Cyclopentylpyrazoleamine derivatives and their use

Abstract

This disclosure belongs to the field of medicinal chemistry and relates to cyclopentylpyrazoleamine derivatives and their use, and more specifically to compounds represented by formula (I), their isomers, or pharmaceutically acceptable salts thereof. [Formula 1] TIFF2026516638000131.tif29170

Description

[Technical Field]

[0001] This invention claims the following priority:

[0002] This invention relates to: 1) the priority rights and interests of patent application No. 202310411874.5 filed with the China National Intellectual Property Administration on April 17, 2023; 2) the priority rights and interests of patent application No. 202310815737.8 filed with the China National Intellectual Property Administration on July 4, 2023; and 3) patent application No. 202311288133.9 filed with the China National Intellectual Property Administration on September 28, 2023. The present invention claims priority and rights to the above-mentioned applications, 4) priority and rights to patent application No. 202410431164.3 filed with the China National Intellectual Property Administration on 10 April 2024, and 5) priority and rights to patent application No. 202410445541.9 filed with the China National Intellectual Property Administration on 13 April 2024, the disclosures of the above-mentioned applications being incorporated herein by reference as a whole.

[0003] (Technical field) This disclosure belongs to the field of medicinal chemistry and relates to cyclopentylpyrazoleamine derivatives and their use, and more specifically to compounds represented by formula (I), their isomers, or pharmaceutically acceptable salts thereof. [Background technology]

[0004] Cyclin-dependent kinases (CDKs) belong to the serine / threonine protein kinase family and are directly involved in regulating the cell cycle, promoting ordered cell growth, proliferation, and apoptosis. The cell cycle is divided into four phases: G1, S, G2, and M. Of these, the G1-S regulatory point is the most important, and its control is closely related to CDKs. CDKs bind to cyclins to form protein kinase complexes. These complexes catalyze the phosphorylation of substrates, regulate cell cycle processes, and sequentially complete DNA replication and mitosis, leading to cell division and proliferation. The cell cycle is subject to two types of regulation: repression and promotion, and normally these two are in a dynamic balance. However, if the signal that promotes cell proliferation becomes stronger or the signal that suppresses cell proliferation weakens, the balance is disrupted, leading to uncontrolled cell proliferation and tumor development. Studies have shown that CDK overexpression is present in many malignant tumors.

[0005] Studies have shown that CDKs directly involved in cell cycle regulation mainly include CDK1, CDK2, CDK4, and CDK6, which play a crucial role in cell cycle regulation. CDK2 belongs to the CDKs family and is a cell cycle-dependent kinase that is critically important for the completion of the G1 phase of mitosis and the transition from G1 to S phase. In late G1 phase, CDK2 binds to and activates cyclin E, promoting continuous phosphorylation of pRb, ensuring that the cell smoothly passes through G1 phase and enters S phase. Slowing down of E2F is a major condition for the completion of S phase, and in early S phase, CDK2 binds to cyclin A, slowing down the E2F transcription factor, thereby promoting the smooth completion of S phase. On the other hand, continuous activity of E2F causes apoptosis in cells, so selectively inhibiting CDK2 / cyclin A activity increases the concentration of E2F, causing the cell cycle to arrest in S phase or inducing apoptosis, thus achieving therapeutic objectives for tumor cells. [Overview of the project] [Means for solving the problem]

[0006] The present disclosure provides a compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0007]

Chemical formula

[0008] (wherein, X 1 , X 2 and X 3 are each independently selected from N and C(R a ), Z 1 , Z 2 and Z 3 are each independently selected from O, S, N(R b ), S(O), S(O)2, C(O) or C(R a R a ), L 1 and L 2 are each independently a single bond, -N(R b )-, -N=, -O-, -S-, -(CH2) m -, -(CD2) m -, -(CHD) m -, -C(=O)-, -S(=O)-, -S(=O)2-, -S(=O)(=N(R b ))-, -S(=O)(R c )-, -P(=O)(R c )- or -P(=O)(NR b R b )-, R 1 is selected from H, deuterium, C 1-3 alkyl, C 1-3 alkoxy, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, a 3- to 6-membered heterocyclyl, phenyl or a 5- to 6-membered heteroaryl, and the C 1-3 alkyl or C 1-3Each alkoxy independently contains one, two, or three R atoms. d It may be replaced by the above C 3-6 Cycloalkyl, C 3-6 Cycloalkenyls, 3-6 membered heterocyclyls, phenyls, or 5-6 membered heteroaryls can independently be one or more R e It may also be replaced with A is

[0009] [ka]

[0010] Alternatively, selected from 3- to 6-membered heterocyclines containing one or two N atoms, the 3- to 6-membered heterocyclines independently contain one or more R atoms. z It may also be replaced with R 2 , R 3 and R 4 These are H, deuterium, halogen, OH, CN, NH2, and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Selected from cycloalkenyls or 3-6 member heterocyclyls, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyls or 3-6 member heterocyclyls independently contain one or more R z It may also be replaced with Alternatively, R 2 and R 3 C 3-6 Cycloalkyl, C 3-6 Forming a cycloalkenyl or a 3-6 member heterocycline, R 4 H, deuterium, halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 Selected from alkoxy, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6Cycloalkyl, C 3-6 Cycloalkenyls or 3-6 member heterocyclyls independently contain one or more R z It may also be replaced with Alternatively, R 2 , R 3 and R 4 C 5-8 Forming a bicycloalkyl or a 5-8 membered bicycloheteroalkyl, the C 5-8 Bicycloalkyl or 5-8 membered bicycloheteroalkyl groups independently contain one or more R groups. z It may also be replaced with Each R a These are, independently, hydrogen, deuterium, halogen, OH, CN, NH2, COOH, NO2, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 Alkylene, C 1-3 Alkylamino, (C 1-3 Selected from alkyl)2amino, the C 1-3 Alkyl or C 1-3 Alkoxy can be one or more R independently. x It may also be replaced with Alternatively, C(R a R a ) Two R a C 3-6 Cycloalkyl, C 3-6 Forming a cycloalkenyl or a 3-6 membered heterocycline, the C 3-6 Cycloalkyl, C 3-6 Cycloalkenyls or 3-6 member heterocyclyls independently contain one or more R y It may also be replaced with Each R b These are H and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy, -C(=O)H, -S(=O)2C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Selected from cycloalkenyls or 3-6 member heterocyclyls, the C1-3 Alkyl or C 1-3 Alkoxy may each independently be substituted with one, two or three Rs x and the C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl or 3- to 6-membered heterocyclyl may each independently be substituted with one or more Rs y and R c is selected from halogen, OH, CN or C 1-3 alkyl, and the C 1-3 alkyl may each independently be substituted with one or more Rs x and each R d is independently selected from deuterium, halogen, OH, CN or NH2 each R e is independently selected from deuterium, halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy may each independently be substituted with one or more Rs x and each R x is independently selected from deuterium, halogen, OH, CN or NH2 each R y is independently selected from deuterium, halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy may each independently be substituted with one or more substituents selected from deuterium, halogen, OH, CN or NH2 each R z is independently selected from deuterium, halogen, OH, CN, NH2, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3The alkoxy may be independently substituted with one or more substituents selected from deuterium, halogen, OH, CN or NH2, m is selected from 1, 2 or 3, The carbon atom marked with "*" is a chiral carbon atom and exists in the form of a single (R) or (S) enantiomer, or exists in an enantiomer-rich form, Or each L 1 、L 2 、R 1 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e 、R x 、R y or R z may each independently be substituted with one or more substituents.)

[0011] In some embodiments of the present disclosure, each R a 、R b 、R c 、R d 、R e 、R x 、R y or R z may each independently be substituted with one or more substituents.

[0012] In some embodiments of the present disclosure, each R d 、R x 、R y or R z may each independently be substituted with one or more substituents.

[0013] In some other embodiments of the present disclosure, the R 1 、R 2 、R 3 、R 4 、R a 、R d 、R e 、R x 、R y or Rz Each of these may be independently substituted with one or more deuterium atoms.

[0014] In some other embodiments of this disclosure, the R 1 , R 2 , R 3 , R 4 , R a , R d , R e , R x , R y or R z Each of these may be independently substituted with one, two, three, four, or five deuterium atoms, or each may be independently substituted with three or five deuterium atoms.

[0015] In some embodiments of this disclosure, the R 1 , R 2 , R 3 , R 4 , R a , R d , R e , R x , R y and R z At least one of these groups contains a deuterium atom.

[0016] In some embodiments of this disclosure, the phrase "may be replaced by one or more ○○" may be independently replaced by ○○ selected from one, two, three, four, five, or six.

[0017] In some embodiments of this disclosure, the phrase "may be replaced by one or more ○○" may be independently replaced by ○○ selected from one, two, three, four, or five.

[0018] In some embodiments of this disclosure, the phrase "may be replaced by one or more ○○" may be independently replaced by ○○ selected from one, two, three, or four.

[0019] In some embodiments of this disclosure, the phrase "may be replaced by one or more ○○" may be independently replaced by ○○ selected from one, two, or three.

[0020] In some embodiments of this disclosure, each “heterocyclyl” described herein may be independently selected from “heterocycloalkyl” or “heterocycloalkenyl.”

[0021] In some embodiments of the present disclosure, each “3- to 6-membered heterocyclyl” described herein may be independently selected from “3- to 6-membered heterocycloalkyl” or “3- to 6-membered heterocycloalkenyl”.

[0022] In some embodiments of the present disclosure, each “3- to 6-membered heterocyclyl” described herein may be independently selected from “3- to 6-membered heterocycloalkyl.”

[0023] In some embodiments of this disclosure, each L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R a , R b , R c , R d , R e , R x , R y or R zThese are, independently of each other, deuterium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxy, carboxyaldehyde group, imine group, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, haloalkenyl, cycloalkenyl, halocycloalkenyl, alkynyl, haloalkynyl, cycloalkynyl, halocycloalkynyl, heteroalkyl, haloheteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocycloalkylthio, acyl, acyloxy, carbamate group, amide group, ureido group, epoxy group, and ester group, among others. The group may be substituted with one or more substituents, and the group may be oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S( They may be substituted with one or more substituents from among O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl, or aryloxy.

[0024] In some embodiments of this disclosure, X 1 , X 2and X 3 All of these are C(R a ) will be selected from.

[0025] In some embodiments of this disclosure, X 1 , X 2 and X 3 One of them is selected from N.

[0026] In some embodiments of this disclosure, X 1 It is selected from N, and X 2 and X 3 All of these are C(R a ) will be selected from.

[0027] In some embodiments of this disclosure, X 2 It is selected from N, and X 1 and X 3 All of these are C(R a ) will be selected from.

[0028] In some embodiments of this disclosure, X 3 It is selected from N, and X 1 and X 2 All of these are C(R a ) will be selected from.

[0029] In some embodiments of this disclosure, each R a These are, independently, hydrogen, deuterium, halogen, OH, CN, NH2, COOH, NO2, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 Alkylene, C 1-3 Alkylamino, (C 1-3 Selected from alkyl)2amino, the C 1-3 Alkyl or C 1-3 Alkoxy can be one or more R independently. x It may also be replaced with Alternatively, C(R a R a ) Two R a C3-6 forms a cycloalkyl or 3- to 6-membered heterocycloalkyl, and the C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl is independently optionally substituted with one or more R y .

[0030] In some embodiments of the present disclosure, each R a is independently selected from hydrogen, F, Cl, Br, I, CN, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxyC 1-3 alkylene, and the C 1-3 alkyl or C 1-3 alkoxy is independently optionally substituted with one, two or three R x .

[0031] In some other embodiments of the present disclosure, each R a is independently selected from hydrogen, F, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxyC 1-3 alkylene, and the C 1-3 alkyl or C 1-3 alkoxy is independently optionally substituted with one, two or three R x .

[0032] In some other embodiments of the present disclosure, each R a is independently selected from hydrogen, F, methyl, ethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl, and the methyl, ethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl is independently optionally substituted with one, two or three R x .

[0033] In some embodiments of the present disclosure, each R aEach is independently selected from hydrogen, F, methyl, or methoxymethyl, and each methyl or methoxymethyl is independently selected from 1, 2, or 3 R x It may be replaced with .

[0034] In some embodiments of this disclosure, each R a Each of these is independently selected from hydrogen, F, methyl, or methoxymethyl.

[0035] In some embodiments of this disclosure, each R a Each of these is independently selected from hydrogen, F, or methoxymethyl.

[0036] In some embodiments of this disclosure, each R a Each of these is independently selected from hydrogen or methyl.

[0037] In some embodiments of this disclosure, each R a Each of these is independently selected from hydrogen.

[0038] In some embodiments of this disclosure, X 1 , X 2 and X 3 All of these are selected from CH.

[0039] In some embodiments of this disclosure, X 1 C(R a ) is selected from X 2 and X 3 All of these are selected from CH.

[0040] In some embodiments of this disclosure, X 1 It is selected from C(F), X 2 and X 3 All of these are selected from CH.

[0041] In some embodiments of this disclosure, X 1 It is selected from C(CH2OCH3), X 2 and X3 All of these are selected from CH.

[0042] In some embodiments of this disclosure, Z 1 , Z 2 and Z 3 These are, independently, S(O), S(O)2, or C(R) a R a ) will be selected from.

[0043] In some embodiments of this disclosure, Z 2 This is selected from S(O) or S(O)2.

[0044] In some embodiments of this disclosure, Z 2 is selected from S(O) or S(O)2, Z 1 and Z 3 Each of them is independent of C(R a R a ) will be selected from.

[0045] In some embodiments of this disclosure, Z 2 is selected from S(O) or S(O)2, Z 1 and Z 3 Each of these is independently selected from CH2 or CH(CH3).

[0046] In some embodiments of this disclosure, Z 2 It is selected from S(O)2, Z 1 and Z 3 All of these are selected from CH2.

[0047] In some embodiments of this disclosure, Z 2 It is selected from S(O)2, Z 1 It is selected from CH(CH3), Z 3 It is selected from CH2.

[0048] In some embodiments of this disclosure, Z 2 It is selected from S(O)2, Z 1 and Z 3All of these are selected from CH(CH3).

[0049] In some embodiments of this disclosure, Z 2 is selected from S(O), Z 1 and Z 3 All of these are selected from CH2.

[0050] In some embodiments of this disclosure, C(R a R a ) Two R a Together with a commonly linked carbon atom, these form a cyclopropyl, cyclobutyl, oxyranil, azilidinil, oxetanil, thietanil, or azetidine group, and each of these cyclopropyl, cyclobutyl, oxyranil, azilidinil, oxetanil, thietanil, or azetidine groups independently forms one or more R y It may be replaced with .

[0051] In some embodiments of this disclosure, C(R a R a ) Two R a Together with the commonly linked carbon atoms, it forms a cyclopropyl or azetidine group.

[0052] In some embodiments of this disclosure, L 1 This is a single bond, -N(R b )-, -O-, -S(=O)2-, -S-, -(CH2) m - or -C (=O)- will be selected.

[0053] In some embodiments of this disclosure, L 1 This is a single bond, -NH-, -N(C 1-3 Selected from alkyl)-, -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, or -C(=O)-.

[0054] In some embodiments of this disclosure, L 1The bond is selected from a single bond, -NH-, -N(CH3)-, -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, or -C(=O)-.

[0055] In some embodiments of this disclosure, L 1 The bond is selected from a single bond, -NH-, -N(CH3)-, -S(=O)2-, -CH2-, or -C(=O)-.

[0056] In some embodiments of this disclosure, L 1 The bond is selected from either a single bond or an -NH-.

[0057] In some embodiments of this disclosure, L 1 It is selected from single bonds.

[0058] In some embodiments of this disclosure, L 2 This is a single bond, -NH-, -N(C 1-3 Alkyl)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -C(=O)-, -S(=O)-, -S(=O)2- or -S(=O)(C 1-3 Selected from alkyl.

[0059] In some embodiments of this disclosure, L 2 The bond is selected from a single bond, -NH-, -N(CH3)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -C(=O)-, -S(=O)-, -S(=O)2-, or -S(=O)(CH3)-.

[0060] In some embodiments of this disclosure, L 2 The bond is selected from a single bond, -NH-, or -S(=O)2-.

[0061] In some embodiments of this disclosure, L 2 The bond is selected from either a single bond or -S(=O)2-.

[0062] In some embodiments of this disclosure, L 2It is selected from single bonds.

[0063] In some embodiments of this disclosure, -L 2 -L 1 - is a single bond, -NH-, -N(CH3)-, -C(=O)-, -CH2-, -CH2-CH2-, -S(=O)2-, -CH2-NH-, -NH-CH2-, -C H2-N(CH3)-, -N(CH3)-CH2-, -C(=O)-CH2-, -CH2-C(=O)-, -C(=O)-NH-, -NH-C(=O)-, -NH-S Selected from (=O)2-, -S(=O)2-NH-, -N(CH3)-S(=O)2-, -S(=O)2-N(CH3)-, -N(CH3)-C(=O)-, -C(=O)-N(CH3)-, -N(CH3)-CH2-CH2-, -CH2-CH2-N(CH3)-, -NH-CH2-CH2-, or -CH2-CH2-NH-.

[0064] In some embodiments of this disclosure, -L 2 -L 1 The - is selected from a single bond, -NH-, -CH2-, -NH-S(=O)2-, or -S(=O)2-NH-.

[0065] In some embodiments of this disclosure, -L 2 -L 1 - is selected from a single bond, -NH-, -CH2-, or -S(=O)2-NH-.

[0066] In some embodiments of this disclosure, -L 2 -L 1 The - is selected from a single bond or -S(=O)2-NH-.

[0067] In some embodiments of this disclosure, -L 2 -L 1 - is selected from single bonds.

[0068] In some embodiments of this disclosure, R 1 H, deuterium, C 1-3 Alkyl, C 1-3Alkoxy, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 3-6 Selected from cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, the C 1-3 Alkyl or C 1-3 Each alkoxy independently contains one, two, or three R atoms. d It may be replaced by the above C 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups, phenyl groups, or 5-6 membered heteroaryl groups can be independently represented by one or more R groups. e It may be replaced with .

[0069] In some embodiments of this disclosure, R 1 H, C 1-3 Alkyl, C 1-3 Alkoxy, -NH2, -NH(C 1-3 A 4-6 member heterocycloalkyl group comprising one or two atoms selected from alkyl, cyclopropyl, cyclobutyl, cyclopentyl, N, O, and S atoms, or a 5-6 member heteroaryl group comprising one or two N atoms, wherein the C 1-3 Alkyl or C 1-3 Each alkoxy independently contains one, two, or three R atoms. d The 4-6 member heterocycloalkyl or 5-6 member heteroaryl groups may be substituted with 1, 2, or 3 R groups, each independently. e It may be replaced with .

[0070] In some embodiments of this disclosure, R 1 The group is selected from a 4-6 membered heterocycloalkyl group containing one or two atoms selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, cyclopentyl, N, O, and S atoms, or a 5-6 membered heteroaryl group containing one or two N atoms, wherein the methyl, ethyl, or methoxy group is independently comprised of one, two, or three R atoms. dThe 4-6 member heterocycloalkyl or 5-6 member heteroaryl groups may be substituted with 1, 2, or 3 R groups, each independently. e It may be replaced with .

[0071] In some embodiments of this disclosure, R 1 R is selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, oxazolyl, or pyrimidinyl, and the methyl, ethyl, or methoxy is independently one, two, or three R d The cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, oxazolyl, or pyrimidinyl may be substituted with one, two, or three R e It may be replaced with .

[0072] In some embodiments of this disclosure, R 1 This is selected from H or methyl.

[0073] In some embodiments of this disclosure, R 1 It is selected from H.

[0074] In some embodiments of this disclosure, the constituent units

[0075] [ka]

[0076] teeth,

[0077] [ka]

[0078] [ka]

[0079] Selected from.

[0080] In some embodiments of this disclosure, the constituent units

[0081] [ka]

[0082] teeth,

[0083] [ka]

[0084] [ka]

[0085] Selected from.

[0086] In some embodiments of this disclosure, the constituent units

[0087] [ka]

[0088] teeth,

[0089] [ka]

[0090] Selected from.

[0091] In some embodiments of this disclosure, each R d Each of these is independently selected from F, Cl, Br, I, or OH.

[0092] In some embodiments of this disclosure, each R dEach of these is independently selected from F or OH.

[0093] In some embodiments of this disclosure, each R e These are F, Cl, Br, I, =O, or C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Each alkyl group independently has 1, 2, or 3 R x It may be replaced with .

[0094] In some embodiments of this disclosure, each R x Each of these is independently selected from halogens.

[0095] In some embodiments of this disclosure, each R x Each of these is selected independently from F.

[0096] In some embodiments of this disclosure, each R e These are F, Cl, Br, I, =O, or C, respectively, independently. 1-3 Selected from alkyl groups.

[0097] In some other embodiments of this disclosure, each R e Each of these is independently selected from F or methyl.

[0098] In some other embodiments of this disclosure, each R y Each of these is independently selected from halogens.

[0099] In some other embodiments of this disclosure, each R y Each of these is selected independently from F.

[0100] In some embodiments of this disclosure, each R b These are H and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy, -C(=O)H, -S(=O)2C 1-3 Alkyl, C 3-6Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-3 Alkyl or C 1-3 Each alkoxy independently contains one, two, or three R atoms. x It may be replaced by the above C 3-6 Cycloalkyl or 3-6 member heterocycloalkyl groups can independently have one or more R groups. y It may be replaced with .

[0101] In some embodiments of this disclosure, each R b These are H and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-3 Alkyl or C 1-3 Each alkoxy independently contains one, two, or three R atoms. x It may be replaced by the above C 3-6 Each cycloalkyl or 3-6 membered heterocycloalkyl group independently contains 1, 2, or 3 R groups. y It may be replaced with .

[0102] In some other embodiments of this disclosure, each R b Each of these is independently selected from H, -C(=O)H, -S(=O)2CH3, or methyl, and each of the methyl atoms is independently selected from 1, 2, or 3 R x It may be replaced with .

[0103] In some embodiments of this disclosure, each R b These are, independently, H or C 1-3 Selected from alkyl, the C 1-3 Each alkyl group independently has 1, 2, or 3 R x It may be replaced with .

[0104] In some embodiments of this disclosure, each R bEach is independently selected from H or methyl, and each methyl is independently selected from 1, 2 or 3 R x It may be replaced with .

[0105] In some embodiments of this disclosure, each R b Each of these is independently selected from H or methyl.

[0106] In some embodiments of this disclosure, R c C 1-3 Selected from alkyl, the C 1-3 Each alkyl group independently has 1, 2, or 3 R x It may be replaced with .

[0107] In some embodiments of this disclosure, R c The methyl group is selected from methyl groups, and each methyl group independently comprises one, two, or three R groups. x It may be replaced with .

[0108] In some embodiments of this disclosure, R c It is selected from methyl.

[0109] In some embodiments of this disclosure, m is selected from 1 or 2.

[0110] In some embodiments of this disclosure, A is

[0111] [ka]

[0112] Selected from.

[0113] In some embodiments of this disclosure, R 2 , R 3 and R 4 These are H, deuterium, halogen, OH, CN, NH2, and C, respectively, independently. 1-3 Alkyl, C 1-3Alkoxy, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 member heterocycloalkyl groups can independently have one or more R groups. z It may also be replaced with Alternatively, R 2 and R 3 C 3-6 Forming a cycloalkyl or 3-6 member heterocycloalkyl, R 4 H, deuterium, halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 Selected from alkoxy, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 member heterocycloalkyl groups can independently have one or more R groups. z It may also be replaced with Alternatively, R 2 , R 3 and R 4 C 5-8 Forming a bicycloalkyl or a 5-8 membered bicycloheteroalkyl, the C 5-8 Bicycloalkyl or 5-8 membered bicycloheteroalkyl groups independently contain one or more R groups. z It may be replaced with .

[0114] In some embodiments of this disclosure, R 2 , R 3 and R 4 These are H, deuterium, and C, respectively, independently. 1-3 Alkyl or C 3-6 Selected from cycloalkyl, the C 1-3 Alkyl or C 3-6 Each cycloalkyl group independently has 1, 2, or 3 R z It may be replaced with .

[0115] In some embodiments of this disclosure, R2 , R 3 and R 4 Each is independently selected from H, deuterium, methyl, ethyl, or cyclopropyl, and each of the methyl, ethyl, or cyclopropyl is independently selected from 1, 2, or 3 R z It may be replaced with .

[0116] In some other embodiments of this disclosure, each R z These are, independently, deuterium, halogen, OH, and C. 1-3 Alkyl or C 1-3 Selected from alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy may be independently substituted with one or more substituents selected from deuterium, halogens, OH, CN, or NH2.

[0117] In some embodiments of this disclosure, each R z Each of these is independently deuterium, halogen, OH, or C 1-3 Selected from alkyl groups. In some other embodiments of this disclosure, each R z Each of them is independent of C 1-3 Selected from alkoxy.

[0118] In some embodiments of this disclosure, each R z Each is independently selected from halogen, OH, or methyl. In some other embodiments of the present disclosure, each R z Each is independently selected from methoxy.

[0119] In some embodiments of this disclosure, each R z Each of these is independently selected from F, OH, methyl, or methoxy.

[0120] In some embodiments of this disclosure, each R z Each of these is independently selected from F, OH, or methyl.

[0121] In some embodiments of this disclosure, each R z Each of these is independently selected from F or OH.

[0122] In some embodiments of this disclosure, each R z Each is independently selected from methyl.

[0123] In some embodiments of this disclosure, R 2 , R 3 and R 4 Each of these is independently selected from H, deuterium, methyl, -CD3, difluoromethyl, trifluoromethyl, ethyl, 2-hydroxyethyl, or cyclopropyl.

[0124] In some other embodiments of this disclosure, R 2 , R 3 and R 4 Each of these is independently selected from H, methyl, difluoromethyl, trifluoromethyl, 2-hydroxyethyl, or cyclopropyl.

[0125] In some embodiments of this disclosure, R 2 , R 3 and R 4 At least one of them is selected from H.

[0126] In some other embodiments of this disclosure, R 2 is selected from H or methyl, and R 3 and R 4 Each of these is independently selected from H, methyl, difluoromethyl, trifluoromethyl, 2-hydroxyethyl, or cyclopropyl.

[0127] In some other embodiments of this disclosure, R 2 is selected from H or methyl, and R 3 is selected from H or methyl, and R 4 This is selected from H, methyl, difluoromethyl, trifluoromethyl, 2-hydroxyethyl, or cyclopropyl.

[0128] In some embodiments of this disclosure, R 2 , R 3 and R 4 All of these are H.

[0129] In some other embodiments of this disclosure, R 2 is selected from H, R 3 is selected from H, R 4 This is selected from H, methyl, difluoromethyl, trifluoromethyl, 2-hydroxyethyl, or cyclopropyl.

[0130] In some other embodiments of this disclosure, R 2 is selected from H, R 3 is selected from methyl, R 4 This is selected from H, methyl, difluoromethyl, trifluoromethyl, 2-hydroxyethyl, or cyclopropyl.

[0131] In some other embodiments of this disclosure, R 2 is selected from methyl, R 3 is selected from methyl, R 4 This is selected from H, methyl, difluoromethyl, trifluoromethyl, 2-hydroxyethyl, or cyclopropyl.

[0132] In some embodiments of this disclosure, R 2 and R 3 C 3-4 Forming a cycloalkyl or 3-4 member heterocycloalkyl, R 4 H or C 1-3 Selected from alkyl, the C 1-3 Alkyl, C 3-4 Each cycloalkyl or 3-4 membered heterocycloalkyl group independently contains 1, 2, or 3 R atoms. z It may be replaced with .

[0133] In some embodiments of this disclosure, R 2and R 3 Together with a commonly linked carbon atom, it forms cyclopropyl, oxyranyl, or aziridinyl, R 4 R is selected from H, methyl, or ethyl, and each of the methyl, ethyl, cyclopropyl, oxyranyl, or aziridinyl is independently one, two, or three R z It may be replaced by R. In some other embodiments of this disclosure, 2 and R 3 Together with commonly linked carbon atoms, these form cyclobutyl, and each cyclobutyl independently contains 1, 2, or 3 R z It may be replaced with .

[0134] In some embodiments of this disclosure, R 2 and R 3 Together with the commonly linked carbon atoms, it forms a cyclopropyl group, R 4 is selected from H or methyl, and the cyclopropyl is independently one, two or three R z It may be replaced by R. In some other embodiments of this disclosure, 2 and R 3 Together with the commonly linked carbon atoms, it forms cyclobutyl, R 4 is selected from H or methyl, and the cyclobutyl is independently composed of 1, 2 or 3 R z It may be replaced with .

[0135] In some embodiments of this disclosure, R 2 and R 3 Together with the commonly linked carbon atoms, it forms a cyclopropyl group, R 4 is selected from H or methyl, and the cyclopropyl may be independently substituted with one, two or three F atoms. In some other embodiments of the present disclosure, R 2 and R 3 Together with the commonly linked carbon atoms, it forms cyclobutyl, R 4The hydroxyl group is selected from H or methyl, and the cyclobutyl group may be independently substituted with one, two, or three methoxy groups.

[0136] In some embodiments of this disclosure, R 2 and R 3 Together with the commonly linked carbon atoms, it forms cyclopropyl or 2,2-difluorocyclopropyl, R 4 R is selected from H or methyl. In some other embodiments of the present disclosure, 2 and R 3 Together with the commonly linked carbon atoms, it forms 2-fluorocyclopropyl or 3-methoxycyclobutyl, R 4 This is selected from H or methyl.

[0137] In some embodiments of this disclosure, R 2 and R 3 Together with the commonly linked carbon atoms, it forms a cyclopropyl group, R 4 is selected from H. In some other embodiments of this disclosure, R 2 and R 3 Together with the commonly linked carbon atoms, it forms 2-fluorocyclopropyl or 3-methoxycyclobutyl, R 4 It is selected from H.

[0138] In some embodiments of this disclosure, R 2 , R 3 and R 4 C 5-8 Forming a bicycloalkyl or a 5-8 membered bicycloheteroalkyl, the C 5-8 Bicycloalkyl or 5-8 membered bicycloheteroalkyl is a crosslinking ring, and the C 5-8 Bicycloalkyl or 5-8 membered bicycloheteroalkyl groups independently contain one or more R groups. z It may be replaced with .

[0139] In some embodiments of this disclosure, R 2 , R3 and R 4 C 5-8 Form a bicycloalkyl group, and the C 5-8 Bicycloalkyl is a crosslinking ring, and the C 5-8 Bicycloalkyl groups independently have one or more R z It may be replaced with .

[0140] In some embodiments of this disclosure, R 2 , R 3 and R 4 Along with the carbon atoms that are commonly linked,

[0141] [ka]

[0142] Forming, The aforementioned

[0143] [ka]

[0144] These are independently one or more R z It may be replaced with .

[0145] In some embodiments of this disclosure, R 2 , R 3 and R 4 Along with the carbon atoms that are commonly linked,

[0146] [ka]

[0147] It forms.

[0148] In some embodiments of the present disclosure, A is selected from 3-membered, 4-membered, 5-membered, and 6-membered heterocyclines containing one or two N atoms, and the 3-membered, 4-membered, 5-membered, and 6-membered heterocyclines independently contain one or more R z The heterocyclyl may be substituted with the nitrogen atom, and optionally, the heterocyclyl may form a covalent bond with the parent structure via the nitrogen atom.

[0149] In some embodiments of this disclosure, A is selected from a 4- to 6-membered heterocycline containing one or two N atoms, and the 4- to 6-membered heterocycline independently contains one or more R z The heterocyclyl may be substituted with the nitrogen atom, and optionally, the heterocyclyl may form a covalent bond with the parent structure via the nitrogen atom.

[0150] In some embodiments of the present disclosure, A is selected from an azetidine group, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, or piperazinyl, and the azetidine group, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, or piperazinyl is independently one or more R z It may be replaced with .

[0151] In some embodiments of this disclosure, A is selected from an azetidine group or a piperazinyl group, and the azetidine group or piperazinyl group is independently one or more R z It may be replaced with .

[0152] In some embodiments of this disclosure, A is

[0153] [ka]

[0154] Selected from, The aforementioned

[0155] [ka]

[0156] These are independently one or more R z It may be replaced with .

[0157] In some embodiments of this disclosure, A is

[0158] [ka]

[0159] Selected from, The aforementioned

[0160] [ka]

[0161] These are independently one or more R z It may be replaced with .

[0162] In some embodiments of this disclosure, A is

[0163] [ka]

[0164] Selected from, The aforementioned

[0165] [ka]

[0166] These may be independently substituted with one or more methyl groups.

[0167] In some embodiments of this disclosure, A is

[0168] [ka]

[0169] Selected from.

[0170] In some other embodiments of this disclosure, A is

[0171] [ka]

[0172] Selected from.

[0173] In some other embodiments of this disclosure, A is

[0174] [ka]

[0175] Selected from.

[0176] In some embodiments of the present disclosure, the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (Ia) and (Ib).

[0177] [ka]

[0178] (In the formula, X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , L 1 , L 2 , R 1 And A is defined as the compound represented by formula (I). In some embodiments of the present disclosure, the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formula (I-1).

[0179] [ka]

[0180] (In the formula, X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , L 1 , L 2 , R 1 , R 2 , R 3 and R 4 This is defined as the compound represented by formula (I). In some embodiments of the present disclosure, the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (I-1a) and (I-1b).

[0181] [ka]

[0182] (In the formula, X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , L 1 , L 2 , R 1 , R 2 , R 3 and R 4 This is defined as the compound represented by formula (I). In some embodiments of the present disclosure, the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (I-2) and (I-3).

[0183] [ka]

[0184] (In the formula, X 1 , X2 , X 3 , Z 1 , Z 3 , L 1 , L 2 , R 1 And A is defined as the compound represented by formula (I). In some embodiments of the present disclosure, the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (I-2a), (I-3a), (I-2b), and (I-3b).

[0185] [ka]

[0186] (In the formula, X 1 , X 2 , X 3 , Z 1 , Z 3 , L 1 , L 2 , R 1 And A is defined as the compound represented by formula (I). In some embodiments of the present disclosure, the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (I-2a') and (I-2b').

[0187] [ka]

[0188] (In the formula, X 1 , X 2 , X 3 , Z 1 , Z 3 , L 1 , L 2 , R 1 And A is defined as the compound represented by formula (I). In some embodiments of the present disclosure, the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (I-4) and (I-5).

[0189] [ka]

[0190] (In the formula, X 1 , X 2 , X 3 , Z 1 , Z 3 , L 1 , L 2 , R 1 , R 2 , R 3 and R 4 This is defined as the compound represented by formula (I).

[0191] In some embodiments of the present disclosure, the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (I-4a), (I-5a), (I-4b), and (I-5b).

[0192] [ka]

[0193] (In the formula, X 1 , X 2 , X 3 , Z 1 , Z 3 , L 1 , L 2 , R 1 , R 2 , R 3 and R 4 This is defined as the compound represented by formula (I). In some embodiments of the present disclosure, the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (I-4a') and (I-4b').

[0194] [ka]

[0195] (In the formula, X 1 , X 2 , X 3 , Z 1 , Z 3 , L 1 , L 2 , R 1 , R 2 , R 3 and R 4 This is defined as the compound represented by formula (I). In some embodiments of the present disclosure, the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (I-6a), (I-7a), (I-6b), and (I-7b).

[0196] [ka]

[0197] [ka]

[0198] (In the formula, X 1 , X 2 , X 3 , L 1 , L 2 , R 1 , R 2 , R 3 and R 4 This is defined as the compound represented by formula (I). In some embodiments of the present disclosure, the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (I-6a) and (I-6b).

[0199] [ka]

[0200] (In the formula, X 1 , X 2 , X 3 , L 1 , L 2 , R 1 , R 2 , R 3 and R 4 This is defined as the compound represented by formula (I). In some embodiments, the disclosure does not include the following compounds, their isomers, or pharmaceutically acceptable salts thereof.

[0201] [ka]

[0202] In some embodiments, this disclosure includes the variables defined above and their embodiments, as well as any combination thereof.

[0203] In another aspect, the disclosure further provides compounds of the following formulas, their isomers, or pharmaceutically acceptable salts thereof.

[0204] [ka]

[0205] [ka]

[0206] [ka]

[0207] In another aspect, the disclosure further provides compounds of the following formulas, their isomers, or pharmaceutically acceptable salts thereof.

[0208] [ka]

[0209] [ka]

[0210] [ka]

[0211] [ka]

[0212] [ka]

[0213] [ka]

[0214] [ka]

[0215] [ka]

[0216] In another aspect, the Disclosure further provides pharmaceutical compositions comprising a compound relating to the Disclosure, its isomer, or a pharmaceutically acceptable salt thereof in a therapeutic or prophylactic effective amount. In some embodiments, the pharmaceutical compositions of the Disclosure further comprise pharmaceutically acceptable additives.

[0217] In another aspect, the Disclosure further provides the use of the compounds relating to the Disclosure, their isomers or pharmaceutically acceptable salts or pharmaceutical compositions thereof for the manufacture of pharmaceuticals for the treatment or prevention of disease.

[0218] In another aspect, the Disclosure further provides a method for treating or preventing a disease, comprising administering a compound relating to the Disclosure, an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a mammal (preferably human) in need of treatment or prevention in a therapeutic or prophylactic effective amount.

[0219] In another aspect, the Disclosure further provides the use of the compounds relating to the Disclosure, their isomers or pharmaceutically acceptable salts or pharmaceutical compositions thereof for treating or preventing diseases.

[0220] In another aspect, the Disclosure further provides compounds relating to the Disclosure, their isomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for treating or preventing diseases.

[0221] In some embodiments, the disease of this disclosure is selected from CDK2-mediated diseases.

[0222] In another aspect, in some embodiments of this disclosure, the CDK2-mediated disease is selected from tumors or cancers.

[0223] In this disclosure, the term "isomer" includes, but is not limited to, stereoisomers or tautomers.

[0224] In some embodiments, the "isomer" is selected from stereoisomers.

[0225] (Effects of the invention) The compounds disclosed herein, as novel structure CDK2 inhibitors, exhibit good inhibitory activity against CDK2-induced signaling, good inhibitory activity against both CDK2 CycA2 kinase and CDK2 CycE1 kinase, and possess favorable characteristics in at least one aspect of in vitro and in vivo inhibitory activity, safety (e.g., low toxicity), and CDK2 selectivity. The compounds disclosed herein have favorable pharmacokinetic properties and can be developed as a new type of CDK2 inhibitory drug.

[0226] definition Unless otherwise specified, the following terms and phrases used herein have the following definitions. Certain terms or phrases should not be considered uncertain or unclear in the absence of a specific definition, but should be understood according to their ordinary meaning. Trademarks used herein are intended to refer to the corresponding product or its active ingredient.

[0227] The term "pharmaceutically acceptable" as used herein means that, within the bounds of sound medical judgment, a compound, material, composition, and / or dosage form is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and that the benefits / risks are in line with a reasonable balance.

[0228] The term “pharmaceutically acceptable salt” refers to a salt of a compound of the present disclosure, which is prepared by a compound having certain substituents found in the present disclosure with a relatively non-toxic acid or base. If a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. If a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Since certain compounds of the present disclosure contain both basic and acidic functional groups, they can be converted into either a base addition salt or an acid addition salt.

[0229] The pharmaceutically acceptable salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing an acid group or a base. Generally, such salts are prepared by reacting these compounds in the form of a free acid or free base with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of both.

[0230] The compounds of this disclosure may exist in the form of specific stereoisomers. This disclosure assumes that all such compounds include cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomer or diastereomeric-rich mixtures, all of which are within the scope of this disclosure. Substituents such as alkyl groups may have other chiral carbon atoms. All such isomers and mixtures thereof are within the scope of this disclosure. Substituents such as alkyl groups may have other chiral carbon atoms. All such isomers and mixtures thereof are within the scope of this disclosure.

[0231] Unless otherwise specified, wedge-shaped solid line connections

[0232] [ka]

[0233] and wedge-shaped dashed connections

[0234] [ka]

[0235] This indicates the absolute arrangement of the center of the solid, and the solid lines represent the connections between straight lines.

[0236] [ka]

[0237] and dashed line connections

[0238] [ka]

[0239] This indicates the relative arrangement of the centers of the three-dimensional object.

[0240] The compounds and intermediates of this disclosure may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The term “tautomer” or “tautomer form” refers to structural isomers of different energies that can interconvert across a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety in which a proton can move between two ring nitrogen atoms. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0241] The compounds of this disclosure may contain atomic isotopes in unnatural proportions in one or more atoms constituting the compound. For example, the compound may contain tritium ( 3 H), Iodine-125( 125 I) or C-14 ( 14 They can be labeled with radioactive isotopes such as C). As another example, hydrogen can be replaced with deuterium to form deuterated drugs, in which case the bond between deuterium and carbon is stronger than the usual hydrogen-carbon bond, and deuterated drugs have advantages over undeuterated drugs such as reduced toxic side effects, improved drug stability, enhanced potency, and extended biological half-life. All transformations of the isotopic composition of the compounds of this disclosure, whether radioactive or not, are included within the scope of this disclosure. For example, compounds in which one or more hydrogen atoms of the compound of formula (I) of this disclosure are replaced with deuterium atoms are also included within the scope of the compound of formula (I) of this disclosure.

[0242] The terms "may" or "may" mean that the events or conditions described below may occur, but are not necessarily required to occur, and include both the occurrence and non-occurrence of such events or conditions.

[0243] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of that atom is normal and the substituted compound is stable. Substituents may include deuterium and hydrogen variants. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. Oxo substitution does not occur in aromatic groups. The term "may be substituted" means that the atom may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary based on chemical feasibility.

[0244] The term "one or more substituted" means that any one or more hydrogen atoms on a particular atom are substituted by a substituent, which may include deuterium and hydrogen variants. The number of substituents may be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, based on chemical feasibility.

[0245] The terms “substituents” as used herein include, but are not limited to, the terms “alkyl,” “alkoxy,” “cycloalkyl,” “cycloalkenyl,” “heterocyclyl,” “heterocycloalkyl,” “heterocycloalkenyl,” “heteroaryl,” “alkyl ring,” “heteroalkyl ring,” “heteroaromatic ring,” etc., as referred to in the context, and the corresponding non-limiting or exemplary groups. Non-limiting examples of such “substituents” include deuterium, tritium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azide group, sulfoxide group, sulfo n group, sulfonamide group, carboxyl, carboxylaldehyde group, imine group, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, haloalkenyl, cycloalkenyl, halocycloalkenyl, alkynyl, haloalkynyl, cycloalkynyl, halocycloalkynyl, heteroalkyl, haloheteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkyl, arylalkyloxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, These include heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, ureido group, epoxy group, and ester group, and the aforementioned groups include oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, and halodial Killamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkyl,It may be substituted with one or more substituents selected from heterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl, or aryloxy.

[0246] In some embodiments of this specification, the "substituent" is deuterium, tritium, hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl, aldehyde group, imide group, C 1-12 Alkyl, halogenated C 1-12 Alkyl, 3-12 member cycloalkyl, halogenated 3-12 member cycloalkyl, C 2-12 Alkenyl, halogenated C 2-12 Alkenyl, 3-12 member cycloalkenyl, halogenated 3-12 member cycloalkenyl, C 2-12 Alkynyl, halogenated C 2-12 Alkynyl, 8-12 member cycloalkynyl, halogenated 8-12 member cycloalkynyl, C 1-12 Heteroalkyl, halogenated C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkilen, 6-10 member aryl C 1-12 Alkoxy, 6-10 member aryl C 1-12 Alkylthio, 5-10 member heteroaryl, 5-10 member heteroaryloxy, 5-10 member heteroarylthio, 5-10 member heteroarylalkylene, 5-10 member heteroarylalkoxy, 5-10 member heteroarylalkylthio, 3-12 member heterocyclyl, 3-12 member heterocyclyloxy, 3-12 member heterocyclylthio, 3-12 member heterocyclylC 1-12 Alkilen, 3-12 member heterocyclyl C 1-12 Alkoxy, 3-12 member heterocyclyl C 1-12 Alkylthio, C 1-12 Ashiru, C 1-12Acyloxy, carbamate group, C 1-12 Amide group, ureido group, epoxy group, C 2-12 Selected from ester groups and oxo groups, the substituents are oxo, hydroxyl, amino, nitro, halogen, cyano, and C 1-12 Alkyl, C 2-12 Alkenil, C 2-12 Alkinyl, C 1-12 Alkoxy, C halogenated 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, di-C halogenated 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2,-NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 Alkyl) 2, 3-12 member cycloalkyl, 3-12 member cycloalkyl C 1-12 Alkylene, 3-12 member cycloalkyloxy, 3-12 member heterocyclyl, 3-12 member heterocyclyl C 1-12 Alkylene, 3-12 member heterocyclyloxy, 3-12 member heterocycloalkyl, 3-12 member heterocycloalkyl C 1-12 Alkylene, 3-12 member heterocycloalkyloxy, 5-10 member heteroaryl, 5-10 member heteroaryl C 1-12 Alkylene, 5-10 member heteroaryloxy, 6-10 member aryl, 6-10 member aryl C 1-12 It may be substituted with one or more substituents selected from alkylenes or 6- to 10-membered aryloxys.

[0247] C in this specification m-n This means that the part in question has an integer number of carbon atoms within a predetermined range. For example, "C 1-6 " means that the group may have one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms. For example, C 1-3 This means that the group may have one carbon atom, two carbon atoms, or three carbon atoms.

[0248] When any variable (such as R) appears one or more times in the composition or structure of a compound, the definition of each case is independent. Therefore, for example, if a group is substituted with 0 to 2 Rs, the group may optionally be substituted with up to 2 Rs, and the Rs in each case are independent choices. Furthermore, combinations of substituents and / or their variants are only permissible if such combinations result in a stable compound.

[0249] When one variable is selected from a single bond, it means that the two groups bonded to it are directly linked. For example, if the L in ALZ represents a single bond, it means that the structure is actually AZ.

[0250] If the connection direction of a listed linking element is not specified, the connection direction is arbitrary, for example,

[0251] [ka]

[0252] So, if the linking group L is -MW-, then -MW- links ring A and ring B in the same direction as the reading order from left to right,

[0253] [ka]

[0254] It is possible to form ring A and ring B in the opposite direction to the reading order from left to right,

[0255] [ka]

[0256] It is also possible to form such a combination. The combination of the linking group, substituents and / or their variants is only permissible if such a combination results in a stable compound.

[0257] Unless otherwise specified, if a group has one or more connectable sites, any one or more sites of that group can be bonded to another group via a chemical bond. If the bond is in a non-fixed position and hydrogen atoms are present at the connectable sites, when the chemical bond is connected, the number of hydrogen atoms at those sites decreases in proportion to the number of chemical bonds formed, resulting in a group with the corresponding valency. The chemical bond connecting the site to another group is a linear solid bond.

[0258] [ka]

[0259] , dashed line connection

[0260] [ka]

[0261] , or wavy line

[0262] [ka]

[0263] It can be represented as follows. For example, the solid line bond of -OCH3 represents a connection to other groups via the oxygen atom of that group.

[0264] [ka]

[0265] The dashed lines in the diagram indicate that the group is connected to other groups via both ends of the nitrogen atom of that group.

[0266] [ka]

[0267] The wavy line indicates that the phenyl group is linked to other groups via the carbon atoms at positions 1 and 2.

[0268] [ka]

[0269] This indicates that any linkable site on the piperidinyl group can be linked to another group via one chemical bond, and at least

[0270] [ka]

[0271] This includes four linking methods, even if the H atom is shown on the -N- side.

[0272] [ka]

[0273] teeth,

[0274] [ka]

[0275] Although it contains a group in a linked form like the one shown, when it is linked to one chemical bond, the number of H atoms at that site decreases by one, resulting in the corresponding monovalent piperidinyl group.

[0276] Unless otherwise specified, the term "C" 1-3 The term "alkyl" is used to indicate a linear or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl is C 1-2 and C 2-3 It contains alkyl groups, etc., and may be monovalent (methyl, etc.), divalent (methylene, etc.), or polyvalent (methine, etc.). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), and propyl (including n-propyl and isopropyl).

[0277] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms linked to the rest of the molecule via one oxygen atom. 1-3 Alkoxy is C 1-2 , C 2-3 , including C3 and C2 alkoxys. 1-3 Examples of alkoxys include, but are not limited to, methoxy, ethoxy, and propoxy (including n-propoxy and isopropoxy).

[0278] Unless otherwise specified, the term "C" 1-3 "Alkylene" refers to a divalent hydrocarbon group consisting of 1 to 3 carbon atoms in a linear or branched chain, either by itself or as part of another substituent. 1-3 Non-exclusive examples of alkylenes include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), and propylene (-CH2CH2CH2- or -CH2CH(CH3)-).

[0279] Unless otherwise specified, C n-n+m or C n -C n+m This includes all specific cases of n ~ n+m carbon atoms, for example C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11, and C 12 This includes all ranges from n to n+m, for example, C 1-12 C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 This includes, for example, n-membered to n+m-membered rings, where the number of atoms in the ring is n to n+m. For example, 3- to 12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also include all ranges from n to n+m. For example, 3- to 12-membered rings include 3- to 6-membered, 3- to 9-membered, 5- to 6-membered, 5- to 7-membered, 6- to 7-membered, 6- to 8-membered, and 6- to 10-membered rings.

[0280] Unless otherwise specified, the term "C" 3-6 "Cycloalkyl" refers to monocyclic and bicyclic saturated cyclic hydrocarbon groups consisting of 3 to 6 carbon atoms, and the aforementioned C 3-6 Cycloalkyl is C 3-5 , C 4-5 and C 5-6 It contains cycloalkyls, etc., and may be monovalent, divalent, or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0281] Unless otherwise specified, the term "C" 3-6 "Cycloalkenyl" refers to a monocyclic or bicyclic partially unsaturated (but not fully unsaturated aromatic) cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, and the aforementioned C 3-6 Cycloalkenyl is C 3-5 , C 4-5 and C 5-6 It contains cycloalkenyls, etc., and may be monovalent, divalent, or polyvalent. 3-6 Examples of cycloalkenyls include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl.

[0282] Unless otherwise specified, the term "3- to 6-membered heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocycle, bridging ring, fused ring, or spirocycle. Unless otherwise stated, this heterocyclyl is typically a 3- to 6-membered, 4- to 6-membered, or 5- to 6-membered ring (e.g., 3-, 4-, 5-, or 6-membered ring) containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron. Non-limiting examples of 3- to 6-membered heterocyclyls include, but are not limited to, oxyranil, tetrahydrofuranil, dihydrofuranil, pyrrolidinil, N-methylpyrrolidinil, dihydropyrrolyl, piperidinil, piperazinil, pyrazolidinil, 4H-pyranil, morpholinil, thiomorpholinil, tetrahydrothienyl, etc.

[0283] Unless otherwise specified, the term "3-6 member heterocycloalkyl" refers, either by itself or in combination with other terms, to a saturated cyclic group consisting of 3 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, the remainder being carbon atoms, the nitrogen atom may be quaternized, and the nitrogen and sulfur heteroatoms may be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). These are monocyclic. Furthermore, for the "3- to 6-membered heterocycloalkyl," the heteroatoms may occupy positions where the heterocycloalkyl is linked to the rest of the molecule. The 3- to 6-membered heterocycloalkyl includes 3-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyls. Examples of 3- to 6-membered heterocycloalkyls include oxyranyl, thyranyl, azilidinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrothiophene-1,1-dioxide-3-yl, tetrahydrothiophene-1,1,-dioxide-2-yl, and tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.). Examples include, but are not limited to, tetrahydropyranil, piperidinil (including 1-piperidinil, 2-piperidinil, and 3-piperidinil), piperazinil (including 1-piperidinil and 2-piperidinil), morpholinil (including 3-morpholinil and 4-morpholinil), dioxanil, dithianil, isoxazolidinil, isothiazolidinil, 1,2-oxazinil, 1,2-thiadinil, hexahydropyridazinil, homopiperadinil, or homopiperidinil.

[0284] Unless otherwise specified, the term "3-6 member heterocycloalkenyl" alone or in combination with other terms refers to a partially unsaturated (but not fully unsaturated heteroaromatic) cyclic group consisting of 3 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, the remainder being carbon atoms, the nitrogen atom may be quaternized, and the nitrogen and sulfur heteroatoms may be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). These are monocyclic. Furthermore, in the case of the "3- to 6-membered heterocycloalkenyl," the heteroatom may occupy a position where the heterocycloalkyl is linked to the rest of the molecule. The 3- to 6-membered heterocycloalkenyl includes 3-membered, 4-membered, 5-membered, and 6-membered heterocycloalkenyls, etc. Examples of 3- to 6-membered heterocycloalkenyls include, but are not limited to, dihydropyridyl, dihydropyrrolyl, or tetrahydropyridyl.

[0285] Unless otherwise specified, the term "5-6 member heteroaryl" refers to a cyclic group having a conjugated π-electron system consisting of 5-6 ring atoms, of which one, two, or three ring atoms are heteroatoms independently selected from O, S, and N, the remainder being carbon atoms, the nitrogen atom may be quaternized, and the carbon, nitrogen, and sulfur atoms may be oxidized (i.e., C=O, NO, and S(O)). p(where p is 1 or 2). The 5-6 member heteroaryl may be linked to the rest of the molecule via heteroatoms or carbon atoms. The 5-6 member heteroaryl includes 5-member and 6-member heteroaryls. Examples of the 5-6 member heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl Examples include, but are not limited to, tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridinyl (including 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyridinyl and 4-pyridinyl, etc.).

[0286] Unless otherwise specified, the term "C" 5-8 "Bicycloalkyl" refers to a saturated hydrocarbon ring consisting of 5 to 8 carbon atoms, and is a bicyclic formula including a spiro ring, a fused ring, and a bridging ring. 5-8 Bicycloalkyl is C 5-8 or C 5-6 It contains bicycloalkyl and may be monovalent, divalent, or polyvalent. 5-8 Examples of bicycloalkyls include, but are not limited to, bicyclo[1.1.1]pentane.

[0287] Unless otherwise specified, the term "5-8 membered bicycloheteroalkyl" refers to a saturated cyclic group consisting of 5-8 cyclo atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, the remainder are carbon atoms, the nitrogen atom may be quaternized, and the carbon, nitrogen, and sulfur heteroatoms may be oxidized (i.e., C=O, NO, and S(O)). p (where p is 1 or 2). It is a bicyclic compound containing a spiro ring, a fused ring, and a bridging ring. Furthermore, for the "5-8 membered bicycloheteroalkyl," the heteroatoms may occupy positions where the heteroalkyl ring is linked to the rest of the molecule. The 5-8 membered bicycloheteroalkyl includes a 5-6 membered heteroalkyl ring, etc. Examples of 5-8 membered bicycloheteroalkyl include, but are not limited to, 2-azabicyclo[1.1.1]pentane.

[0288] Unless otherwise specified, the term "condensed ring" refers to a non-aromatic, saturated or partially unsaturated ring system formed by two or more cyclic structures sharing two adjacent atoms, including condensed carbocyclic and condensed heterocyclic rings, where the ring atoms of the condensed heterocyclic ring contain one or more heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0289] Unless otherwise specified, the term "hetero" includes heteroatoms of sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron.

[0290] The term "to treat" means administering a compound or formulation relating to this disclosure in order to improve or resolve a disease or one or more symptoms associated with the disease, and includes the following: (i) To suppress a disease or symptom, that is, to prevent its progression; (ii) To alleviate a disease or symptom, that is, to reduce or eliminate the disease or symptom.

[0291] The term “prevent” means administering the compound or formulation relating to this disclosure in order to prevent a disease or one or more symptoms associated with such disease, and includes preventing the occurrence of the disease or condition in a mammal (in particular, when such mammal is susceptible to the condition but has not yet been diagnosed as having the condition).

[0292] The term “therapeutic or prophylactically effective amount” means an amount of the Compound of the Disclosure that (i) treats a particular disease, condition or disorder, (ii) reduces, improves or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays a particular disease, condition or disorder as described herein. The amount of the Compound of the Disclosure that constitutes a “therapeutic or prophylactically effective amount” will vary depending on the Compound, the disease and its severity, the method of administration, and the age of the mammal being treated, but can generally be determined by a person skilled in the art based on their own knowledge and the content of the Disclosure.

[0293] The therapeutic or prophylactic dose of the compounds disclosed herein may be determined, for example, based on the specific therapeutic or prophylactic use, the method of administration of the compound, the patient's health and condition, and the judgment of the prescribing physician. The proportion or concentration of the compounds disclosed herein in a pharmaceutical composition is not fixed and depends on various factors, including the dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds disclosed herein may be provided for parenteral administration as a physiologically buffered aqueous solution containing the compound at a concentration of about 0.1–10% w / v. Some typical dose ranges are about 0.001 mg / kg to about 1000 mg / kg body weight per day. The dose is thought to depend on variations in the type and progression of the disease or condition, the general health status of the particular patient, the relative biological potency of the selected compound, the formulation of the excipients, and the route of administration. The effective dose can be obtained by extrapolating dose-response curves obtained from in vitro or animal model test systems.

[0294] The terms "comprise" or "comprise," and their English variations such as "comprises" or "comprising," should be understood in an open and non-exclusive sense, meaning "to include, but not to limit."

[0295] "Pharmaceutical composition" refers to a composition containing one or more compounds relating to this disclosure, their isomers or pharmaceutically acceptable salts, and other components such as physiologically / pharmaceutically usable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism and to promote the absorption of the active ingredient in order to exert biological activity.

[0296] The pharmaceutical compositions of this disclosure can be prepared by combining the compounds of this disclosure with appropriate pharmaceutically acceptable additives.

[0297] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable additives known in the art.

[0298] The compounds of this disclosure can be produced by various synthesis methods well known to those skilled in the art, including specific embodiments illustrated below, embodiments formed in combination with other chemical synthesis methods, and equivalent alternative embodiments well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of this disclosure.

[0299] The chemical reactions in the specific embodiments of this disclosure are completed in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the necessary reagents and materials. To obtain the compounds of this disclosure, those skilled in the art may, as applicable, modify or select synthesis steps or reaction schemes based on existing embodiments.

[0300] The raw materials or intermediates used in the embodiments of this disclosure can be obtained commercially or manufactured by methods of the prior art.

[0301] One important consideration in designing synthetic routes in this industry is the selection of a suitable protecting group for a reactive functional group (e.g., an amino group in this disclosure). For example, Greene's Protective Groups in Organic Synthesis (4th Ed.), Hoboken, New Jersey: John Wiley & Sons, Inc. can be referenced.

[0302] In some embodiments, some of the compounds of this disclosure can be prepared by those skilled in the art of organic synthesis with reference to the following scheme.

[0303] Scheme 1:

[0304] [ka]

[0305] Scheme 2:

[0306] [ka]

[0307] Scheme 3:

[0308] [ka]

[0309] (In the formula, R 2 , R 3 , R 4 and R a This is as described for the compound of formula (I). The structure of the compounds of the present invention can be confirmed by conventional methods familiar to those skilled in the art. If the compounds of the present invention have an absolute configuration, this absolute configuration can be identified by conventional means of the art. Examples include single-crystal X-ray diffraction (S×RD) and microcrystal electron diffraction.

[0310] The present disclosure will be explained below with reference to examples, but the examples are not intended to limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification. [Modes for carrying out the invention]

[0311] The present disclosure will be described in detail below with reference to examples, but this does not mean that there are any disadvantageous limitations to the present invention. This specification describes the present disclosure in detail and also discloses specific embodiments thereof. It will be obvious to those skilled in the art that various modifications and improvements can be made to specific embodiments of the present disclosure without departing from the gist and scope of the present disclosure.

[0312] Example 1: Preparation of Compound 1

[0313] [ka]

[0314] Benzyl (1-(tert-butyl)-3-((1S,3R)-3-(4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazole-5-yl)carbamate (0.95 g), N,N-diisopropylethylamine (0.70 g), and cyclobutylamine (0.20 g) were reacted in tetrahydrofuran (30 mL) with stirring at room temperature. After the reaction was complete, the solvent was distilled off the reaction mixture under reduced pressure. The residue was washed with ethyl acetate, aqueous sodium hydroxide (1N), and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 1A (0.90 g). MS(ESI): m / z 455.3[M+H] + . Intermediate 1A (0.826 g) and palladium carbon (palladium content 5%, water content 50% (w / w), 0.15 g) were reacted in tetrahydrofuran (10 mL) and ethyl acetate (10 mL) under a hydrogen atmosphere at room temperature with stirring. After the reaction was complete, the mixture was filtered and concentrated to obtain intermediate 1B (0.435 g). MS(ESI): m / z 321.18[M+H] + . Intermediate 1B (0.3g), 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide (0.347g), chloro(2-dicyclohexylphosphin-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.11g), 2-dicyclohexylphosphin-2',4',6'-triisopropylbiphenyl (0.067g), and potassium phosphate (0.596g) were added to N,N-dimethylformamide (30mL). After addition, the mixture was stirred and reacted under nitrogen protection at 110°C. After the reaction was complete, the mixture was filtered, concentrated, and further separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 1C (0.35g). MS(ESI):m / z 487.30[M+H] + . Intermediate 1C (0.35 g) was reacted with ethanol (2 mL) and dilute hydrochloric acid (1 N, 20 mL) by stirring with microwave at 100°C. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure. The residue was adjusted to an alkaline pH with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative liquid chromatography at medium-low pressure (C18 column, acetonitrile / water (20 / 80), eluate containing 1 / 1000 aqueous ammonia) to obtain compound 1 (65 mg). MS (ESI): m / z 431.1753 [M+H] + .

[0315] 1H NMR(500MHz,DMSO)δ11.73(s,1H),8.47(s,1H),7.54-7.28(m,2H),7.22(d,1H),7.14(d,1H),5.63(s,1H),4.98(d,1H),4.40(s,2H),4 .32(s,2H),3.97-3.91(m,1H),3.10-2.97(m,1H),2.44(td,1H),2.09(ddd,2H),2.01(q,1H),1.88(p,3H),1.71(q,2H),1.55(dp,3H). Example 2: Preparation of Compound 2

[0316] [ka]

[0317] Referring to the method for producing compound 1 in Example 1, cyclobutylamine was replaced with isopropylamine, and 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide was replaced with 5-bromo-1,3-dihydrobenzo[c]thiophene to obtain the key intermediate 2D (75 mg) of Example 2. MS(ESI): m / z 387.29[M+H] + .

[0318] Under conditions of -15°C, 2D (75 mg) and m-chloroperbenzoic acid (30 mg) were reacted in a solution of dichloromethane (30 mL) with stirring. After the reaction was complete, water was added to quench the reaction, the compound was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and further separated by column chromatography (eluent: dichloromethane / methanol) to obtain compound 2 (30 mg) of Example 2. MS(ESI): m / z 403.1803[M+H] + 1H NMR(500MHz,DMSO-d6)δ11.68(s,1H),8.37(s,1H),7.42(s,1H),7.18(d,2H),6.94(s,1H),5.62(s,1H),4.99(s,1H),4.31-4.23(m,2H), 3.96-3.87(m,2H),3.56-3.59(m,1H),3.03(q,1H),2.43-2.50(m,1H),2.02-2.00(m,1H),1.99(ddd,1H),1.92-1.86(m,3H),1.73(s,6H). Example 3: Preparation of Compound 3

[0319] [ka]

[0320] Referring to the method for producing Compound 1 in Example 1, cyclobutylamine was replaced with (S)-1-cyclopropylethylamine hydrochloride to obtain Compound 3 (21 mg) in Example 3. MS(ESI): m / z 445.1906[M+H] + .

[0321] 1 H NMR(500MHz,DMSO-d6)δ11.73(s,1H),8.47(s,1H),7.40(s,1H),7.21(d,1H),7. 14(d,1H),7.00(d,1H),5.63(s,1H),4.99(d,1H),4.40(s,2H),4.32(s,2H),3.02 (dt,2H),2.47-2.39(m,1H),2.01(q,1H),1.90(q,1H),1.76-1.68(m,2H),1.60( s,1H),1.08(d,3H),0.81(s,1H),0.42-0.29(m,2H),0.24(dd,1H),0.10(dd,1H). Example 4: Preparation of Compound 4

[0322] [ka]

[0323] Referring to the method for producing Compound 1 in Example 1, cyclobutylamine was replaced with tert-butylamine to obtain Compound 4 (15 mg) in Example 4. MS(ESI): m / z 433.1903[M+H] + .

[0324] 1 H NMR(500MHz,DMSO-d6)δ11.72(s,1H),8.46(s,1H),7.40(s,1H),7.21(d,1H),7.14(d,1H),6.76(s,1H),5.63(s,1H),4.97(s,1 H),4.40(s,2H),4.32(s,2H),3.02(q,1H),2.45(dt,1H),2.01(q,1H),1.89(ddd,1H),1.71(dt,2H),1.58(s,1H),1.21(s,9H). Example 5: Preparation of Compound 5

[0325] [ka]

[0326] Referring to the method for producing Compound 1 in Example 1, cyclobutylamine was replaced with (R)-1-cyclopropylethylamine hydrochloride to obtain Compound 5 (15 mg) in Example 5. MS(ESI): m / z 445.1906[M+H] + .

[0327] 1 H NMR(500MHz,DMSO-d6)δ11.73(s,1H),8.47(s,1H),7.40(s,1H),7.21(d,1H),7. 14(d,1H),7.00(d,1H),5.63(s,1H),4.99(d,1H),4.40(s,2H),4.32(s,2H),3.02 (dt,2H),2.47-2.39(m,1H),2.01(q,1H),1.90(q,1H),1.76-1.68(m,2H),1.60( s,1H),1.08(d,3H),0.81(s,1H),0.42-0.29(m,2H),0.24(dd,1H),0.10(dd,1H). Example 6: Preparation of Compound 6

[0328] [ka]

[0329] Referring to the method for producing Compound 1 in Example 1, cyclobutylamine was replaced with 2,2-dimethylazetidine hydrochloride to obtain Compound 6 (5 mg) in Example 6. MS(ESI): m / z 463.2017[M+H] + .

[0330] Example 7: Preparation of Compound 7

[0331] [ka]

[0332] Referring to the method for producing compound 1 in Example 1, cyclobutylamine was replaced with bicyclo[1.1.1]pentane-1-amine hydrochloride to obtain compound 7 (30 mg) in Example 7. MS(ESI): m / z 443.1758[M+H] + .

[0333] 1 H NMR(500MHz,DMSO-d6)δ11.73(s,1H),8.47(s,1H),7.75(s,1H),7.40(s,1H),7.21(d,J=8.5Hz,1H),7.13(d,J=8.4Hz,1H),5.63(s,1H), 4.99(s,1H),4.40(s,2H),4.32(s,2H),3.03(m,1H),2.49-2.41(m,1H),2.35(s,1H),2.01(s,1H),1.90(m,7H),1.71(m,2H),1.59(s,1H). Example 8: Preparation of Compound 8

[0334] [ka]

[0335] 14 g of methyl 2,3-dimethylbenzoate, 30 g of N-bromosuccinimide, and 1.02 g of benzoyl peroxide were reacted in 40 mL of 1,2-dichloroethane with stirring at 80°C. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the mixture was further separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 8A (28 g).

[0336] 8A (26g) and sodium sulfide notahydrate (24g) were reacted in ethanol (500mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure, washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and further separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 8B (6.71g).

[0337] 1 H NMR (500MHz, DMSO-d6) δ7.83(d,1H), 7.58(d,1H), 7.39(t,1H), 4.51(s,2H), 4.31(s,2H), 3.86(s,3H).

[0338] Under conditions of -20°C, 8B (6.71 g) and m-chloroperbenzoic acid (21 g) were reacted with dichloromethane (250 mL) by stirring. After the reaction was complete, the mixture was washed with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and further separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 8C (5.4 g).

[0339] 1 H NMR(500MHz,DMSO-d6)δ7.96(d,1H),7.66(d,1H),7.54(t,1H),4.72(s,2H),4.57(s,2H),3.88(s,3H) Under ice bath conditions, concentrated nitric acid (2.5 g) was slowly added dropwise to a stirred solution of 8C (5.4 g) concentrated sulfuric acid (30 mL). After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and further separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 8D (4.56 g).

[0340] 1 H NMR(500MHz,DMSO)δ8.62(d,J=2.4Hz,1H),8.57-8.55(m,1H),4.89(s,2H),4.72(s,2H),3.93(s,3H). Under conditions of -5°C, diisobutylaluminum hydride (28 mL, 1.5 M) was slowly added dropwise to a solution of 8D (4.56 g) in tetrahydrofuran (100 mL), and the mixture was stirred to allow the reaction to proceed. After the reaction was complete, the mixture was washed with saturated potassium sodium tartrate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and further separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 8E (3.5 g).

[0341] 1H NMR(500MHz,DMSO)δ8.24(d,J=2.4Hz,1H),8.19(d,J=2.4Hz,1H),5.65(t,J=5.6Hz,1H),4.67(s,2H),4.62(s,2H),4.60(d,J=5.5Hz,2H). Under conditions of -5°C, iodine methane (3.05 g) was slowly added dropwise to a solution of 8E (3.5 g) and sodium hydride (1.72 g) in DMF (50 mL), and the mixture was stirred to allow the reaction to proceed. After the reaction was complete, water was added to quench the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and further separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 8F (2.0 g). MS(ESI): m / z: 270.06 [MH] - .

[0342] Pd-C (0.8g) was slowly added to a solution of 8F (2.0g) in tetrahydrofuran (50mL), and after purging with hydrogen gas 2-3 times, the mixture was stirred and reacted at room temperature. After the reaction was complete, the mixture was filtered and concentrated to obtain intermediate 8G (1.8g).

[0343] 8G (1 g), copper bromide (1.24 g), and tert-butyl nitrite (0.67 g) were reacted in acetonitrile (15 mL) under nitrogen protection in an oil bath at 40°C. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the intermediate 8H (800 mg) was obtained by further separation by column chromatography (eluent: dichloromethane / methanol).

[0344] Referring to the method for producing compound 1 in Example 1, the intermediate 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide was replaced with intermediate 8H to obtain compound 8 (18 mg) in Example 8. MS(ESI): m / z 477.2172[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.72(s,1H),8.46(s,1H),7.33(s,1H),7.25(s, 1H),6.94(d,1H),5.62(s,1H),5.27(t,1H),5.02-4.95(m,1H),4.54(d,2H) ),4.41(s,2H),3.58(dd,1H),3.07-2.99(m,1H),2.44(dd,1H),2.01(q,1H ),1.90(ddd,1H),1.70(dd,,2H),1.61(d,1H),1.56(s,6H),1.03(dd,6H). Example 9: Preparation of Compound 9

[0345] [ka]

[0346] Under conditions of -5°C, iodine methane (3.0 g) was slowly added dropwise to a solution of 8E (1.75 g) and sodium hydride (0.85 g) in DMF (30 mL), and the mixture was stirred to allow the reaction to proceed. After the reaction was complete, water was added to quench the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and further separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 9A (1.0 g).

[0347] Referring to the method for producing compound 8 in Example 8, intermediate 9A was used instead of intermediate 8F to obtain compound 9 (18 mg) in Example 9. MS(ESI):m / z m / z:491.2330[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.77(s,1H),8.49(s,1H),7.32(d,2H),6.94(d,1H) ,5.62(s,1H),5.28(s,1H),5.00(s,1H),4.61(d,1H),4.53-4.44(m,2H),3.6 3-3.52(m,1H),3.09-3.00(m,1H),2.46(dt,1H),2.03-1.98(m,1H),1.94-1. 87(m,1H),1.72(d,2H),1.61(s,3H),1.56(s,3H),1.50(d,3H),1.04(dd,6H). Example 10: Preparation of Compound 10

[0348] [ka]

[0349] Referring to the method for producing compound 1 in Example 1, cyclobutylamine was replaced with ethylamine to obtain compound 10 (150 mg) in Example 10. MS(ESI): m / z 405.1598[M+H] + .

[0350] 1H NMR(500MHz,DMSO-d6)δ11.73(s,1H),8.47(s,1H),7.41(s,1H),7.22(d,1H),7.13(d,1H),7.02(t,1H),5.63(d,1H),4.99(q,1H),4.4 0(s,2H),4.32(s,2H),3.04(t,1H),2.99(p,2H),2.45(dt,1H),2.01(q,1H),1.91(q,1H),1.79-1.68(m,2H),1.61(d,1H),0.99(t,3H). Example 11: Preparation of Compound 11

[0351] [ka]

[0352] Referring to the method for producing compound 8 in Example 8, 5-bromo-1-fluoro-2,3-xylene was used instead of methyl 2,3-dimethylbenzoate to obtain the key intermediate 11C (410 mg) of Example 11.

[0353] Referring to the method for producing compound 1 in Example 1, the intermediate 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide was replaced with intermediate 11C to obtain compound 11 (80 mg) in Example 11. MS(ESI): m / z 437.1656[M+H] + 1H NMR(500MHz,DMSO-d6)δ11.83(s,1H),8.79(s,1H),7.36-7.24(m,1H),7.09(s,1H),6.93(d,1H),5.64(d,1H),4.99(s,1H),4. 48(s,2H),4.35(s,2H),3.13-2.99(m,1H),2.46(p,1H),2.01(q,1H),1.89(ddt,1H),1.72(d,2H),1.59(s,1H),1.03(dd,6H). Example 12: Preparation of Compound 12

[0354] [ka]

[0355] (1-(tert-butyl)-3-((1S,3R)-3-hydroxylcyclopentyl)-1H-pyrazole-5-yl)benzyl carbamate (2.00 g), triethylamine (1.70 g), and bis(2,5-dioxopyrrolidine-1-yl) carbonate (4.30 g) were reacted in acetonitrile (20 mL) with stirring at 40°C. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the mixture was further separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 12A (1.73 g). MS(ESI): m / z 499.32[M+H] + .

[0356] Referring to the method for producing compound 1 in Example 1, cyclobutylamine was replaced with trifluoroethylamine, and benzyl(1-(tert-butyl)-3-((1S,3R)-3-(4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazole-5-yl)carbamate was replaced with intermediate 12A to obtain compound 12 (44 mg) of Example 12. MS(ESI): m / z 459.1316[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.74(s,1H),8.47(s,1H),7.87(t,1H),7.41(s,1H),7.22(d,1H),7.14(d,1H),5.64(s,1H),5.06(qd,1H),4.4 0(s,2H),4.32(s,2H),3.76(td,2H),3.06(p,1H),2.49-2.45(m,1H),2.01(dd,1H),1.98-1.89(m,1H),1.75(qd,2H),1.67-1.59(m,1H). Example 13: Preparation of Compound 13

[0357] [ka]

[0358] Referring to the method for producing compound 12 in Example 12, difluoroethylamine was used instead of trifluoroethylamine to obtain compound 13 (60 mg) in Example 13. MS(ESI): m / z 441.1408[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.73(s,1H),8.46(s,1H),7.51(t,1H),7.41(s, 1H),7.22(d,1H),7.13(d,1H),6.14-5.81(m,1H),5.64(s,1H),5.03(tdd, 1H),4.40(s,2H),4.32(s,2H),3.43-3.33(m,2H),3.05(p,1H),2.49-2.36 (m,1H),2.02(q,1H),1.97-1.86(m,1H),1.73(td,2H),1.67-1.58(m,1H). Example 14: Preparation of Compound 14

[0359] [ka]

[0360] Referring to the method for producing compound 2 in Example 2, tert-butylamine was used instead of isopropylamine to obtain compound 14 (60 mg) in Example 14. MS(ESI): m / z 417.1954[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.69(s,1H),8.37(s,1H),7.41(s,1H),7.18(d,2H),6.76(s,1H),5.62(s,1H),4.97(s,1H),4.36-4 .18(m,2H),4.03-3.84(m,2H),3.02(q,1H),2.46(dt,1H),2.08-1.96(m,1H),1.89(ddd,1H),1.77-1.52(m,3H),1.21(s,9H). Example 15: Preparation of Compound 15

[0361] [ka]

[0362] Referring to the method for producing compound 1 in Example 1, intermediate 5-bromo-2,3-dihydrobenzo[c]thiophene-2,2-dioxide was replaced with intermediate 5-bromo-2,3-dihydrobenzothiophene-1,1-dioxide, and intermediate 1B was replaced with 2B to obtain compound 15 (30 mg) in Example 15. MS(ESI): m / z 419.1752[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.90(s,1H),8.99(s,1H),7.52-7.41(m,2H),7.29(d,J=8.0Hz,1H),6.94(d,J=7.8Hz,1H),5.70(s,1H),5.00(s,1H),3.58 (m,1H),3.47(m,2H),3.24(t,J=6.9Hz,2H),3.10-3.01(m,1H),2.49-2.41 (m,1H),2.02(m,1H),1.90(m,1H),1.73(m,2H),1.60(s,1H),1.03(m,6H). Example 16: Preparation of Compound 16

[0363] [ka]

[0364] Referring to the method for producing compound 2 in Example 2, bicyclo[1.1.1]pentane-1-amine hydrochloride was used instead of isopropylamine to obtain compound 16 (35 mg) in Example 16. MS(ESI): m / z 427.1804[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.69(s,1H),8.37(s,1H),7.59(d,2H),7.18(d,2H),5.62(s,1H),4.99(s,1H),4 .27(dd,2H),3.91(dd,2H),3.13-2.95(m,1H),2.49-2.40(m,1H),2.35(s,1H),1.98(d,8H),1.66(d,3H). Example 17: Preparation of Compound 17

[0365] [ka]

[0366] Intermediate A (5g) and palladium carbon (palladium content 5%, water content 50% (w / w), 0.5g) were reacted in tetrahydrofuran (50mL) and ethyl acetate (50mL) under a hydrogen atmosphere at room temperature with stirring. After the reaction was complete, the mixture was filtered and concentrated to obtain intermediate 17A (2.9g). MS(ESI): m / z 222.31[M+H] + . 17A (2.9g), 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide (5g), chloro(2-dicyclohexylphosphin-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (2.1g), 2-dicyclohexylphosphin-2',4',6'-triisopropylbiphenyl (1.3g), and potassium phosphate (8.6g) were added to 1,4-dioxane (100mL). After addition, the mixture was stirred and reacted under nitrogen protection at 110°C. After the reaction was complete, the mixture was filtered, concentrated, and further separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 17B (4g). MS(ESI): m / z 388.25[M+H] + . Under conditions of -78°C, lithium triethylborohydride (25.8 mL, 1 mol / L) was slowly added dropwise to a stirring solution of tetrahydrofuran (50 mL) containing 17B (4 g). After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and further separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 17C (1.65 g). MS(ESI): m / z 390.26[M+H] + . 17C (1.65 g), p-nitrochloroformate (0.9 g), 4-dimethylaminopyridine (0.1 g), and pyridine (1 g) were reacted in dichloromethane (30 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the mixture was further separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 17D (1.02 g). MS (ESI): m / z 555.25 [M+H] + .

[0367] 17D (1.02 g) was reacted with formic acid (50 mL) by stirring at 100°C. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the intermediate 17E (0.25 g) was separated by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 499.20 [M+H] + .

[0368] 17E (0.25 g), N,N-diisopropylethylamine (0.32 g), and 2,2-dimethylazetidine hydrochloride (0.18 g) were reacted in tetrahydrofuran (10 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the mixture was further separated by column chromatography (eluent: dichloromethane / methanol) to obtain compound 17 (30 mg) of Example 17. MS(ESI): m / z 445.1904[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.76(s,1H),8.46(s,1H),7.46-7.34(m,1H),7.21(s ,1H),7.13(d,J=8.4Hz,1H),5.62(d,J=5.2Hz,1H),5.06-4.94(m,1H),4.40(s ,2H),4.32(s,2H),3.69(m,2H),3.06(m,1H),2.42(m,1H),2.08-1.98(m,1H), 1.98-1.91(m,2H),1.87(s,1H),1.73(m,2H),1.65(m,1H),1.39-1.31(m,6H). Example 18: Preparation of Compound 18

[0369] [ka]

[0370] Referring to the method for producing compound 17 in Example 17, intermediate B was used instead of intermediate A to obtain compound 18 (35 mg) in Example 18. MS(ESI): m / z 445.1905[M+H] + . 1 H NMR(500MHz,DMSO-d6)δ11.77(s,1H),8.47(s,1H),7.40(s,1H),7.21(s,1H),7.13(d,J =8.4Hz,1H),5.65(s,1H),5.12-4.87(m,1H),4.40(s,2H),4.32(s,2H),3.77-3.61(m,2H ),3.05(p,J=8.5Hz,1H),2.48-2.35(m,1H),2.07-1.99(m,1H),1.95(t,J=7.6Hz,2H),1. 92-1.82(m,1H),1.73(q,J=9.9Hz,2H),1.65(td,J=11.0,4.0Hz,1H),1.41-1.29(m,6H). Example 19: Preparation of Compound 19

[0371] [ka]

[0372] Referring to the method for producing compound 2 in Example 2, ethylamine was used instead of isopropylamine to obtain compound 19 (85 mg) in Example 19. MS(ESI): m / z 389.1654[M+H] + 1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),8.37(s,1H),7.42(s,1H),7.18(d,J=4.5Hz,2H),7.02(m,1H),5.62(s,1H),4.99(m,1H),4.27(m,2H) ),3.92(m,2H),3.09-3.01(m,1H),3.01-2.91(m,2H),2.45(m,1H),2.00(m,1H),1.96-1.86(m,1H),1.72(m,2H),1.60(m,1H),0.99(m,3H). Example 20: Preparation of Compound 20

[0373] [ka]

[0374] Referring to the method for producing compound 2 in Example 2, compound 20 (25 mg) of Example 20 was obtained by using 3-S-1,3-dimethylpiperazine instead of isopropylamine. MS(ESI): m / z 458.2236[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.71(s,1H),8.36(s,1H),7.42(s,1H),7.18(q,J=8.4Hz,2H),5.61(s,1H),5.03(tdd,J=6 .6,5.4,2.4Hz,1H),4.27(dd,J=24.4,15.8Hz,2H),4.06(s,1H),3.91(dd,J=22.8,15.8Hz,2H),3.64(d,J=13.1Hz,1 H),3.08(p,J=8.1Hz,1H),2.97(td,J=12.7,3.4Hz,1H),2.64(d,J=11.0Hz,1H),2.54(s,1H),2.42(dt,J=14.5,8.0 Hz,1H),2.10(s,3H),2.02(q,J=9.2Hz,1H),1.91(td,J=13.0,5.3Hz,2H),1.80-1.67(m,4H),1.12(d,J=6.8Hz,3H). Example 21: Preparation of Compound 21

[0375] [ka]

[0376] Referring to the method for producing compound 1 in Example 1, compound 21 (19 mg) of Example 21 was obtained by using 3-S-1,3-dimethylpiperazine instead of cyclobutylamine. MS(ESI): m / z 474.2183[M+H] + .

[0377] 1 H NMR(500MHz,DMSO-d6)δ11.75(s,1H),8.46(s,1H),7.40(s,1H),7.27-7.10(m,2H),5.68(d,J=56.2Hz, 1H),5.06-5.01(m,1H),4.40(s,2H),4.32(s,2H),4.06(s,1H),3.64(d,J=13.6Hz,1H),3.09(q,J=8.3Hz ,1H),3.01-2.95(m,1H),2.63(d,J=10.7Hz,1H),2.55(d,J=16.5Hz,1H),2.42(dt,J=14.2,7.2Hz,1H), 2.10(s,3H),2.04-1.98(m,1H),1.92(dd,J=11.3,4.1Hz,2H),1.79-1.69(m,4H),1.11(d,J=6.9Hz,3H). Example 22: Preparation of Compound 22 and Compound 23

[0378] [ka]

[0379] Chiral separation and preparation of compound 2 (100 mg) was performed using SFC, and the chromatographic conditions were as follows.

[0380] Equipment: Supercritical fluid chromatography Column: CHIRALART Cellulose-SB (Innovation 012, 30*250mm, 5μm) Mobile phase A: Carbon dioxide Mobile phase B: methanol Detection wavelength: 254nm Compound 2 (0.1 g) was weighed, dissolved in 1.5 ml of dichloromethane, and filtered through a 0.45 μm organic membrane to obtain the filtrate.

[0381] Manufacturing gradient: Injection volume=1.5ml Isocratic elution (see table below)

[0382] [Table 1]

[0383] Compound 22 (45 mg) was obtained. MS(ESI):m / z 403.1804[M+H] + ;UPCC:Purity:100%, RT=2.025min 254nm.

[0384] 1 H NMR(500 MHz,DMSO-d6)δ11.69(s,1H),8.37(s,1H),7.42(s,1H),7.18(q,J=8.3Hz,2H),6.94(d,J=7. 8Hz,1H),5.62(s,1H),4.99(s,1H),4.36-4.19(m,2H),3.92(dd,J=25.3,15.8Hz,2H),3.58(d d,J=13.3,6.7Hz,1H),3.09-2.98(m,1H),2.45(dt,J=14.4,7.3Hz,1H),2.01(q,J=8.2Hz,1H ),1.96-1.85(m,1H),1.70(dd,J=15.6,9.2Hz,2H),1.60(s,1H),1.03(dd,J=6.7,1.9Hz,6H). Compound 23 (45 mg) was obtained. MS(ESI):m / z 403.1801[M+H] + ;UPCC:Purity:100%,RT=3.441min 254nm 1H NMR(500 MHz,DMSO-d6)δ11.69(s,1H),8.37(s,1H),7.42(s,1H),7.17(t,J=7.3Hz,2H),6.94(d ,J=7.8Hz,1H),5.62(s,1H),4.99(s,1H),4.34-4.21(m,2H),3.98-3.86(m,2H),3.58(d d,J=13.7,7.1Hz,1H),3.11-2.98(m,1H),2.45(dt,J=14.2,7.4Hz,1H),2.01(q,J=8.3H) z,1H),1.96-1.86(m,1H),1.78-1.68(m,2H),1.60(s,1H),1.03(dd,J=6.8,1.9Hz,6H). UPCC detection method: Column: CHIRALPAK IB-3 (4.6 x 100 mm, 3 μm) Column temperature: 40℃ Flow rate: 2.0ml / min ABPR: 1600 psi Mobile phase: CO2-methanol (60:40) Isocratic elution: 10 min Example 23: Preparation of Compound 24

[0385] [ka]

[0386] Referring to the method for producing compound 2 in Example 2, cyclopropylamine was used instead of isopropylamine to obtain compound 24 (19 mg) in Example 23. MS(ESI): m / z 401.1642[M+H] + 1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),8.36(s,1H),7.41(s,1H),7.23(s,1H),7.17(s, 2H),5.62(s,1H),5.00(s,1H),4.27(dd,J=24.7,15.8Hz,2H),3.92(dd,J=24.2,15.8H z,2H),3.04(s,1H),2.44(q,J=7.2Hz,2H),2.01(d,J=9.0Hz,1H),1.90(dd,J=10.6,6. 9Hz,1H),1.71(s,2H),1.60(s,1H),0.55(dt,J=7.2,3.7Hz,2H),0.37(p,J=4.5Hz,2H). Example 24: Preparation of Compound 25

[0387] [ka]

[0388] Referring to the method for producing compound 2 in Example 2, 1-methylcyclopropylamine was used instead of isopropylamine to obtain compound 25 (10 mg) in Example 24. MS(ESI): m / z 415.1807[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.68(s,1H),8.36(s,1H),7.42(s,1H),7.34(s,1H),7.17( d,J=8.1Hz,2H),5.62(s,1H),4.98(s,1H),4.27(dd,J=24.7,15.8Hz,2H),3.91(dd, J=24.3,15.8Hz,2H),3.03(s,1H),2.46(d,J=7.9Hz,1H),2.00(s,1H),1.89(s,1H), 1.69(s,2H),1.57(s,1H),1.23(s,3H),0.59(t,J=3.2Hz,2H),0.47(q,J=4.5Hz,2H). Example 25: Preparation of Compound 26

[0389] [ka]

[0390] Referring to the method for producing compound 17 in Example 17, 5-bromo-1,3-dihydrobenzo[c]thiophene was used instead of 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide to obtain the key intermediate 26E (130 mg) of Example 25. MS(ESI): m / z 413.57[M+H] + Under conditions of -20°C, 26E (130 mg) and m-chloroperbenzoic acid (67 mg) were reacted in a solution of dichloromethane (30 mL) with stirring. After the reaction was complete, water was added to quench the reaction, the compound was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and further separated by column chromatography (eluent: dichloromethane / methanol) to obtain compound 26 (80 mg) of Example 25. MS(ESI): m / z 429.1962[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.72(s,1H),8.37(s,1H),7.40(s,1H),7.16(d,J=7.9Hz ,2H),5.62(d,J=4.2Hz,1H),5.09-4.93(m,1H),4.27(m,2H),3.91(m,2H),3.73(t, J=7.6Hz,1H),3.65(t,J=7.6Hz,1H),3.05(m,1H),2.42(m,1H),2.08-1.99(m,1H) ,1.95(t,J=7.6Hz,2H),1.86(m,1H),1.74(m,2H),1.65(m,1H),1.43-1.28(m,6H). Example 26: Preparation of Compound 27

[0391] [ka]

[0392] Referring to the method for producing compound 2 in Example 2, (1R,2S)-2-fluorocyclopropyl-1-amine was used instead of isopropylamine to obtain compound 27 (20 mg) in Example 26. MS(ESI): m / z 419.1555[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.70(s,1H),8.38(s,1H),7.40(d,J=22.4Hz,2H),7.22-7.13(m,2H), 5.63(s,1H),5.03(s,1H),4.62(d,J=65.0Hz,1H),4.27(dd,J=24.8,15.8Hz,2H),3.91(dd,J=24 .8,15.8Hz,2H),3.36(d,J=7.3Hz,1H),3.09-3.00(m,1H),2.47(s,1H),2.02(q,J=7.9Hz,1H), 1.91(ddd,J=13.6,11.4,7.4Hz,1H),1.73(d,J=8.9Hz,2H),1.63(s,1H),1.24(d,J=7.2Hz,2H). Example 27: Preparation of Compound 28

[0393] [ka]

[0394] Referring to the method for producing compound 2 in Example 2, 3-methoxycyclobutylamine was used instead of isopropylamine to obtain compound 28 (105 mg) in Example 27. MS(ESI): m / z 445.1906[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.69(s,1H),8.37(s,1H),7.49-7.30(m,2H),7.18( d,J=5.7Hz,2H),5.62(s,1H),4.98(d,J=8.0Hz,1H),4.33-4.21(m,2H),3.92 (m,2H),3.59-3.45(m,1H),3.14-2.97(m,4H),2.49-2.35(m,3H),2.18-2.05 (m,1H),2.01(m,1H),1.89(m,1H),1.80-1.64(m,4H),1.61(d,J=13.4Hz,1H). Example 28: Preparation of Compound 29 and Compound 30

[0395] [ka]

[0396] The method for producing compounds 22 and 23 in Example 22 was used as a reference, compound 26 (80 mg) was isolated and produced by SFC, and compound 29 (35 mg) was obtained. MS(ESI):m / z 429.1960[M+H] + ;UPCC:Purity:100%, RT=1.232min 254nm.

[0397] 1 H NMR(500MHz,DMSO-d6)δ11.72(s,1H),8.37(s,1H),7.40(t,J=4.1Hz,1H),7.17(s,2H),5.62(d,J= 4.3Hz,1H),5.14-4.90(m,1H),4.35-4.19(m,2H),3.91(dd,J=22.0,15.8Hz,2H),3.69(dt,J=37.2 ,7.7Hz,2H),3.05(p,J=8.5Hz,1H),2.42(ddd,J=26.2,14.4,7.3Hz,1H),2.08-1.98(m,1H),1.95( t,J=7.6Hz,2H),1.91-1.82(m,1H),1.73(q,J=10.0Hz,2H),1.69-1.59(m,1H),1.40-1.32(m,6H). Compound 30 (35 mg) was obtained. MS (ESI): m / z 429.1964 [M+H] + ;UPCC:Purity:100%, RT=2.262min 254nm.

[0398] 1H NMR(500MHz,DMSO-d6)δ11.72(s,1H),8.37(s,1H),7.49-7.34(m,1H),7.16(d,J=7.9Hz,2H),5.62(d ,J=4.1Hz,1H),5.07-4.94(m,1H),4.27(dd,J=24.6,15.7Hz,2H),3.91(dd,J=22.0,15.8Hz,2H),3.69 (dt,J=36.9,7.7Hz,2H),3.05(p,J=8.5Hz,1H),2.42(ddd,J=26.4,14.5,7.4Hz,1H),2.07-1.98(m,1H ),1.95(t,J=7.6Hz,2H),1.91-1.82(m,1H),1.80-1.69(m,2H),1.68-1.59(m,1H),1.37-1.29(m,6H). The UPCC detection method is the same as in Example 22.

[0399] Example 29: Preparation of Compound 31 and Compound 32

[0400] [ka]

[0401] Referring to the manufacturing methods for compounds 22 and 23 in Example 22, chiral separation of compound 25 (65 mg) was performed by SFC to obtain compound 31 (20 mg). MS(ESI): m / z 415.1803[M+H] + ;UPCC:Purity:100%, RT=1.501min 254nm.

[0402] 1H NMR(500MHz,DMSO-d6)δ11.68(s,1H),8.36(s,1H),7.38(d,J=36.5Hz,2H),7.18(s,2H),5.62(s,1H),4.98(s,1H),4.34-4.19(m,2H),3.92(dd,J =24.6,15.8Hz,2H),3.03(s,1H),2.00(s,1H),1.89(s,1H),1.70(s,2H) ,1.57(s,1H),1.23(s,3H),0.59(d,J=2.7Hz,2H),0.47(q,J=3.5Hz,2H). Compound 32 (19 mg) was obtained. MS (ESI): m / z 415.1804 [M+H] + ;UPCC:Purity:99.15%,RT=2.107min 254nm.

[0403] 1 H NMR(500MHz,DMSO-d6)δ11.68(s,1H),8.36(s,1H),7.38(d,J=39.0Hz,2H),7.17(d ,J=8.1Hz,2H),5.62(s,1H),4.98(s,1H),4.35-4.21(m,2H),3.91(dd,J=23.6,15. 8Hz,2H),3.03(s,1H),2.47-2.41(m,1H),2.05-1.97(m,1H),1.90(d,J=9.2Hz,1H) ,1.70(s,2H),1.57(s,1H),1.23(s,3H),0.59(q,J=4.5Hz,2H),0.49-0.43(m,2H).

[0404] The UPCC extraction method is the same as in Example 22.

[0405] Example 30: Production of Compound 33 and Compound 34

[0406]

change

[0407] Referring to the manufacturing methods for compounds 22 and 23 in Example 22, chiral separation of compound 16 (20 mg) was performed by SFC to obtain compound 33 (8.7 mg, RT=5.467 min (HPLC)). MS(ESI): m / z 427.1803[M+H]+.

[0408] Compound 34 (8.4 mg, RT=10.181 min (HPLC)) was obtained. MS(ESI):m / z 427.1796[M+H]+.

[0409] HPLC detection method: Column: CHIRALART Cellulose-SB (4.6 x 250 mm, 5 μm) Mobile phase: N-hexane / ethanol (30% / 70%) isocratic elution Flow rate: 1.0mL / min Column temperature: 25℃ Detection wavelength: 254 nm.

[0410] Example 31: Preparation of Compound 35 and Compound 36

[0411] [ka]

[0412] Referring to the manufacturing methods for compounds 22 and 23 in Example 22, chiral separation of compound 14 (25 mg) was performed by SFC to obtain compound 35 (10.3 mg, RT=5.769 min (HPLC)). MS(ESI): m / z 417.1953[M+H]+.

[0413] Compound 36 (11.8 mg, RT=12.739 min (HPLC)) was obtained. MS(ESI): m / z 417.1956[M+H]+.

[0414] The HPLC detection method is the same as in Example 30.

[0415] Example 32: Preparation of Compound 37 and Compound 38

[0416] [ka]

[0417] Referring to the manufacturing methods for compounds 22 and 23 in Example 22, chiral separation of compound 19 (85 mg) was performed by SFC to obtain compound 37 (28.2 mg, RT=6.348 min (HPLC)). MS(ESI): m / z 389.1648[M+H]+.

[0418] Compound 38 (27.5 mg, RT=13.435 min (HPLC)) was obtained. MS(ESI):m / z 389.1650[M+H]+.

[0419] The HPLC detection method is the same as in Example 30.

[0420] Example 33: Preparation of Compound 39 and Compound 40

[0421] [ka]

[0422] Referring to the production methods for compounds 22 and 23 in Example 22, chiral separation of compound 28 (105 mg) was performed by SFC to obtain compound 39 (41.2 mg, RT=7.083 min (HPLC)). MS(ESI): m / z 445.1911[M+H] + .

[0423] Compound 40 (42.9 mg, RT=13.003 min (HPLC)) was obtained. MS(ESI): m / z 445.1905 [M+H] + .

[0424] The HPLC detection method is the same as in Example 30.

[0425] Example 34: Preparation of Compound 41 and Compound 42

[0426] [ka]

[0427] Referring to the production methods for compounds 22 and 23 in Example 22, chiral separation of compound 27 (25 mg) was performed by SFC to obtain compound 41 (7.3 mg, RT=6.288 min (HPLC)). MS(ESI): m / z 419.1553[M+H] + .

[0428] Compound 42 (7.4 mg, RT=13.602 min (HPLC)) was obtained. MS(ESI): m / z 419.1553 [M+H] + .

[0429] The HPLC detection method is the same as in Example 30.

[0430] Experimental Example 1: In vitro kinase inhibitory activity 1.1 Measurement of CDK2 / CycA2 kinase inhibitory activity CDK2 / CycA2 kinase solution (concentration 0.078 ng / μl) was added to the detection wells to a total volume of 6 μL per well. Using a nanoliter pipette, each compound dissolved in DMSO was added to the detection wells to achieve a final concentration of 1000 nM to 0.244 nM. Two overlapping wells were used, and a control was placed in each well. After incubating the system for 30 minutes, ATP (concentration 50 μM or 5000 μM) and ULight-Myelin Basic Protein Peptide substrate (PerkinElmer, concentration 0.25 μM) were mixed in a 1:1 ratio and added to each well in 4 μL portions. After reacting at room temperature for 2 hours, 5 μL of EDTA was added to terminate the reaction. Finally, 5 μL of detection antibody (PerkinElmer, concentration 8 nM) was added, and the mixture was incubated at room temperature for 1 hour. Detection was performed using a PerkinElmer Envision multimode plate reader (excitation 320nm, emission 615nm / 665nm), and the IC was fitted with 4 parameters. 50 The result was calculated.

[0431] 1.2 Measurement of CDK2 CycE1 kinase inhibitory activity CDK2 CycE1 kinase solution (concentration 0.015 ng / μL) was added to the detection wells to a total volume of 6 μL per well. Using a nanoliter pipette, each compound dissolved in DMSO was added to the detection wells to achieve a final concentration of 300 nM to 0.07 nM. Two overlapping wells were created, and a control was placed in each well. After incubating the system for 30 minutes, ATP (concentration 50 μM or 5000 μM) and ULight-Myelin Basic Protein Peptide substrate (PerkinElmer, concentration 0.25 μM) were mixed in a 1:1 ratio and added to each well in 4 μL portions. After reacting at room temperature for 2 hours, 5 μL of EDTA was added to terminate the reaction. Finally, 5 μL of detection antibody (PerkinElmer, concentration 8 nM) was added, and the system was incubated at room temperature for 1 hour. Detection was performed using a PerkinElmer Envision multimode plate reader (excitation 320 nm, emission 615 nm / 665 nm), and IC was obtained by fitting with 4 parameters. 50 The result was calculated.

[0432] The experimental results are shown in Table 1. A is 0 nM <IC 50 ≤10nM, B is 10nM <IC 50 ≤50nM, C is 50nM <IC 50 ≤100nM, D is 100nM <IC 50 ≤1000nM, E is 1000nM <IC 50 It represents.

[0433] [Table 2-1]

[0434] [Table 2-2]

Claims

1. A compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, X １ , X ２ and X ３ These are N and C(R) independently of each other. ａ ) are selected from, Z １ , Z ２ and Z ３ are each independently selected from O, S, N, N(R ｂ ), S(O), S(O) ２ , C(O), C(R ａ ), or C(R ａ R ａ ), L １ and L ２ Each of these is independently a single bond, -N(R) ｂ )-, -N=, -O-, -S-, -(CH ２ ) ｍ -, - (CD) ２ ) ｍ -, - (CHD) ｍ -, -C(=O)-, -S(=O)-, -S(=O) ２ -, -S(=O)(=N(R ｂ ))-,-S(=O)(R ｃ )-, -P(=O)(R ｃ ) - or - P (= O) (NR ｂ R ｂ ) - Selected from, R １ H, deuterium, C １－３ Alkyl, C １－３ Alkoxy, -NH ２ ,-NH(C １－３ Alkyl), -N(C １－３ Alkyl) ２ , C ３－６ Cycloalkyl, C ３－６ Selected from cycloalkenyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, the C １－３ Alkyl or C １－３ Each alkoxy independently contains one, two, or three R atoms. ｄ It may be replaced by the above C ３－６ Cycloalkyl, C ３－６ Cycloalkenyls, 3-6 membered heterocyclyls, phenyls, or 5-6 membered heteroaryls can independently be one or more R groups. ｅ It may also be replaced with A is, 【Chemistry 2】 Alternatively, selected from 3- to 6-membered heterocyclines containing one or two N atoms, the 3- to 6-membered heterocyclines independently contain one or more R atoms. ｚ It may also be replaced with R ２ , R ３ and R ４ These are H, deuterium, halogen, OH, CN, and NH, respectively, independently. ２ , C １－３ Alkyl, C １－３ Alkoxy, C ３－６ Cycloalkyl, C ３－６ Selected from cycloalkenyls or 3-6 member heterocyclyls, the C １－３ Alkyl, C １－３ Alkoxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkenyls or 3- to 6-membered heterocyclyls independently have one or more R ｚ It may also be replaced with Or, R ２ and R ３ C ３－６ Cycloalkyl, C ３－６ Forming a cycloalkenyl or a 3-6 member heterocycline, R ４ H, deuterium, halogen, OH, CN, NH ２ , C １－３ Alkyl or C １－３ Selected from alkoxy, the C １－３ Alkyl, C １－３ Alkoxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkenyls or 3- to 6-membered heterocyclyls independently have one or more R ｚ It may also be replaced with Or, R ２ , R ３ and R ４ C ５－８ Forming a bicycloalkyl or a 5-8 membered bicycloheteroalkyl, the C ５－８ Bicycloalkyl or 5-8 membered bicycloheteralkyl groups independently contain one or more R groups. ｚ It may also be replaced with, Each R ａ These are, independently, hydrogen, deuterium, halogen, OH, CN, and NH. ２ COOH, NO ２ , C １－３ Alkyl, C １－３ Alkoxy, C １－３ Alkoxy C １－３ Alkylene, C １－３ Alkylamino, (C １－３ Alkyl) ２ Selected from amino acids, the C １－３ Alkyl or C １－３ Alkoxy can be one or more R independently. ｘ It may also be replaced with Alternatively, two Rs in C(R ａ R ａ ), together with the carbon atoms linked in common, form a C ａ cycloalkyl, C ３－６ cycloalkenyl or 3- to 6-membered heterocyclyl, and the C ３－６ cycloalkyl, C ３－６ cycloalkenyl or 3- to 6-membered heterocyclyl may be independently substituted with one or more Rs ３－６ ｙ ｙ and may be optionally substituted with one or more Rs, Each R ｂ is independently selected from H, C １－３ alkyl, C １－３ alkoxy, -C(=O)H, -S(=O) ２ C １－３ alkyl, C ３－６ cycloalkyl, C ３－６ cycloalkenyl or 3-6 membered heterocyclyl, wherein said C １－３ alkyl or C １－３ alkoxy may each independently be substituted with one, two or three R ｘ groups, and said C ３－６ cycloalkyl, C ３－６ cycloalkenyl or 3-6 membered heterocyclyl may each independently be substituted with one or more R ｙ groups; R ｃ is halogen, OH, CN or C １－３ Selected from alkyl, the C １－３ Alkyl molecules can be one or more R groups independently. ｘ It may also be replaced with Each R ｄ Each of these is independently deuterium, halogen, OH, CN, or NH ２ Selected from, Each R ｅ These are, independently, deuterium, halogen, OH, CN, and NH. ２ , = O, C １－３ Alkyl or C １－３ Selected from alkoxy, the C １－３ Alkyl or C １－３ Alkoxy can be one or more R independently. ｘ It may also be replaced with Each R ｘ Each of these is independently deuterium, halogen, OH, CN, or NH ２ Selected from, Each R ｙ These are, independently, deuterium, halogen, OH, CN, and NH. ２ , = O, C １－３ Alkyl or C １－３ Selected from alkoxy, the C １－３ Alkyl or C １－３ Alkoxys are independently deuterium, halogen, OH, CN, or NH ２ It may be substituted with one or more substituents selected from the following: Each R ｚ These are, independently, deuterium, halogen, OH, CN, and NH. ２ , C １－３ Alkyl or C １－３ Selected from alkoxy, the C １－３ Alkyl or C １－３ Alkoxys are independently deuterium, halogen, OH, CN, or NH ２ It may be substituted with one or more substituents selected from the following: m is selected from 1, 2, or 3. Carbon atoms marked with an asterisk (*) are chiral carbon atoms, and exist either as a single (R) or (S) enantiomer, or as a single enantiomer-rich form. Alternatively, each L １ , L ２ , R １ , R ２ , R ３ , R ４ , R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｘ , R ｙ or R ｚ Each of these may be independently substituted with one or more substituents.

2. X １ , X ２ and X ３ All of them are C(R ａ ) selected from, or X １ , X ２ and X ３ One of them is selected from N, or X １ X is selected from N. ２ and X ３ All of them are C(R ａ ) selected from, or X ２ X is selected from N. １ and X ３ All of them are C(R ａ ) selected from, or X ３ X is selected from N. １ and X ２ All of them are C(R ａ A compound represented by formula (I) according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

3. Each R ａ These are, independently, hydrogen, F, Cl, Br, I, CN, and C. １－３ Alkyl, C １－３ Alkoxy or C １－３ Alkoxy C １－３ Selected from alkylene, C １－３ Alkyl or C １－３ Each alkoxy independently contains one, two, or three R atoms. ｘ It may be replaced by, or each R ａ These are, independently, hydrogen, F, and C. １－３ Alkyl, C １－３ Alkoxy or C １－３ Alkoxy C １－３ Selected from alkylene, C １－３ Alkyl or C １－３ Each alkoxy independently contains one, two, or three R atoms. ｘ It may be replaced by, or each R ａ Each is independently selected from hydrogen, F, methyl, or methoxymethyl, and each methyl or methoxymethyl is independently selected from 1, 2, or 3 R ｘ It may be replaced by, or each R ａ Each of these is independently selected from hydrogen, F, methyl, or methoxymethyl, and comprises a compound represented by formula (I) according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

4. Z １ Z ２ and Z ３ These are S(O), S(O) respectively, independently. ２ or C(R ａ R ａ ) is selected from, or Z ２ is S(O) or S(O) ２ Selected from, Z １ and Z ３ Each of them is independently C(R) ａ R ａ A compound represented by formula (I) according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

5. L １ is a single bond, -N(R ｂ )-, -O-, -S (=O) ２ -, -S-, -(CH ２ ) ｍ - or -C (=O)- is selected, or L １ This is a single bond, -NH-, -N(CH ３ ) -, -S (=O) ２ -ien-CH ２ -ien-CH ２ -CH ２ -ien-CH ２ -CH ２ -CH ２ - or -C (=O)- is selected, or L １ It is selected from a single bond or -NH-, L ２ This is a single bond, -NH-, -N(C) １－３ Alkyl)-,-CH ２ -ien-CH ２ -CH ２ -ien-CH ２ -CH ２ -CH ２ -, -C(=O)-, -S(=O)-, -S(=O) ２ - or -S (=O) (C １－３ Selected from alkyl) or L ２ This is a single bond, -NH-, -N(CH ３ ) -, -CH ２ -ien-CH ２ -CH ２ -ien-CH ２ -CH ２ -CH ２ -, -C(=O)-, -S(=O)-, -S(=O) ２ - or -S (=O) (CH ３ ) - Selected from, or L ２ is a single bond or -S (=O) ２ - Selected from, -L ２ -L １ - represents a single bond, -NH-, -N(CH ３ )-, -C(=O)-, -CH ２ -ien-CH ２ -CH ２ -, -S (=O) ２ -ien-CH ２ -NH-, -NH-CH ２ -ien-CH ２ -N(CH ３ )-,-N(CH ３ ) - CH ２ -, -C(=O)-CH ２ -ien-CH ２ -C(=O)-, -C(=O)-NH-, -NH-C(=O)-, -NH-S(=O) ２ -, -S (=O) ２ -NH-, -N(CH ３ ) - S (= O) ２ -, -S (=O) ２ -N(CH ３ )-,-N(CH ３ )-C(=O)-, -C(=O)-N(CH ３ )-,-N(CH ３ ) - CH ２ -CH ２ -ien-CH ２ -CH ２ -N(CH ３ )-,-NH-CH ２ -CH ２ - or -CH ２ -CH ２ -NH- is selected, or -L ２ -L １ - represents a single bond, -NH-, -CH ２ - or -S (=O) ２ -NH- is selected, or -L ２ -L １ - is a compound represented by formula (I) according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from single bonds.

6. R １ H, deuterium, C １－３ Alkyl, C １－３ Alkoxy, -NH ２ ,-NH(C １－３ Alkyl), -N(C １－３ Alkyl) ２ , C ３－６ Selected from cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, the C １－３ Alkyl or C １－３ Each alkoxy independently contains one, two, or three R atoms. ｄ It may be replaced by the above C ３－６ Cycloalkyl groups, 3-6 membered heterocycloalkyl groups, phenyl groups, or 5-6 membered heteroaryl groups can be independently represented by one or more R groups. ｅ It may be replaced with, or R １ H, methyl, methoxy, -NH ２ ,-NH(CH ３ ), -NH(CH ２ CH ３ ), selected from cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, oxazolyl or pyrimidinyl, wherein the methyl, ethyl or methoxy atoms are each independently one, two or three R ｄ The cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, oxazolyl, or pyrimidinyl may be substituted with one, two, or three R ｅ It may be replaced with, or R １ is a compound represented by formula (I) as described in claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from H.

7. Each R ｄ Each of these is independently selected from F, Cl, Br, I, or OH, or each R ｄ Each is independently selected from F or OH. Each R ｅ These are, independently, F, Cl, Br, I, =O, or C. １－３ Selected from alkyl, the C １－３ Each alkyl group independently has one, two, or three R atoms. ｘ It may be replaced by, or each R ｅ Each is independently selected from F or methyl, Each R ｘ Each is independently selected from halogens, or each R ｘ Each is independently selected from F, Each R ｙ Each is independently selected from halogens, or each R ｙ Each of these is independently selected from F, and is a compound represented by formula (I) as described in claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

8. Each R ｂ These are H and C, which are independent of each other. １－３ Alkyl, C １－３ Alkoxy, -C(=O), H, -S(=O) ２ C １－３ Alkyl, C ３－６ Selected from cycloalkyl or 3- to 6-membered heterocycloalkyl, the C １－３ Alkyl or C １－３ Each alkoxy independently contains one, two, or three R atoms. ｘ It may be replaced by the above C ３－６ Cycloalkyl or 3- to 6-membered heterocycloalkyl groups independently have one or more R groups. ｙ It may be replaced by, or each R ｂ These are, independently, H or C １－３ Selected from alkyl, the C １－３ Each alkyl group independently has one, two, or three R atoms. ｘ It may be replaced by, or each R ｂ Each of these is independently selected from H or methyl, and comprises a compound represented by formula (I) according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

9. R ｃ C １－３ Selected from alkyl, the C １－３ Each alkyl group independently has one, two, or three R atoms. ｘ It may be replaced with, or R ｃ is a compound represented by formula (I) as described in claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from methyl.

10. R ２ , R ３ and R ４ These are H, deuterium, and C, respectively, independently. １－３ Alkyl or C ３－６ Selected from cycloalkyl, the C １－３ Alkyl or C ３－６ Each cycloalkyl group independently has one, two, or three R atoms. ｚ It may be replaced with, or R ２ , R ３ and R ４ Each is independently selected from H, deuterium, methyl, ethyl, or cyclopropyl, and each of the methyl, ethyl, or cyclopropyl is independently one, two, or three R ｚ It may be replaced with, or R ２ , R ３ and R ４ These are, independently, H, deuterium, methyl, and -CD. ３ , selected from difluoromethyl, trifluoromethyl, ethyl, 2-hydroxyethyl or cyclopropyl, or R ２ , R ３ and R ４ Each of these is independently selected from H, methyl, difluoromethyl, trifluoromethyl, 2-hydroxyethyl, or cyclopropyl. Or, R ２ and R ３ C ３－４ Forming a cycloalkyl or a 3-4 member heterocycloalkyl, R ４ is H or C １－３ Selected from alkyl, the C １－３ Alkyl, C ３－４ Each cycloalkyl or 3-4 membered heterocycloalkyl group independently contains 1, 2, or 3 R atoms. ｚ It may be replaced with, or R ２ and R ３ Together with the commonly linked carbon atoms, it forms cyclopropyl or cyclobutyl, R ４ is selected from H or methyl, and the cyclopropyl or cyclobutyl is independently one, two or three R ｚ It may also be replaced with Or, R ２ , R ３ and R ４ C ５－８ Forming a bicycloalkyl group, the C ５－８ Bicycloalkyl is a crosslinking ring, and the C ５－８ Bicycloalkyl groups independently have one or more R ｚ It may be replaced with, or R ２ , R ３ and R ４ Along with the carbon atoms that are commonly linked, 【Transformation 3】 A compound represented by formula (I) as described in claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, which forms a compound.

11. A is, 【Chemistry 4】 【Transformation 5】 Selected from the above, 【Transformation 6】 【Transformation 7】 These are independently one or more R ｚ It may be replaced by, or A is 【Transformation 8】 Selected from the above, 【Chemistry 9】 These may be independently substituted with one or more methyl groups, or A may be 【Chemistry 10】 or 【Chemistry 11】 A compound represented by formula (I) according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

12. Each R ｚ These are, independently, deuterium, halogen, OH, and C. １－３ Alkyl or C １－３ Selected from alkoxy, the C １－３ Alkyl or C １－３ Alkoxys are independently deuterium, halogen, OH, CN, or NH ２ They may be substituted with one or more substituents selected from, or each R ｚ These are, independently, deuterium, halogen, OH, and C. １－３ Alkyl or C １－３ Selected from alkoxys, or each R ｚ Each of these is independently selected from F, OH, methyl, or methoxy, and comprises a compound represented by formula (I) according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

13. A compound is selected from those represented by formula (I-1), Alternatively, a compound may be selected from those represented by formulas (I-2) and (I-3), Alternatively, a compound represented by formula (I) according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compounds represented by formula (I-4) and formula (I-5). 【Chemistry 12】 (In the formula, X １ , X ２ , X ３ Z １ Z ２ Z ３ , L １ , L ２ , R １ , R ２ , R ３ and R ４ (This is as defined in claim 1.) 【Chemistry 13】 (In the formula, X １ , X ２ , X ３ Z １ Z ３ , L １ , L ２ , R １ The sum A is as defined in claim 1. 【Chemistry 14】 (In the formula, X １ , X ２ , X ３ Z １ Z ３ , L １ , L ２ , R １ , R ２ , R ３ and R ４ (This is as defined in claim 1.)

14. The following compounds, their isomers, or pharmaceutically acceptable salts thereof. 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】

15. The following compounds, their isomers, or pharmaceutically acceptable salts thereof. [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】

16. A pharmaceutical composition comprising a therapeutic or prophylactic effective amount of a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 15, and optionally further comprising a pharmaceutically acceptable additive.

17. Use of a compound according to any one of claims 1 to 15, an isomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 16, in the manufacture of a pharmaceutical for treating or preventing a disease.

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