １～１０ Alkyl, C １～１０ Heteroalkyl, amino, or -S (=O) ２ -C １～１０ Independently selected from the group consisting of alkyls, Ring B is selected from the group consisting of a 5-7 membered heterocyclic ring, a 5-7 membered carbocyclic ring, a benzene ring, or a 5-7 membered heteroaromatic ring. R ｂ These are halogen, hydroxyl, cyano, amino, oxo, and C, respectively. １～１０ Alkyl, C １～１０ Heteroalkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, -CO-C ３～１０ Cycloalkyl, -CO-C １～１０ Alkyl, -CONR ｅ R ｆ , -C(O)OC １～１０ Alkyl, -SO ２ NR ｇ R ｈ , -SO ２ -C １～１０ Alkyl, -SO ２ -C ２～６ Alkenyl, -SO ２ -C ２～６ Alkinyl, -SO ２ -C ３～１０ Cycloalkyl, -SO ２ -3 to 10-membered heterocyclyl, -C １～６ Alkyl-C ３～１０ Cycloalkyl, -C １～６ Alkyl-3 to 10-membered heterocyclyl, -C １～６ Alkyl-C ６～１０ Ariel, -C １～６ Alkyl-5 to 10-membered heteroaryl or 【Transformation 3】 Independently selected from the group consisting of C １～１０ alkyl, C １～１０ heteroalkyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ２～６ alkenyl, C ２～６ alkynyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, -CO-C ３～１０ cycloalkyl, -CO-C １～１０ alkyl, -CONR ｅ R ｆ , -C(O)OC １～１０ alkyl, -SO ２ NR ｇ R ｈ , -SO ２ -C １～１０ alkyl, -SO ２ -C ２～６ alkenyl, -SO ２ -C ２～６ alkynyl, -SO ２ -C ３～１０ cycloalkyl, -SO ２ -3- to 10-membered heterocyclyl, -C １～６ alkyl-C ３～１０ cycloalkyl, -C １～６ alkyl-3- to 10-membered heterocyclyl, -C １～６ alkyl-C ６～１０ aryl, -C １～６ alkyl-5- to 10-membered heteroaryl and 【Chemistry 4】 These are deuterium, halogen, hydroxyl, cyano, amino, and C. １～１０ Alkyl, halogenated C １～１０ Alkyl, hydroxy-C １～１０ Alkyl, C １～１０ Heteroalkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl or -CONR ｉ R ｊ They may be substituted with one, two, three, or four substituents independently selected from the group consisting of the above, R' is H, C １～１０ Alkyl, C ３～１０ Selected from the group consisting of cycloalkyl or CN, R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , R ｈ , R ｉ and R ｊ is H or C １～１０ Each is independently selected from the group consisting of alkyl groups, Alternatively, two R's ｂ The bases are connected to each other, C ３～１０ Forming a cycloalkyl or 3-10 membered heterocycline, C ３～１０ Cycloalkyl and 3- to 10-membered heterocyclyls include deuterium, halogen, hydroxyl, cyano, amino, and C. １～１０ Alkyl, halogenated C １～１０ Alkyl, C １～１０ Heteroalkyl, C ３～１０ They may be substituted with one, two, three, or four substituents independently selected from the group consisting of cycloalkyls or 3- to 10-membered heterocyclines. n is selected from the group consisting of 0, 1, 2, 3, or 4.

2. The compound has structural formula II: 【Transformation 5】 (In the formula, 【Transformation 6】 This indicates that the ring to which it belongs is an aromatic ring system. 【Transformation 7】 This represents either a single bond or a double bond. R １ and R ２ is hydrogen or C １～６ Each is independently selected from the group consisting of alkyls, or R １ and R ２ These, together with the carbon atoms to which they are bonded and adjacent nitrogen atoms, form a 4- to 8-membered aza-cyclic ring. X ２ It is selected from the group consisting of C or N, X ３ C(R) ３ ) or N(R ３ Selected from the group consisting of, X ４ It is selected from the group consisting of N or CH, X ５ is selected from the group consisting of C or N, and X ５ If X is N, ３ is C(R ３ ) and R ３ C ６～１０ Ariel, C ３～１０ Selected from the group consisting of cycloalkyl or 5-10 membered heteroaryls, C ６～１０ Ariel, C ３～１０ Cycloalkyl and 5- to 10-membered heterocyclyls have one, two, or three R ３ａ Each of these may be substituted by the base, R ３ａ These are halogen, cyano, hydroxyl, and C, respectively. １～１０ Alkyl, C １～１０ Heteroalkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl or -NR ４ R ５ Independently selected from the group consisting of C １～１０ Alkyl, C １～１０ Heteroalkyl, C ３～１０ Cycloalkyls and 3- to 10-membered heterocyclines are halogens, cyano, hydroxyl, or C １～６ Each of these substituents may be independently selected from the group consisting of alkyl groups, R ４ and R ５ is hydrogen or C １～１０ Each is independently selected from the group consisting of alkyl groups, Z １ CR ６ R ７ And, Z ２ CR ８ R ９ , N, NR １０ , O, S, -C(O)- or -SO ２ - Selected from the group consisting of, Z ３ CR １１ CR １２ R １３ , N, NR １４ , O, -C(O)-, -SO ２ - or -S(O)(NR １５ Selected from the group consisting of ) Z ４ CR １６ CR １７ R １８ , N, NR １９ , O, S, -C(O)-, -SO ２ - or -S(O)(NR ２０ Selected from the group consisting of ) Z １ Z ２ Z ３ and Z ４ One or two of these may not exist, X ５ Z １ Z ２ Z ３ and Z ４ The ring containing is a stable ring structure. R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ These are hydrogen, halogen, hydroxyl, cyano, amino, and C. １～１０ Alkyl, C １～１０ Heteroalkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, -C １～６ Alkyl-C ３～１０ Cycloalkyl, -C １～６ Alkyl-3 to 10-membered heterocyclyl, -C １～６ Alkyl-C ６～１０ Ariel, -C １～６ Alkyl-5 to 10-membered heteroaryl, -CO-C ３～１０ Cycloalkyl, -CO-C １～１０ Alkyl, -CONR ２１ R ２２ , -C(O)OC １～１０ Alkyl, -SO ２ NR ２３ R ２４ , -SO ２ -C １～１０ Alkyl, -SO ２ -C ２～６ Alkenyl, -SO ２ -C ２～６ Alkinyl, -SO ２ -C ３～１０ Cycloalkyl, -SO ２ - 3 to 10 member heterocyclines or 【Transformation 8】 Each of the groups consisting of C is independently selected. １～１０ Alkyl, C １～１０ Heteroalkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, -C １～６ Alkyl-C ３～１０ Cycloalkyl, -C １～６ Alkyl-3 to 10-membered heterocyclyl, -C １～６ Alkyl-C ６～１０ Ariel, -C １～６ Alkyl-5 to 10-membered heteroaryl, -CO-C ３～１０ Cycloalkyl, -CO-C １～１０ Alkyl, -CONR ２１ R ２２ , -C(O)OC １～１０ Alkyl, -SO ２ NR ２３ R ２４ , -SO ２ C １～１０ Alkyl, -SO ２ -C ２～６ Alkenyl, -SO ２ -C ２～６ Alkinyl, -SO ２ -C ３～１０ Cycloalkyl, -SO ２ - 3 to 10-membered heterocyclines and 【Chemistry 9】 These are deuterium, halogen, hydroxyl, cyano, amino, and C. １～１０ Alkyl, halogenated C １～１０ Alkyl, hydroxy-C １～１０ Alkyl, C １～１０ Heteroalkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, -CONR ２５ R ２６ They may be substituted with one, two, three, or four substituents independently selected from the group consisting of the above, R' is H, C １～１０ Alkyl, C ３～１０ Selected from the group consisting of cycloalkyl or CN, R ２１ , R ２２ , R ２３ , R ２４ , R ２５ and R ２６ is H or C １～１０ Each is independently selected from the group consisting of alkyl groups, Alternatively, R ６ and R ７ , R ８ and R ９ , R １２ and R １３ or R １７ and R １８ They are connected to each other, C ３～１０ Forming a cycloalkyl or 3-10 membered heterocycline, C ３～１０ Cycloalkyl or 3- to 10-membered heterocyclines may contain deuterium, halogen, hydroxyl, cyano, amino, or C. １～１０ Alkyl, halogenated C １～１０ Alkyl, C １～１０ Heteroalkyl, C ３～１０ (May be substituted with one, two, three, or four substituents independently selected from the group consisting of cycloalkyls and 3- to 10-membered heterocyclines.) A compound according to claim 1, an isomer thereof, an isotope-labeled compound, or a pharmaceutically acceptable salt thereof, having the above.

3. R ６ , R ７ , R ８ , R ９ , R １１ , R １２ , R １３ , R １６ , R １７ and R １８ However, each is independent of hydrogen, halogen, hydroxyl, cyano, and C. １～１０ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C １～１０ Alkoxy, C ２～５ Alkenil, C ２～５ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, -COC １～１０ Alkyl, -CONR ２１ R ２２ , -C(O)OC １～１０ Alkyl, -SO ２ NR ２３ R ２４ or -SO ２ C １～１０ It is alkyl, C １～１０ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C １～１０ Alkoxy, C ２～５ Alkenil, C ２～５ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, -CO-C １～１０ Alkyl, -CONR ２１ R ２２ , -C(O)OC １～１０ Alkyl, -SO ２ NR ２３ R ２４ and -SO ２ C １～１０ Alkyl, halogen, hydroxyl, cyano, amino, C １～６ Alkyl, halogenated C １～６ Alkyl, hydroxy-C １～６ Alkyl, C １～６ Heteroalkyl, C ３～６ Cycloalkyl, 3-6 membered heterocyclyl and -CONR ２５ R ２６ They may be substituted with one, two, three, or four substituents independently selected from the group consisting of the above, Alternatively, R ６ and R ７ , R ８ and R ９ , R １２ and R １３ or R １７ and R １８ However, they are connected to each other, C ３～１０ Forms a cycloalkyl group, C ３～１０ Cycloalkyls are halogen, hydroxyl, cyano, amino, and C. １～６ Alkyl, halogenated C １～６ Alkyl, C １～６ Heteroalkyl, C ３～６ It may be substituted with one or two substituents independently selected from the group consisting of cycloalkyl or 3- to 6-membered heterocyclyl molecules. R １０ , R １４ , R １５ , R １９ and R ２０ However, each independently, hydrogen and C １～１０ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C １～１０ Alkoxy, -CO-C １～１０ Alkyl, -CO-C ３～１０ Cycloalkyl, -CONR ２１ R ２２ , -C(O)OC １～１０ Alkyl, -SO ２ NR ２３ R ２４ , -SO ２ -C １～１０ Alkyl, -SO ２ -C ２～６ Alkenyl, -SO ２ -C ２～６ Alkinyl, -SO ２ -C ３～１０ Cycloalkyl, -SO ２ -3 to 10-membered heterocyclyl, -C １～６ Alkyl-C ３～１０ Cycloalkyl, -C １～６ Alkyl-3 to 10-membered heterocyclyl, -C １～６ Alkyl-C ６～１０ Ariel, -C １～６ Alkyl-5 to 10-membered heteroaryl or 【Chemistry 10】 C １～１０ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ２～５ Alkenil, C ２～５ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C １～１０ Alkoxy, -CO-C １～１０ Alkyl, -CO-C ３～１０ Cycloalkyl, -CONR ２１ R ２２ , -C(O)OC １～１０ Alkyl, -SO ２ NR ２３ R ２４ , -SO ２ -C １～１０ Alkyl, -SO ２ -C ２～６ Alkenyl, -SO ２ -C ２～６ Alkinyl, -SO ２ -C ３～１０ Cycloalkyl, -SO ２ -3 to 10-membered heterocyclyl, -C １～６ Alkyl-C ３～１０ Cycloalkyl, -C １～６ Alkyl-3 to 10-membered heterocyclyl, -C １～６ Alkyl-C ６～１０ Ariel, -C １～６ Alkyl-5 to 10-membered heteroaryl and 【Chemistry 11】 However, deuterium, halogen, hydroxyl, cyano, amino, C １～６ Alkyl, halogenated C １～６ Alkyl, hydroxy-C １～６ Alkyl, C １～６ Heteroalkyl, C ３～６ Cycloalkyl, 3-6 membered heterocyclyl or -CONR ２５ R ２６ They may be substituted with one, two, three, or four substituents independently selected from the group consisting of the above, R' is H, C １～１０ Alkyl, C ３～１０ Selected from the group consisting of cycloalkyl or CN, R ２１ , R ２２ , R ２３ , R ２４ , R ２５ and R ２６ However, H or C １～６ Each is independently selected from the group consisting of alkyl groups. The compound according to claim 2, its isomer, isotope-labeled compound, or pharmaceutically acceptable salt thereof.

4. The compound has structural formulas IIA, IIB, or IIC: 【Chemistry 12】 (In the formula, R ３ C ６～１０ Ariel, C ３～１０ Selected from the group consisting of cycloalkyl or 5-10 membered heteroaryls, C ６～１０ Ariel, C ３～１０ Cycloalkyl and 5- to 10-membered heteroaryls have one, two or three R ３ａ Each of these may be substituted by the base, R ３ａ These are halogen, cyano, hydroxyl, and C, respectively. １～１０ Alkyl, C １～１０ Heteroalkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl or -NR ４ R ５ Independently selected from the group consisting of C １～１０ Alkyl, C １～１０ Heteroalkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl and -NR ４ R ５ These are halogens, cyano, hydroxyl, or C １～６ Each of these substituents may be independently selected from the group consisting of alkyl groups, R ４ and R ５ Each of them is independently of hydrogen or C １～１０ (It is alkyl.) A compound according to claim 2 or 3, an isomer thereof, an isotope-labeled compound, or a pharmaceutically acceptable salt thereof, having the above.

5. R ３ However, it is a 5-6 member heteroaryl, and a 5-6 member heteroaryl is C １～６ The compound according to claim 4, its isomers, or pharmaceutically acceptable salts thereof, which may be substituted with one or two substituents independently selected from the group consisting of alkyl groups.

6. Z １ However, CR ６ R ７ And, Z ２ However, CR ８ R ９ Or selected from the group consisting of -C(O)-, Z ３ However, CR １１ CR １２ R １３ , N, NR １４ Selected from the group consisting of O or -C(O)-, Z ４ However, absent, CR １６ CR １７ R １８ , N, NR １９ Or selected from the group consisting of -C(O)-, R ６ , R ７ , R ８ , R ９ , R １１ , R １２ , R １３ , R １６ , R １７ and R １８ However, hydrogen, hydroxyl, C １～１０ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ６～１０ Each is independently selected from the group consisting of aryls or 5- to 10-membered heteroaryls, C １～１０ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ６～１０ Aryl and 5-10 member heteroaryls are halogens, C １～６ Alkyl or halogenated C １～６ Each atom may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. Alternatively, R ６ and R ７ , R ８ and R ９ , R １２ and R １３ or R １７ and R １８ However, they are connected to each other, C ３～１０ Forms a cycloalkyl group, C ３～１０ Cycloalkyls are halogen, hydroxyl, cyano, amino, and C. １～６ Alkyl, halogenated C １～６ Alkyl, C １～６ Heteroalkyl, C ３～６ It may be substituted with one or two substituents independently selected from the group consisting of cycloalkyl or 3- to 6-membered heterocyclyl molecules. R １４ and R １９ However, hydrogen, C １～１０ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, -CO-C １～１０ Alkyl, -CO-C ３～１０ Cycloalkyl, -C(O)OC １～１０ Alkyl, -SO ２ -C １～１０ Alkyl, -SO ２ -C ２～６ Alkenyl, -SO ２ -C ２～６ Alkinyl, -SO ２ -C ３～１０ Cycloalkyl, -SO ２ -3 to 10-membered heterocyclyl, -C １～４ Alkyl-C ３～１０ Cycloalkyl, -C １～４ Alkyl-3 to 10-membered heterocyclyl, -C １～４ Alkyl-C ６～１０ Ariel, -C １～４ Alkyl-5 to 10-membered heteroaryl or 【Chemistry 13】 Each of the groups consisting of C is independently selected. １～１０ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, -CO-C １～１０ Alkyl, -CO-C ３～１０ Cycloalkyl, -C(O)OC １～１０ Alkyl, -SO ２ -C １～１０ Alkyl, -SO ２ -C ２～６ Alkenyl, -SO ２ -C ２～６ Alkinyl, -SO ２ -C ３～１０ Cycloalkyl, -SO ２ -3 to 10-membered heterocyclyl, -C １～４ Alkyl-C ３～１０ Cycloalkyl, -C １～４ Alkyl-3 to 10-membered heterocyclyl, -C １～４ Alkyl-C ６～１０ Ariel, -C １～４ Alkyl-5 to 10-membered heteroaryl and 【Chemistry 14】 However, deuterium, halogen, hydroxyl, cyano, C １～６ Alkyl, halogenated C １～６ Alkyl, hydroxy-C １～６ Alkyl, C １～６ Heteroalkyl, C ３～６ Cycloalkyl, 3-6 membered heterocyclyl, -CONR ２５ R ２６ Each of these may be substituted with one, two, or three substituents independently selected from the group consisting of the following: R' is H, C １～１０ Alkyl, C ３～１０ Selected from the group consisting of cycloalkyl or CN, R ２５ and R ２６ However, hydrogen or C １～６ Each is independently selected from the group consisting of alkyl groups. A compound according to any one of claims 2 to 5, an isomer thereof, an isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

7. Z １ However, CR ６ R ７ And, R ６ and R ７ However, hydrogen or C １～１０ Each is independently selected from the group consisting of alkyl groups. A compound according to any one of claims 2 to 6, an isomer thereof, an isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

8. Z ２ However, CR ８ R ９ Or selected from the group consisting of -C(O)-, R ８ and R ９ However, hydrogen or C １～１０ Each is independently selected from the group consisting of alkyl groups. A compound according to any one of claims 2 to 7, an isomer thereof, an isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

9. Z ３ However, CR １１ CR １２ R １３ , N, NR １４ Selected from the group consisting of O or -C(O)-, R １１ , R １２ and R １３ However, hydrogen, hydroxyl, C １～１０ Alkyl, C ３～１０ A cycloalkyl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group is independently selected from the group consisting of C １～１０ Alkyl, C ３～１０ Cycloalkyls, 3-10 membered heterocyclyls, and 5-10 membered heteroaryls are C １～６ Alkyl or halogenated C １～６ Each atom may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. R １４ However, hydrogen, C １～１０ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, -CO-C １～１０ Alkyl, -CO-C ３～１０ Cycloalkyl, -C(O)OC １～１０ Alkyl, -SO ２ NR ２３ R ２４ , -SO ２ -C １～１０ Alkyl, -SO ２ -C ２～６ Alkenyl, -SO ２ -C ２～６ Alkinyl, -SO ２ -C ３～１０ Cycloalkyl, -SO ２ -3 to 10-membered heterocyclyl, -C １～４ Alkyl-C ３～１０ Cycloalkyl, -C １～４ Alkyl-3 to 10-membered heterocyclyl or 【Chemistry 15】 Selected from the group consisting of C １～１０ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, -CO-C １～１０ Alkyl, -CO-C ３～１０ Cycloalkyl, -C(O)OC １～１０ Alkyl, -SO ２ -C １～１０ Alkyl, -SO ２ -C ２～６ Alkenyl, -SO ２ -C ２～６ Alkinyl, -SO ２ -C ３～１０ Cycloalkyl, -SO ２ -3 to 10-membered heterocyclyl, -C １～４ Alkyl-C ３～１０ Cycloalkyl, -C １～４ Alkyl-3 to 10-membered heterocyclyl and 【Chemistry 16】 However, halogen, hydroxyl, cyano, C １～６ Alkyl or halogenated C １～６ Each of these substituents may be independently selected from the group consisting of alkyl groups, R' is H, C １～１０ Alkyl, C ３～１０ Selected from the group consisting of cycloalkyl or CN, R ２３ and R ２４ However, hydrogen or C １～１０ Each is independently selected from the group consisting of alkyl groups. A compound according to any one of claims 2 to 8, an isomer thereof, an isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

10. Z ４ However, absent, CR １６ CR １７ R １８ , N, NR １９ Or selected from the group consisting of -C(O)-, R １６ , R １７ and R １８ However, hydrogen, C １～１０ Alkyl or C ３～１０ Each is independently selected from the group consisting of cycloalkyls, C １～１０ Alkyl and C ３～１０ Cycloalkyls are halogens, C １～６ Alkyl or halogenated C １～６ Each atom may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. Alternatively, R １７ and R １８ However, they are connected to each other, C ３～１０ Forms a cycloalkyl group, C ３～１０ Cycloalkyls are halogen, hydroxyl, cyano, amino, and C. １～６ Alkyl, halogenated C １～６ Alkyl, C １～６ Heteroalkyl, C ３～６ It may be substituted with one or two substituents independently selected from the group consisting of cycloalkyl or 3- to 6-membered heterocyclyl molecules. R １９ However, hydrogen, C １～１０ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, -SO ２ -C １～１０ Alkyl, -C １～４ Alkyl-C ３～１０ Cycloalkyl, -C １～４ Alkyl-3 to 10-membered heterocyclyl, -C １～４ Alkyl-C ６～１０ Aryl or -C １～４ Selected from the group consisting of alkyl-5 to 10-membered heteroaryls, C １～１０ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered heterocyclyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, -SO ２ C １～１０ Alkyl, -C １～４ Alkyl-C ３～１０ Cycloalkyl, -C １～４ Alkyl-3 to 10-membered heterocyclyl, -C １～４ Alkyl-C ６～１０ Aryl and -C １～４ Alkyl-5 to 10-membered heteroaryls, halogens, hydroxyls, cyanos, C １～６ Alkyl, halogenated C １～６ Alkyl, hydroxy-C １～６ Alkyl, C １～６ Heteroalkyl, C ３～６ Cycloalkyl and -CONR ２５ R ２６ Each of these may be substituted with one, two, or three substituents independently selected from the group consisting of the following: R ２５ and R ２６ However, hydrogen or C １～６ Each is independently selected from the group consisting of alkyl groups. A compound according to any one of claims 2 to 9, an isomer thereof, an isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

11. The compounds are as follows: 【Chemical Engineering 17A】 【Chemistry 17B】 [Chemical 17C] [Chemical 17D] [Chemical 17E] [Chemical 17F] A compound according to any one of claims 1 to 10, an isomer thereof, an isotope-labeled compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, an isomer thereof, an isotope-labeled compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. Use of a compound, an isomer thereof, an isotope-labeled compound, or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for treating cancer.

14. The use according to claim 13, wherein the cancer is colon cancer.

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