Cyclic compound and medical application thereof

Abstract

The invention belongs to the field of medicine, relates to a ring-fused compound and medical application thereof, and particularly relates to a preparation method of the compound, a pharmaceutical composition and application of the compound in treating diseases.

Description

Technical Field

[0001] This disclosure relates to cyclic compounds, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in treating diseases. Background Technology

[0002] KIF18A is a mitotic kinase protein belonging to the Kinesin-8 family. KIF18A regulates proper chromosome positioning and spindle tension during mitosis. The absence of KIF18A in humans leads to longer spindles and increased chromosome oscillations during the G2 / M phase of the cell cycle. Studies have shown that KIF18A is overexpressed in whole-genome-doubling (WGD) tumor cells but is non-essential in normal cells. Inhibition of KIF18A can induce mitotic arrest in WGD tumor cells without affecting normal cells. Therefore, KIF18A is a promising anti-tumor target. Summary of the Invention

[0003] This disclosure relates to compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0004]

[0005] in,

[0006] Ring A is selected from one or more R. A Substituted 5-12-membered bridged heterocyclic alkyl groups;

[0007] Ring B is selected from one or more Rs. B The following groups are substituted: 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl;

[0008] Ring C is selected arbitrarily by one or more R C The following groups are substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, or 3-12 membered heterocyclic groups;

[0009] Each R A R B 、or R C Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC1-6 Alkylamino;

[0010] Z 1 Z 2 or Z 3 Each is independently selected from N or CR Z1 ;

[0011] Each R Z1 Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino;

[0012] L 1 Selected from single bond, -O-, -S-, -NR L1 -、-C(R L1 )2-, -C(O)-, -S(O)-, -S(O)2-, -C(O)NR L1 -、-NR L1 C(O)-、-S(O)2NR L1 -、-NR L1 S(O)2-、-C(R L1 )2S(O)2-、-S(O)2C(R L1 )2-、-NR L1 S(O)2NR L1 -、-S(O)(=NH)-、-NR L1 S(O)(=NH)-、-S(O)(=NH)NR L1 -、-C(R L1 )2S(O)(=NH)-, or -NR L1 S(O)(=NH)NR L1 -;

[0013] Each R L1 Each is independently selected from H, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C1-6 Alkylamino or halogenated diC 1-6 Alkylamino;

[0014] R 1 Selected from one or more R 1a The following groups are substituted: C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkyl C 1-4 Alkylene or 3-12 membered heterocyclic alkyl C 1-4 Alkylene;

[0015] Each R 1a Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, or optionally influenced by one or more R. 1b The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, or di-C 1-6 Alkylamino;

[0016] Each R 1b Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-6 Alkoxy, C 1-6 alkylamino, or di-C 1-6 Alkylamino;

[0017] L 2 Selected from -C(O)O-, -OC(O)-, -C(O)NR L2 -、-NR L2 C(O)-、-S(O)2NR L2 - or -NR L2 S(O)2-;

[0018] R L2 Selected from H, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0019] X 1 X 2 Each is independently selected from N or CR X1 ;

[0020] ---Selected from single or double bonds;

[0021] When --- is selected as a single key, X 3 X 4 Each is independently selected from N, C, or CRX1 ;

[0022] When --- is selected from a double bond, X 3 X 4 Selected from C;

[0023] Each R X1 Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino;

[0024] Ring D is selected from one or more R. D The following groups are substituted: 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0025] Each R D Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino;

[0026] The R A R B R C R Z1 R L1 R Y R L2 R X1 、or R D It may be optionally substituted by one or more substituents.

[0027] The ring A and ring B described in this disclosure share a single ring atom.

[0028] In some implementations, ring A and ring B share a single carbon atom.

[0029] In some implementations, ring A is selected from one or more R... A Substituted 5-10-membered bridged heterocyclic alkyl groups.

[0030] In some implementations, ring A is selected from one or more R... A Substituted 6-9-membered bridged heterocyclic alkyl groups.

[0031] In some implementations, ring A is selected from one or more R... A Substituted 7-8-membered bridged heterocyclic alkyl groups.

[0032] In some implementations, ring B is selected from one or more Rs. B The following groups are substituted: 3-4 membered cycloalkyl or 4-5 membered heterocycloalkyl.

[0033] In some implementations, ring B is selected from one or more Rs. B The following groups may be substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, or piperazineyl.

[0034] In some implementations, ring B is selected from one or more Rs. B The following groups are substituted: cyclopropyl or cyclobutyl.

[0035] In some implementations, ring B is selected from one or more Rs. B Substituted cyclopropyl group.

[0036] In some implementation schemes, structural units Selected from Where n is selected from 0, 1, 2, 3, 4, 5, or 6.

[0037] In some implementation schemes, structural units Selected from Where n is selected from 0, 1, 2, 3, 4, 5, or 6; m is selected from 0, 1, 2, 3, or 4.

[0038] In some implementations, n is selected from 0, 1, 2, 3, or 4. In some implementations, n is selected from 0, 1, or 2.

[0039] In some implementations, m is selected from 0, 1, or 2.

[0040] In some implementations, ring C is selected from one or more Rs. C The following groups may be substituted: 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, or 3-10 membered heterocyclic groups.

[0041] In some implementations, ring C is selected from one or more Rs. C The following groups can be substituted: 4-9 membered cycloalkyl, 4-9 membered cycloalkenyl, or 4-9 membered heterocyclic groups.

[0042] In some implementations, ring C is selected from one or more Rs. C The following groups can be substituted: 4-7 membered cycloalkyl, 4-7 membered cycloalkenyl, or 4-7 membered heterocyclic groups.

[0043] In some implementations, ring C is selected from one or more Rs. C The following groups can be substituted: 5-6 membered cycloalkyl, 5-6 membered cycloalkenyl, or 5-6 membered heterocyclic groups.

[0044] In some embodiments, the 3-12 membered heterocyclic group described in this disclosure is selected from 3-12 membered heterocyclic alkyl groups. In some embodiments, the 3-10 membered heterocyclic group described in this disclosure is selected from 3-10 membered heterocyclic alkyl groups. In some embodiments, the 4-9 membered heterocyclic group described in this disclosure is selected from 4-9 membered heterocyclic alkyl groups. In some embodiments, the 4-7 membered heterocyclic group described in this disclosure is selected from 4-7 membered heterocyclic alkyl groups.

[0045] In some implementations, ring C is selected from one or more Rs. C The following groups are substituted: 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl.

[0046] In some implementations, ring C is selected from one or more Rs. C The following groups are substituted: 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl.

[0047] In some implementations, ring C is selected from one or more Rs. C The following groups are substituted: 4-9 membered cycloalkyl or 4-9 membered heterocycloalkyl.

[0048] In some implementations, ring C is selected from one or more Rs. C The following groups are substituted: 4-7 membered cycloalkyl or 4-7 membered heterocycloalkyl.

[0049] In some implementations, ring C is selected from one or more Rs. C The following groups are substituted: 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl.

[0050] In some implementations, ring C is selected from one or more Rs. C The following groups are substituted: cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl.

[0051] In some implementations, ring C is selected from one or more Rs. C The following groups are substituted:

[0052] In some implementations, each R A R B 、or R C Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino or halogenated diC 1-4 Alkylamino.

[0053] In some implementations, each R A R B 、or R C Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, deuterated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino or halogenated diC 1-3 Alkylamino.

[0054] In some implementations, each R A R B 、or R C Each is independently selected from deuterium, oxo, thio, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuterylmethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0055] In some implementations, each RA R B 、or R C Each is independently selected from deuterium, oxo, -F, -Cl, -OH, -CN, methyl, or methoxy.

[0056] In some implementations, each R C Each is independently selected from deuterium, -F, -Cl, -OH, -CN, or methyl.

[0057] In some implementation schemes, structural units Selected from

[0058] In some implementations, ring C is selected from...

[0059] In some implementation schemes, Z 1 Z 2 and Z 3 For CR Z1 .

[0060] In some implementation schemes, Z 1 Z 2 or Z 3 One or two of them are N.

[0061] In some implementation schemes, Z 1 For N, Z 2 and Z 3 For CR Z1 .

[0062] In some implementation schemes, Z 2 For N, Z 1 and Z 3 For CR Z1 .

[0063] In some implementation schemes, Z 3 For N, Z 1 and Z 2 For CR Z1 .

[0064] In some implementation schemes, Z 1 and Z 2 For N, Z 3 For CR Z1 .

[0065] In some implementation schemes, Z 1 and Z 3 For N, Z 2 For CR Z1 .

[0066] In some implementation schemes, Z2 and Z 3 For N, Z 1 For CR Z1 .

[0067] In some implementations, each R Z1 Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino or halogenated diC 1-4 Alkylamino.

[0068] In some implementations, each R Z1 Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, deuterated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino or halogenated diC 1-3 Alkylamino.

[0069] In some implementations, each R Z1 Each is independently selected from H, deuterium, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuterylmethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0070] In some implementations, each R Z1 Each is independently selected from H, deuterium, -F, -Cl, or methyl.

[0071] In some implementations, each R Z1 Selected from H.

[0072] In some implementations, L1 Selected from single bond, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-、-C(R L1 )2S(O)2-、-S(O)2C(R L1 )2-、-NR L1 S(O)2NR L1 -、-S(O)(=NH)-、-NR L1 S(O)(=NH)-、-S(O)(=NH)NR L1 -、-C(R L1 )2S(O)(=NH)-, or -NR L1 S(O)(=NH)NR L1 -

[0073] In some implementations, L 1 Selected from single bond, -S(O)2NR L1 -、-NR L1 S(O)2-、-NR L1 S(O)2NR L1 -、-S(O)(=NH)-、-NR L1 S(O)(=NH)-, or -C(R) L1 )2S(O)(=NH)-.

[0074] In some implementations, each R L1 Each is independently selected from H, deuterium, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino or halogenated diC 1-4 Alkylamino.

[0075] In some implementations, each R L1 Each is independently selected from H, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, deuterated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino or halogenated diC 1-3 Alkylamino.

[0076] In some implementations, each R L1 Each is independently selected from H, deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideutermethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0077] In some implementations, each R L1 Each is independently selected from H, deuterium, -F, -Cl, or methyl.

[0078] In some implementations, each R L1 Selected from H, deuterium, or methyl.

[0079] In some implementations, L 1 Selected from single bonds, -S(O)2NH-, -NHS(O)2-, -NHS(O)2NH-, -NHS(O)2N(CH3)-, -S(O)(=NH)-, -NHS(O)(=NH)-, or -CH2S(O)(=NH)-.

[0080] In some implementation schemes, R 1 Selected from one or more R 1a The following groups are substituted: C 1-5 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl C 1-3 Alkylene or 3-10 membered heterocyclic alkyl C 1-3 Alkylene.

[0081] In some implementation schemes, R 1 Selected from one or more R 1a The following groups are substituted: C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkyl C 1-2 Alkylene or 4-10 membered heterocyclic alkyl C 1-2 Alkylene.

[0082] In some implementation schemes, R 1 Selected from one or more R 1aThe following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, pyrrolyl, tetrahydrofuranyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, cyclopropylmethylene, cyclobutylmethylene, aziridinemethylene, oxaziridinemethylene, pyrrolylmethylene, or tetrahydrofuranylmethylene.

[0083] In some implementation schemes, R 1 Selected from one or more R 1a The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, oxacyclobutyl, thiazolyl, pyrrolyl, tetrahydrofuranyl, isothiazolyl, thiadiazolyl, or cyclopropylmethylene.

[0084] In some implementation schemes, R 1 Selected from one or more R 1a The following groups are substituted: methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl. Or cyclopropylmethylene.

[0085] In some implementations, each R 1a Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, or optionally influenced by one or more R. 1b The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino.

[0086] In some implementations, each R 1a Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, or optionally influenced by one or more R. 1b The following groups are substituted: C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylamino, or di-C 1-3 Alkylamino.

[0087] In some implementations, each R 1a Each is independently selected from deuterium, oxo, thio, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, or optionally influenced by one or more R. 1bThe following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, or diethylamino.

[0088] In some implementations, each R 1a Each is independently selected from deuterium, oxo, -F, -Cl, -OH, or optionally influenced by one or more R groups. 1b The following groups may be substituted: methyl, ethyl, methoxy, or ethoxy.

[0089] In some implementations, each R 1b Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino.

[0090] In some implementations, each R 1b Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-3 Alkoxy, C 1-3 alkylamino, or di-C 1-3 Alkylamino.

[0091] In some implementations, each R 1b Each is independently selected from deuterium, oxo, thio, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, or diethylamino.

[0092] In some implementations, each R 1b Each is independently selected from deuterium, oxo, -F, -Cl, -OH, or methoxy.

[0093] In some implementations, each R 1a Each is independently selected from deuterium, oxo, -F, -Cl, -OH, methyl, methoxy, ethoxy, hydroxymethylene, or

[0094] In some implementation schemes, R 1 Selected from methyl, trideuteryl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, Isopropyl, tert-butyl Cyclopropyl Cyclobutyl, Cyclopropylmethylene, or

[0095] In some implementations, structural unit -L 1 -R 1 Selected from

[0096] In some implementations, L 2 Selected from -C(O)O-, -OC(O)-, -C(O)NR L2 - or -NR L2 C(O)-.

[0097] In some implementations, L 2 Selected from -C(O)NR L2 - or -NR L2 C(O)-.

[0098] In some implementation schemes, R L2 Selected from H, deuterium, C 1-4 Alkyl, deuterated C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0099] In some implementation schemes, R L2 It is selected from H, deuterium, methyl, deuterated methyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0100] In some implementation schemes, R L2 Selected from H, deuterium, or methyl.

[0101] In some implementation schemes, R L2 Selected from H.

[0102] In some implementations, L 2 Selected from -NHC(O)-.

[0103] In some implementation schemes, X 1 X 2 X 3 X 4 One, two, or three are selected from N.

[0104] In some implementation schemes, X 1 Selected from N, X 2 Selected from CR X1 .

[0105] In some implementation schemes, X 1 Selected from CR X1 X 2 Selected from N.

[0106] In some implementation schemes, X 1 X 2 Selected from CR X1 .

[0107] In some implementation schemes, X 1 X 2 Selected from N.

[0108] In some implementations, when --- is selected from a single bond, X 3 and X 4 They are not both C.

[0109] In some implementations, when --- is selected from a single bond, X 3 Selected from N, X 4 Selected from C or CR X1 When --- is selected from a double bond, X 3 X 4 Selected from C.

[0110] In some implementations, when --- is selected from a single bond, X 3 Selected from C or CR X1 X 4 Selected from N; X is selected when --- is selected from a double bond. 3 X 4 Selected from C.

[0111] In some implementations, --- is selected from single bonds, X 1 X 2 Selected from N or CR X1 X 3 X 4 Choose from N or C.

[0112] In some implementations, --- is selected from single bonds, X 1 X 3 Selected from N, X 2 Selected from CR X1 X 4 Selected from C.

[0113] In some implementations, --- is selected from double bonds, X 1 X 2 Selected from N or CR X1 X 3 X 4 Selected from C.

[0114] In some implementations, --- is selected from double bonds, X 1 Selected from N, X 2 Selected from CR X1 X 3 X 4 Selected from C.

[0115] In some implementations, each R X1 Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino or halogenated diC 1-4 Alkylamino.

[0116] In some implementations, each R X1 Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, deuterated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino or halogenated diC 1-3 Alkylamino.

[0117] In some implementations, each R X1 Each is independently selected from H, deuterium, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuterylmethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0118] In some implementations, each R X1 Each is independently selected from H, deuterium, -F, -Cl, or methyl.

[0119] In some implementations, each R X1 Selected from H.

[0120] In some implementations, ring D is selected from one or more Rs. D The following groups may be substituted: 3-6 membered cycloalkenyl, 4-6 membered heterocycloalkenyl, phenyl, or 5-6 membered heteroaryl.

[0121] In some implementations, ring D is selected from one or more Rs. D The following groups may be substituted: cyclopentenyl, cyclohexenyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, dioxacyclopentenyl, phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazoleyl, oxazolyl, thiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0122] In some implementations, ring D is selected from one or more Rs. D Substituted imidazole group.

[0123] In some implementation schemes, structural units It is a 9-10 membered heteroaryl group, preferably, the cyclic heteroatom of the 9-10 membered heteroaryl group is selected from N, O or S (for example, containing at least 1, 2 or 3 N atoms).

[0124] In some implementation schemes, structural units It is a 9-membered heteroaryl group, preferably, the cyclic heteroatom of the 9-membered heteroaryl group is selected from N, O or S (for example, containing at least 1, 2 or 3 N atoms).

[0125] In some implementation schemes, structural units Selected from Where p is selected from 0, 1, or 2.

[0126] In some implementation schemes, structural units Selected from Where p is selected from 0, 1, or 2.

[0127] In some implementations, p is selected from 0 or 1.

[0128] In some implementation schemes, structural units Selected from

[0129] In some implementations, each R D Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino or halogenated diC 1-4 Alkylamino.

[0130] In some implementations, each R D Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, deuterated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino or halogenated diC 1-3 Alkylamino.

[0131] In some implementations, each R D Each is independently selected from deuterium, oxo, thio, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuterylmethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0132] In some implementations, each R D Each is independently selected from deuterium, -F, -Cl, or methyl.

[0133] In some implementations, the R A R B R C R Z1 R L1 R Y R L2 R X1 、or R D Optionally substituted with one or more substituents selected from deuterium, oxo, halogen, -OH, -NH2, -CN, mercapto, nitro, nitroso, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, Halogenated -C 1-12 Alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halogenated -C 2-12 alkenyl, 3-12-membered cycloalkenyl, halo-3-12-membered cycloalkenyl, C 2-12 Alkyne group, halogenated -C 2-12Alkynyl, 8-12 membered cycloalkynyl, halogenated-8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halogenated-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 aryl, 6-10 aryloxy, 6-10 arylthio, 6-10 arylC 1-12 Alkylene, 6-10 aryl C 1-12 Alkoxy, 6-10 aryl C 1-12 Alkylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, 5-10 heteroarylalkylene, 5-10 heteroarylalkoxy, 5-10 heteroarylalkylthio, 3-12 heterocyclic, 3-12 heterocyclic oxy, 3-12 heterocyclic thio, 3-12 heterocyclic C 1-12 Alkylene, 3-12 membered heterocyclic C 1-12 Alkoxy, 3-12 membered heterocyclic C 1-12 Alkylthio, C 1-12 Acyl group, C 1-12 Acyloxy group, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester groups, oxo groups, and thio groups, wherein the substituents are optionally substituted by one or more substituents selected from: deuterium, oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, diC 1-12 Alkylamino, halogenated C 1-12 Alkylamino, Halogenated diC 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl group, -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 group, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl group, -S(O)2N(C) 1-12 Alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12Alkylene, 3-12 membered cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic alkyl group, 3-12-membered heterocyclic alkyl group C 1-12 Alkylene, 3-12-membered heterocyclic alkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryl C 1-12 alkylene, 5-10 heteroaryloxy, 6-10 aryl, 6-10 aryl C 1-12 Alkylene or 6-10 aryloxy groups.

[0134] In some implementations, the R A R B R C R Z1 R L1 R Y R L2 R X1 、or R D Optionally substituted with one or more substituents selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkyl group.

[0135] In some embodiments, the heterocyclic group described in this disclosure is selected from heterocyclic alkyl groups. In some embodiments, the heterocyclic group described in this disclosure is selected from heterocyclic alkenyl groups.

[0136] In some embodiments, the 3-12-membered, 3-10-membered, 4-9-membered, 4-7-membered, or 4-6-membered heterocyclic groups described in this disclosure are selected from 3-12-membered, 3-10-membered, 4-9-membered, 4-7-membered, or 4-6-membered heterocyclic alkyl groups. In some embodiments, the 3-12-membered, 3-10-membered, 4-9-membered, 4-7-membered, or 4-6-membered heterocyclic groups described in this disclosure are selected from 3-12-membered, 3-10-membered, 4-9-membered, 4-7-membered, or 4-6-membered heterocyclic alkenyl groups.

[0137] In some implementations, the C described in this disclosure 1-12 Selected from C 1-10 C 1-8 C 1-6 C 1-4 C 1-3 or C 1-2 .

[0138] In some implementations, the C described in this disclosure 1-6 Alkyl groups are selected from C 1-4 Alkyl, C 1-3 Alkyl, or C 1-2 alkyl.

[0139] In some implementations, the C described in this disclosure 1-4 Alkylene is selected from C 1-3 Alkylene or C 1-2 Alkylene.

[0140] In some embodiments, the halogens described in this disclosure are selected from F, Cl, Br, or I.

[0141] In some embodiments, the halogenation described in this disclosure is selected from fluorinated, chlorinated, or brominated compounds. In some embodiments, the halogenation is selected from fluorinated or chlorinated compounds. In some embodiments, the halogenation described in this disclosure is selected from fluorinated compounds.

[0142] In some implementations, "one or more" as used in this disclosure may refer to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" refers to one, two, three, four, five, or six; or, "one or more" refers to one, two, three, or four.

[0143] In some implementations, the 3-12 yuan mentioned in this disclosure is selected from 3-10 yuan, 3-8 yuan, 3-6 yuan, 4-9 yuan, 4-7 yuan, 4-6 yuan, 5-8 yuan, 5-7 yuan, or 5-6 yuan.

[0144] In some embodiments, the heterocyclic alkyl group described in this disclosure contains one or two heteroatoms selected from N or O.

[0145] In some embodiments, the heterocyclic alkyl group described in this disclosure contains one nitrogen atom.

[0146] In some embodiments, the heterocyclic alkyl group described in this disclosure contains one oxygen atom.

[0147] In some embodiments, the heterocyclic alkyl group described in this disclosure contains one N atom and one O atom.

[0148] In some embodiments, the heterocyclic or heteroaryl groups described in this disclosure contain one or two heteroatoms selected from N, O, or S.

[0149] In some embodiments, the heterocyclic or heteroaryl groups described in this disclosure contain one or two N atoms.

[0150] In some embodiments, the heterocyclic or heteroaryl group described in this disclosure contains one N atom and one O atom.

[0151] In some embodiments, the heterocyclic or heteroaryl group described in this disclosure contains one N atom and one S atom.

[0152] In some embodiments, the heterocyclic groups or heterocyclic alkyl groups described in this disclosure include monocyclic, spirocyclic, fused, or bridged rings.

[0153] In some embodiments, all hydrogen atoms in the compound of formula (I) of this disclosure or its pharmaceutically acceptable salt may optionally be substituted with one or more deuterium atoms.

[0154] This disclosure relates to compounds of formulas (I-1), (I-2), (II), (III), and (IV), or pharmaceutically acceptable salts thereof.

[0155]

[0156] Among them, rings A, B, C, and Z 1 Z 2 Z 3 L 1 R 1 L 2 --- X 1 X 2 X 3 X 4 , ring D, R L2 R D p is as defined in this disclosure.

[0157] In some embodiments of this disclosure, this disclosure includes the variables defined above and their implementations, as well as any combination thereof.

[0158] This disclosure also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0159]

[0160]

[0161] On the other hand, this disclosure relates to pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof. In some embodiments of this disclosure, the pharmaceutical compositions further include pharmaceutically acceptable excipients.

[0162] On the other hand, this disclosure relates to methods of treating mammalian diseases, including administering to a mammal, preferably a human, a therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

[0163] On the other hand, this disclosure relates to the use of the compounds described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of this disclosure, in the preparation of medicaments for treating diseases.

[0164] On the other hand, this disclosure relates to the use of the compounds described herein or their pharmaceutically acceptable salts, or the pharmaceutical compositions of this disclosure, in the treatment of diseases.

[0165] On the other hand, this disclosure relates to compounds described in this disclosure or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of this disclosure, for the treatment of diseases.

[0166] In some embodiments of this disclosure, the disease is selected from KIF18A-related diseases.

[0167] In some embodiments of this disclosure, the disease (e.g., KIF18A-related disease) is selected from cancers (e.g., ovarian cancer).

[0168] Technical effect

[0169] The disclosed compounds exhibit high KIF18A inhibitory activity and cell proliferation inhibitory activity, and demonstrate good drug-like properties in in vitro and in vivo metabolic stability, pharmacokinetics, bioavailability, and / or pharmacodynamic studies. For example, the disclosed compounds showed good stability in in vitro liver microsomal stability experiments.

[0170] definition

[0171] Unless otherwise stated, the following terms as used in this disclosure have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0172] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0173] The term "substituent" as used herein includes all substituents mentioned in the context of this document, including, for example, those defined by the terms "alkyl," "alkylene," "heteroalkyl," "alkoxy," "alkylamino," "dialkylamino," "alkynthio," "alkenyl," "alkynyl," "cycloalkyl," "cycloalkenyl," "heterocyclic," "heterocyclic," "aryl," "heteroaryl," and other related groups, as well as corresponding non-limiting or exemplary groups. Some non-limiting examples of said "substituent" include deuterium, hydroxyl, mercapto, halogen, and amino groups. Nitro, nitroso, cyano, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl, carboxaldehyde group, imine group, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkyl, heteroarylalkoxy, heteroarylalkylthio The group may contain heterocyclic groups, heterocyclic oxy groups, heterocyclic thio groups, heterocyclic alkylene groups, heterocyclic alkoxy groups, heterocyclic alkylthio groups, acyl groups, acyloxy groups, carbamate groups, amide groups, urea groups, epoxy groups, and ester groups, wherein said groups are optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, 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, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, aryl alkylene or aryloxy.

[0174] In some embodiments herein, the substituent is selected from deuterium, hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, Halogenated -C 1-12 Alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halogenated -C 2-12 alkenyl, 3-12-membered cycloalkenyl, halo-3-12-membered cycloalkenyl, C 2-12 Alkyne group, halogenated -C 2-12Alkynyl, 8-12 membered cycloalkynyl, halogenated-8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halogenated-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 aryl, 6-10 aryloxy, 6-10 arylthio, 6-10 arylC 1-12 Alkylene, 6-10 aryl C 1-12 Alkoxy, 6-10 aryl C 1-12 Alkylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, 5-10 heteroarylalkylene, 5-10 heteroarylalkoxy, 5-10 heteroarylalkylthio, 3-12 heterocyclic, 3-12 heterocyclic oxy, 3-12 heterocyclic thio, 3-12 heterocyclic C 1-12 Alkylene, 3-12 membered heterocyclic C 1-12 Alkoxy, 3-12 membered heterocyclic C 1-12 Alkylthio, C 1-12 Acyl group, C 1-12 Acyloxy group, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester groups, oxo groups, and thio groups, wherein the substituents are optionally substituted by one or more substituents selected from: deuterium, oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, diC 1-12 Alkylamino, halogenated C 1-12 Alkylamino, Halogenated diC 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl group, -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 group, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl group, -S(O)2N(C) 1-12 Alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12Alkylene, 3-12 membered cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic alkyl group, 3-12-membered heterocyclic alkyl group C 1-12 Alkylene, 3-12-membered heterocyclic alkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryl C 1-12 alkylene, 5-10 heteroaryloxy, 6-10 aryl, 6-10 aryl C 1-12 Alkylene or 6-10 aryloxy groups.

[0175] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group “optionally” being halogenated means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0176] C in this article m-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0177] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

[0178] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0179] When one of the variables is selected as a covalent bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a covalent bond, it means that the structure is actually AZ.

[0180] When the linking group listed does not specify its linking direction, the linking direction is arbitrary. For example, in ALZ, the linking group L is -MW-, which means that the structure can be AMWZ or AWMZ.

[0181] When a substituent is cross-bonded to two atoms on a ring, it can bond to any atom on that ring. For example, structural units. This indicates that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0182] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0183] The term "hydroxyl group" refers to the -OH group.

[0184] The term "cyano" refers to the -CN group.

[0185] The term "thiol" refers to the -SH group.

[0186] The term "amino" refers to the -NH2 group.

[0187] The term "nitro" refers to the -NO2 group.

[0188] The term "alkylene" refers to a compound with the general formula C1. n H 2n Saturated straight-chain or branched divalent hydrocarbon groups, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6 "Alkylene" refers to an alkylene containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -CH2CH(CH3)-), butylene (-CH2CH2CH2CH2-, -CH2CH(CH3)CH2- or -CH2CH2CH(CH3)-), etc. The alkylene may optionally be substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0189] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The saturated hydrocarbon group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl group can be straight-chain or branched, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. For example, the term "C..." 1-6"Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). The alkyl group is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy. Similarly, the alkyl portion (i.e., alkyl group) of alkoxy, alkylamino, dialkylamino, and alkylthio groups has the same definition as above.

[0190] The term "alkoxy" refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl portion is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0191] The term "alkylamino" refers to -NH-alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0192] The term "dialkylamino" refers to -N(alkyl)2, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0193] The term "alkylthio" refers to -S-alkyl, which typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0194] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc. The alkenyl group may optionally be substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkoxy, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0195] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butyrynyl (-C≡CC≡CH), etc. The alkynyl group may optionally be substituted by one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0196] The term "cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, or 5- to 6-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc. The cycloalkyl group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, 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, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkylene, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0197] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbon ring having at least one double bond and which may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, or 5- to 6-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc. The cycloalkenyl group may optionally be substituted by one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, 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, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, aryl alkylene or aryloxy.

[0198] The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated) and can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 12-membered, 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 3- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclic groups include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, pyrrolyl, N-methylpyrrolyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophene, etc. The heterocyclic group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, 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, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, aryl alkylene or aryloxy.

[0199] The term "heterocyclic alkenyl" refers to a partially unsaturated (but not fully unsaturated) heteroaromatic ring that can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 12-membered, 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 3- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclic alkenyl groups include, but are not limited to, dihydrofuranyl, dihydropyrroleyl, 2H-pyranyl, dihydrothiophenyl, etc. The heterocyclic alkenyl group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, 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, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, aryl alkylene or aryloxy.

[0200] The term "heterocyclic alkyl" refers to a fully saturated cyclic group that may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocyclic alkyl group is typically a 3- to 12-membered, 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 3- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron. Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutylcycloyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. The heterocyclic alkyl group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, 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, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, aryl alkylene or aryloxy.

[0201] The term "bridged heterocyclic alkyl" refers to a fully saturated cyclic group formed by sharing two non-directly bonded atoms between any two rings. Unless otherwise indicated, the bridged heterocyclic alkyl is typically a 5- to 12-membered, 5- to 10-membered, 6- to 9-membered, 6- to 8-membered, or 7- to 8-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron. Examples of bridged heterocyclic alkyls include, but are not limited to, those mentioned above. The bridged heterocyclic alkyl group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, 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, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, aryl alkylene or aryloxy.

[0202] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracene. The aryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, 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, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0203] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one ring atom selected from N, O, or S, with the remaining ring atoms being C, typically having 5 to 14, 5 to 12, 5 to 10, 5 to 8, 5 to 7, or 5 to 6-membered rings. Preferred heteroaryls have a single 4 to 8-membered ring, especially a 5 to 6-membered ring, or multiple fused rings containing 5 to 14, especially 5 to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, isoindoleyl, etc. The heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, 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, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0204] Unless otherwise specified, the term "deuterated C" refers to... 1-12 "alkyl" refers to the above "C 1-12 In the alkyl group, any number and position of H atoms are replaced by deuterium atoms. The C 1-12 Deuterated alkyl groups can be C10-3 ... 1-6 Deuterated alkyl or C 1-3 Deuterated alkyl groups. Examples of deuterated alkyl groups include, but are not limited to, -CH2D, -CHD2, and -CD3. wait.

[0205] The group -L in this disclosure 1 - A reading order from left to right or right to left can be used, corresponding to the left and right groups connected to the group in the general formula. In some embodiments of this disclosure, -L 1 - Adopt a left-to-right reading order, for example, when -L 1 When - is -NHS(O)2-, the structure for

[0206] The group -L in this disclosure 2- A reading order from left to right or right to left can be used, corresponding to the right-hand and left-hand groups connected to the group in the general formula. In some embodiments of this disclosure, -L 2 - Adopt a left-to-right reading order, for example, when -L 2 When - is -NHC(O)-, the structure for

[0207] The term "treatment" means administering the compounds or preparations described in this disclosure to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0208] (i) Suppress the disease or disease state, that is, curb its development;

[0209] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0210] The term “prevention” means administering the compounds or preparations described in this disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0211] The term "therapeutic effective amount" means (i) the amount of the disclosed compound used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the disclosed compound constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the content of this disclosure.

[0212] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0213] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0214] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds to an organism.

[0215] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0216] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0217] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0218] This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0219] Certain isotope-labeled compounds of this disclosure (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e.14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this disclosure can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0220] In addition, heavier isotopes (such as deuterium) are used. 2 H)) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain situations, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen being replaced by at least one deuterium.

[0221] The compounds disclosed herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0222] The compounds disclosed herein may have one or more blocked isomers, unless otherwise stated, which are photoactive isomers resulting from the restriction of free rotation between single bonds. The chiral axis compounds of this disclosure can be isolated in racemic form. When the energy barrier for free rotation of the single bonds in the chiral axis compounds of this disclosure is sufficiently high, their blocked isomers can be isolated in photoactive pure form.

[0223] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds of the disclosed invention with suitable pharmaceutically acceptable excipients.

[0224] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0225] In all methods of administration of the compounds of general formula I described herein, the daily dose is from 0.001 to 2000 mg / kg body weight. The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this disclosure.

[0226] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0227] The compound of formula (IV) disclosed herein can be prepared by those skilled in the art of organic synthesis with reference to route 1, wherein ring A, ring B, ring C, and ring L... 1 R 1 R L2 R D p is as defined in this disclosure; LG is a leaving group, for example, LG may be independently selected from -F, -Cl, -Br or -I, preferably from -Br.

[0228]

[0229] Route 1

[0230] Each product obtained from the reactions described above can be obtained using conventional separation techniques, including but not limited to filtration, distillation, crystallization, and chromatographic separation. Starting materials can be synthesized in-house or purchased from commercial sources (e.g., but not limited to Adrich or Sigma). These materials can be characterized using conventional methods, such as physical constants and spectral data. The compounds described in this disclosure can be synthesized to obtain single isomers or mixtures of isomers.

[0231] The following abbreviations are used in this disclosure:

[0232] DIEA represents diisopropylethylamine; Pd2(dba)3 represents tris(dibenzylacetone)dipalladium; EA represents ethyl acetate; PE represents petroleum ether; DMF represents N,N-dimethylformamide; t-BuXPhos represents 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl; DCM represents dichloromethane; MeOH represents methanol; EtOH represents ethanol; Me represents methyl; DMSO represents dimethyl sulfoxide; HATU represents 2-( 7-Zazabenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate; THF represents tetrahydrofuran; DEAD represents diethyl azodicarboxylate; Ph represents phenyl; Et represents ethyl; PMB represents p-methoxybenzyl; DIPEA represents diisopropylethylamine; Boc represents tert-butyloxycarbonyl; TBS represents tert-butyldimethylsilyl; XantPhos represents 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene; X-phos Pd G3 represents methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); X-Phos represents 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Xantphos Pd G3 represents methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphoxanthracene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); TFA represents trifluoroacetic acid.

[0233] Commercially available compounds are listed under supplier catalog names.

[0234] For clarity, the invention is further illustrated by embodiments, but these embodiments are not intended to limit the scope of this disclosure. This disclosure has been described in detail herein, and specific embodiments thereof have been disclosed. Various changes and modifications to the embodiments of this disclosure will be apparent to those skilled in the art without departing from the spirit and scope of this disclosure.

[0235] All reagents used in this disclosure are commercially available and can be used without further purification. Detailed Implementation

[0236] Preparation Example A-4

[0237]

[0238] Step A:

[0239] In a 500 mL single-necked flask, compound A-1 (25 g), 4,4-difluoropiperidine hydrochloride (15.65 g), DMF (200 mL), and DIPEA (36.2 mL) were added sequentially. The mixture was heated at 100 °C for 5 h under N2 protection. After the reaction was complete, heating was stopped, 700 mL of water was added, and the mixture was extracted with ethyl acetate (200 mL * 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent PE / EA = 50 / 1) to give compound A-2 (27.81 g). 1 H NMR (500MHz, DMSO-d6) δ8.20(s,1H),7.92(d,1H),7.58(d,1H),4.41-4.32(m,4H),2.14-2.06(m,4H).

[0240] Step B:

[0241] In a 1000 mL single-necked flask, compound A-2 (23.5 g), tert-butyl carbamate (10.42 g), cesium carbonate (48.3 g), X-phos Pd G3 (1.254 g), and 1,4-dioxane (300 mL) were added. The mixture was heated and stirred at 100 °C for 5 hours under N2 protection. After the reaction was complete, heating was stopped, 200 mL of water was added, and the mixture was extracted with ethyl acetate (150 mL * 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent PE / EA = 10 / 1) to give compound A-3 (18 g). MS (ESI+, [M+H)) + m / z: 354.13.

[0242] Step C:

[0243] In a 1000 mL single-necked flask, compound A-3 (200 mg), DCM (10 mL), and trifluoroacetic acid (0.5 mL) were added, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, 20 mL of water and 10 mL of DCM were added. Under ice bath conditions, an aqueous solution of sodium hydroxide was added to adjust the pH of the aqueous phase to approximately 9. The mixture was extracted separately, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness to obtain compound A-4, which was directly used in the next step. MS (ESI+, [M+H)) + m / z: 254.03.

[0244] Example 1

[0245]

[0246] Step A:

[0247] Compound 1-1 (2.9 g), 3-azaspiro[bicyclo[3.2.1]octane-8,1'-cyclopropane] hydrochloride (1.5 g), DMSO (25 mL), and potassium carbonate (7.55 g) were added sequentially to a 100 mL single-necked flask, and the reaction was carried out at 160 °C for 12 h. After the reaction was completed, 100 mL of water was added, and the pH of the solution was adjusted to approximately 5 with a 6 N hydrochloric acid aqueous solution. The solution was extracted with EA (3 × 30 mL), the organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 3 / 1) to obtain compound 1-2 (1.5 g). MS (ESI+, [M+H) + )m / z:384.15. 1 H NMR(500MHz,DMSO-d6)δ7.96(d,1H),7.71(dd,1H),7.63(d,1H),3.22(d,2H),2.96(dd,2H) ,1.96-1.89(m,2H),1.87-1.82(m,2H),1.52(s,2H),0.78-0.72(m,2H),0.46-0.39(m,2H).

[0248] Step B:

[0249] In a 100 mL single-necked flask, compounds 1-2 (1.5 g) and potassium carbonate (1.62 g) were added sequentially, dissolved in DMF (20 mL), and then iodomethane (1.67 g) was added. The mixture was stirred at room temperature for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with EA (50 mL), washed with saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification was performed by silica gel column chromatography (eluent: PE / EA = 18 / 1) to give compounds 1-3 (1.3 g). MS (ESI+, [M+H)) + m / z: 398.18.

[0250] Step C:

[0251] In a 100 mL single-necked flask, compounds 1-3 (1.3 g), methanesulfonamide (0.4 g), allyl palladium(II) chloride dimer (0.06 g), t-BuXPhos (0.14 g), and potassium carbonate (0.9 g) were added sequentially. The mixture was dissolved in dioxane (20 mL) and reacted at 100 °C for 4 h under nitrogen protection. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with EA (50 mL), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification was achieved by silica gel column chromatography (eluent: PE / EA = 2 / 1) to give compounds 1-4 (0.8 g). MS (ESI+, [M+H)) + m / z: 365.27.

[0252] Step D:

[0253] Compounds 1-4 (450 mg), methanol (5 mL), and ammonia (5 mL) were added sequentially to a 30 mL microwave-safe tube, and the mixture was microwave-heated at 90 °C for 5 h. After the reaction was complete, the reaction solution was concentrated by rotary evaporation under reduced pressure, and then extracted with 30 mL of water and ethyl acetate (15 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM / MeOH = 30 / 1) to obtain compounds 1-5 (147 mg). MS (ESI+, [M+H)) + m / z: 350.25.

[0254] Step E:

[0255] In a 50 mL single-necked flask, compounds 1-5 (105 mg), A-2 (172 mg), Pd2(dba)3 (27.5 mg), XantPhos (34.8 mg), and cesium carbonate (196 mg) were added sequentially. The solutions were dissolved in dioxane (8 mL) and the mixture was heated at 100 °C for 12 h under nitrogen protection. After the reaction was complete, 50 mL of distilled water was added, and the mixture was extracted with EA (50 mL), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification was then performed by silica gel column chromatography (eluent: DCM / MeOH = 100 / 1) to obtain compound 1 (50 mg). 1 H NMR(500MHz,DMSO-d6)δ10.62(s,1H),10.05(s,1H),8.91(s,1H),8.09(d,1H),7.75(d,1H),7.56(d,1H),7.21(d,1H),7.04(dd,1H),4.51-4.27(m ,4H),3.08(s,3H),3.06-2.97(m,4H),2.13-2.01(m,6H),1.88-1.74(m,2 H),1.46(s,2H),0.67-0.58(m,2H),0.44-0.34(m,2H).HRMS(ESI+,[M+H] + )m / z:586.2418.

[0256] Example 2

[0257]

[0258] Step A:

[0259] Referring to step C of Example 1, methylsulfonamide was replaced with 2-hydroxy-1-sulfonamide to prepare compound 2-1 (410 mg). MS (ESI+, [M+H)+ m / z: 395.16.

[0260] Step B:

[0261] Referring to step D of Example 1, compound 2-2 (110 mg) was prepared by replacing compound 1-4 with compound 2-1. MS (ESI-, [MH]) - m / z: 378.16.

[0262] Step C:

[0263] Following step E of Example 1, compound 2 (100 mg) was prepared by replacing compound 1-5 with compound 2-2.

[0264] 1 H NMR(500MHz,DMSO-d6)δ10.63(s,1H),10.03(s,1H),8.90(s,1H),8.09(d,1H),7.74 (d,1H),7.56(d,1H),7.23(d,1H),7.13-6.92(m,1H),4.94(s,1H),4.49-4.32(m,4H ),3.76-3.65(m,2H),3.38-3.32(m,2H),3.08-2.92(m,4H),2.19-2.02(m,6H),1.95 -1.82(m,2H),1.46(s,2H),0.73-0.58(m,2H),0.45-0.32(m,2H).HRMS(ESI+,[M+H] + )m / z:616.2509.

[0265] Example 3

[0266]

[0267] Step A:

[0268] Following step A of Example 1, compound 3-1 was prepared by replacing 3-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane] hydrochloride with 8-azaspiro[bicyclo[3.2.1]octane-8,1'-cyclopropane] hydrochloride. MS(ESI+,[M+H) + m / z: 384.15.

[0269] Step B:

[0270] In a 250 mL single-necked flask, compound 3-1 (1 g), HATU (1.984 g), ammonium chloride (1.396 g), DMF (25 mL), and DIPEA (3.37 g) were added sequentially, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, 100 mL of water was added, and the mixture was extracted with EA (100 mL), washed with saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification was then performed by silica gel column chromatography (eluent: PE / EA = 1 / 1) to give compound 3-2 (0.958 g). MS (ESI+, [M+H)) + m / z: 383.12.

[0271] Step C:

[0272] In a 100 mL single-necked flask, compound 3-2 (0.8 g), methanesulfonamide (0.3 g), cuprous iodide (0.020 g), N'-(2,6-dimethylphenyl)-N-(pyridin-2-ylmethyl)oxalamide (0.030 g), and cesium carbonate (1.705 g) were added sequentially. The mixture was dissolved in tert-butanol (20 mL) and reacted at 100 °C for 16 h under nitrogen protection. After the reaction was complete, the solvent was removed by vacuum distillation, 50 mL of water was added, and the mixture was extracted with EA (100 mL). The extract was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification was achieved by silica gel column chromatography (eluent: PE / EA = 1 / 1) to give compound 3-3 (0.469 g). MS (ESI+, [M+H)) + m / z: 350.22.

[0273] Step D:

[0274] Compound 3-3 (0.250 g), compound A-2 (0.340 g), Pd2(dba)3 (0.066 g), XantPhos (0.083 g), and cesium carbonate (0.700 g) were added sequentially to a 100 mL single-necked flask and dissolved in dioxane (10 mL). The mixture was heated to 100 °C for 16 h under N2 protection. After the reaction was complete, the solvent was removed by vacuum distillation, 50 mL of water was added, and the mixture was extracted with EA (100 mL). The extract was washed with saturated brine (50 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain compound 3 (83 mg). 1H NMR(500MHz,DMSO-d6)δ11.27(s,1H),10.08(s,1H),8.82(s,1H),8.07(s,1H), 7.87(d,1H),7.55(s,1H),7.08(d,1H),6.96(dd,1H),4.44-4.30(m,4H),3.83- 3.75(m,2H),3.08(s,3H),2.49-2.43(m,2H),2.17-2.05(m,4H),2.04-1.86(m, 4H),1.04-0.95(m,2H),0.63-0.54(m,2H),0.20-0.10(m,2H).HRMS(ESI+,[M+H] + m / z: 586.2415.

[0275] Example 4

[0276]

[0277] Step A:

[0278] Compound 3-1 (650 mg) and dichloromethane (30 mL) were added sequentially to a 100 mL single-necked flask. Under nitrogen protection and after cooling in an ice bath, oxalyl chloride (431 mg) and DMF (1 drop) were added at low temperature, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, the solvent and excess oxalyl chloride were evaporated under reduced pressure to obtain an acyl chloride intermediate. This intermediate was added to a solution of compound A-4 (425 mg) and DIPEA (725 mg) in dichloromethane (30 mL), and stirred at room temperature for 2 h. After the reaction was complete, the solvent was evaporated under reduced pressure, and the reaction system was dissolved in ethyl acetate (80 mL). The mixture was washed five times with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain compound 4-1 (210 mg). MS (ESI+, [M+H)) + m / z: 619.14.

[0279] Step B:

[0280] Referring to step C of Example 1, compound 4 (140 mg) was prepared by replacing compound 1-3 with compound 4-1 and methylsulfonamide with 2-hydroxy-1-sulfonamide.

[0281] 1H NMR(500MHz,DMSO-d6)δ11.29(s,1H),10.03(s,1H),8.83(s,1H),8.08(s,1H), 7.86(d,1H),7.55(s,1H),7.14-7.05(m,1H),7.01-6.93(m,1H),4.88(s,1H),4 .46-4.30(m,4H),3.87-3.70(m,4H),3.29(s,2H),2.46(s,2H),2.18-1.87(m,8 H),1.05-0.95(m,2H),0.67-0.54(m,2H),0.22-0.10(m,2H).HRMS(ESI+,[M+H] + m / z: 616.2518.

[0282] Example 5

[0283]

[0284] Step A:

[0285] In a 250 mL double-necked flask, triphenylphosphine (9.40 g), hexachloroethane (8.48 g), and chloroform (50 mL) were added. The mixture was heated and stirred at 70 °C for 6 h under N2 protection. After cooling, triethylamine (6.6 mL) was added, and the mixture was transferred to an ice bath for further cooling and stirring. A chloroform (15 mL) solution of compound 5-1 (5 g) was added dropwise, and the mixture was stirred in an ice bath for another 1 h. A tetrahydrofuran (15 mL) solution of imidazole (2.4 g) was added, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure. Hexane (300 mL) was added, and the mixture was stirred until homogeneous and then filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA = 4 / 1) to obtain compound 5-2 (1.5 g). 1 H NMR (500MHz, DMSO-d6) δ7.98(t,1H),7.49(t,1H),7.10-7.06(m,1H),3.46(s,3H),0.87(s,9H),0.01(d,6H).

[0286] Step B:

[0287] Compound 5-2 (1 g) was added to a 100 mL double-necked flask and dissolved in 25 mL of diethyl ether. Under nitrogen protection, methyl trifluoromethanesulfonate (0.46 mL) was added dropwise, and stirring was continued for 1 h under ice bath conditions. After the reaction was completed, the mixture was filtered, washed with diethyl ether, and the filter cake was dried to obtain compound 5-3 (1.47 g). 1H NMR(500MHz, CDCl3)δ9.10(s,0.4H),8.89(s,0.6H),7.54-7.52(m,0.4H),7.43-7.42(m,0.6H),7.41-7.39(m,0.4H),7.19-7.17(m, 0.6H),4.10(s,1.4H),3.99(s,1.6H),3.60(s,1.4H),3.02(s,1.6H),0.96(s,4.6H),0.92(s,4.4H),0.31(s,3H),0.16-0.11(m,3H).

[0288] Step C:

[0289] In a 250 mL single-necked flask, compound 5-4 (2.5 g), 3-azaspiro[bicyclo[3.2.1]octane-8,1'-cyclopropane] hydrochloride (2.58 g), DMSO (50 mL), and potassium carbonate (6.53 g) were added sequentially. The mixture was heated to 130 °C for 7 h under N2 protection. After the reaction was complete, 100 mL of water was added, and the pH of the solution was adjusted to approximately 5 with a 6N hydrochloric acid solution. The solution was extracted with EA (3 × 30 mL), the organic phases were combined, and the mixture was concentrated to obtain compound 5-5 (3.68 g). MS (ESI+, [M+H)) + m / z: 303.02.

[0290] Step D:

[0291] Referring to step A of Example 4, compound 3-1 was replaced with compound 5-5 to prepare compound 5-6. MS(ESI+,[M+H) + m / z: 538.33.

[0292] Step E:

[0293] In a 100 mL single-necked flask, compound 5-6 (1.1 g), EtOH (20 mL), saturated ammonium chloride aqueous solution (5 mL), and reduced iron powder (0.571 g) were added. The mixture was heated and stirred at 80 °C for 4 h under nitrogen protection. After the reaction was complete, 30 mL of water and 30 mL of EA were added. The mixture was filtered with diatomaceous earth as a filter aid. The filtrate was separated, dried over anhydrous sodium sulfate on the organic phase, filtered again, and concentrated to obtain compound 5-7 (0.9 g). MS (ESI+, [M+H)) + m / z: 508.28.

[0294] Step F:

[0295] Compound 5-7 (350 mg), compound 5-3 (584 mg), and acetonitrile (8 mL) were added to a 50 mL single-necked flask. The mixture was heated and stirred at 80 °C for 1 h under nitrogen protection. After the reaction was complete, 50 mL of distilled water was added, and the mixture was extracted with EA (50 mL). The extract was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 2 / 1) to give compound 5-8 (220 mg). MS (ESI+, [M+H)) + m / z: 699.48. 1 H NMR(500MHz,DMSO-d6)δ10.66(s,1H),9.41(s,1H),8.91(s,1H),8.08(d,1H ),7.74(d,1H),7.55(d,1H),7.35(d,1H),7.05(dd,1H),4.44-4.32(m,4H),3 .08-2.98(m,7H),2.15-2.02(m,6H),1.88-1.76(m,2H),1.49-1.43(m,2H),0 .89(s,9H),0.65-0.59(m,2H),0.42-0.36(m,2H),0.07(s,3H),0.04(s,3H).

[0296] Step G:

[0297] In a 100 mL single-necked flask, compound 5-8 (247 mg), ethyl acetate (8 mL), and 4 M HCl-EA solution (1 mL) were added, and the mixture was stirred at room temperature for 0.5 h. After the reaction was complete, 50 mL of distilled water was added, and the pH of the solution was adjusted to approximately 8 with saturated sodium bicarbonate solution. The solution was extracted with EA (50 mL), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH / DCM = 1 / 20) to obtain compound 5 (150 mg). 1 H NMR(500MHz,DMSO-d6)δ11.00(s,1H),8.94(s,1H),8.07(d,1H),7.77(d,1H) ,7.55(d,1H),7.01(s,1H),6.96-6.86(m,3H),4.45-4.33(m,4H),3.18(s,3H ),3.09-3.02(m,2H),3.00-2.93(m,2H),2.18-2.04(m,6H),1.93-1.80(m,2H ),1.49-1.42(m,2H),0.68-0.62(m,2H),0.44-0.36(m,2H).HRMS(ESI+,[M+H] +m / z: 585.2557.

[0298] Example 6

[0299]

[0300] Step A:

[0301] In a 50 mL single-necked flask, compound 4-1 (410 mg), tert-butyl carbamate (85 mg), cesium carbonate (324 mg), Pd2(dba)3 (30.4 mg), X-Phos (31.6 mg), and 1,4-dioxane (8 mL) were added. The mixture was heated and stirred at 100 °C for 3 h under nitrogen protection. After the reaction was complete, 50 mL of distilled water was added, and the mixture was extracted with EA (50 mL), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: PE / EA = 3 / 1) to give compound 6-1 (390 mg). MS (ESI+, [M+H)) + m / z: 608.42.

[0302] Step B:

[0303] Compound 6-1 (390 mg), DCM (8 mL), and trifluoroacetic acid (1 mL) were added to a 100 mL single-necked flask and stirred at room temperature for 4 h. After the reaction was complete, 50 mL of distilled water was added, and the pH of the solution was adjusted to approximately 8 with saturated sodium bicarbonate solution. The solution was extracted with DCM (50 mL), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The solution was purified by silica gel column chromatography (eluent: PE / EA = 3 / 2) to give compound 6-2 (260 mg). MS (ESI+, [M+H)) + m / z: 508.30.

[0304] Step C:

[0305] Referring to step F of Example 5, compound 5-7 was replaced with compound 6-2 to prepare compound 6-3. MS(ESI+,[M+H) + m / z: 699.50.

[0306] Step D:

[0307] Referring to step G of Example 5, compound 6 was prepared by replacing compound 5-8 with compound 6-3. 1H NMR(500MHz,DMSO-d6)δ11.46(s,1H),8.84(s,1H),8.07(d,1H),7.77(d,1H), 7.54(d,1H),6.94(s,2H),6.84(s,1H),6.75(d,1H),4.42-4.26(m,4H),3.79-3 .70(m,2H),3.17(s,3H),2.49-2.40(m,1H),2.16-2.06(m,4H),2.06-1.80(m,5 H),1.06-0.91(m,2H),0.62-0.54(m,2H),0.19-0.13(m,2H).HRMS(ESI+,[M+H] + m / z: 585.2567.

[0308] Example 7

[0309]

[0310] Compound 4-1 (0.115 g), 1,1-dioxoisothiazol (0.045 g), Pd2(dba)3 (0.017 g), XantPhos (0.022 g), and cesium carbonate (0.182 g) were added sequentially to a 100 mL single-necked flask and dissolved in dioxane (10 mL). The mixture was heated to 100 °C for 5 h under N2 protection. After the reaction was complete, the solvent was removed by vacuum distillation, 50 mL of water was added, and the mixture was extracted with EA (100 mL). The extract was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to give compound 7 (42 mg). 1 H NMR(500MHz,DMSO-d6)δ11.24(s,1H),8.83(s,1H),8.08(d,1H),7.90(d,1H),7.55(d, 1H),7.00(d,1H),6.89(dd,1H),4.41-4.33(m,4H),3.85-3.77(m,4H),3.61-3.54(m,2H ),2.49-2.46(m,2H),2.45-2.39(m,2H),2.16-2.06(m,4H),2.04-1.97(m,2H),1.94-1 .84(m,2H),1.04-0.95(m,2H),0.64-0.55(m,2H),0.19-0.10(m,2H).HRMS(ESI+,[M+H] + m / z: 612.2566.

[0311] Example 8

[0312]

[0313] Step A:

[0314] Referring to step A of Example 4, compound 3-1 was prepared by replacing compound 3-1 with compound 1-2, yielding compound 8-1 (200 mg). MS (ESI+, [M+H) + m / z: 619.14.

[0315] Step B:

[0316] In a 100 mL single-necked flask, compound 8-1 (190 mg), 1,1-dioxoisothiazol (74 mg), cuprous iodide (4 mg), N'-(2,6-dimethylphenyl)-N-(pyridin-2-ylmethyl)oxalamide (5 mg), cesium carbonate (246 mg), and isopropanol (10 mL) were added sequentially. The mixture was refluxed at 100 °C for 6 h under nitrogen protection. After the reaction was completed, the solvent was removed by vacuum distillation, 60 mL of water was added, and the mixture was extracted three times with EA (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 20 / 1) to obtain compound 8 (110 mg).

[0317] 1 H NMR(500MHz,DMSO-d6)δ10.58(s,1H),8.89(s,1H),8.08(d,1H),7.75(d,1H),7.5 4(d,1H),7.12(d,1H),7.01-6.93(m,1H),4.43-4.30(m,4H),3.86-3.76(m,2H),3 .60-3.52(m,2H),3.06-3.00(m,4H),2.45-2.38(m,2H),2.12-2.02(m,6H),1.84- 1.76(m,2H),1.45(s,2H),0.64-0.58(m,2H),0.39-0.32(m,2H).HRMS(ESI+,[M+H] + m / z: 612.2569.

[0318] Example 9

[0319]

[0320] Compound 5-7 (100 mg), pyridine (1 mL), and methylaminosulfonyl chloride (38 mg) were added sequentially to a 25 mL single-necked flask and stirred at room temperature for 8 h. After the reaction was completed, 30 mL of water was added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed five times with saturated brine (5 mL), dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to silica gel column chromatography (PE / EA = 3 / 1) to prepare compound 9 (60 mg).

[0321] 1 H NMR(500MHz,DMSO-d6)δ10.68(s,1H),9.97(s,1H),8.91(s,1H),8.08(s,1H),7.73 (d,1H),7.55(s,1H),7.51-7.43(m,1H),7.19(d,1H),7.03-6.99(m,1H),4.44-4.34 (m,4H),3.01(s,4H),2.49-2.46(m,3H),2.14-2.02(m,6H),1.86-1.79(m,2H),1.4 6(s,2H),0.66-0.60(m,2H),0.41-0.36(m,2H).HRMS(ESI+,[M+H]+)m / z: 601.2509.

[0322] Example 10

[0323]

[0324] Following the preparation method of Example 9, compound 10 (80 mg) was prepared by replacing compound 5-7 with compound 6-2.

[0325] 1 H NMR(500MHz,DMSO-d6)δ11.17(s,1H),9.85(s,1H),8.68(s,1H),7.93(d,1H),7.69(d,1 H),7.40(d,1H),7.37-7.26(m,1H),6.89(d,1H),6.83-6.72(m,1H),4.27-4.05(m,4H),3 .92-3.75(m,2H),3.64(d,2H),2.42-2.24(m,4H),2.05-1.90(m,4H),1.86(s,1H),1.80- 1.71(m,2H),0.85-0.77(m,2H),0.74-0.61(m,2H),0.48-0.37(m,2H).HRMS(ESI+,[M+H] + m / z: 601.2513.

[0326] Example 11

[0327]

[0328] Step A:

[0329] In a 50 mL single-necked flask, compound 3-1 (1 g), DMF (10 mL), potassium carbonate (0.36 g), and iodomethane (0.37 g) were added sequentially. The mixture was stirred at room temperature for 4 h under nitrogen protection. After the reaction was complete, 30 mL of distilled water was added, and the mixture was extracted with EA (20 mL × 3), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification was then performed by silica gel column chromatography (eluent: PE / EA = 1 / 5) to obtain compound 11-1 (0.77 g). 1 H NMR(500MHz,DMSO-d6)δ7.18(d,1H),7.11(d,1H),7.08-6.92(m,1H),3.97-3.80(m,2H),3.70(s,3H),2.13 -1.94(m,2H),1.96-1.80(m,2H),1.78-1.65(m,2H),0.78-0.71(m,2H),0.57-0.38(m,2H).MS(ESI+,[M+H] + m / z: 398.08.

[0330] Step B:

[0331] In a 100 mL single-necked flask, compound 11-1 (0.77 g), methyl cyclopentyl ether (10 mL), (4-methoxybenzyl)imino)dimethyl-6-thione (1.13 g), cesium carbonate (1.72 g), Xantphos (0.10 g), and Xantphos PdG3 (0.24 g) were added sequentially. The mixture was heated to 110 °C and stirred for 8 h under nitrogen protection. After the reaction was complete, 30 mL of distilled water was added, and the mixture was extracted with EA (20 mL × 3), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification was achieved by silica gel column chromatography (eluent: PE / EA = 10 / 1-1 / 5) to give compound 11-2 (0.25 g). MS (ESI+, [M+H)) + m / z: 483.27.

[0332] Step C:

[0333] In a 100 mL single-necked flask, compound 11-2 (0.21 g), lithium hydroxide (50 mg), THF (2 mL), methanol (2 mL), and water (1 mL) were added sequentially. Under nitrogen protection, the mixture was heated to 50 °C and stirred for 2 h. After the reaction was complete, 30 mL of distilled water was added, and the mixture was extracted with EA (20 mL). The aqueous phase was adjusted to pH 2-3 with 2N hydrochloric acid solution and then extracted with EA (20 mL * 3). The mixture was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 11-3 (0.14 g). MS (ESI+, [M+H)) + m / z: 469.21. Step D:

[0334] In a 100 mL single-necked flask, compound 11-3 (0.14 g), DMF (5 mL), HATU (0.17 g), compound A-4 (0.23 g), and DIPEA (0.12 g) were added sequentially. The mixture was stirred at room temperature for 2 h under nitrogen protection. After the reaction was complete, 30 mL of distilled water was added, and the mixture was extracted with EA (20 mL × 3), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification was performed by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain compound 11-4 (80 mg). 1 H NMR(500MHz,DMSO-d6)δ11.26(s,1H),8.84(d,1H),8.10(d,1H),7.85(d,1H) ,7.56(d,1H),7.26(s,1H),7.24-7.17(m,3H),6.88-6.79(m,2H),4.59(d,1H ),4.37(s,5H),3.79-3.68(m,5H),2.84(s,3H),2.15-2.03(m,7H),1.96-1.8 1(m,5H),0.94(d,2H),0.65-0.51(m,2H),0.24-0.09(m,2H).MS(ESI+,[M+H] + m / z: 704.35.

[0335] Step E:

[0336] In a 25 mL single-necked flask, compound 11-4 (70 mg) and TFA (5 mL) were added sequentially. The mixture was stirred at 50 °C for 6 h under nitrogen protection. After the reaction was completed, the solvent was dried by a stream of nitrogen, and the mixture was purified by silica gel column chromatography (eluent: DCM / MeOH = 50 / 1) to obtain compound 11 (20 mg). 1H NMR(500MHz, CDCl3)δ11.16(s,1H),8.82(s,1H),8.10(d,1H),7.54(d,2H),7.19(s,1H),7.13(d,1H),4.49-4.38(m,4H),4.25(d,1H),3.91( s,2H),2.94(s,3H),2.58(d,3H),2.22-1.88(m,7H),0.98(d,2H),0.91-0.78(m,2H),0.67-0.53(m,2H),0.24-0.11(m,2H).HRMS(ESI+,[M+H] + m / z: 584.2609

[0337] Experiment 1: KIF18A protein motility inhibition experiment

[0338] KIF18A(1-374) protein (Cytoskeleton Inc) was diluted to 50 nM using a buffer containing tubulin (Cytoskeleton Inc) and paclitaxel. 3 μL of this solution was added to each well. Different compounds dissolved in DMSO were added to the wells using a nanoparticle pipette to achieve a final concentration of 1000 nM - 0.244 nM. Two replicates were used, and a control was included. The mixture was incubated for 15 min. 2 μL of ATP (187.5 nM) was added to each well, and the mixture was incubated at room temperature for 15 min. Then, 5 μL of ADP-Glo ​​reagent (Promega) was added to each well, and the mixture was incubated at room temperature for 40 min. Finally, 10 μL of Kinase Detection reagent (Promega) was added to each well, and the mixture was incubated at room temperature for 40 min. The Luminescence module of an Envision microplate reader was used for detection, and a four-parameter fitting method was employed to calculate the IC50. 50 .

[0339] Some experimental results are shown in Table 1.

[0340] Table 1

[0341]

[0342] Experiment Example 2: Cell Proliferation Inhibition Experiment

[0343] 2.1 Assay of OVCAR3 cell proliferation inhibition activity

[0344] Collect OVCAR3 cells in good growth condition into centrifuge tubes and adjust the cell density to 4 × 10⁻⁶. 4The compound was seeded at a concentration of 100 μL / well in a 96-well plate and cultured overnight. The compound was then added using a nanoparticle pipette to a final concentration of 2000 nM - 0.91 nM, with two replicates. A control was also included. After culturing for 4 days, the assay reagent CCK-8 (Beijing Tongren Chemical, 10 μL / well) was added. After incubation for 2 hours, the absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 .

[0345] Some experimental results are shown in Table 2.

[0346] Table 2

[0347] Example <![CDATA[OVCAR3 IC 50 (nM)]]> 1 ≤10nM 2 ≤10nM 3 ≤10nM 4 ≤10nM

[0348] Experimental Example 3: Liver Microsomal Stability Test

[0349] Liver microsomal incubation samples were prepared by incubating liver microsomal solution (0.5 mg / ml) in mixed PBS buffer (pH 7.4), along with the test compound and NADPH + MgCl2 solution at 37°C and 300 rpm for 1 hour. Samples at 0 hours were prepared by incubating liver microsomal solution (0.5 mg / ml) in mixed PBS buffer (pH 7.4), along with the test compound. After adding acetonitrile solution containing an internal standard, protein precipitation was performed to prepare the supernatant, which was then diluted for LC / MS / MS analysis.

[0350] Some experimental results are shown in Table 3.

[0351] Table 3

[0352]

[0353] Experimental Example 4: Mouse Pharmacokinetics

[0354] ICR mice, weighing 18–22 g, were randomly divided into groups of 9 mice each after acclimatization for 3–5 days. The test compound solution was administered intravenously at a dose of 1 mg / kg, and the test compound solution was administered orally at a dose of 10 mg / kg.

[0355] Blood was collected intravenously at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, and 24h, and blood was also collected by gavage at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, and 24h. Blood was also collected from the orbital rim to prepare plasma samples for testing.

[0356] Take 30 μL of the plasma sample to be tested and the standard sample, add acetonitrile solution containing internal standard, and obtain the supernatant by protein precipitation. After dilution, use it for LC / MS / MS determination.

[0357] Pharmacokinetic parameters were fitted using a non-compartmental model.

[0358] Conclusion: The compound of this application can be absorbed orally and has excellent in vivo exposure and / or absolute bioavailability.

[0359] Example 5: In vivo efficacy evaluation

[0360] 5.1 Pharmacodynamic evaluation in the OVCAR-3 human ovarian cancer B-NDG mouse xenograft model

[0361] OVCAR-3 cells (source: Zhejiang Meisen) were subcutaneously inoculated in the right axilla of SPF-grade female B-NDG mice (source: Biocytogen), at a dose of 1×10⁻⁶. 7 Each mouse (PBS:Matrix gel = 1:1), F1 generation. Tumor tissue from F1 generation mice was subcutaneously inoculated into the right axilla of SPF-grade female nude mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) using the inoculation method. Tumors were inoculated until the average tumor volume reached 100-200 mm². 3 At that time, the animals were divided into a control group and a treatment group, with 5 animals in each group.

[0362] Day 0 was designated as the grouping day, and medication was administered once daily via gavage. Tumor volume was measured 2-3 times per week, and mouse weight was recorded. General mouse behavior was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[0363] The detection indicators and calculation formulas are as follows:

[0364] Tumor volume, TV (mm) 3 )=1 / 2×(a×b 2 ); where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0365] Relative to tumor volume, RTV = TV t / TV0; where TV0 is the tumor volume on day 0, TV t This represents the tumor volume at each measurement.

[0366] Relative tumor proliferation rate, T / C (%) = T RTV / C RTV ×100%; where, T RTV For the treatment group, RTV; C RTV The solvent control group is RTV.

[0367] Tumor growth inhibition rate, TGI(%) = (1-TW / TW0)×100%; where TW is the tumor weight in the treatment group and TW0 is the tumor weight in the solvent control group.

[0368] Weight change rate, WCR (%) = (Wt) t-Wt0) / Wt0×100%; where Wt0 is the mouse body weight on day 0, Wt t The mouse's weight at each measurement.

[0369] Some experimental results are shown in Table 4.

[0370] Table 4

[0371] Group dose Frequency of administration TGI (%) Compound 1 5mg / kg QD×22 days 97.5％ .

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, Ring A is selected from one or more R. A Substituted 5-12-membered bridged heterocyclic alkyl groups; Ring B is selected from one or more Rs. B The following groups are substituted: 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl; Ring C is selected arbitrarily by one or more R C The following groups are substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, or 3-12 membered heterocyclic groups; Each R A R B 、or R C Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; Z 1 Z 2 or Z 3 Each is independently selected from N or CR Z1 ; Each R Z1 Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; L 1 Selected from single bond, -O-, -S-, -NR L1 -、-C(R L1 )2-, -C(O)-, -S(O)-, -S(O)2-, -C(O)NR L1 -、-NR L1 C(O)-、-S(O)2NR L1 -、-NR L1 S(O)2-、-C(R L1 )2S(O)2-、-S(O)2C(R L1 )2-、-NR L1 S(O)2NR L1 -、-S(O)(=NH)-、-NR L1 S(O)(=NH)-、-S(O)(=NH)NR L1 -、-C(R L1 )2S(O)(=NH)-, or -NR L1 S(O)(=NH)NR L1 -; Each R L1 Each is independently selected from H, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; R 1 Selected from one or more R 1a The following groups are substituted: C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkyl C 1-4 Alkylene or 3-12 membered heterocyclic alkyl C 1-4 Alkylene; Each R 1a Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, or optionally influenced by one or more R. 1b The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, or di-C 1-6 Alkylamino; Each R 1b Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-6 Alkoxy, C 1-6 alkylamino, or di-C 1-6 Alkylamino; L 2 Selected from -C(O)O-, -OC(O)-, -C(O)NR L2 -、-NR L2 C(O)-、-S(O)2NR L2 - or -NR L2 S(O)2-; R L2 Selected from H, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl; X 1 X 2 Each is independently selected from N or CR X1 ; ---Selected from single or double bonds; When --- is selected as a single key, X 3 X 4 Each is independently selected from N, C, or CR X1 ; When --- is selected from a double bond, X 3 X 4 Selected from C; Each R X1 Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; Ring D is selected from one or more R. D The following groups are substituted: 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; Each R D Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; The R A R B R C R Z1 R L1 R Y R L2 R X1 、or R D It may be optionally substituted by one or more substituents.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from one or more Rs arbitrarily. A Substituted 5-10-membered bridged heterocyclic alkyl groups; Alternatively, ring A is selected from one or more Rs. A Substituted 6-9-membered bridged heterocyclic alkyl groups; Alternatively, ring A is selected from one or more Rs. A Substituted 7-8-membered bridged heterocyclic alkyl groups; Or, structural unit Selected from Where n is selected from 0, 1, 2, 3, 4, 5, or 6; Alternatively, ring B is selected from one or more R's. B The following groups are substituted: 3-4 membered cycloalkyl or 4-5 membered heterocycloalkyl; Alternatively, ring B is selected from one or more R's. B The following groups may be substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, or piperazineyl; Alternatively, ring B is selected from one or more R's. B The following groups are substituted: cyclopropyl or cyclobutyl; Alternatively, ring B is selected from one or more R's. B Substituted cyclopropyl; Or, structural unit Selected from Where n is selected from 0, 1, 2, 3, 4, 5, or 6; m is selected from 0, 1, 2, 3, or 4; Or, structural unit Selected from 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, Ring C is selected from one or more Rs arbitrarily. C The following groups are substituted: 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, or 3-10 membered heterocyclic groups; Alternatively, ring C is selected from one or more Rs. C The following groups are substituted: 4-7 membered cycloalkyl, 4-7 membered cycloalkenyl, or 4-7 membered heterocyclic group; Alternatively, ring C is selected from one or more Rs. C The following groups are substituted: 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl; Alternatively, ring C is selected from one or more Rs. C The following groups are substituted: 4-7 membered cycloalkyl or 4-7 membered heterocycloalkyl; Alternatively, ring C is selected from one or more Rs. C The following groups are substituted: cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl. Alternatively, ring C is selected from 4. The compound of formula (I) according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein, Each R A R B 、or R C Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino or halogenated diC 1-4 Alkylamino; Or, each R A R B 、or R C Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, deuterated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino or halogenated diC 1-3 Alkylamino; Or, each R A R B 、or R C Each is independently selected from deuterium, oxo, thio, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, -COOH, -CHO, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuterylmethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino; Or, each R A R B 、or R C Each is independently selected from deuterium, oxo, -F, -Cl, -OH, -CN, methyl, or methoxy; Or, each R C Each is independently selected from deuterium, -F, -Cl, -OH, -CN, or methyl.

5. The compound of formula (I) according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from one or more R 1a The following groups are substituted: C 1-5 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl C 1-3 Alkylene or 3-10 membered heterocyclic alkyl C 1-3 Alkylene; Or, R 1 Selected from one or more R 1a The following groups are substituted: C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkyl C 1-2 Alkylene or 4-10 membered heterocyclic alkyl C 1-2 Alkylene; Or, R 1 Selected from one or more R 1a The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thiazolyl, pyrrolyl, tetrahydrofuranyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, cyclopropylmethylene, cyclobutylmethylene, aziridinemethylene, oxaziridinemethylene, pyrrolylmethylene, or tetrahydrofuranylmethylene; Or, R 1 Selected from one or more R 1a The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, oxacyclobutyl, thiazolyl, pyrrolidinyl, tetrahydrofuranyl, isothiazolyl, thiadiazolyl, or cyclopropylmethylene. Or, R 1 Selected from one or more R 1a The following groups are substituted: methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl. Or cyclopropylmethylene; Or, R 1 Selected from methyl, trideuteryl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, Isopropyl, tert-butyl Cyclopropyl Cyclobutyl, Cyclopropylmethylene, or Alternatively, structural unit - L 1 -R 1 Selected from 6. The compound of formula (I) according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein, Ring D is selected from one or more R. D The following groups are substituted: 3-6 membered cycloalkenyl, 4-6 membered heterocycloalkenyl, phenyl, or 5-6 membered heteroaryl; Alternatively, ring D is selected from one or more R. D The following groups may be substituted: cyclopentenyl, cyclohexenyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, dioxacyclopentenyl, phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazoleyl, oxazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; Alternatively, ring D is selected from one or more R. D Substituted imidazole group; Or, structural unit It consists of 9-10 heteroaryl groups; Or, structural unit Selected from Where p is selected from 0, 1, or 2; Or, structural unit Selected from Where p is selected from 0, 1, or 2; Or, structural unit Selected from 7. The compound of formula (I) according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, selected from compounds of formulas (I-1), (I-2), (II), (III), and (IV) or pharmaceutically acceptable salts thereof. in, Ring A, Ring B, Ring C, Z 1 Z 2 Z 3 L 1 R 1 L 2 --- X 1 X 2 X 3 X 4 , ring D, R L2 R D p is as defined in any one of claims 1-11.

8. The compound of formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds or pharmaceutically acceptable salts thereof:

9. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof; optionally, further comprising a pharmaceutically acceptable excipient.

10. Use of the compound of formula (I) according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for treating a disease.

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