Bicyclic macrocycles as next-generation egfr inhibitors

Abstract

The present application provides a kind of double macrocyclic compound as a new generation of EGFR inhibitor, it is compound or its pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer, the compound shown in the present application shows about 500 nM-100 nM (IC 50 ) biological activity in EGFR mutant cell (such as LR / CS or D / TM / CS) proliferation activity inhibition test.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to bimacrocyclic compounds as EGFR inhibitors. Background Technology

[0002] Lung cancer is one of the most common malignant tumors, and it is divided into two types: small cell lung cancer and non-small cell lung cancer (NSCLC). Non-small cell lung cancer accounts for about 85% of all lung cancers, and epidermal growth factor receptor (EGFR) is the most common driver gene in non-small cell lung cancer.

[0003] EGFR is a transmembrane glycoprotein belonging to the ErbB family of tyrosine kinase receptors. EGFR is abnormally activated by various mechanisms, such as receptor overexpression, mutation, ligand-dependent receptor dimerization, and ligand-independent activation. Sustained activation of its kinase activity initiates downstream signaling pathways for cell proliferation, differentiation, and survival. Small molecule inhibitors of EGFR kinase can inhibit tyrosine kinase activation, thereby suppressing tumor cell proliferation and promoting tumor cell apoptosis, making it a hot research area in lung cancer development.

[0004] Osimertinib is a drug developed to target EGFR (del19 or L858R) mutations that are resistant to first- and second-generation drugs, often accompanied by the T790M mutation. It has shown significant clinical efficacy, but resistance can develop with continued treatment. In 2015 (Nature Medicine, 2015, 21, 560–562), data on resistance in 15 patients taking osimertinib were first reported, with the EGFR C797S mutation being one of the main mechanisms leading to osimertinib resistance, accounting for approximately 40%. Furthermore, recent literature reports that 22-25% of patients who develop resistance after second-line osimertinib treatment have the C797S mutation (Nature Cancer, 2021, 377-391).

[0005] In addition to C797S, there are many other EGFR mutation types. Therefore, developing EGFR inhibitors that can overcome a wider range of drug resistance mutations and have high brain penetration properties will solve an urgent clinical need. Summary of the Invention

[0006] In this invention, we used major clinically observed mutation types, including del19, L858R, del19 / T790M, L858R / T790M, del19 / C797S, L858R / C797S, del19 / T790M / C797S, L858R / T790M / C797S, and EGFRwt, to conduct cellular-level evaluations and validate them on constructed Ba / F3 cells. Ultimately, we discovered a series of novel chemical entities with strong biological activity. Furthermore, they exhibited weak inhibition against wild-type, demonstrating high selectivity and safety.

[0007] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0008] (I)

[0009] in,

[0010] Ring A is selected from 5-10 membered heteroaryl, phenyl, or 5-12 membered monocyclic heterocyclic or 5-12 membered bicyclic heterocyclic;

[0011] Ring B is selected from 5-10 membered heteroaryl, phenyl, or 5-12 membered monocyclic heterocyclic or 5-12 membered bicyclic heterocyclic;

[0012] X1 can be independently selected from self-bonds, -O-, -N-, -OCH2-, -CH2O-, -S-, -CH2-, -CH2CH2 or -N(R) a )-;

[0013] X2 can be independently selected from self-bonds, -O-, -S-, -N-, -CH2-, -NHCH2-, -CH2NH-, -CH2CH2- or -N(R) a );

[0014] X3 is selected from N, CH, or CF;

[0015] R1 is independently chosen from H and -LC. 1-6 Alkyl, -L-deuterated C 1-6 Alkyl, -L-halogenated C 1-6 Alkyl, -LC 1-6 Alkoxy, -LC 3-7 Cycloalkyl or -L-4-12-membered heterocyclic group, wherein R1 may optionally be halogenated, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substitution;

[0016] R2 is independently chosen from H, halogen, -LC.1-6 Alkyl, -L-deuterated C 1-6 Alkyl, -L-halogenated C 1-6 Alkyl, -OLR a -L-OR a -LN(R) a R b -LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic group, -L-CH2-N(R) a R b R2 can be optionally replaced by one, two, or three halogens, C, or -L-CH2- (4-6 membered heterocyclic group). 1-6 Alkyl, CN, NH2, -SR a -S(O)2R a SF5, -S(O)(=N)R a C 1-6 Alkoxy or C 3-7 Cycloalkyl substitution;

[0017] R3 can be independently selected from its self-bond, H, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic group, C(=O), S(O)2, C(=O)(NR) a R3 may optionally be converted to halogens, C, or -C(=O)O-. 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substitution;

[0018] R3 forms a 6-20 member heterocyclic group with ring B, and the heterocyclic group may optionally be further reacted with R w replace;

[0019] W1 can be independently selected from self-bonds, O, -OCH2, -CH2O-, S, S(O)2, C 1-6 Alkyl, C 1-6 Alkylene, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic groups or -N(R) a );

[0020] W2 independently selects self-bonds, O, -OCH2, -CH2O-, S, S(O)2, C 1-6 Alkyl, C 1-6Alkylene, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic groups or -N(R) a );

[0021] R4 is independently chosen from H and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -LC 3-7 Cycloalkyl or -L-4-12-membered heterocyclic groups;

[0022] R5 is independently selected from H and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -LC 3-7 Cycloalkyl or -L-4-12-membered heterocyclic group; R5 may optionally form a 3-6-membered cycloalkyl or 4-12-membered heterocyclic group with R4, wherein the cycloalkyl or heterocyclic group may optionally be further reacted with one, two or three halogens, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substitution;

[0023] R6 is independently selected from H and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -LC 3-7 Cycloalkyl or -L-4-12-membered heterocyclic groups;

[0024] R7 can be independently selected from H and C. 1-6 Alkyl or halogen;

[0025] R8 is independently selected from H and C. 1-6 Alkyl or halogen;

[0026] L can be independently selected as a self-key, C 1-6 Alkyl, C 1-6 Alkylene, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, -N(Me)-C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(O)2-C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 2-6 Ethyne group;

[0027] R w Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, CN, -OH, -OLR a -L-OR a S(O)2, S(O)(=NR a ), -LN(R a R b ), halogen, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 3-7 cycloalkyl or 4-8 membered heterocyclic groups;

[0028] R a Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, CN, -C(O)NH2, Halogenated C 1-6 Alkyl or C 3-7 cycloalkyl;

[0029] R b Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, CN, -C(O)NH2, Halogenated C 1-6 Alkyl or C 3-7 cycloalkyl;

[0030] m is selected from 0, 1, 2, or 3;

[0031] n is selected from 0, 1, 2, or 3;

[0032] p is selected from 0, 1, 2, or 3;

[0033] q is selected from 0, 1, 2 or 3.

[0034] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and optionally a pharmaceutically acceptable excipient.

[0035] In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present invention and pharmaceutically acceptable excipients, and further comprising other therapeutic agents.

[0036] In another aspect, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for treating and / or preventing EGFR kinase-mediated diseases.

[0037] In another aspect, the present invention provides a method for treating and / or preventing EGFR kinase-mediated diseases in a subject, comprising administering the subject a compound or composition of the present invention.

[0038] In another aspect, the present invention provides compounds or compositions thereof for the treatment and / or prevention of EGFR kinase-mediated diseases.

[0039] In a specific implementation, the diseases treated by the present invention include cancers selected from the following: lung cancer (including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lung adenocarcinoma, and lung squamous cell carcinoma).

[0040] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed embodiments, examples and claims.

[0041] definition

[0042] Chemical definition

[0043] The definitions of specific functional groups and chemical terms are described in more detail below.

[0044] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0045] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C 1-2 Alkyl groups are preferred. C 1-6Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0046] “C 1-6 "Alkylene" refers to the removal of C 1-6 The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylenes are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0047] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0048] Therefore, "C" 1-6"Halogenated alkyl" refers to the above "C 1-6 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Halogenated alkyl groups. Exemplary alkyl halogenated groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The alkyl halogenated group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0049] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-10 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl and C 3-5 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkyl groups. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the linkage is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. The cycloalkyl group may optionally be substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0050] "3-10 membered heterocyclic groups" refer to groups with a 3- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon or nitrogen atom, provided that the valence allows. In some embodiments, a 4-9 membered heterocyclic group is preferred, which is a 4-9 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 5-8 membered heterocyclic group is preferred, which is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3-8 membered heterocyclic group is preferred, which is a 3-8 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; a 3-7 membered heterocyclic group is preferred, which is a 3-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 4-7 membered heterocyclic group is preferred, which is a 4-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 4-6 membered heterocyclic group is preferred, which is a 4-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; and a 5-6 membered heterocyclic group is preferred, which is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the cycloalkyl ring, or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, disulfuranyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxasulfuranyl, and thioheptanyl.Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclic group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0051] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0052] "5-10-membered heteroaryl" refers to a group comprising a 4n+2 aromatic ring system of a 5-10-membered monocyclic or bicyclic ring (e.g., having 6 or 10 shared π electrons arranged in a ring) having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-9-membered heteroaryl is preferred, which is a 4n+2 aromatic ring system of a 5-9-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5-6 membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirmonoheptatrienyl, oxadiazinyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0053] The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0054] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -OC(=NR) bb )R aa -OC(=NR) bb OR aa -C(=NR) bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa -NR bb SO2R aa -SO2N(R) bb )2、-SO2R aa -SO2OR aa -OSO2R aa -S(=O)R aa -OS(=O)R aa 、-Si(R aa3. -OSi(R) aa 3. -C(=S)N(R) bb )2、-C(=O)SR aa -C(=S)SR aa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0055] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or =NOR cc replace;

[0056] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0057] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0058] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0059] R ddEach is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2, 、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2Ree -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0060] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0061] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0062] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl group), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3、-C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0063] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0064] Other definitions

[0065] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0066] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0067] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0068] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0069] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Attached Figure Description

[0070] Figure 1 The ¹H-NMR spectrum of compound P1;

[0071] Figure 2 The ¹H-NMR spectrum of compound P2;

[0072] Figure 3 The image shows the ¹H-NMR spectrum of compound P3. Detailed Implementation

[0073] In this document, “compounds of the present invention” refers to compounds of formula (I) (including sub-formulas, such as formula (II), (II-1), (II-2), (II-3), etc.) or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof, and mixtures thereof.

[0074] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0075] (I)

[0076] in,

[0077] Ring A is selected from 5-10 membered heteroaryl, phenyl, or 5-12 membered monocyclic heterocyclic or 5-12 membered bicyclic heterocyclic;

[0078] Ring B is selected from 5-10 membered heteroaryl, phenyl, or 5-12 membered monocyclic heterocyclic or 5-12 membered bicyclic heterocyclic;

[0079] X1 can be independently selected from self-bonds, -O-, -N-, -OCH2-, -CH2O-, -S-, -CH2-, -CH2CH2 or -N(R) a )-;

[0080] X2 can be independently selected from self-bonds, -O-, -S-, -N-, -CH2-, -NHCH2-, -CH2NH-, -CH2CH2- or -N(R) a );

[0081] X3 is selected from N, CH, or CF;

[0082] R1 is independently chosen from H and -LC. 1-6 Alkyl, -L-deuterated C 1-6 Alkyl, -L-halogenated C 1-6 Alkyl, -LC 1-6 Alkoxy, -LC 3-7 Cycloalkyl or -L-4-12-membered heterocyclic group, wherein R1 may optionally be halogenated, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substitution;

[0083] R2 is independently chosen from H, halogen, -LC. 1-6 Alkyl, -L-deuterated C 1-6 Alkyl, -L-halogenated C 1-6 Alkyl, -OLR a -L-OR a -LN(R) a Rb -LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic group, -L-CH2-N(R) a R b R2 can be optionally replaced by one, two, or three halogens, C, or -L-CH2- (4-6 membered heterocyclic group). 1-6 Alkyl, CN, NH2, -SR a -S(O)2R a SF5, -S(O)(=N)R a C 1-6 Alkoxy or C 3-7 Cycloalkyl substitution;

[0084] R3 can be independently selected from its self-bond, H, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic group, C(=O), S(O)2, C(=O)(NR) a R3 may optionally be converted to halogens, C, or -C(=O)O-. 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substitution;

[0085] R3 forms a 6-20 member heterocyclic group with ring B, and the heterocyclic group may optionally be further reacted with R w replace;

[0086] W1 can be independently selected from self-bonds, O, -OCH2, -CH2O-, S, S(O)2, C 1-6 Alkyl, C 1-6 Alkylene, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic groups or -N(R) a );

[0087] W2 independently selects self-bonds, O, -OCH2, -CH2O-, S, S(O)2, C 1-6 Alkyl, C 1-6 Alkylene, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic groups or -N(R) a );

[0088] R4 is independently chosen from H and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -LC 3-7 Cycloalkyl or -L-4-12-membered heterocyclic groups;

[0089] R5 is independently selected from H and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -LC 3-7 Cycloalkyl or -L-4-12-membered heterocyclic group; R5 may optionally form a 3-6-membered cycloalkyl or 4-12-membered heterocyclic group with R4, wherein the cycloalkyl or heterocyclic group may optionally be further reacted with one, two or three halogens, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substitution;

[0090] R6 is independently selected from H and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -LC 3-7 Cycloalkyl or -L-4-12-membered heterocyclic groups;

[0091] R7 can be independently selected from H and C. 1-6 Alkyl or halogen;

[0092] R8 is independently selected from H and C. 1-6 Alkyl or halogen;

[0093] L can be independently selected as a self-key, C 1-6 Alkyl, C 1-6 Alkylene, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, -N(Me)-C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 2-6 Ethyne group;

[0094] R w Each can be independently selected from H and C. 1-6Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, CN, -OH, -OLR a -L-OR a S(O)2, S(O)(=NR a ), -LN(R a R b ), halogen, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 3-7 cycloalkyl or 4-8 membered heterocyclic groups;

[0095] R a Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, CN, -C(O)NH2, Halogenated C 1-6 Alkyl or C 3-7 cycloalkyl;

[0096] R b Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, CN, -C(O)NH2, Halogenated C 1-6 Alkyl or C 3-7 cycloalkyl;

[0097] m is selected from 0, 1, 2, or 3;

[0098] n is selected from 0, 1, 2, or 3;

[0099] p is selected from 0, 1, 2, or 3;

[0100] q is selected from 0, 1, 2 or 3.

[0101] In another, more specific embodiment, the present invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0102] (II)

[0103] in,

[0104] Ring B is selected from 5-10 membered heteroaryl, phenyl, or 5-12 membered monocyclic heterocyclic or 5-12 membered bicyclic heterocyclic;

[0105] R 1a Each can be independently selected from H and -C. 1-6 Alkyl, -deuterated C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl group, -CH2-OMe, -C 3-7Cycloalkyl or 4-12 membered heterocyclic groups;

[0106] R 1b Each can be independently selected from H and -C. 1-6 Alkyl, -deuterated C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-7 Cycloalkyl or 4-12 membered heterocyclic groups;

[0107] R2 is independently chosen from H, halogen, -LC. 1-6 Alkyl, -L-deuterated C 1-6 Alkyl, -L-halogenated C 1-6 Alkyl, -OLR a -L-OR a -LN(R) a R b -LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic group, -L-CH2-N(R) a R b R2 can be optionally replaced by one, two, or three halogens, C, or -L-CH2- (4-6 membered heterocyclic group). 1-6 Alkyl, CN, NH2, -SR a -S(O)2R a SF5, -S(O)(=N)R a C 1-6 Alkoxy or C 3-7 Cycloalkyl substitution;

[0108] W1 can be independently selected from self-bonds, O, -OCH2, -CH2O-, S, S(O)2, C 1-6 Alkyl, C 1-6 Alkylene, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic groups or -N(R) a );

[0109] W2 independently selects self-bonds, O, -OCH2, -CH2O-, S, S(O)2, C 1-6 Alkyl, C 1-6 Alkylene, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic groups or -N(R) a );

[0110] R4 is independently chosen from H and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -LC 3-7 Cycloalkyl or -L-4-12-membered heterocyclic groups;

[0111] R5 is independently selected from H and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -LC 3-7 Cycloalkyl or -L-4-12-membered heterocyclic group; R5 may optionally form a 3-6-membered cycloalkyl or 4-12-membered heterocyclic group with R4, wherein the cycloalkyl or heterocyclic group may optionally be further reacted with one, two or three halogens, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substitution;

[0112] R6 is independently selected from H and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -LC 3-7 Cycloalkyl or -L-4-12-membered heterocyclic groups;

[0113] R7 can be independently selected from H or F;

[0114] R8 can be independently selected from H or F;

[0115] L can be independently selected as a self-key, C 1-6 Alkyl, C 1-6 Alkylene, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, -N(Me)-C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 2-6 Ethyne group;

[0116] R w Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkylene, C1-6 Alkoxy, CN, -OH, -OLR a -L-OR a S(O)2, S(O)(=NR a ), -LN(R a R b ), halogen, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 3-7 cycloalkyl or 4-8 membered heterocyclic groups;

[0117] R a Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, CN, -C(O)NH2, Halogenated C 1-6 Alkyl or C 3-7 cycloalkyl;

[0118] R b Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, CN, -C(O)NH2, Halogenated C 1-6 Alkyl or C 3-7 cycloalkyl;

[0119] n is selected from 0, 1, 2, or 3;

[0120] p is selected from 0, 1, 2, or 3;

[0121] q is selected from 0, 1, 2 or 3.

[0122] In another, more specific embodiment, the present invention relates to a compound of formula (II-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0123] (Ⅱ-1)

[0124] in,

[0125] Ring B is selected from 5-10 membered heteroaryl, phenyl, or 5-12 membered monocyclic heterocyclic or 5-12 membered bicyclic heterocyclic;

[0126] R 1a Each can be independently selected from H and -C. 1-6 Alkyl, -deuterated C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl group, -CH2-OMe, -C 3-7 Cycloalkyl or 4-12 membered heterocyclic groups;

[0127] R 1bEach can be independently selected from H and -C. 1-6 Alkyl, -deuterated C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-7 Cycloalkyl or 4-12 membered heterocyclic groups;

[0128] R2 is independently chosen from H, halogen, -LC. 1-6 Alkyl, -L-deuterated C 1-6 Alkyl, -L-halogenated C 1-6 Alkyl, -OLR a -L-OR a -LN(R) a R b -LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic group, -L-CH2-N(R) a R b R2 can be optionally replaced by one, two, or three halogens, C, or -L-CH2- (4-6 membered heterocyclic group). 1-6 Alkyl, CN, NH2, -SR a -S(O)2R a SF5, -S(O)(=N)R a C 1-6 Alkoxy or C 3-7 Cycloalkyl substitution;

[0129] R4 is independently chosen from H and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -LC 3-7 Cycloalkyl or -L-4-12-membered heterocyclic groups;

[0130] L can be independently selected as a self-key, C 1-6 Alkyl, C 1-6 Alkylene, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, -N(Me)-C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 2-6 Ethyne group;

[0131] Rw Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, CN, -OH, -OLR a -L-OR a S(O)2, S(O)(=NR a ), -LN(R a R b ), halogen, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 3-7 cycloalkyl or 4-8 membered heterocyclic groups;

[0132] R a Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, CN, -C(O)NH2, Halogenated C 1-6 Alkyl or C 3-7 cycloalkyl;

[0133] R b Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, CN, -C(O)NH2, Halogenated C 1-6 Alkyl or C 3-7 cycloalkyl;

[0134] n is selected from 0, 1, 2 or 3.

[0135] In another, more specific embodiment, the present invention relates to a compound of formula (II-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0136] (Ⅱ-2)

[0137] in,

[0138] R 1b Each can be independently selected from H and -C. 1-6 Alkyl, -deuterated C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-7 Cycloalkyl or 4-12 membered heterocyclic groups;

[0139] R2 atoms are independently chosen from H, halogen, and -C. 1-6 Alkyl, -deuterated C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -OLR a -L-ORa -LN(R) a R b -LC 3-7 Cycloalkyl, -L-4-12-membered heterocyclic group, -L-CH2-N(R) a R b R2 can be optionally replaced by one, two, or three halogens or C. 1-6 Alkyl substitution;

[0140] R4 is selected from H, methyl, deuterated methyl, trifluoromethyl, methoxy, cyclopropyl, or oxecyclobutyl;

[0141] L can be independently selected as a self-key, C 1-6 Alkyl, C 1-6 Alkylene, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, -N(Me)-C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 2-6 Ethyne group;

[0142] R w Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, CN, -OH, -OLR a -L-OR a S(O)2, S(O)(=NR a ), -LN(R a R b ), halogen, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 3-7 cycloalkyl or 4-8 membered heterocyclic groups;

[0143] R a Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, CN, -C(O)NH2, Halogenated C 1-6 Alkyl or C 3-7 cycloalkyl;

[0144] R b Each can be independently selected from H and C. 1-6Alkyl, C 1-6 Alkoxy, CN, -C(O)NH2, Halogenated C 1-6 Alkyl or C 3-7 Cycloalkyl.

[0145] In another, more specific embodiment, the present invention relates to compounds of formula (II-3), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof:

[0146] (Ⅱ-3)

[0147] in,

[0148] R2 is selected from H, F, Cl, methyl, ethyl, deuterated ethyl, trifluoroethyl, -OMe, -OEt, -OCD2CD3, -OCD3. , or R2 can optionally be converted by one, two, or three halogens, C 1-6 Alkyl, CN, NH2, -S(O)2Me, SF5, -S(O)(=N)Me, methoxy or cyclopropyl substitution;

[0149] R4 is selected from H, methyl, deuterated methyl, trifluoromethyl, methoxy, cyclopropyl, or oxecyclobutyl;

[0150] R w Selected from H, methyl, methoxy, ethoxy, -CN, -OH, -CH2OH, -CH2CH2OH, -S(O)(=NMe), -CH2-N(Me)2, F, -CF3 or cyclopropyl.

[0151] In another, more specific embodiment, the invention relates to a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, selected from:

[0152] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0153] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0154] The compounds of this invention may also exist as tautomers. A compound is not limited to any particular tautomer, but is intended to encompass all tautomer forms.

[0155] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (A), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotopically labeled compounds of formula (A) of the present invention and their prodrugs can generally be prepared by using readily available isotopically labeled reagents instead of non-isotopically labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0156] Dosage

[0157] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0158] Example 1: Preparation of Key Intermediates

[0159] Synthesis of intermediate a1

[0160]

[0161] Step 1: Dissolve starting material a1-1 (21.5 g, 101.9 mmol) and potassium tert-butoxide (42.3 g, 306 mmol) in 300 mL of anhydrous tetrahydrofuran. Add iodine solution in tetrahydrofuran (38.8 g, 153 mmol, 100 mL) dropwise. React in an ice bath for 4 hours. LC-MS analysis confirms complete reaction, at which point the reaction is stopped. Add 300 mL of saturated sodium thiosulfate aqueous solution to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a yellow solid a1-2 (23 g), yield: 67%. LC-MS: ESI-MS (m / z): [M+H] + = 338.0 / 340.0.

[0162] 1 H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 2.83 (s, 3H).

[0163] Step 2: Under nitrogen protection, intermediate a1-2 (23 g, 68.2 mmol) and p-toluenesulfonic acid (2.34 g, 13.6 mmol) from the previous step were dissolved in 150 mL of toluene. 3,4-Dihydro-2H-pyran (14.3 g, 171 mmol) was added, and the mixture was heated to 90 °C and reacted for 3 hours. The reaction was stopped after LC-MS detection of completeness. 300 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (petroleum ether / ethyl acetate, 10 / 1) to give a yellow solid a1 (23 g), yield: 80%. LC-MS: ESI-MS (m / z): [M+H] + = 421.9 / 423.9.

[0164] 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 5.97 (dd, J = 1.8, 9.3 Hz,1H), 3.89 (br d, J = 11.6 Hz, 1H), 3.81 - 3.71 (m, 1H), 2.90 (s, 3H), 2.46 -2.30 (m, 1H), 2.15 - 1.97 (m, 2H), 1.81 - 1.68 (m, 1H), 1.54 - 1.34 (m, 2H).

[0165] Synthesis of intermediate a2

[0166]

[0167] Step 1: Under nitrogen protection, intermediate a1 (1.0 g, 2.38 mmol), starting material potassium vinylborate a2-1 (1.59 g, 11.9 mmol), and sodium carbonate (757 mg, 7.2 mmol) were dissolved in 30 mL of a mixed solution of 1,4-dioxane and water (v / v, 5 / 1). Catalyst [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (abbreviation: Pd(Dppf)Cl2) (176 mg, 0.24 mmol) was added, and the reaction was heated to 60 °C for 12 hours, after which the reaction was stopped. 100 mL of ice water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1) to give a yellow solid a2-2 (270 mg), yield: 35%. LC-MS: ESI-MS(m / z): [M+H] + = 322.2 / 324.2.

[0168] 1 H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 6.94 (dd, J = 11.4, 18.0 Hz,1H), 6.05 (d, J = 18.1 Hz, 1H), 5.84 (dd, J = 2.4, 9.3 Hz, 1H), 5.58 (d, J =11.6 Hz, 1H), 4.10 - 3.92 (m, 1H), 3.74 (dt, J = 2.8, 11.0 Hz, 1H), 2.97 (s,3H), 2.74 - 2.59 (m, 1H), 2.29 - 2.10 (m, 2H), 1.81 - 1.58 (m, 4H).

[0169] Step 2: Under nitrogen protection, intermediate a2-2 (270 mg, 0.84 mmol) and starting material a2-3 (111 mg, 1.0 mmol) from the previous step were dissolved in 8 mL of 1,4-dioxane. Catalyst [(2-di-tert-butylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (abbreviation: t-BuBrettPhos Pd G3) (72 mg, 0.084 mmol) and potassium carbonate (235 mg, 1.7 mmol) were added. The mixture was heated to 130 °C and reacted for 12 hours, after which the reaction was stopped. Add 50 mL of ice water to the mixture, extract with ethyl acetate, dry to anhydrous sodium sulfate, filter, concentrate, and separate the crude product by column chromatography (dichloromethane / methanol, 20 / 1) to give the target intermediate a2 (130 mg), yield: 44%. LC-MS: ESI-MS (m / z): [M+H] + = 354.3.

[0170] 1H NMR (400 MHz, CDCl3) δ 7.74 - 7.31 (m, 1H), 7.01 (dd, J = 11.5,17.9 Hz, 1H), 6.11 (br d, J = 17.9 Hz, 1H), 5.90 (br d, J = 7.6 Hz, 1H), 5.59(d, J = 11.7 Hz, 1H), 3.96 (br d, J = 11.6 Hz, 1H), 3.86 - 3.72 (m, 1H), 3.53(s, 3H), 3.07 - 2.90 (m, 3H), 2.44 (br s, 3H), 2.28 - 2.04 (m, 3H), 1.88 -1.76 (m, 1H), 1.72 - 1.64 (m, 2H).

[0171] Synthesis of intermediates a3 and a6

[0172]

[0173] Step 1: Under nitrogen protection, raw material a3-1 (500 mg, 1.58 mmol) and raw material a2-3 (210 mg, 1.90 mmol) were dissolved in 10 mL of 1,4-dioxane. Catalyst [(2-di-tert-butylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (abbreviation: t-BuBrettPhos Pd G3) (130 mg, 0.16 mmol) and potassium carbonate (440 mg, 3.16 mmol) were added. The mixture was heated to 115 °C and reacted for 16 hours. The reaction was then stopped and the mixture was filtered. Add 50 mL of ice water to the mixture, extract with ethyl acetate, dry to anhydrous sodium sulfate, filter, concentrate, and separate the crude product by column chromatography (dichloromethane / methanol, 15 / 1) to give intermediate a3-2 (300 mg), yield: 55%. LC-MS: ESI-MS (m / z): [M+H] + = 362.1.

[0174] Step 2: Under nitrogen protection, the intermediate a3-2 (150 mg, 0.41 mmol) and the starting material a3-3 (86 mg, 0.49 mmol) from the previous step were dissolved in 5 mL of anhydrous tetrahydrofuran, and triphenylphosphine was added. (220 mg, 0.82 mmol) was reacted at room temperature for 0.5 h. The reaction solution was cooled to 0 °C, and diisopropyl azodicarbonate (DIAD) (180 mg, 0.9 mmol) was added to the mixture. The mixture was reacted in an ice bath for 0.5 h, then heated to room temperature and reacted for another 1 h before stopping the reaction. 15 mL of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography (n-hexane / ethyl acetate, 1 / 4) to give intermediate a3 (100 mg), yield: 47%. LC-MS: ESI-MS (m / z): [M+H] + = 519.3.

[0175] Following the synthetic route of intermediate a3, and using similar starting materials / intermediates (such as intermediate a2), the following target compounds were synthesized:

[0176] Table 1: Structure and LC-MS of intermediate a6

[0177]

[0178] Synthesis of intermediate a4

[0179]

[0180] Step 1: Under nitrogen protection, intermediate a3-2 (2.0 g, 17.86 mmol) and starting material a3-3 (3.44 g, 19.64 mmol) were dissolved in 50 mL of anhydrous tetrahydrofuran, and triphenylphosphine was added. (9.37 g, 35.72 mmol) was reacted at room temperature for 0.5 h. The reaction solution was cooled to 0 °C, and diisopropyl azodicarbonate (DIAD) (7.27 g, 36.0 mmol) was added to the mixture. The mixture was reacted in an ice bath for 0.5 h, then heated to room temperature and reacted for another 2 h before stopping the reaction. 200 mL of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography (n-hexane / ethyl acetate, 1 / 3) to give intermediate a4-1 (2.5 g), yield: 52%. LC-MS: ESI-MS (m / z): [M+H] + = 270.3.

[0181] Step 2: Under nitrogen protection, intermediate a4-1 (2.3 g, 8.55 mmol) from the previous step was dissolved in 40 mL of acetonitrile. N-bromosuccinimide (abbreviation: NBS) (1.67 g, 9.40 mmol) was slowly added, and the reaction was carried out at room temperature for 4 hours. The reaction solution was cooled to 0°C, and 105 mL of ice water was added to the mixture. Extraction was performed with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (n-hexane / ethyl acetate, 1 / 4) to obtain intermediate a4 (1.5 g), yield: 51%. LC-MS: ESI-MS (m / z): [M+H] + = 348.2.

[0182] Synthesis of intermediate a5

[0183]

[0184] Step 1: Under nitrogen protection at 0°C, intermediate a4 (1.38 g, 3.96 mmol) and sodium hydride (NaH) (0.32 g, 7.92 mmol, 60%) were dissolved in 20 mL of anhydrous N-bromosuccinimide. Iodomethane (MeI) (0.84 g, 5.94 mmol) was added, and the reaction was stopped at room temperature for 2.5 hours. 100 mL of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography (Hex / EA, 3 / 1) to give intermediate a5-1 (0.8 g), yield: 56%. LC-MS: ESI-MS (m / z): [M+H] + = 362.0.

[0185] Step 2: Under nitrogen protection, intermediate a5-1 (740 mg, 2.04 mmol), triethylamine (620 mg, 6.12 mmol), and pinacolborane a5-2 (780 mg, 6.12 mmol) from the previous step were dissolved in 4 mL of 1,4-dioxane. The catalyst bis(cyanobenzene)palladium dichloride (abbreviation: PdCl2(MeCN)2) (53 mg, 0.2 mmol) and the ligand 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (abbreviation: Xphos) (97 mg, 0.2 mmol) were added. The mixture was heated to 110 °C and reacted for 2 hours. The reaction solution was then cooled to room temperature and filtered. The solvent in the filtrate was removed under reduced pressure. The crude product was separated by column chromatography (n-hexane / ethyl acetate, 4 / 1) to obtain intermediate a5 (0.7 g), yield: 84%. LC-MS: ESI-MS(m / z): [M+H] + = 410.3.

[0186] Synthesis of intermediates b1, b4, b7, b11

[0187]

[0188] Step 1: Under nitrogen protection, starting material b1-1 (6000 mg, 42.3 mmol) and potassium carbonate (5800 mg, 42 mmol) were dissolved in 50 mL of N-bromosuccinimide. Ethyl iodine (6600 mg, 42 mmol) was added, and the reaction was carried out at room temperature for 16 hours. The reaction was then stopped. 200 mL of ice water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate, 8 / 1) to give a pale yellow solid b1-2 (4.0 g), yield: 56%. LC-MS: ESI-MS (m / z): [M+H] + = 171.

[0189] 1 H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J =6.8 Hz, 3H), 3.81 (s, 3H), 4.11 (q, J = 7.2 Hz, 2H), 6.17-6.34 (m, 1H), 13.05 - 13.16 (m, 1H).

[0190] Step 2: Under nitrogen protection, intermediate b1-2 (1.5 g, 8.82 mmol) and starting material b1-3 (3.11 g, 17.6 mmol) from the previous step were dissolved in 40 mL of anhydrous tetrahydrofuran, and triphenylphosphine was added. (5.08 g, 19.4 mmol) was reacted at room temperature for 0.5 h. The reaction solution was cooled to 0 °C, and diisopropyl azodicarbonate (DIAD) (3.92 g, 19.4 mmol) was added to the mixture. The mixture was reacted in an ice bath for 0.5 h, then heated to room temperature and reacted for another 4 h before stopping the reaction. 150 mL of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography (dichloromethane / methanol, 20 / 1) to give intermediate b1-4 (2.5 g), yield: 86%. LC-MS: ESI-MS (m / z): [M+H] + = 329.

[0191] 1H NMR (400 MHz, CDCl3) δ 0.06 (s, 6H), 0.82 (s, 9H), 1.39 (t, J=7.2Hz, 3H), 3.85 (s, 3H), 3.89 (t, J = 5.6 Hz, 2H), 4.14-4.22 (m, 2H), 4.56 (t,J=5.6 Hz, 2H), 6.17 (s, 1H).

[0192] Step 3: Under nitrogen protection and in an ice bath, dissolve intermediate b1-4 (2.5 g, 7.62 mmol) from the previous step in 40 mL of anhydrous tetrahydrofuran, and slowly add lithium aluminum hydride. (319 mg, 8.4 mmol) was reacted in an ice bath for 2 hours. The mixture was then extracted with ethyl acetate (150 mL of ice water), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography (petroleum ether / ethyl acetate, 2 / 1) to give intermediate b1 (2.0 g), yield: 87%. LC-MS: ESI-MS (m / z): [M+H] + =301.

[0193] 1 H NMR (400 MHz, DMSO-d6) δ 0.08 (s, 6H), 0.79 (s, 9H), 1.25 (t, J=7.2Hz, 3H), 3.81 (t, J=5.6 Hz, 2H), 3.94-4.04 (m, 4H), 4.41 (d, J=5.6 Hz, 2H), 5.19 (t, J=5.6 Hz, 1H), 5.54 (s, 1H).

[0194] Following the synthetic route of intermediate b1, and using similar starting materials / intermediates, the following target compound was synthesized:

[0195] Table 2: Structure and LC-MS of intermediates b4, b7, and b11

[0196]

[0197] Synthesis of intermediates b2-b3, b8-b10

[0198]

[0199] Step 1: In an ice bath, intermediate b1 (2.0 g, 6.67 mmol) was dissolved in 20 mL of acetonitrile. NIS (1.5 g, 6.67 mmol) was slowly added, and the reaction was carried out at room temperature for 2 hours. The reaction was then stopped. 100 mL of ice water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1) to give an oily substance b2-1 (2.5 g), yield: 88%. LC-MS: ESI-MS (m / z): [M+H] + = 427.

[0200] 1 H NMR (400 MHz, CDCl3) δ 0.01 (s, 6H), 0.83 (s, 9H), 1.42 (t, J = 7.2Hz, 3H), 3.24 (t, J = 5.6 Hz, 1H), 3.92 (t, J = 4.8 Hz, 2H), 4.18 - 4.30 (m,4H), 4.59 (d, J=5.6 Hz, 2H).

[0201] Step 2: Under nitrogen protection and in an ice bath, dissolve intermediate b2-1 (2.5 g, 5.87 mmol) and triphenylphosphine (1.85 g, 7.0 mmol) from the previous step in 40 mL of anhydrous dichloromethane, and add carbon tetrabromide. (2.53 g, 7.6 mmol) was reacted at room temperature for 1 hour, then the reaction was stopped. 80 mL of ice water was added to the mixture, and the mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography (dichloromethane / methanol, 20 / 1) to give intermediate b2 (2.5 g), yield: 87%. LC-MS: ESI-MS (m / z): [M+H] + = 489 / 491.

[0202] Following the synthetic route of intermediate b2, and using similar starting materials / intermediates (such as intermediates b4, b7, b11, etc.), the following target compounds were synthesized:

[0203] Table 3: Structures and LC-MS results of intermediates b3, b8, b9, and b10

[0204] Synthesis of intermediate C1

[0205]

[0206] Step 1: In an ice bath, intermediate a6 (300 mg, 0.59 mmol) was dissolved in 2 mL of anhydrous N-bromosuccinimide. Sodium hydride (NaH) (35 mg, 0.89 mmol, 60%) was slowly added, and the mixture was stirred for 10 minutes. Then, intermediate b9 (310 mg, 0.59 mmol) was added, and the reaction was continued in an ice bath for 1 hour. The reaction was then stopped. 8 mL of ice water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to silica gel column chromatography (Hex / EA, 1 / 1) to give an oily substance c1 (300 mg), yield: 54%. LC-MS: ESI-MS (m / z): [M+H] + = 947.4.

[0207] Synthesis of intermediate C2

[0208]

[0209] Step 1: In an ice bath, intermediate B10 (6.0 g, 13.01 mmol) and starting material C2-1 (2.89 g, 15.61 mmol) were dissolved in 52 mL of dimethyl sulfoxide. A solution of potassium tert-butoxide (15.6 mL, 15.6 mmol) in tetrahydrofuran was slowly added. The mixture was stirred at room temperature for 1 hour, then the reaction was stopped. 200 mL of ice water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (Hex / EA, 8 / 1) to give an oily product C2-2 (7.0 g), yield: 95%. LC-MS: ESI-MS (m / z): [M+H] + = 566.2.

[0210] Step 2: In an ice bath, dissolve intermediate C2-2 (7.0 g, 12.38 mmol) from the previous step in a mixture of 58 mL acetone and water (v / v, 25 / 4). Slowly add potassium osmium tetroxide dihydrate (910 mg, 2.48 mmol) and N-methylmorpholine-N-oxide (NMO) (4.35 g, 37.14 mmol). React at room temperature for 1 hour, then stop the reaction. Add 20 mL of saturated sodium sulfite aqueous solution and 200 mL of ice water to the mixture. Extract three times with ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (n-hexane / tetrahydrofuran, 2 / 1) to obtain an oily substance C2-3 (6.0 g), yield: 81%. LC-MS: ESI-MS (m / z): [M+H] + = 600.1.

[0211] Step 3: In an ice bath, dissolve intermediate C2-3 (1.0 g, 1.67 mmol) from the previous step in 10 mL of tetrahydrofuran. Slowly add a tetrabutylammonium fluoride (2.18 g, 8.35 mmol, 1 M) solution in tetrahydrofuran and ethylenediamine (1.03 g, 17.14 mmol). Heat to 60 °C and react for 10 hours, then stop the reaction. Add 80 mL of ice water to the mixture, extract three times with ethyl acetate, combine the organic phases, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (n-hexane / tetrahydrofuran, 4 / 1) to give an oily substance C2-4 (430 mg), yield: 51%. LC-MS: ESI-MS (m / z): [M+H] + =470.0.

[0212] Step 4: Dissolve intermediate C2-4 (430 mg, 0.92 mmol) and imidazole (75 mg, 1.1 mmol) from the previous step in 10 mL of dichloromethane. Slowly add tert-butyldimethylchlorosilane (141 mg, 0.94 mmol), and react at 20°C for 2 hours. Stop the reaction. Add 30 mL of ice water to the mixture, extract three times with dichloromethane, combine the organic phases, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (n-hexane / ethyl acetate, 3 / 1) to give an oily substance C2-5 (450 mg), yield: 84%. LC-MS: ESI-MS (m / z): [M+H] + = 584.1.

[0213] Step 5: Under nitrogen protection and in an ice bath, dissolve intermediate C2-5 (450 mg, 0.77 mmol) and triphenylphosphine (606 mg, 2.31 mmol) in 15 mL of 2-methyltetrahydrofuran. Slowly add diisopropyl azodicarbonate (467 mg, 2.31 mmol, 1M), heat to 20°C, and react for 10 hours. Stop the reaction. Add 30 mL of ice water to the mixture, extract three times with dichloromethane, combine the organic phases, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (n-hexane / ethyl acetate, 20 / 1) to give intermediate C2 (350 mg), yield: 80%. LC-MS: ESI-MS (m / z): [M+H] + =566.2.

[0214] Synthesis of intermediates C3-C5

[0215]

[0216] Step 1: Under nitrogen protection and in an ice bath, intermediate C2 (500 mg, 0.88 mmol) and 2,6-dimethylpyridine (566 mg, 5.28 mmol) were dissolved in 12 mL of dichloromethane. Trimethylsilyltrifluoromethanesulfonate (TMSOTf) (782 mg, 3.52 mmol) was slowly added. The reaction was carried out at room temperature for 1 hour, and then stopped. 10 mL of ammonia and 30 mL of ice water were added to the reaction solution, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and removing the solvent under reduced pressure. The crude product was separated by thin-layer chromatography (TLC) (n-hexane / tetrahydrofuran, 1 / 1) to give intermediate C3 (350 mg), yield: 85%. LC-MS: ESI-MS (m / z): [M+H] + = 466.1.

[0217] 1 H NMR (400 MHz, CDCl3) δ 4.64 (s, 1H), 4.36-4.19 (m, 3H), 4.00 (d, J= 15.5 Hz, 1H), 3.90 (dd, J = 5.7, 10.3 Hz, 1H), 3.76 (d, J = 15.4 Hz, 1H), 2.97 (dd, J = 7.8, 14.1 Hz, 1H), 2.74 (ddd, J = 1.3, 8.3, 14.4 Hz, 1H), 1.86-1.76 (m, 1H), 1.73-1.63 (m, 2H), 1.42-1.38 (m, 3H), 0.92-0.77 (m, 10H), 0.08 (s, 3H), 0.01 (s, 3H).

[0218] Step 2: Under nitrogen protection in an ice bath, intermediate C3 (240 mg, 0.52 mmol) was dissolved in 3 mL of methanol, and (2R)-2-methylethylene oxide C4-1 (61 mg, 1.05 mmol) was slowly added. The mixture was heated to 60 °C and reacted for 10 hours, after which the reaction was stopped. 30 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated by TLC (n-hexane / tetrahydrofuran, 4 / 1) to give intermediate C4 (200 mg), yield: 74%. LC-MS: ESI-MS (m / z): [M+H] + = 524.5.

[0219] Following the synthetic route of intermediate C4, similar starting materials / intermediates (such as...) are used. (etc.), synthesize the following target compounds:

[0220] Table 4: Structure and LC-MS of intermediate c5

[0221]

[0222] Example 2 Synthesis of target molecule P1

[0223]

[0224] Step 1: Under nitrogen protection, intermediate C1 (470 mg, 0.5 mmol), tetrabutylammonium chloride (TBACl) (120 mg, 0.44 mmol), and sodium bicarbonate (92 mg, 1.1 mmol) were dissolved in 1 mL of N-bromosuccinimide. Palladium acetate (9.9 mg, 0.044 mmol) was added as a catalyst, and the mixture was heated to 100 °C and reacted for 1 hour. The reaction was then stopped. 5 mL of ice water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by thin-layer chromatography (TLC) (petroleum ether / ethyl acetate, 1 / 1) to give a pale yellow solid P1-1 (100 mg), yield: 24%. LC-MS: ESI-MS (m / z): [M+H] + = 819.4.

[0225] Step 2: Under nitrogen protection, compound P1-1 (100 mg, 0.12 mmol) from the previous step was dissolved in 2 mL of anhydrous N-bromosuccinimide, and cesium fluoride (130 mg, 0.84 mmol) was added. The reaction mixture was heated to 50 °C and reacted for 1 hour, then cooled to room temperature. 10 mL of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound P1-2 (60 mg), yield: 70%. LC-MS: ESI-MS (m / z): [M+H] + = 705.4.

[0226] Step 3: Under nitrogen protection in an ice bath, compound P1-2 (86 mg, 0.12 mmol) from the previous step was dissolved in 1 mL of dichloromethane. Methanesulfonic anhydride (Ms2O) (31 mg, 0.18 mmol) and N,N-diisopropylethylamine (DIEA) (47 mg, 0.36 mmol) were slowly added, and the mixture was reacted at room temperature for 1 hour. 10 mL of ice water was added to the mixture, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash reversed column chromatography (column: C18; acetonitrile / water, 2 / 1) to give compound P1-3 (80 mg), yield: 84%. LC-MS: ESI-MS (m / z): [M+H] + = 783.4.

[0227] Step 4: Under nitrogen protection and in an ice bath, compound P1-3 (270 mg, 0.34 mmol) and 2,6-dimethylpyridine (lutidine) (181 mg, 1.7 mmol) were dissolved in 2 mL of dichloromethane. Trimethylsilyltrifluoromethanesulfonate (TMSOTf) (230 mg, 1.02 mmol) was slowly added, and the reaction was carried out at room temperature for 1 hour. The solvent was removed under reduced pressure to give compound P1-4 (200 mg), yield: 85%. LC-MS: ESI-MS (m / z): [M+H] + = 683.3.

[0228] Step 5: Under nitrogen protection, dissolve compound P1-4 (200 mg, 0.29 mmol) from the previous step in 2 mL of N-bromosuccinimide in an ice bath, and slowly add potassium carbonate. (120 mg, 0.87 mmol) was reacted at 60°C for 1 hour. 10 mL of ice water was added to the reaction mixture, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, and solvent removal under reduced pressure. The crude product was separated by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase A: water (0.075% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min) to give compound P1-5 (100 mg), yield: 58%. LC-MS: ESI-MS (m / z): [M+H] + = 587.3.

[0229] Step 6: Dissolve compound P1-5 (50 mg, 0.085 mmol) from the previous step in a 1,4-dioxane hydrochloric acid solution (1 mL, 2 M) and react at room temperature for 1 hour. Add 10 mL of ice water to the reaction solution, adjust the pH to approximately 8 with sodium bicarbonate aqueous solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, and remove the solvent under reduced pressure. Separate the crude product by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase A: water (10 mM NH4CO3), mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound P1 (6.4 mg), yield: 15%. LC-MS: ESI-MS (m / z): [M+H] + = 503.4.

[0230] 1 H NMR (400 MHz, CD3OD) δ 8.23 ​​(br s, 1H), 7.41 (br d, J = 16.7 Hz,1H), 7.17 (d, J = 16.7 Hz, 1H), 4.72-4.56 (m, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.28-4.08 (m, 2H), 4.05-3.92 (m, 1H), 3.77-3.57 (m, 4H), 3.06 (br d, J = 8.8Hz, 1H), 2.94-2.80 (m, 1H), 2.76 (s, 3H), 2.69-2.60 (m, 1H), 2.56 (s, 3H), 1.89-1.61 (m, 3H), 1.50 (t, J = 7.0 Hz, 4H), 1.36-1.28 (m, 1H), 1.11 (br d, J= 6.2 Hz, 3H).

[0231] Example 3 Synthesis of target molecules P2-P3

[0232]

[0233] Step 1: Under nitrogen protection and in an ice bath, intermediates C4 (220 mg, 0.42 mmol), triphenylphosphine (Ph3P) (220 mg, 0.84 mmol), and intermediate A2 (223 mg, 0.63 mmol) were dissolved in 10 mL of 2-methyltetrahydrofuran. Di-tert-butyl azodicarbonate (DBAD) (193 mg, 0.84 mmol) was added, and the mixture was heated to 20°C and reacted for 10 hours. The reaction was then stopped. 15 mL of ice water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (PE / THF, 3 / 1) to give a yellow solid P2-1 (170 mg), yield: 42%. LC-MS: ESI-MS (m / z): [M+H] + = 859.3. [Two SN2 reactions, configuration retained]

[0234] 1 H NMR (400 MHz, CDCl3) δ 7.81-7.69 (m, 1H), 7.07-6.94 (m, 1H), 6.16-6.07 (m, 1H), 5.95-5.85 (m, 1H), 5.64-5.45 (m, 1H), 4.74-4.55 (m, 1H), 4.30-4.17 (m, 4H), 4.11-4.00 (m, 1H), 3.89-3.81 (m, 1H), 3.81-3.75 (m, 1H), 3.73-3.64 (m, 4H), 3.08-2.99 (m, 3H), 2.78-2.56 (m, 4H), 2.42-2.33 (m, 3H), 2.26-2.11 (m, 2H), 1.83-1.53 ​​(m, 8H), 1.37 (dt, J = 1.9, 7.0 Hz, 4H), 1.21-1.14(m, 3H), 0.86-0.84 (m, 9H), 0.06 (d, J = 3.5 Hz, 3H), 0.01-0.02 (m, 3H).

[0235] Step 2: Under nitrogen protection, compound P2-1 (160 mg, 0.19 mmol), tetrabutylammonium chloride (TBACl) (106 mg, 0.38 mmol), and sodium bicarbonate (80 mg, 0.95 mmol) were dissolved in 6 mL of N-bromosuccinimide. Palladium acetate (Pd(OAc)2) (8.53 mg, 0.038 mmol) was added as a catalyst. The mixture was heated to 100 °C and reacted for 1 hour, after which the reaction was stopped. 5 mL of ice water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid P2-2 (120 mg), yield: 88%. LC-MS: ESI-MS (m / z): [M+H] + =731.4.

[0236] Step 3: The compound P2-2 (200 mg, 0.27 mmol) from the previous step was dissolved in HCl in a 1,4-dioxane solution (2 mL, 2 M) and reacted at room temperature for 1 hour. 10 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated by preparative HPLC (column: 52-Welch Xtimate C18 150×30 mm, 5 μm; mobile phase A: water (10 mM ammonium carbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound P2 (2.66 mg), yield: 44%. LC-MS: ESI-MS (m / z): [M+H] + =533.4.

[0237] 1H NMR (400 MHz, CD3OD) δ 8.34-8.26 (m, 1H), 7.55-7.44 (m, 1H), 7.24-7.10 (m, 1H), 4.59 (br d, J = 3.2 Hz, 2H), 4.37 (d, q, J = 3.0, 7.0 Hz, 2H),4.31-4.19 (m, 2H), 3.95 (dd, J = 4.5, 11.4 Hz, 1H), 3.73 (br d, J = 14.3 Hz,1H), 3.68-3.63 (m, 3H), 3.15-3.04 (m, 1H), 3.01-2.92 (m, 1H), 2.85-2.74 (m,5H), 2.54 (s, 3H), 1.86-1.64 (m, 3H), 1.49 (t, J = 7.1 Hz, 3H), 1.15 (br d, J= 6.6 Hz, 3H), 1.07-0.89 (m, 1H).

[0238] Following the synthetic route of compound P2, and using similar starting materials / intermediates (such as intermediate C5), the following target compounds were synthesized:

[0239] Table 5: Structure and LC-MS of target molecule P3

[0240]

[0241] Example 4

[0242] The effects of small molecule inhibitors on the proliferation of three Ba / F3 cell lines (Ba / F3-EGFR-wt, Ba / F3-L858R / C797S, and Ba / F3-EGFR-del19-T790M-C797S) were detected using Promega CellTiter-Glo reagent.

[0243] (Ba / F3-EGFR-L858R / C797S, Ba / F3-EGFR-del19-T790M-C797S) Culture medium: 1640 medium, 10% FBS, Glutamax and penicillin-streptomycin.

[0244] (Ba / F3-FL-EGFR-wt) culture medium: 1640 medium, 10% FBS, Glutamax, 100 ng / mL EGF and penicillin-streptomycin.

[0245] The cell lines were cultured at 37°C in a 5% CO2 incubator. Cells in the logarithmic growth phase were passaged periodically and seeded onto cell culture plates. 95 μL of cell suspension was added to each well of the cell culture plate, and cell-free culture medium (containing 0.1% DMSO) was added to the Min control wells. For compound detection, 5 μL of 20× compound working solution was added to the cell culture plate. 5 μL of DMSO-cell culture medium mixture was added to the Max control wells, with a final DMSO concentration of 0.1%.

[0246] The culture plates were incubated at 37 °C in a 5% CO2 incubator for 72 hours. Cell viability was detected using CellTiter-Glo luminescence assay. Data analysis:

[0247] Cell proliferation inhibition rate data were processed using the following formula:

[0248] Inhibition Rate(Inh%)=100- (RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100%.

[0249] Among them: RLU Drug RLU represents the relative luminescent units of the cell to which the drug is added. Min RLU represents the light-emitting unit of the culture medium. Max This indicates the relative luminescent units of the cells to which DMSO was added.

[0250] The inhibition rates corresponding to different concentrations of the compound were calculated in Excel, and then GraphPad Prism software was used to plot the inhibition rate curves and calculate relevant parameters, including the maximum and minimum cell inhibition rates, and IC50. 50 value.

[0251] WT = wild type = wild type

[0252] D = 19del = Exon 19 deletion mutation

[0253] LR = L858R = L858R point mutation

[0254] D / CS = 19del / C797S = Exon 19 deletion mutation combined with C797S mutation

[0255] LR / CS = L858R / C797S = L858R point mutation combined with C797S mutation

[0256] D / TM / CS = 19del / T790M / C797S = Exon 19 deletion mutation combined with T790M and C797S double mutation.

[0257] LR / TM / CS = L858R / T790M / C797S = L858R point mutation combined with T790M and C797S double mutation

[0258] Table 6: Antiproliferative inhibitory effects of representative compounds on wild-type EGFR (wt), mutant EGFR (L858R / C797S), and mutant EGFR (del19 / T790M / C797S) transfected into BaF3 cells.

[0259]

[0260] Experimental conclusion: Based on the above assay, the compound of this invention showed an inhibitory effect of approximately 500 nM-100 nM (IC50) on the proliferation activity of EGFR mutant cells (such as LR / CS or D / TM / CS). 50 Biological activity of ); preferably 10 nM to 100 nM (IC50). 50 Biological activity of );

[0261] Furthermore, in some embodiments, the compounds of the present invention exhibit proliferative activity against EGFR-wt cells: a portion (IC50) 50 >100 nM; some greater than >500 nM; some greater than >1000 nM; the molecules of this invention exhibit selectivity for EGFRwt.

Claims

1. A compound of formula (II-2), or a pharmaceutically acceptable salt or stereoisomer thereof: (Ⅱ-2) in, R 1b Each can be independently selected from H and -C. 1-6 Alkyl, -deuterated C 1-6 Alkyl, -halogenated C 1-6 alkyl; R2 is independently selected from -OLR a ; R4 is selected from H, methyl, deuterated methyl, and trifluoromethyl; L can be independently selected as a self-key; R w Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Alkylene, -OH; R a Each can be independently selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 3-7 Cycloalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of general formula (II-3): (Ⅱ-3) in, R2 is selected from -OMe and -OEt; R4 is selected from H, methyl, deuterated methyl, and trifluoromethyl; R w Selected from H, methyl, and -OH.

3. A compound, a stereoisomer, or a pharmaceutically acceptable salt, wherein the compound is selected from: , , , , , , , , , , , or .

4. Use of the compound of claim 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing EGFR kinase-mediated diseases.

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