Macrocyclic compounds and medical uses thereof

Abstract

The present application relates to macrocyclic compounds and their medical uses, the structure is shown as formula (I). The present application also relates to the preparation method of the compounds, pharmaceutical compositions and their use as KRas G12C inhibitors in the treatment of cancer.

Description

Technical Field

[0001] This application relates to macrocyclic compounds, methods for their preparation, pharmaceutical compositions containing the compounds, and their use as Kras G12C inhibitors in the treatment of cancer. Background Technology

[0002] The Ras gene is an important proto-oncogene, named after its discovery in rat sarcoma virus. The Ras protein it encodes is located on the inner side of the cell membrane, can bind to GTP / GDP, and can hydrolyze GTP with the assistance of GTPase activator protein (GAP). By interconverting between its active (GTP-bound) and inactive (GDP-bound) conformations, the Ras protein controls the "on" and "off" of signal transduction processes such as growth factors and cytokines, playing an important role in life processes such as cell proliferation, differentiation, aging, and apoptosis (Bos JL et al., Cell, 2007, 129(5):865-877). The human Ras gene family has three members: Harvey rat sarcoma virus oncogene homolog (Hras), neuroblastoma rat sarcoma virus oncogene homolog (Nras), and Kersten rat sarcoma virus oncogene homolog (Kras). Among them, Kras is mainly expressed in the intestine, lung, and thymus (Rajalingam K et al., Biochim Biophys Acta, 2007, 1773(8):1177-1195).

[0003] Studies have shown that Ras gene mutations exist in more than 30% of human tumors, with Kras mutations accounting for approximately 86% (Riely GJ et al., Proc Am Thorac Soc, 2009, 6(2):201-205). Of the Kras mutations, mutations at glycine position 12 (G12) account for approximately 80%, while G12C mutations (where glycine at position 12 is replaced by cysteine) account for approximately 14% of all G12 mutations (Prior IA et al., Cancer Res, 2012, 72(10):2457-2467; Hobbs GA et al., Cancer Cell, 2016, 29(3):251-253). Mutations at G12 reduce the catalytic activity of GAP, ultimately leading to sustained Ras activation, which prevents Ras from effectively regulating cell signal transduction, thereby promoting tumor development and progression.

[0004] In recent years, people have been using Kras G12C Significant progress has been made in drug development using allosteric sites of mutants. Kras, for example, has already entered clinical trials. G12C Inhibitors include AMG-510, MRTX-849, GDC-6036, BI-1701963, and ARS-3248, with some structures shown below.

[0005] Invention Details

[0006] This application relates to compounds of formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof.

[0007]

[0008] in,

[0009] X is selected from N or CR X ;

[0010] Y is selected from N or CR Y ;

[0011] Z is selected from N or CR. Z ;

[0012] The premise is that at least one of X, Y, and Z is not selected from N;

[0013] R X R Y R Z Each is independently selected from H, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, vinyl, or ethynyl;

[0014] Selected from 4-10 membered heterocyclic alkyl groups containing at least two nitrogen atoms;

[0015] Each R 1 Independently selected from halogens, oxo groups, -OH, -NH2, -CN, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 Alkoxy C 1-3 Alkyl, C 1-6 alkylamino, or di-C 1-6 Alkylamino;

[0016] m is selected from 0, 1, 2, 3, or 4;

[0017] R 2 Selected from -C(O)C≡CR 2b -SO2C≡CR 2b -C(O)C(R) 2a )=C(R 2b)2, or -SO2C(R 2a )=C(R 2b )2;

[0018] R 2a Selected from H, halogens, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0019] Each R 2b Independently selected from H, halogen, -CN, or optionally by 1, 2, or 3 R 2c The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, C 1-4 Alkoxy C 1-3 Alkyl, C 1-4 Alkylamino C 1-3 Alkyl, diC 1-4 Alkylamino C 1-3 Alkyl, 3-7 membered cycloalkyl C 1-3 Alkyl, or 4-7 membered heterocyclic alkyl C 1-3 alkyl;

[0020] Each R 2c It is independently selected from halogen, oxo, -OH, -NH2, or -CN;

[0021] W is selected from O, S, or NR. W1 ;

[0022] R W1 Selected from H or C 1-4 alkyl;

[0023] R 3a R 3b Each is independently selected from H or C 1-3 Alkyl; or, R 3a R 3b Together they form = O;

[0024] R 4 Selected from H, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 Alkylamino C 1-3 Alkyl, diC 1-4 Alkylamino C 1-3 Alkyl, diC 1-4 Alkylaminoacyl C 1-3 Alkyl, Halogenated C1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-4 Alkylamino C 1-3 Alkyl, di(halogenated C) 1-4 alkyl)aminoC 1-3 Alkyl group, or optionally with 1, 2, 3 or 4 R groups. 4a The following groups are substituted: 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 3-7 membered cycloalkyl C 1-3 Alkyl, or 4-7 membered heterocyclic alkyl C 1-3 alkyl;

[0025] Each R 4a Independently selected from halogens, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-2 alkyl carbonyl, C 1-4 Alkylamino, diC 1-4 Alkylamino, 3-7 membered cycloalkyl, or 4-7 membered heterocycloalkyl;

[0026] Ring B is selected from phenyl, naphthyl, 5-10-membered heteroaryl, benzo5-6-membered cycloalkenyl, benzo5-6-membered heterocyclic, 5-6-membered heteroaryl-5-6-membered cycloalkenyl, or 5-6-membered heteroaryl-5-6-membered heterocyclic, wherein the 5-6-membered cycloalkenyl or 5-6-membered heterocyclic moiety is optionally substituted by one or two =O;

[0027] Each R 5 Independently selected from halogens, -CN, -OH, -NH2, -C(O)NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, hydroxyl group C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, diC 1-6 Alkylamino, di(halogenated C) 1-6 Alkyl)amino, or optionally surrounded by 1, 2 or 3 R 5a The following groups are substituted: 3-7 membered cycloalkyl, 3-7 membered cycloalkyl C 1-3 Alkyl, 4-7 membered heterocyclic alkyl, or 4-7 membered heterocyclic alkyl C 1-3 alkyl;

[0028] Each R 5a Independently selected from oxo, halogen, -CN, -OH, -NH2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino;

[0029] n is selected from 0, 1, 2, 3, 4, 5, or 6.

[0030] In some implementations, X is selected from CR X Y is selected from N; Z is selected from N. In some implementations, X is selected from N; Y is selected from CR. Y Z is selected from N. In some implementations, X is selected from N; Y is selected from N; Z is selected from CR. Z .

[0031] In some implementations, X is selected from N; Y is selected from CR. Y Z is selected from CR Z In some implementations, X is selected from CR. X Y is selected from N; Z is selected from CR. Z In some implementations, X is selected from CR. X Y is selected from CR Y Z is selected from N.

[0032] In some implementations, X is selected from CR X Y is selected from CR Y Z is selected from CR Z .

[0033] In some implementation schemes, R X R Y R Z Each is independently selected from H, F, Cl, Br, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkyl, fluorinated C 1-4 Alkyl or ethynyl. In some embodiments, R X R Y R Z Each is independently selected from H, F, Cl, Br, -CN, methyl, ethyl, methoxy, trifluoromethyl, or ethynyl. In some embodiments, R X R Y R Z Each is independently selected from H, F, Cl, or Br.

[0034] In some implementation schemes, R X Selected from H, F, Cl, Br, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkyl, C 1-4 Fluoroalkoxy or ethynyl; R Y R Z Each is independently selected from H, F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkyl group. In some embodiments, R X Selected from H, F, Cl, Br, -CN, methyl, ethyl, methoxy, trifluoromethyl, or ethynyl; R Y R Z Each is independently selected from H, F, Cl, Br, -CN, methyl, or methoxy. In some embodiments, R Y Selected from H;R X R Z Each is independently selected from H, F, Cl, or Br.

[0035] In some implementation schemes, Selected from 4-10 membered heterocyclic alkyl groups containing two nitrogen atoms. In some embodiments, Selected from 4-9 membered heterocyclic alkyl groups containing two nitrogen atoms. In some embodiments, The heterocyclic alkyl group is selected from 4-7 membered heterocyclic alkyl groups containing two nitrogen atoms. In some embodiments, the heterocyclic alkyl group is selected from monocyclic heterocyclic alkyl groups or spirocyclic heterocyclic alkyl groups. In some embodiments, the heterocyclic alkyl group is selected from monocyclic heterocyclic alkyl groups.

[0036] In some implementation schemes, Selected from

[0037] In some implementation schemes, Selected from

[0038] In some implementation schemes, Selected from In some implementation schemes, Selected from

[0039] In some implementation schemes, R 1 Independently selected from F, Cl, Br, oxo, -OH, -NH2, -CN, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 alkylamino, or di-C 1-4 Alkylamino. In some embodiments, R 1 Independently selected from F, Cl, oxo, -OH, -NH2, -CN, methyl, ethyl, difluoromethyl, trifluoromethyl, cyanomethyl, methoxy, or dimethylamino. In some embodiments, R 1 Selected from methyl.

[0040] In some implementations, m is selected from 0, 1, 2, or 3.

[0041] In some implementation schemes, R 2 Selected from -C(O)C≡CR 2b -C(O)C(R) 2a ) = C(R 2b )2, or -SO2C(R 2a )=C(R 2b )2. In some implementation schemes, R 2 Selected from -C(O)C≡CR 2b -C(O)C(R) 2a =CHR 2b 、or -SO2C(R 2a =CHR 2b In some implementations, R 2 Selected from -C(O)C(R) 2a )=CH(R 2b ).

[0042] In some implementation schemes, R 2a Selected from H, F, Cl, methyl, or ethyl. In some embodiments, R 2a Selected from H or F. In some implementations, R 2a Selected from H.

[0043] In some implementation schemes, R 2b Independently selected from H or optionally by 1, 2 or 3 Rs 2c The following groups are substituted: C 1-4 Alkyl, diC 1-3 Alkylamino C 1-2 Alkyl, or 4-6 membered heterocyclic alkyl C1-2 alkyl. In some embodiments, ... In some embodiments, R 2b Independently selected from H or optionally by 1, 2 or 3 Rs 2c The substituted groups include: methyl, dimethylaminomethyl, morpholinomethyl, piperidinylmethyl, tetrahydropyrrolylmethyl, or aziridinebutylmethyl. In some embodiments, R 2bIndependently selected from H or dimethylaminomethyl. In some embodiments, R 2b Selected from H.

[0044] In some implementation schemes, R 2c Independently selected from F, Cl, oxo, -OH, -NH2, or -CN. In some embodiments, R 2c It is independently selected from F or Cl.

[0045] In some implementation schemes, R 2 Selected from the following groups: In some implementation schemes, R 2 Selected from the following groups: In some implementation schemes, R 2 Selected from the following groups:

[0046] In some implementations, W is selected from O or NR. W1 In some implementations, W is selected from O.

[0047] In some implementation schemes, R W1 Selected from H, methyl, or ethyl. In some embodiments, R W1 Selected from methyl.

[0048] In some implementation schemes, R 3a R 3b Each is independently selected from H or methyl.

[0049] In some implementations, when W is selected from NR W1 At that time, R 3a R 3b Together they form = O.

[0050] In some implementation schemes, R 4 Selected from H, C 1-6 Alkyl, C 1-4 Alkylamino C 1-3 Alkyl, diC 1-4 Alkylamino C 1-3 Alkyl, diC 1-4 Alkylaminoacyl C 1-3 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-4 Alkylamino C 1-3 Alkyl, di(halogenated C) 1-4 alkyl)aminoC 1-3 Alkyl group, or optionally with 1, 2, 3 or 4 R groups. 4a The following groups are substituted: 4-7 membered heterocyclic alkyl groups, or 4-7 membered heterocyclic alkyl C groups. 1-3Alkyl group. In some embodiments, R 4 Selected from H, C 1-6 Alkyl, C 1-4 Alkylamino C 1-3 Alkyl, diC 1-4 Alkylamino C 1-3 Alkyl, diC 1-4 Alkylaminoacyl C 1-3 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-4 Alkylamino C 1-3 Alkyl, di(halogenated C) 1-4 alkyl)aminoC 1-3 Alkyl group, or optionally with 1, 2, 3 or 4 R groups. 4a The following groups are substituted: aziridine, aziridine methyl, aziridine ethyl, tetrahydropyrrolyl, tetrahydropyrrolyl methyl, tetrahydropyrrolyl ethyl, morpholinyl, morpholinyl methyl, morpholinyl ethyl, piperazine, piperidinyl, piperidinyl methyl, piperidinyl ethyl. In some implementation schemes, R 4 Selected from H, or optionally by 1, 2, 3 or 4 Rs 4a Substituted tetrahydropyrrolemethyl.

[0051] In some implementation schemes, R 4a Independently selected from F, Cl, Br, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino. In some embodiments, R 4a Independently selected from F, Cl, -OH, oxo, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, methylamino, ethylamino, dimethylamino, or diethylamino. In some embodiments, R 4a Independently selected from F, Cl, -OH, oxo, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, methylamino, ethylamino, dimethylamino, or diethylamino. In some embodiments, R 4a It is independently selected from F, methyl, ethyl, methoxy, dimethylamino, or diethylamino.

[0052] In some implementation schemes, R 4 Selected from H, In some implementation schemes, R 4 Selected from H, In some implementation schemes, R4 Selected from H. In some implementations, R 4 Selected from

[0053] In some embodiments, ring B is selected from phenyl, indenyl, 2,3-dihydroindenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, pyrroleyl, furanyl, thiopheneyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, benzopyrazolyl, etc. Benzimidazolyl, benzotriazolyl, benzothiazolyl, benzoisothiazolyl, indoleyl, indolinyl Benzoxazolyl, Benzisoxazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, or

[0054] In some embodiments, ring B is selected from phenyl, pyridyl, naphthyl, benzopyrazolyl, and others. Benzimidazole, benzotriazolyl, benzothiazolyl, benzoisothiazolyl, indole, Benzisoxazolyl, isoquinolinyl, or

[0055] In some embodiments, ring B is selected from phenyl, pyridyl, benzothiazolyl, benzopyrazolyl, or isoquinolinyl.

[0056] In some implementation schemes, R 5 Independently selected from F, Cl, Br, -CN, -OH, -NH2, -C(O)NH2, C 1-4 Alkyl, C 2-4 alkynyl group, hydroxyl group C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkylamino, halogenated C 1-4 Alkylamino, diC 1-4 Alkylamino, di(halogenated C) 1-4 Alkyl)amino, or optionally surrounded by 1, 2 or 3 R 5a The substituted groups are 3-6 membered cycloalkyl groups or 4-6 membered heterocycloalkyl groups. In some embodiments, R 5 Independently selected from F, Cl, -OH, -NH2, -C(O)NH2, methyl, ethyl, ethynyl, difluoromethyl, trifluoromethyl, methoxy, methylamino, dimethylamino, or optionally surrounded by 1, 2 or 3 Rs. 5aThe substituted groups include: cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazineyl, or morpholinyl. In some embodiments, R 5 It is independently selected from F, Cl, -OH, -NH2, methyl, trifluoromethyl, methoxy, or methylamino.

[0057] In some implementations, each R 5a Independently selected from oxo, F, Cl, Br, -CN, -OH, -NH2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino. In some embodiments, each R 5a It is independently selected from oxo, F, Cl, Br, -CN, -OH, -NH2, methyl, ethyl, trifluoromethyl, methoxy, methylamino, or dimethylamino.

[0058] In some implementations, n is selected from 0, 1, 2, 3, or 4.

[0059] In some implementation schemes, ring B is selected from...

[0060] In some implementation schemes, ring B is selected from...

[0061] In some implementations, n is selected from 0.

[0062] In some implementations, the C 1-6 Alkyl groups are selected from C 1-4 Alkyl group. In some embodiments, the C 1-4 Alkyl groups are selected from C 1-3 Alkyl or C 1-2 alkyl.

[0063] In some embodiments, the halogenation is selected from fluorinated, chlorinated, brominated, or iodinated. In some embodiments, the halogenation is selected from fluorinated or chlorinated.

[0064] In some embodiments, the heterocyclic alkyl group contains one or two heteroatoms selected from N or O.

[0065] In some embodiments, the heterocyclic alkyl group contains one nitrogen atom.

[0066] In some embodiments, the heterocyclic alkyl group contains two nitrogen atoms.

[0067] In some embodiments, the heterocyclic alkyl group contains one oxygen atom.

[0068] In some embodiments, the heterocyclic alkyl group contains one N atom and one O atom.

[0069] In some embodiments, the heterocyclic group contains one or two heteroatoms selected from N or O.

[0070] In some embodiments, the heterocyclic group contains one N atom.

[0071] In some embodiments, the heterocyclic group contains two nitrogen atoms.

[0072] In some embodiments, the heterocyclic group contains one N atom and one O atom.

[0073] In some embodiments, the heteroaryl group contains one, two, or three heteroatoms selected from S, N, or O.

[0074] In some embodiments, the heteroaryl group contains three nitrogen atoms.

[0075] In some embodiments, the heteroaryl group contains one or two heteroatoms selected from S and N.

[0076] In some embodiments, the heteroaryl group contains one or two N atoms.

[0077] In some embodiments, the heteroaryl group contains one N atom and one S atom.

[0078] In some embodiments, the heteroaryl group contains one N atom and one O atom.

[0079] In some embodiments, the heterocyclic alkyl group comprises a monocyclic, spirocyclic, or bridged ring.

[0080] This application relates to compounds of formula (II) or pharmaceutically acceptable salts thereof.

[0081]

[0082] Among them, R 1 R 2 R 3a R 3b R 4 R 5 The parts W, X, Y, Z, m, n, A, and B are defined as above.

[0083] This application relates to compounds of formula (Ia) or (Ib) or (Ic) or (Id) or pharmaceutically acceptable salts thereof.

[0084]

[0085] Among them, R 1 R 2 R 3a R 3b R 4 R 5 R W The components X, Y, Z, m, n, A, and B are defined as above.

[0086] This application relates to compounds of formula (IIa), (IIb), (IIc), or (IId), or pharmaceutically acceptable salts thereof.

[0087]

[0088]

[0089] Among them, R 1 R 2 R 3a R 3b R 4 R 5 R W The components X, Y, Z, m, n, A, and B are defined as above.

[0090] This application relates to compounds of formula (III), (IV), or (IVa) or pharmaceutically acceptable salts thereof.

[0091]

[0092] Among them, R 1 R 2 R 5 R X R Z The parts m, n, A, and B are defined as above.

[0093] This application also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0094]

[0095]

[0096] This application also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0097]

[0098] This application also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0099]

[0100]

[0101] On the other hand, this application relates to pharmaceutical compositions comprising compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV), or (IVa), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of this application further include pharmaceutically acceptable excipients.

[0102] On the other hand, this application relates to the treatment of mammal Kras G12C Methods for treating related diseases include administering, to a mammal, preferably a human, a therapeutically effective amount of a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IV), or formula (IVa), its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0103] On the other hand, this application relates to compounds of formula (I) or (Ia) or (Ib) or (Ic) or (Id) or (II) or (IIa) or (IIb) or (IIc) or (IId) or (III) or (IV) or (IVa), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of treatments for Kras. G12C Uses in medications for related diseases.

[0104] On the other hand, this application relates to compounds of formula (I) or (Ia) or (Ib) or (Ic) or (Id) or (II) or (IIa) or (IIb) or (IIc) or (IId) or (III) or (IV) or (IVa), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the treatment of Kras. G12C Uses in related diseases.

[0105] On the other hand, this application relates to the treatment of Kras G12CCompounds of formula (I) or (Ia) or (Ib) or (Ic) or (Id) or (II) or (IIa) or (IIb) or (IIc) or (IId) or (III) or (IV) or (IVa) related to the disease, their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0106] In some embodiments of this application, the Kras G12C The preferred related disease is cancer.

[0107] In some embodiments of this application, the cancer includes lung cancer, preferably non-small cell lung cancer.

[0108] definition

[0109] Unless otherwise stated, the following terms as used in this application shall 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0119] The term "hydroxyl group" refers to the -OH group.

[0120] The term "cyano" refers to the -CN group.

[0121] The term "thiol" refers to the -SH group.

[0122] The term "amino" refers to the -NH2 group.

[0123] The term "nitro" refers to the -NO2 group.

[0124] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group. This alkyl group can be straight-chain or branched. 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.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

[0125] The term "alkoxy" refers to -O-alkyl.

[0126] The term "alkylamino" refers to -NH-alkyl.

[0127] The term "dialkylamino" refers to -N(alkyl)2.

[0128] The term "alkylsulfonyl" refers to -SO2-alkyl.

[0129] The term "alkylthio" refers to -S-alkyl.

[0130] The term "alkylaminoacylalkyl" refers to alkylNHC(O)alkyl-.

[0131] The term "dialkylaminoacylalkyl" refers to (alkyl)2NC(O)alkyl-.

[0132] 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. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0133] 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. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), and 1,3-butyrynyl (-C≡CC≡CH).

[0134] 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 ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0135] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 5- to 8-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl.

[0136] 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, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 7-membered ring, preferably a 5- to 6-membered ring, containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen (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.

[0137] 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 heterocycle is typically a 3- to 12-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. 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.

[0138] 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, anthracene, etc.

[0139] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic heterocyclic system containing at least one ring atom selected from N, O, and S, with the remaining ring atoms being C. Preferred heteroaryls have a single 4- to 8-membered ring, particularly a 5- to 8-membered ring, or multiple fused rings containing 6 to 14, particularly 6 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.

[0140] The term "treatment" means administering the compound or preparation described in this application to prevent, improve, or eliminate a disease or one or more symptoms related to said disease, and includes:

[0141] (i) To prevent the occurrence of disease or disease state in mammals, especially when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state;

[0142] (ii) To suppress the disease or disease state, that is, to curb its development;

[0143] (iii) Alleviate the disease or disease state, even if the disease or disease state subsides.

[0144] The term "therapeutic effective amount" means the amount of the compound of this application 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 compound of this application 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 present disclosure.

[0145] 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.

[0146] 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.

[0147] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0148] 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.

[0149] 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”.

[0150] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. 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, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0151] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by 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 application 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.

[0152] Certain isotope-labeled compounds of this application (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 application 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.

[0153] 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.

[0154] The compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

[0155]

[0156] The compounds of this application may have one or more transisomers, unless otherwise stated, where transisomers refer to photoactive isomers resulting from the restriction of free rotation between single bonds. The chiral axis compounds of this application can be isolated in racemic form. When the energy barrier for free rotation of the single bonds in the chiral axis compounds of this application is sufficiently high, their transisomers can be isolated in photoactive pure form. Non-limiting examples of transisomers include, but are not limited to:

[0157]

[0158] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0159] Typical routes of administration for the compounds of this application or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0160] The pharmaceutical composition of this application 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.

[0161] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this application to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, gels, pastes, suspensions, etc., for oral administration to patients.

[0162] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0163] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0164] In all methods of administration of the compound of general formula I described herein, the daily dose is from 0.01 to 200 mg / kg body weight. The compound of this application 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 it 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 application.

[0165] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0166] In some implementations, when R 4 When selected from H, the compound of formula (Ia) of this application can be prepared by those skilled in the art of organic synthesis via route 1, wherein PG 1 Selected from N-atom protecting groups, PG 2 Selected from O atom protecting groups, R 1 R 2 R 3a R 3b R 4 R 5 The parts m, n, W, X, Y, Z, A, and B are defined as above.

[0167]

[0168] Route 1

[0169] Under suitable conditions, compound 1 reacts with compound 2 to give intermediate 3, intermediate 3 is halogenated to give intermediate 4, which then undergoes a substitution reaction with compound 5 to give intermediate 6, which is then degraded by PG. 2The protecting group yields intermediate 7. Intermediate 7 is oxidized to give intermediate 8, which is then cyclized to give intermediate 9. Intermediate 9 is coupled with the corresponding compound 10 to give intermediate 11, which is then degraded by PG. 1 The protecting group yields intermediate 12, which is then reacted with the corresponding acyl halide to give compound (Ia).

[0170] 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 application can be synthesized to obtain single isomers or mixtures of isomers.

[0171] This application uses the following abbreviations:

[0172] Boc represents tert-butyloxycarbonyl; Bn represents benzyl; TBS represents tert-butyldimethyl; KSCN represents potassium thiocyanate; (BPin)2 represents pinacol diboronate; DMAP represents 4-dimethylaminopyridine; DIPEA represents N,N-diisopropylethylamine; Boc2O represents ditert-butyl dicarbonate; m-CPBA represents m-chloroperoxybenzoic acid. PMBCl represents 4-methoxybenzyl chloride; PMB represents 4-methoxybenzyl; Pd2(dba)3 represents tris(dibenzylacetone)dipalladium; PCy3 represents tricyclohexylphosphine.

[0173] Compounds artificially or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0174] For clarity, the present invention is further illustrated by embodiments, but these embodiments are not intended to limit the scope of this application. This application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments of this application without departing from the spirit and scope of this application.

[0175] All reagents used in this application are commercially available and can be used without further purification. Example

[0176] Preparation Example Z1

[0177]

[0178] Step 1:

[0179] At room temperature, Z1a(6g) was dissolved in dichloromethane (120mL), and benzaldehyde (7.4g) was added to the reaction system. The mixture was stirred at room temperature for 30 min. At 0–5℃, sodium triacetoxyborohydride (11.8g) was added to the reaction system. After the addition was complete, the mixture was allowed to react at room temperature for 24 h. After the reaction was complete, saturated sodium bicarbonate solution (80mL) was slowly added to the reaction system. The mixture separated into layers, and the organic phase was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 150:1–1:1) to obtain... Z1b (5.1g).

[0180] LC-MS: m / z 307 (M+H) + .

[0181] Step 2:

[0182] At room temperature, Z1b (2 g), (2-bromoethoxy)-dimethyl-tert-butylsilane (9.9 g), and tetrabutylammonium hydrogen sulfate (0.5 g) were dissolved in toluene (30 mL). 50% sodium hydroxide solution (17.5 mL) was added dropwise to the reaction system, and the reaction was carried out at room temperature for 45 h. After the reaction was complete, water (40 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was collected and washed once with water (50 mL) and once with saturated brine (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40:1–10:1) to obtain... Z1c (1.1g).

[0183] LC-MS: m / z 465 (M+H) + .

[0184] Step 3:

[0185] At room temperature, Z1c 1 g of palladium on carbon (0.1 g) and 10% palladium on carbon (10 mL) were dissolved in methanol and hydrogenated at room temperature for 24 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure until no liquid flowed out, yielding the title compound. Z1 (660mg).

[0186] LC-MS: m / z 375 (M+H) + .

[0187] Preparation Example Z2

[0188]

[0189] Step 1:

[0190] At room temperature, Z2aDissolve 10g of the product in toluene (50mL), add 19g of thionyl chloride to the reaction system, and then heat to 65-70℃ and react for 5 hours. After the reaction is complete, concentrate the reaction solution under reduced pressure until no liquid flows out, to obtain the crude product. Z2b (11g). No purification required; can be used directly in the next reaction.

[0191] Step 2:

[0192] Under ice bath conditions, potassium thiocyanate (4.2 g) was dissolved in acetone (50 mL), and then added dropwise to the reaction system. Z2b Add 6g of acetone (30mL) solution, and after the addition is complete, heat to 50-55℃ and react for 0.5h. Cool the reaction system to 0-5℃, and add 7.6g of 2-bromo-5-fluoroaniline (20mL) of acetone solution dropwise. After the addition is complete, heat to 50-55℃ and react for 2h. After the reaction is complete, add the reaction solution to water (600mL), and a solid precipitates. Filter the solution, add the solid to sodium hydroxide solution (2.5mol / L, 145mL), heat to 80℃ and stir for 30min, then cool to room temperature. Adjust the pH to 9-10 with concentrated hydrochloric acid, extract with ethyl acetate (2*200mL), collect the organic phase, wash with saturated brine (2*100mL), collect the organic phase, dry to anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Z2d (9.8g). No purification required; can be used directly in the next reaction.

[0193] LC-MS: m / z 249 (M+H) + .

[0194] Step 3:

[0195] Under ice bath conditions, Z2d Dissolve 5g of N-bromosuccinimide in 100mL of methanesulfonic acid. Add 3.6g of N-bromosuccinimide to the reaction system. After the addition is complete, heat to 60℃ and react for 4 hours. After the reaction is complete, pour the reaction solution into ice water (1L), adjust the pH to 10-11 with ammonia, and a solid will precipitate. Filter the solution and add the solid to methanol (20mL). Heat to 50℃ and stir for 1 hour. Cool to room temperature and filter to obtain the final product. Z2e (3.6g). LC-MS: m / z 247 (M+H) + .

[0196] Step 4:

[0197] At room temperature, Z2e2 g of pinacol diboronate (10 g), 584 mg of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, and 2.4 g of potassium acetate were dissolved in 200 mL of dioxane. The mixture was purged with argon five times, and the mixture was heated to 100 °C and stirred for 40 h under argon protection. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:1 to 10:1) to obtain the title compound. Z2 (1.1g).

[0198] LC-MS: m / z 213(M+H) + .

[0199] Preparation Example Z3

[0200]

[0201] Title Compound Z3 The synthesis reference preparation example Z1 was used. Z3a replace Z1a ,have to Z3 (500mg).

[0202] LC-MS: m / z 375 (M+H) + .

[0203] Preparation Example Z4

[0204]

[0205] Step 1:

[0206] Under ice bath conditions, potassium thiocyanate (12.4 g) was dissolved in acetone (200 mL), and then added dropwise to the reaction system. Z2b 17.8 g of acetone (100 mL) solution was added, and the mixture was heated to 50–55 °C and reacted for 0.5 h. The reaction system was cooled to 0–5 °C, and 25 g of 2-bromo-3,5-difluoroaniline (100 mL) of acetone solution was added dropwise. After the addition was complete, the mixture was heated to 50–55 °C and reacted for 2 h. After the reaction was completed, the reaction solution was added to 2.5 L of water, and a solid precipitated out. The solid was filtered, and it was added to a sodium hydroxide solution (2.5 mol / L, 400 mL). The mixture was heated to 80 °C and stirred for 30 min. Then it was cooled to room temperature, and the pH was adjusted to 9–10 with concentrated hydrochloric acid. The mixture was filtered under reduced pressure, washed with water, and dried to obtain the crude product. Z4a (24.2g). No purification required; can be used directly in the next reaction.

[0207] LC-MS: m / z 267(M+H) + .

[0208] Step 2:

[0209] Under ice bath conditions, Z4a (24.2g) was dissolved in methanesulfonic acid (200mL), and N-bromosuccinimide (16.1g) was added to the reaction system. After the addition was complete, the temperature was raised to 80℃ and the reaction was carried out for 4 hours. After the reaction was completed, the reaction solution was poured into ice water (2L), and the pH was adjusted to 10-11 with ammonia. A solid precipitated out. The solid was filtered under reduced pressure, washed with water, and dried to obtain the desired product. Z4b (22.9g). No purification required; can be used directly in the next reaction.

[0210] LC-MS: m / z 265 (M+H) + .

[0211] Step 4:

[0212] At room temperature, Z4b Dissolve 5.0 g of DMAP (50 mg) and 3.2 g of DIPEA in 100 mL of tetrahydrofuran, and slowly add 5.3 g of Boc₂O while stirring for 12 h. After the reaction is complete, quench the reaction with 5 mL of methanol and 5 mL of saturated sodium bicarbonate, concentrate under reduced pressure to obtain the crude product, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1–10:1). Z4c (4.9g).

[0213] LC-MS: m / z 365 (M+H) + .

[0214] Step 5:

[0215] Will Z4c (3.0 g) and triisopropyl borate (4.6 g) were dissolved in 60 mL of anhydrous tetrahydrofuran. The mixture was purged with argon five times and stirred at -78 °C under argon protection. 2.4 M butyllithium (10.3 mL) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to -35 °C and the mixture was stirred for 30 min. The reaction was quenched by adding 30 mL of saturated ammonium chloride solution to the reaction system at -35 °C. At room temperature, 200 mL of water and two 200 mL solutions of ethyl acetate were added to the reaction system for extraction. The organic phases were combined, concentrated to obtain the crude product, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1–3:1) to obtain... Z4 (850mg).

[0216] Preparation Example Z5

[0217]

[0218] Step 1:

[0219] 1-Bromo-2-aminoisoquinoline (500 mg), hexa-n-butyltin (1.2 mL), tris(dibenzylacetone)palladium (205 mg), tricyclohexylphosphine (122 mg), and lithium chloride (460 mg) were dissolved in 10 mL of dioxane, and the mixture was purged with nitrogen five times. The reaction mixture was heated to 115 °C and reacted for 18 h. 50 mL of water was added to the reaction mixture, and the mixture was extracted with 100 mL of ethyl acetate twice. The organic phases were combined, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (dichloromethane:methanol = 100:1–30:1) to obtain... Z5 (200mg).

[0220] LC-MS: m / z 435 (M+H) + .

[0221] Preparation Example Z6

[0222]

[0223] Step 1:

[0224] At room temperature, the raw materials Z6a (4g) and S-methylisothiourea sulfate (3.4g) were dissolved in N,N-dimethylformamide (40mL). Then, N,N-diisopropylethylamine (10g) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (9.2g) were added sequentially to the reaction system. The reaction was carried out at room temperature for 2h, and then heated to 100℃ for 12h. After the reaction was completed, the reaction solution was slowly added to water (500mL), and a solid precipitated out. The solid was filtered, and the obtained solid was stirred at 60℃ for 0.5h with a methyl tert-butyl ether / methanol (volume ratio: 4:3, 35mL) mixture. After cooling to room temperature, the mixture was filtered to obtain... Z6b (2.1g).

[0225] LC-MS: m / z 304.9 (M+H) + .

[0226] Step 2:

[0227] At 0℃, Z6bDissolve 2.0 g of phosphorus oxychloride in 50 mL of toluene. Add 10 g of phosphorus oxychloride dropwise to the reaction system. After the addition is complete, stir at 0 °C for 10 min. Then add 3.8 g of N,N-diisopropylethylamine to the reaction system and stir at 0 °C for 0.5 h. Increase the temperature to 110 °C and react for 6 h. After the reaction is complete, cool the reaction solution to room temperature and then slowly add it to 1000 mL of potassium dihydrogen phosphate solution (2 mol / L). Extract with ethyl acetate (3 x 200 mL). Combine the organic phases and wash with saturated sodium bicarbonate solution (2 x 200 mL) and saturated brine (1 x 200 mL). Collect the organic phase, dry it with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Z6c (1.9g). No purification required; can be used directly in the next reaction.

[0228] LC-MS: m / z 322.9 (M+H) + .

[0229] Step 3:

[0230] At room temperature, Z6c Dissolve 550 mg of N,N-dimethylformamide in 6 mL of water and add dropwise to the reaction system. Z1 A solution of 660 mg N,N-dimethylformamide (5 mL) was stirred at room temperature for 0.5 h. Then, 1.1 g of N,N-diisopropylethylamine was added dropwise to the reaction system, and the reaction was continued at room temperature for 15 h. After the reaction was complete, the reaction solution was added to 100 mL of water and extracted with 100 mL of ethyl acetate. The organic phase was collected and washed once with 50 mL of water and once with 50 mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1–10:1) to obtain... Z6d (760mg).

[0231] LC-MS: m / z 661.3 (M+H) + .

[0232] Step 4:

[0233] At 0℃, Z6d (640 mg) was dissolved in tetrahydrofuran (20 mL). A tetrabutylammonium fluoride (370 mg) solution in tetrahydrofuran (10 mL) was added dropwise to the reaction system. After the addition was complete, the reaction was maintained at 0–5 °C for 1 h, then transferred to room temperature for 3 h. After the reaction was complete, the reaction solution was added to water (300 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed once each with saturated ammonium chloride solution (100 mL) and saturated brine solution (100 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Z6e(580mg). No purification required; can be used directly in the next reaction.

[0234] LC-MS: m / z 547.2 (M+H) + .

[0235] Step 5:

[0236] At 0℃, Z6e Dissolve 580 mg of m-chloroperoxybenzoic acid (415 mg) in 20 mL of dichloromethane. Add dropwise a 10 mL solution of dichloromethane to the reaction system. After addition, allow the mixture to react at room temperature for 6 hours. Once the reaction is complete, slowly add the reaction solution to a 90 mL solution of saturated sodium carbonate / saturated sodium thiosulfate / saturated sodium chloride (volume ratio: 1:1:1). Stir, separate the layers, collect the organic phase, dry to anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Z6f (520mg). No purification required; can be used directly in the next reaction.

[0237] LC-MS: m / z 579.1 (M+H) + .

[0238] Step 6:

[0239] At -10℃ to -5℃, Z6f (520 mg) was dissolved in tetrahydrofuran (30 mL). Bis(trimethylsilyl)aminolithium (1.4 mL, 1 M / tetrahydrofuran) was added dropwise to the reaction system. After the addition was complete, the reaction mixture was reacted at 0–5 °C for 2 h. After the reaction was complete, the reaction solution was added to ice water (200 mL), extracted with ethyl acetate (100 mL), and the organic phase was collected. The organic phase was washed once with saturated brine (100 mL), collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1–1:1) to obtain... Z6 (224mg). LC-MS:m / z 499.2(M+H) + .

[0240] Preparation Example Z7

[0241]

[0242] Step 1:

[0243] At room temperature, Z7a 50g of N-chlorosuccinimide (35g) was dissolved in acetonitrile (400ml), and the mixture was heated to 80℃ and reacted for 2 hours. After the reaction was complete, the heating was turned off, the mixture was cooled to room temperature, and filtered to obtain the final product. Z7b (54g).

[0244] LC-MS: m / z 268.0(M+H)+.

[0245] Step 2:

[0246] At room temperature, Z7b 54g of urea and 64g of diphenyl ether were dissolved in 300ml of diphenyl ether, and the mixture was heated to 180℃ and reacted for 5 hours. After the reaction was complete, the temperature was lowered to 40℃, and the mixture was filtered. The resulting solid was slurried with a methyl tert-butyl ether / methanol mixed solution (volume ratio: 5:1; 300ml), filtered, and then... Z7c (55g).

[0247] LC-MS: m / z 293.0(M+H)+.

[0248] Step 3:

[0249] At room temperature, Z7c (55g) was dissolved in POCl3 (350ml), and N,N-dimethylformamide (5ml) was added. The mixture was then heated to 110℃ and reacted for 12h. After the reaction was completed, the reaction solution was slowly added dropwise to ice water (5L) and extracted with ethyl acetate (5L). The organic phase was collected, washed with saturated brine (2*2.5L), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain... Z7d (25g).

[0250] LC-MS: m / z 328.9(M+H)+.

[0251] Step 4:

[0252] Will Z7d Dissolve 12g of the solution in 70ml of N,N-dimethylformamide, stir at 0°C for 10 minutes, and then add dropwise to the reaction system. Z1 After adding 9.6 g of N,N-dimethylformamide (30 ml) solution, N,N-diisopropylethylamine (17 g) was added dropwise to the reaction system, and the reaction was carried out at 0 °C for 2 h. After the reaction was complete, the reaction solution was poured into water (1000 ml), extracted with ethyl acetate (3 x 500 ml), the organic phases were combined, washed with saturated brine (2 x 500 ml), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain... Z7e (15g).

[0253] LC-MS: m / z 667.1(M+H)+.

[0254] Step 5:

[0255] Will Z7e(11g) was dissolved in tetrahydrofuran (60ml), stirred at 0℃ for 15min, and then a tetrahydrofuran (20ml) solution of tetrabutylammonium fluoride trihydrate (5.2g) was added dropwise to the reaction system. The reaction was carried out at 0℃ for 3h. After the reaction was completed, the reaction solution was poured into water (800ml), extracted with ethyl acetate (3*300ml), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain... Z7f (7.3g).

[0256] LC-MS: m / z 553.0(M+H)+.

[0257] Step 6:

[0258] Sodium di(trimethylsilyl)amino (2M / THF) (NaHMDS; 12.6 ml) was dissolved in tetrahydrofuran (200 ml) under nitrogen protection and stirred at 0 °C. The solution was then added dropwise to the reaction system. Z7f Add 7 g of tetrahydrofuran (200 ml) solution, and continue the reaction for 2 h. After the reaction is complete, add the reaction solution to a saturated ammonium chloride solution (2 L), extract with ethyl acetate (2 x 500 L), collect the organic phase, dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the crude product, and purify by silica gel column chromatography to obtain the title compound. Z7 (2.9g).

[0259] LC-MS: m / z 517.1(M+H)+.

[0260] Preparation Example Z8

[0261]

[0262] Step 1:

[0263] At room temperature, Z8a (25g) was dissolved in DMF (400mL), purged with argon, and stirred in an ice bath for 15min under argon protection. Sodium hydroxide was then added in portions. After the addition was complete, the ice bath was removed, the mixture was allowed to return to room temperature, and the reaction was stirred for 1h. PMBCl (47g) was slowly added dropwise to the system, and the reaction was continued with stirring for 4h. The reaction was quenched with 500mL of saturated ammonium chloride aqueous solution. The reaction mixture was extracted with 2.5L of ethyl acetate, and the organic phases were combined. The organic phases were washed with 500mL*5 of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification was achieved by silica gel column chromatography (petroleum ether: dichloromethane = 3:1 to 1:1) to obtain... Z8b (47g).

[0264] LC-MS: m / z 427.3(M+H)+.

[0265] Step 2:

[0266] Will Z8b 5.0 g of 1,4-dioxane, 2.6 g of lithium chloride, 1.1 g of Pd₂(dba)₃, 0.68 g of PCy₃, and 21 g of hexabutyltin (21 g) were dissolved in 32 mL of 1,4-dioxane. The mixture was purged with argon five times, and the reaction was carried out at 80 °C with stirring for 6 h under argon protection. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 10:1) to obtain the title compound. Z8 (5.8g).

[0267] LC-MS: m / z 639.36(M+H)+.

[0268] Example 1

[0269]

[0270] Step 1:

[0271] At room temperature, Z6 (100mg) Z2 125 mg of palladium acetate (3 mg), 125 mg of potassium phosphate, and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (SPhos, 9.5 mg) were dissolved in 1,4-dioxane / water (4:1, 12.5 mL). The mixture was purged with argon five times, and the mixture was heated to 90 °C and stirred for 10 h under argon protection. After the reaction was completed, the reaction solution was poured into ice water (150 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 ~ pure ethyl acetate) to obtain... 1a (30mg).

[0272] LC-MS: m / z 587.3 (M+H) + .

[0273] Step 8:

[0274] At 0℃, 1a Dissolve 30 mg of the reagent in ethyl acetate (10 mL). Add HCl / methanol (0.8 mL) solution dropwise to the reaction system. After the addition is complete, transfer the mixture to room temperature and react for 15 h. Once the reaction is complete, concentrate the reaction solution under reduced pressure until no liquid flows out. Add water (30 mL) to the residue, extract with dichloromethane (15 mL), collect the aqueous phase, and adjust the pH to 8–9 with saturated sodium bicarbonate solution. Then extract with dichloromethane (15 mL).

[0275] Extraction, collection of the organic phase, and concentration under reduced pressure to obtain the crude product. 1b (25mg). No purification required; use directly in the next reaction.

[0276] LC-MS: m / z 487.2 (M+H)+ .

[0277] Step 9:

[0278] At 0℃, 1b 25 mg of potassium carbonate and 30 mg of potassium carbonate were dissolved in 2-methyltetrahydrofuran / water (1:1, 5 mL). Acryloyl chloride (5.2 mg) was added dropwise to the reaction system. After the addition was complete, the reaction was carried out at 0–5 °C for 10 min. The reaction solution was added to ice water (50 mL), extracted with ethyl acetate (20 mL), and the organic phase was collected. The organic phase was washed with saturated brine (2*20 mL), collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative reversed-phase chromatography (column type: Luna C18 5 μm 21.5*250 mm; mobile phase A: 0.05% formic acid; B: acetonitrile; flow rate: 10 mL / min; elution gradient: 10–50%; time: 60 min; detection wavelength: 254 nm) to obtain the title compound. 1 (10mg). LC-MS: m / z 541.1 (M+H) + .

[0279] 1 H NMR(500MHz,Chloroform-d)δ7.89(d,J=93.8Hz,2H),6.94(s,1H),6.80–6.21(m,3H ),6.20–5.59(m,3H),4.67–4.39(m,4H),4.07(d,J=102.6Hz,6H),3.54–3.15(m,3H).

[0280] Example 2

[0281]

[0282] The synthesis of Example 2 is based on Example 1, using... Z3 replace Z1 Purification using a preparative reversed-phase chromatography column yielded the title compound. 2 (12mg). LC-MS: m / z 541.1 (M+H) + .

[0283] Example 3 (Compound 3)

[0284]

[0285] The synthesis of Example 3 was performed in accordance with Example 1, except that (1H-indazol-4-yl)boronic acid was used instead. Z2 Purification using a preparative reversed-phase chromatography column yielded the title compound. 3 (2.2mg).

[0286] LC-MS: m / z 509.3 (M+H) + .

[0287] Examples 4, 5 and 6

[0288]

[0289] The synthesis of Example 4 is based on Example 1, using... Z7 replace Z6 2-Fluoro-6-hydroxyphenylboronic acid was used instead Z2 The title compound was obtained. 4 .

[0290] Example 4: The compound was purified by preparative column chromatography to obtain the trans-restricted isomer. 5 (7.6 mg) and the transisomer 6 (4.2mg).

[0291] Transtransfer isomer 5: retention time 36 min, LC-MS: m / z 503.2 (M+H) + .

[0292] Purification conditions:

[0293]

[0294] Transtransfer isomer 6: retention time 38 min, LC-MS: m / z 503.2 (M+H) + .

[0295] Purification conditions:

[0296]

[0297] Examples 7, 8 and 9

[0298]

[0299] The synthesis of Example 7 is based on Example 1, with... Z7 replace Z6 Replace with (5-methyl-1H-indazol-4-yl)boronic acid Z2 The title compound was obtained. 7 .

[0300] The compound in Example 7 was purified by preparative column chromatography under the following conditions:

[0301]

[0302]

[0303] Obtaining the reverse isomer 8(2mg) and the deactivated isomer 9 (2.2mg).

[0304] Transtransfer isomer 8: retention time 45 min, LC-MS: m / z 523.2 (M+H) + Transisomer 9: retention time 42 min, LC-MS: m / z 523.2 (M+H) + .

[0305] Examples 10, 11 and 12

[0306]

[0307] The synthesis of Example 10 is based on Example 1, with... Z7 replace Z6 ,use Z4 replace Z2 The title compound was obtained. 10 .

[0308] The compound in Example 10 was purified by preparative column chromatography under the following conditions:

[0309]

[0310] Obtaining the reverse isomer 11 (2.4 mg) and the transisomer 12 (4.9mg).

[0311] Transisomer 11: retention time 35 min, LC-MS: m / z 577.13 (M+H) + Restricted transisomer 12: retention time 32 min, LC-MS: m / z 577.13 (M+H) + .

[0312] Example 13

[0313]

[0314] Step 1:

[0315] At room temperature, Z7 (300mg) Z5(756 mg), methanesulfonic acid (2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (101 mg), copper oxide (139 mg), and cesium fluoride (176 mg) were dissolved in DMF (15 mL). The mixture was purged with argon five times, and the mixture was heated to 80 °C and stirred for 15 h under argon protection. After the reaction was complete, the reaction solution was poured into ice water (100 mL), extracted with ethyl acetate (3 x 30 mL), and the organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain... 2a (125mg).

[0316] Step 2

[0317] Referring to steps 2 and 3 in Example 1, the title compound was obtained. 13 .

[0318] Examples 14 and 15

[0319]

[0320] Example 13 The compound was purified by preparative column chromatography to obtain the trans-restricted isomer. 14 and the inhibited isomer 15 .

[0321] Example 16

[0322]

[0323] Step 1:

[0324] At room temperature, Z7 (1g) Z8 3.8 g of methanesulfonic acid (2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (200 mg), copper oxide (500 mg), and cesium fluoride (500 mg) were dissolved in DMF (100 ml). The mixture was purged with argon five times, and the mixture was heated to 80 °C and stirred for 15 h under argon protection. After the reaction was complete, the reaction solution was poured into ice water (1000 ml) and extracted with ethyl acetate (3 x 200 ml). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain... 3a (525mg).

[0325] Step 2:

[0326] At room temperature, 3a500 mg of N-iodosuccinimide (NIS, 720 mg) was dissolved in acetonitrile (50 ml), and the reaction was carried out at 50 °C for 5 h. After the reaction was completed, the reaction solution was added to a saturated sodium thiosulfate solution (500 ml), extracted with ethyl acetate (3 x 150 ml), the organic phase was collected, and the crude product was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain... 3b (496mg).

[0327] Step 3:

[0328] At room temperature, 3b 490 mg of fluorosulfonyl difluoroacetate (2.6 g) and 1.2 g of cuprous iodide were dissolved in 15 ml of N,N-dimethylacetamide under argon protection and the mixture was heated to 90 °C for 18 h. After the reaction was complete, the reaction solution was added to 150 ml of water and extracted with ethyl acetate (3 x 50 ml). The organic phase was collected, washed with saturated brine (2 x 50 ml), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain... 3c (376mg).

[0329] Step 4

[0330] The title compound was prepared by referring to steps 2 and 3 in Example 1. 16 .

[0331] Examples 17 and 18

[0332]

[0333] The synthesis of Example 16 is based on Example 1, using... Z6 replace Z2 The title compound was obtained. 16 .

[0334] Example 16 The compound was purified by preparative column chromatography to obtain the trans-restricted isomer. 17 and the inhibited isomer 18 .

[0335] Experimental Example 1: In vitro guanine nucleotide exchange inhibitory activity test

[0336] 1. Reagents: His-KRAS G12C (1-169); SOS1 cat (564-1049); Anti-6HIS-Cryptate (purchased from Cisbio); EDA-GTP-DY-647P1 (purchased from Jena Bioscience).

[0337] 2. Prepare buffer solution :

[0338] 1) Analysis buffer: HEPES pH 7.4, NaCl, MgCl2, DTT, BSA, Igepal

[0339] 2) KRAS G12C Working solution: Prepare a solution containing 100 nM His-KRAS using analysis buffer. G12C KRAS and 2nM Anti-6HIS-Cryptate G12C working fluid

[0340] 3) SOS1 cat Working solution: Prepare a solution containing 20 nM SOS1 using analytical buffer. cat SOS1 with 200nM EDA-GTP-DY-647P1 cat working fluid

[0341] 4) Blank control working solution: Prepare a blank control solution containing 2 nM Anti-6HIS-Cryptate using analytical buffer.

[0342] 3. Testing process:

[0343] The entire experiment was conducted at room temperature. Using black-background 384-well plates, 5 μL of KRAS was added to each well in both the experimental and negative control groups. G12C The working solution was added, and simultaneously, 5 μL of blank control working solution was added to each well of the blank control group, and incubated at room temperature for 10 min. Then, using an ultra-micropipette, compounds with an initial concentration of 20 μM, diluted 1:4 in 11 steps, were added to the experimental group, and incubated at room temperature for 30 min. Finally, 5 μL of SOS1 was added to each well. cat After incubating the working solution at room temperature for 10 min, the signal values ​​at 665 nm / 620 nm were detected using a PerkinElmerEnvision HTS multi-label reader. The inhibition rate was calculated as follows: Inhibition rate (%) = (Negative control group average - Experimental group average) / (Negative control group average - Blank group average) × 100%. A four-parameter logarithm of compound concentration was plotted on the x-axis, and the inhibition rate on the y-axis. The IC50 was calculated using a four-parameter logarithm model to fit the curve. 50 value.

[0344] The relevant test results of some of the compounds in the embodiments of this application are shown in Table 1.

[0345] Test Example 2 NCI-H358 (Kras) G12C Mutant cell proliferation inhibition activity test

[0346] NCI-H358 cells (Kras) in good exponential growth phase were harvested. G12C(Mutant), collect cells into centrifuge tubes, centrifuge at 1000 rpm for 5 min using a low-speed benchtop centrifuge, discard the supernatant, and resuspend the cells in 5 mL of complete culture medium (RPMI basal medium + 10% fetal bovine serum (FBS)) using a pipette. Count the cells using a cell counter, dilute the complete culture medium, and adjust the cell density to 6 × 10⁶ cells / mL. 4 Cells / mL were added to adjust the FBS concentration to 5% and the cell density to 3 × 10⁶ cells / mL. 4 Cells were seeded at a rate of 100 μL / well using a multichannel pipette and incubated in a cell culture incubator at 37°C with 5% CO2 saturated humidity. After 24 h of culture, compounds were added using an ultra-micro pipette to achieve a final concentration of 5000 nM - 0.31 nM, with two replicates for each concentration. Cells without the compound served as a negative control. After 72 h, CCK-8 (Beijing Tongren Chemical, CK04) was added at 10 μL / well. One hour later, the absorbance was measured at 450 nm using an Envision microplate reader, and the inhibition rate was calculated. Inhibition rate (%) = (Negative control average - Experimental group average) / (Negative control average - Blank group average) × 100%. The four parameters were analyzed: the logarithm of compound concentration on the x-axis and the inhibition rate on the y-axis. A dose-response curve was fitted, and the IC50 was calculated. 50 .

[0347] The relevant activity test results of some of the compounds in the embodiments of this application are shown in Table 1.

[0348] Experimental Example 3: NCI-H358 cells (Kras) G12C Assay for inhibiting phosphorylation of mutant ERK protein

[0349] NCI-H358 cells (Kras) in good exponential growth phase were harvested. G12C (Mutant), collect cells into centrifuge tubes, centrifuge at 1000 rpm for 5 min using a low-speed benchtop centrifuge, discard the supernatant, and resuspend the cells in 5 mL of complete culture medium (RPMI basal medium + 10% FBS) using a pipette. Count the cells using a cell counter, dilute the complete culture medium, and adjust the cell density to 3 × 10⁶ cells / mL. 5 Cells / mL were added to adjust the FBS concentration to 5% and the cell density to 1.5 × 10⁶ cells / mL. 5The cells were seeded at a rate of 40 μL / well using a multichannel pipette and incubated in a cell culture incubator at 37°C with 5% CO2 saturated humidity. After 24 h of culture, compounds were added using an ultra-micro pipette to achieve a final concentration of 5000 nM - 0.32 nM, with two replicates for each concentration. A control was also included. After 1 hour, the culture medium was discarded, and 40 μL of 4% paraformaldehyde was added to each well. After incubation at room temperature for 20 min, 40 μL of methanol was added to each well, and incubation was continued at room temperature for 10 min. The cells were then washed with PBST. 20 μL of 5% BSA blocking buffer was added to each well, and blocking was performed at room temperature for 1 h. After blocking, the blocking buffer was discarded, and 20 μL of a mixture of pERK antibody (CST, 9101) and GAPDH antibody (R&D, MAB5718) was added to each well. The cells were incubated overnight at 4°C and washed with PBST. Add 20 μL of a mixture of 800 nm and 680 nm fluorescent secondary antibodies (CST, 5151) to each well, incubate at room temperature in the dark for 45 min, and wash with PBST. Scan with a multispectral laser imager, plot the logarithm of compound concentration on the x-axis and the inhibition rate on the y-axis, perform four-parameter analysis, fit a dose-response curve, and calculate EC. 50 .

[0350] Table 1: Results of Compound Activity Tests

[0351]

[0352] Note: A represents IC. 50 ≤50nM;

[0353] B represents 50nM < IC 50 (EC 50 ≤150nM;

[0354] C represents 150nM < IC 50 ≤500nM;

[0355] D represents 500nM < IC 50 ≤999nM;

[0356] — This indicates that no test was conducted.

Claims

1. A compound of formula (Ic), its stereoisomers, or a pharmaceutically acceptable salt thereof, in, X is selected from CR X ; Y is selected from CR Y ; Z is selected from CR Z ; R X R Y R Z Each is independently selected from H, F, Cl, or Br; Selected from ; R 2 Selected from -C(O)C(R) 2a ) C(R 2b )2; R 2a Selected from H or F; Each R 2b Independently selected from H, or dimethylaminomethyl; R 4 Selected from H; Ring B is selected from benzothiazolyl or benzopyrazolel; Each R 5 Independently selected from halogens, -NH2, or C 1-6 alkyl; n is selected from 0, 1, 2, 3, or 4.

2. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R Y Selected from H;R X R Z Each is independently selected from H, F, Cl, or Br.

3. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R 2b Selected independently from H.

4. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R 2 Selected from the following groups: , ,or .

5. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R 2 Selected from the following groups: ,or .

6. The compound of formula (I) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R 5 It is independently selected from -F, -Cl, -NH2, methyl, or ethyl.

7. The compound of formula (I) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R 5 It is independently selected from -F, -Cl, -NH2, or methyl.

8. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Ring B is selected from , , , , , , , , , ,or .

9. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Ring B is selected from , , ,or .

10. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from the compound of formula (IIc), its stereoisomers, or pharmaceutically acceptable salts thereof. ， in, R 1 R 2 R 4 R 5 X, Y, Z, m, n, A, and B are as defined in claim 1.

11. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from the compound of formula (III), its stereoisomers, or pharmaceutically acceptable salts thereof. ， in, R 1 R 2 R 5 R X m, n, A, and B as defined in claim 1; R Z Selected from F, Cl, or Br.

12. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from the compound of formula (IV), its stereoisomers, or pharmaceutically acceptable salts thereof. ， in, R 1 R 2 R 5 m, n, and B are as defined in claim 1; R X R Z Each is independently selected from F or Cl.

13. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from the compound of formula (IVa), its stereoisomers, or pharmaceutically acceptable salts thereof. ， in, R 1 R 2 R 5 R X R Z m, n and B are as defined in claim 1.

14. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from the following compounds or pharmaceutically acceptable salts thereof: ， ， ， 。 15. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from the following compounds or pharmaceutically acceptable salts thereof: ， ， ， 。 16. The compound of formula (Ic) according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from the following compounds or pharmaceutically acceptable salts thereof: ， ， ， ， ， ， ， 。 17. A pharmaceutical composition comprising a compound of formula (Ic) according to any one of claims 1-16, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

18. The compound of formula (Ic) according to any one of claims 1-16, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17, in the preparation of a treatment for Kras G12C Uses in medications for related diseases.

19. The use according to claim 18, wherein, The Kras G12C The related disease is cancer.

20. The use according to claim 19, wherein, The cancer in question is lung cancer.

21. The use according to claim 19, wherein, The cancer in question is non-small cell lung cancer.

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