Fourth-generation egfr inhibitors

Abstract

This invention provides a compound as a fourth-generation EGFR inhibitor, which is a compound or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. This invention also provides pharmaceutical compositions comprising said compound and their use in the treatment of cancer.

Description

Technical Field

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

[0002] Lung cancer is one of the most common malignant tumors, with approximately 1.6 million new cases worldwide each year. It is divided into two types: small cell lung cancer and non-small cell lung cancer (NSCLC), with NSCLC accounting for about 85% of all lung cancers (Nature Reviews Disease Primers, 2015, 1,15009).

[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 mutations (del19 or L858R) resistant to first- and second-generation EGFR inhibitors, 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). Therefore, there is an urgent clinical need to develop new small-molecule inhibitors targeting the C797S mutation to provide patients with safer and more effective fourth-generation EGFR inhibitors. Summary of the Invention

[0005] In this invention, we used major clinically observed mutation types such as del19 and del19 / T790M / C797S 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.

[0006] In one aspect, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof:

[0007] (I)

[0008] in,

[0009] X1 is selected from CH or N;

[0010] X2 is selected from CH, O, S, or N;

[0011] R1 and R2 are independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein R1 and R2 may optionally be -NR a R b C 1-6 Alkyl or halogen components are further substituted;

[0012] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, said group optionally being -NR a R b C 1-6 Alkyl or halogen further substituted;

[0013] Ring A is a 5-10 member heteroaryl group;

[0014] The ring A can be optionally replaced by one, two or three R4s;

[0015] R4 is selected from halogens, OR a C 1-6 Alkylene-OR a -NR a R b C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or 3-7 membered heterocyclic groups;

[0016] R a and R b Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0017] L1 is a linking chain selected from alkyl, alkenyl, or alkynyl groups with a length of 1 to 5 carbon atoms; the carbon atoms may optionally be replaced by O, S, or NH.

[0018] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and optionally a pharmaceutically acceptable excipient.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] In another aspect, the present invention provides compounds or compositions thereof for the treatment and / or prevention of EGFR kinase-mediated diseases.

[0023] 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).

[0024] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed embodiments, examples and claims.

[0025] definition

[0026] Chemical definition

[0027] The definitions of specific functional groups and chemical terms are described in more detail below.

[0028] 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 C4-5 and C 5-6 alkyl.

[0029] “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 1-6 Examples 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).

[0030] “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.

[0031] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0032] 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.

[0033] “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.

[0034] "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.

[0035] “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.

[0036] "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.

[0037] The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0038] 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 aa)3、-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;

[0039] 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;

[0040] 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;

[0041] 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;

[0042] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, 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;

[0043] 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;

[0044] 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;

[0045] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, 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;

[0046] 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.

[0047] 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.

[0048] Other definitions

[0049] 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.

[0050] 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.

[0051] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0052] 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.

[0053] 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. Detailed Implementation Plan

[0054] In this document, “compounds of the present invention” refers to compounds of formula (I) (including sub-formulas, such as formula (II), (II) or (IV)), pharmaceutically acceptable salts thereof, enantiomers, diastereomers, solvates, hydrates or isotopic variants thereof, and mixtures thereof.

[0055] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:

[0056] (I)

[0057] in,

[0058] X1 is selected from CH or N;

[0059] X2 is selected from CH, O, S, or N;

[0060] R1 and R2 are independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein R1 and R2 may optionally be -NR a R b C 1-6 Alkyl or halogen components are further substituted;

[0061] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, said group optionally being -NR a R b C 1-6 Alkyl or halogen further substituted;

[0062] Ring A is a 5-10 member heteroaryl group;

[0063] The ring A can be optionally replaced by one, two or three R4s;

[0064] R4 is selected from halogens, OR a C 1-6 Alkylene-OR a -NR a R b C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or 3-7 membered heterocyclic groups;

[0065] R a and R b Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0066] L1 is a linking chain selected from alkyl, alkenyl, or alkynyl groups with a length of 1 to 5 carbon atoms; the carbon atoms may optionally be replaced by O, S, or NH.

[0067] In another embodiment, the present invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:

[0068] (II)

[0069] in,

[0070] X1 is selected from CH or N;

[0071] X2 is selected from CH, O, S, or N;

[0072] R1 and R2 are independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein R1 and R2 may optionally be -NR a R b C 1-6 Alkyl or halogen further substituted;

[0073] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, said group optionally being -NR a R b C 1-6 Alkyl or halogen further substituted;

[0074] R4 is selected from halogens, OR a C 1-6 Alkylene-OR a -NR a R b C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or 3-7 membered heterocyclic groups;

[0075] R a and R b Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0076] L1 is a linking chain selected from alkyl, alkenyl, or alkynyl groups with 1 to 5 carbon atoms in length; the carbon atoms may optionally be replaced by O, S, or NH.

[0077] n is selected from 0, 1, 2 or 3.

[0078] In another, more specific embodiment, the present invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:

[0079] X1 is selected from CH or N;

[0080] X2 is selected from CH, O, S, or N;

[0081] R1 and R2 are independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein R1 and R2 may optionally be -NR a R b C 1-6 Alkyl or halogen further substituted;

[0082] R3 is selected from H and C. 1-6 Alkyl or C 3-7 cycloalkyl;

[0083] R4 is selected from halogens, OR a C 1-6 Alkylene-OR a -NR a R b C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or 3-7 membered heterocyclic groups;

[0084] R a and R b Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0085] L1 is a linking chain selected from alkyl, alkenyl, or alkynyl groups with 1 to 3 carbon atoms in length; the carbon atoms may optionally be replaced by O, S, or NH.

[0086] n is selected from 0, 1, 2 or 3.

[0087] In another embodiment, the present invention relates to compounds of formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof:

[0088] (III)

[0089] in,

[0090] X1 is selected from CH or N;

[0091] X2 is selected from CH, O, S, or N;

[0092] R1 and R2 are independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein R1 and R2 may optionally be -NR a R b C 1-6 Alkyl or halogen further substituted;

[0093] R3 is selected from H and C. 1-6 Alkyl or C 3-7 cycloalkyl;

[0094] R4 is selected from halogens, OR a C 1-6 Alkylene-OR a -NR a R b C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0095] R a and R b Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0096] L1 is a linking chain selected from alkyl, alkenyl, or alkynyl groups with 1 to 3 carbon atoms in length; the carbon atoms may optionally be replaced by O, S, or NH.

[0097] n is selected from 0, 1, 2 or 3.

[0098] In another embodiment, the present invention relates to a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:

[0099] (IV)

[0100] in,

[0101] X1 is selected from CH or N;

[0102] X2 is selected from CH, O, S, or N;

[0103] R1 and R2 are independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein R1 and R2 may optionally be -NR a R b C 1-6 Alkyl or halogen further substituted;

[0104] R3 is selected from H and C.1-6 Alkyl or C 3-7 cycloalkyl;

[0105] R4 is selected from halogens, OR a C 1-6 Alkylene-OR a -NR a R b C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0106] R a and R b Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0107] L1 is a linking chain selected from alkyl, alkenyl, or alkynyl groups with 1 to 3 carbon atoms in length; the carbon atoms may optionally be replaced by O, S, or NH.

[0108] n is selected from 0, 1, 2 or 3.

[0109] In another embodiment, the invention relates to a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, selected from:

[0110] , , , , , , , , , , , , or .

[0111] Example 1

[0112] Preparation of key intermediates

[0113] Notes on commonly used abbreviations:

[0114] Abbreviations: PE = petroleum ether; EA = ethyl acetate; MeOH = methanol; DCM = dichloromethane; DCE = dichloroethane; CH3CN = acetonitrile; 1,4-dioxane = 1,4-dioxane; DMSO = dimethyl sulfoxide; HFIP = hexafluoroisopropanol; DMF = N,N-dimethylformamide; Hex = n-hexane; IPA = isopropanol; NMP = N-methylpyrrolidone; NMO = N-methylmorpholine-N-oxide; TEA = triethylamine; DIEA = diisopropylethylamine; CuI = cuprous iodide; CuCN = cuprous cyanide; triphosgene = triphosgene; p-TsOH = p-toluenesulfonic acid; T3P = 1-propyl cyclic phosphate anhydride; TsN3 = p-toluenesulfonyl azide; PPA = polyphosphoric acid; SEM-Cl = 2-(trimethylsilyl)ethoxymethyl chloride.

[0115]

[0116] Step 1: In an ice bath, dissolve methyl 2-amino-3-fluoro-5-iodobenzoate a1–1 (3.0 g, 10.2 mmol) and copper bromide (225 mg, 1.02 mmol) in 50 mL of acetonitrile. Slowly add nitrous acid (1.05 g, 10.2 mmol). After the addition is complete, react at room temperature for 4 hours, then stop the reaction. Add 200 mL of ice water to the reaction solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography to obtain a white solid a1-2 (2.1 g), yield: 58%, LCMS: ESI–MS (m / z): 358.8 [M + H] + .

[0117] Step 2: Under nitrogen protection, at -10°C, intermediate a1-2 (2.1 g, 5.85 mmol) from the previous step was dissolved in 18 mL of anhydrous THF. Diisobutylaluminum hydride (DIBAL-H) ​​(17.5 mL, 1 M) was slowly added dropwise until the mixture was completely dissolved. The temperature was raised to room temperature and the reaction was allowed to proceed for 12 hours, after which the reaction was stopped. 20 mL of 1 M dilute hydrochloric acid was added to the system, and the mixture was filtered, extracted with ethyl acetate, and the solvent was removed under reduced pressure to obtain oily intermediate a1-3 (1.8 g). LCMS: ESI–MS (m / z): 330.9 [M + H] + .

[0118] Step 3: Dissolve the crude product a1-3 (1.8 g) and triethylamine (1.74 g, 17.2 mmol) from the previous step in 20 mL of dichloromethane. Slowly add methanesulfonic anhydride (1.5 g, 8.61 mmol). React at room temperature for 1 hour, then stop the reaction. Place the reaction solution in an ice bath, add 40 mL of ice water, extract with dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain intermediate a1-4 (2.0 g), which can be used directly in the next step. LCMS: ESI–MS (m / z): 408.8 [M+ H] + .

[0119] Step 4: Ice bath reaction. Dissolve the starting material 2,2-diethoxyacetamide a1-5 (1.44 g, 9.78 mmol) in 20 mL of anhydrous tetrahydrofuran. Slowly add NaH (390 mg, 9.78 mmol), stir for 15 minutes, then add intermediate a1-4 (1.8 g) from the previous step. Heat to 50 °C and react for 2 hours, then stop the reaction. Add 60 mL of ice water to the system, extract with dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and separate the crude product by flash column chromatography to obtain intermediate a1-6 (1.2 g). Three-step yield: 45%, LCMS: ESI–MS (m / z): 459.9 [M + H] + .

[0120] Step 5: Under nitrogen protection, intermediate a1-6 (1.2 g, 2.61 mmol), potassium carbonate (1.08 g, 7.83 mmol), and the starting material pinacol isopropenylborate a1-7 (460 mg, 2.74 mmol) were dissolved in 11 mL of a mixed solution of 1,4-dioxane and water (v / v, 10 / 1). Catalyst Pd(dppf)Cl2 (95 mg, 0.13 mmol) was added, and the mixture was stirred for 5 minutes. The reaction was then carried out at 80 °C for 5 hours, after which the reaction was stopped. 60 mL of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash column chromatography to obtain intermediate a1-8 (900 mg), yield: 92%, LCMS: ESI–MS (m / z): 374.1 [M + H] + .

[0121] Step 6: Under a hydrogen atmosphere (1 atm), intermediate a1-8 (1.0 g, 2.67 mmol) and palladium on carbon (100 mg) from the previous step were dissolved in 11 mL of ethanol. The reaction was carried out at room temperature for 12 hours, then stopped and filtered. The solvent was removed by vacuum distillation to give intermediate a1-9 (900 mg), yield: 90%, LCMS: ESI–MS (m / z): 376.1 [M + H] + .

[0122] Step 7: Dissolve intermediate a1-9 (900 mg, 2.39 mmol) from the previous step in 5 mL of concentrated sulfuric acid. Stir for 5 minutes, then heat to 50 °C and react for 2 hours. Stop the reaction. Slowly pour the reaction solution into 50 mL of ice water, extract with dichloromethane, dry to anhydrous sodium sulfate, filter, and concentrate to obtain intermediate a1-10 (300 mg), yield: 44%, LCMS: ESI–MS (m / z): 284.0 [M + H] + .

[0123] Step 8: Ice bath. Dissolve intermediate a1-9 (250 mg, 0.88 mmol) and diisopropylethylamine DIEA (340 mg, 2.64 mmol) in 5 mL of dichloromethane. Slowly add trifluoromethanesulfonic anhydride (320 mg, 1.14 mmol), stir, and heat to room temperature for 1 hour. Stop the reaction. Add 30 mL of ice water to the system, extract with dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and separate the crude product by flash column chromatography to obtain intermediate a1 (200 mg), yield: 55%, LCMS: ESI–MS (m / z): 415.9 [M + H] + .

[0124] Following the synthetic route of compound a1, and using a similar starting material / skeleton structure, the following intermediate was synthesized.

[0125] a2 398

[0126] Synthesis of intermediates a3-a5

[0127]

[0128] Step 1: Ice bath reaction. The starting material, 1H-4-pyrazoleboronic acid pinacol ester a3-1 (25.0 g, 130 mmol), was dissolved in 300 mL of anhydrous DMF. NaH (7.7 g, 190 mmol) was slowly added, and the mixture was stirred for 5 minutes. Then, cyclopropylsulfonyl chloride (19.9 g, 140 mmol) was added, and the reaction was allowed to proceed at room temperature for 12 hours. The reaction was then stopped. 1 L of ice water was added to the system, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate a3-2 (35.0 g), yield: 91%. LCMS: ESI–MS (m / z): 299.2 [M + H] + .

[0129] Step 2: Under nitrogen protection, intermediate a3-2 (27.5 g, 92.2 mmol), cesium carbonate (90.2 g, 280 mmol), and the starting material 2-chloro-4-aminopyrimidine a3-3 (11.9 g, 92.2 mmol) were dissolved in 250 mL of a mixed solution of 1,4-dioxane and water (v / v, 5 / 1). Catalyst Pd(dppf)Cl2 (3.4 g, 4.6 mmol) was added, and the mixture was stirred for 5 minutes. The reaction was then carried out at 90 °C for 10 hours. The reaction was stopped, and the mixture was filtered. 1 L of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash column chromatography to obtain intermediate a3 (8.7 g), yield: 36%, LCMS: ESI–MS (m / z): 266.3 [M + H] + .

[0130] Following the synthetic route of compound a3, and using a similar starting material / skeleton structure, the following intermediate was synthesized.

[0131] a4 246 a5 234

[0132] Synthesis of intermediate a6

[0133]

[0134] Step 1: Dissolve the starting material 3-chloro-5-methoxy-8-bromoisoquinoline a6–1 (1.4 g, 5.14 mmol) in 28 mL of dichloromethane in an ice bath. Slowly add BBr3 (3.9 g, 15.4 mmol). After the addition is complete, react at room temperature for 10 hours, then stop the reaction. Add 200 mL of ice water to the reaction solution, extract with dichloromethane, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by flash reversed column chromatography (C18, CH3CN / H2O, 4 / 5) to obtain a yellow solid a6-2 (1.1 g), yield: 83%, LCMS: ESI–MS (m / z): 258 [M + H] + .

[0135] Step 2: Under nitrogen protection, at -60°C, the intermediate a6-2 (1.1 g, 4.26 mmol) and triethylamine (1.72 g, 17.0 mmol) from the previous step were dissolved in 22 mL of anhydrous dichloromethane. Tf₂O (3.6 g, 12.8 mmol) was slowly added. After the addition was complete, the mixture was slowly heated to room temperature and reacted for 1 hour, at which point the reaction was stopped. 20 mL of ice water was added to the system, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reversed-phase column chromatography (C18, CH₃CN / H₂O, 7 / 10) to give a yellow solid a6 (1.2 g), yield: 72%, LCMS: ESI–MS (m / z): 390 [M + H] + .

[0136] Synthesis of intermediate b1

[0137]

[0138] Step 1: Under nitrogen protection, starting material b1-1 (7.0 g, 27.7 mmol) and triethylamine (4.2 g, 41.5 mmol) were dissolved in 40 mL of dichloromethane, and methanesulfonyl chloride (3.21 g, 28.0 mmol) was added. The reaction was carried out at room temperature for 4 hours. The reaction was stopped, and the solvent was removed under reduced pressure to obtain crude product b1-2 (10.8 g).

[0139] Step 2: Dissolve crude product b1-2 (10.8 g) and starting material b1-3 (4.21 g, 27.7 mmol) in 30 mL of DMF, add NaH (1.11 g, 27.7 mmol), and slowly heat to 80 °C for 12 hours. Monitor the reaction completion by LC-MS. Quench the reaction with 100 mL of saturated saline solution, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain crude product b1-4 (15 g). LC-MS: ESI-MS (m / z): 388.3 [M + H] + .

[0140] Step 3: Dissolve the crude product b1-4 (15 g) and LiCl (2.52 g, 60.0 mmol) from the previous step in 40 mL of N,N-dimethylacetamide (DMA), heat to 150 °C and react for 2 hours, then stop the reaction. Add 100 mL of ice water to the reaction solution, extract with dichloromethane, dry to anhydrous sodium sulfate, filter, concentrate, and separate by flash column chromatography to obtain a yellow solid b1-5 (6.42 g). Overall yield of the three steps: 71%. LC-MS: ESI-MS (m / z): 330.1 [M + H] + .

[0141] Step 4: Under a hydrogen atmosphere (2 atm), intermediate b1-5 (6.42 g, 19.5 mmol) and Pd / C (1.28 g, 20%) from the previous step were mixed in 40 mL of methanol, and 2 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 16 hours, after which the reaction was stopped. The mixture was filtered and concentrated to obtain a yellow oil b1 (4.5 g), which was used directly in the next step. LC-MS: ESI-MS (m / z): 164.2 [M + H] + .

[0142] Synthesis of intermediate b2

[0143]

[0144] Step 1: Intermediate b1-2 (70.0 g, 210 mmol) was added to a 500 mL reaction flask, and a 200 mL isopropanol solution of methylamine (28% concentration) was slowly added. The mixture was heated to 70 °C and reacted for 4 hours. The reaction was monitored by LC-MS to ensure complete reaction. The solvent was removed under reduced pressure, and the crude product was separated by flash column chromatography to obtain an oily intermediate b2-1 (39.0 g), yield: 69%, LC-MS: ESI–MS (m / z): 267.4 [M + H] + .

[0145] Step 2: Dissolve intermediate b2-1 (39.0 g, 150 mmol) and triethylamine (44.5 g, 440 mmol) in 400 mL of dichloromethane. Slowly add methanesulfonic anhydride (30.6 g, 180 mmol). React at room temperature for 1 hour, then stop the reaction. Place the reaction solution in an ice bath, add 1 L of ice water, extract with dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain intermediate b2-2 (40 g), which can be used directly in the next step. LCMS: ESI–MS (m / z): 345.5 [M + H] + .

[0146] Step 3: Under a hydrogen atmosphere (1 atm), intermediate b2-2 (40 g, 120 mmol) and trifluoroacetic acid (53.0 g, 460 mmol) from the previous step were dissolved in 200 mL of methanol. Palladium on carbon (4.0 g) was slowly added, and the reaction was carried out at room temperature for 12 hours. The reaction was then stopped, filtered, and the solvent was removed by vacuum distillation. 100 mL of water was added to the mixture, and impurities were removed by extraction with dichloromethane. The aqueous phase was lyophilized to obtain intermediate b3 (27.0 g), yield: 84%, LCMS: ESI–MS (m / z): 179.1 [M + H] + .

[0147] Synthesis of intermediate b3

[0148]

[0149] Step 1: Under nitrogen protection, starting material b3-1 (6.0 g, 61.2 mmol) and potassium carbonate (18.6 g, 135 mmol) were dissolved in 125 mL of acetonitrile. SEM-Cl (17.3 g, 104 mmol) was added, and the reaction was carried out at room temperature for 12 hours. The reaction was then stopped, filtered, and the solvent was removed by vacuum distillation. 50 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash positive column chromatography (PE / EA, 10 / 1) to give a yellow solid b3-2 (6.0 g), yield: 43%, LCMS: ESI–MS (m / z): 229 [M + H] + .

[0150] Step 2: Under nitrogen protection in an ice bath, the intermediate b3-2 (6.0 g, 26.3 mmol) from the previous step was dissolved in 60 mL of acetonitrile. NBS (7.0 g, 39.4 mmol) was added, and the mixture was stirred for 5 minutes. The mixture was then heated to room temperature and reacted for 1 hour. The reaction was stopped, filtered, and the solvent was removed by vacuum distillation. 60 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash positive column chromatography (PE / EA, 10 / 1) to give a yellow solid b3 (5.0 g), yield: 62%, LCMS: ESI–MS (m / z): 307 [M + H] + .

[0151] Synthesis of intermediate b4

[0152]

[0153] Step 1: Under nitrogen protection, the raw material b4-1 (7.9 g, 23.9 mmol), sodium carbonate (4.2 g, 40.0 mmol), and intermediate b3 (2.5 g, 8.0 mmol) were dissolved in 125 mL of a mixed solution of acetonitrile and water (v / v, 10 / 1). Pinacol diborate (10.1 g, 39.9 mmol) and catalyst Pd(Amphos)2Cl2 (1.3 g, 1.60 mmol) were added. After stirring for 5 minutes, the mixture was heated to 100 °C and reacted for 4 hours. The reaction was then stopped, filtered, and the solvent was removed by vacuum distillation. Add 100 mL of water to the mixture, extract with ethyl acetate, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate, and separate the crude product by flash normal column chromatography (PE / EA, 5 / 1) to give a yellow solid b4-2 (2.0 g), yield: 60%, LCMS: ESI–MS (m / z): 422 [M + H] + .

[0154] Step 2: Dissolve intermediate b4-2 (2.0 g, 4.7 mmol) from the previous step in 40 mL of hexafluoroisopropanol, slowly add 4 mL of trifluoroacetic acid, and react at room temperature for 3 hours. Stop the reaction and remove the solvent under reduced pressure. Dissolve the mixture in 10 mL of methanol, adjust the pH to approximately 8 with saturated sodium bicarbonate aqueous solution, remove the solvent under reduced pressure, and separate the crude product by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to obtain a brown solid b4 (850 mg), yield: 56%, LCMS: ESI–MS (m / z): 322 [M + H] + .

[0155] Synthesis of intermediate C1

[0156]

[0157] Step 1: Under nitrogen protection, intermediate a6 (1.2 g, 3.1 mmol), potassium carbonate (0.42 g, 3.1 mmol), and starting material c1-1 (0.96 g, 3.1 mmol) were dissolved in 25 mL of a mixed solution of 1,4-dioxane and water (v / v, 10 / 1). Catalyst Pd(dppf)Cl2 (0.22 g, 0.31 mmol) was added, and the mixture was stirred for 5 minutes. The reaction was then carried out at 60 °C for 5 hours. The reaction was stopped, and the mixture was filtered. 100 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 4 / 5) to give a yellow solid c1-2 (580 mg), yield: 44%, LCMS: ESI–MS (m / z): 426 [M + H] + .

[0158] Step 2: Under nitrogen protection, intermediates c1-2 (580 mg, 1.36 mmol), cesium carbonate (885 mg, 2.7 mmol), and intermediate b2 (242 mg, 1.36 mmol) from the previous step were dissolved in 12 mL of 1,4-dioxane. Xantphos Pd-G4 catalyst (131 mg, 0.14 mmol) was added, and the mixture was stirred for 5 minutes. The mixture was then heated to 100 °C and reacted for 3 hours. The reaction was stopped, and the mixture was filtered. 60 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 9 / 10) to give a yellow solid c1 (450 mg). Yield: 63%. LCMS: ESI–MS (m / z): 524 [M + H] + .

[0159] Example 2

[0160] Preparation of target molecule P1

[0161]

[0162] Step 1: Under nitrogen protection, intermediates c1 (450 mg, 0.86 mmol), cesium carbonate (559 mg, 1.72 mmol), and b4 (276 mg, 0.86 mmol) were dissolved in 9 mL of 1,4-dioxane. Ligand XantPhos (50 mg, 0.09 mmol) and catalyst Pd2(dba)3 (78.6 mg, 0.09 mmol) were added. After stirring for 5 minutes, the mixture was heated to 130 °C and reacted for 4 hours. The reaction was then stopped, and the mixture was filtered. 30 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash reversed column chromatography (C18, CH3CN) to give compound P1-1 (450 mg), yield: 45%, LCMS: ESI–MS (m / z): 809 [M + H] + .

[0163] Step 2: Compound P1-1 (450 mg, 0.39 mmol) from the previous step was dissolved in 23 mL of tetrahydrofuran, and TBAF tetrahydrofuran solution (1 M, 0.78 mL) was added. The reaction was carried out at room temperature for 12 hours, and then stopped. 50 mL of ice water was added to the system, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 7 / 10) to give compound P1-2 (160 mg), yield: 73%, LCMS: ESI–MS (m / z): 565 [M + H] + .

[0164] Step 3: Under nitrogen protection, compound P1-2 (67 mg, 0.12 mmol) and cyanomethylenetri-n-butylphosphine (CMBP) (160 mg, 0.67 mmol) from the previous step were dissolved in 13 mL of anhydrous toluene. The mixture was heated to 130 °C and reacted for 12 hours, after which the reaction was stopped. 50 mL of water was added to the system, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by HPLC column chromatography (column: Xselect CSH Prep C18 OBD Column, 19*250 nm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; retention time 13 min) to obtain compound P1 (2.2 mg), yield: 3%, LCMS: ESI–MS (m / z): 547 [M + H] + .

[0165] 1 H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.13 (d, J = 23.4 Hz, 1H), 8.66 (s, 1H), 8.21 (dd, J = 72.4, 6.7 Hz, 1H), 7.80 (d, J = 41.1 Hz, 1H),7.32 (dd, J = 19.8, 7.8 Hz, 1H), 6.87 – 6.51 (m, 3H), 5.67 (s, 1H), 5.32 (s,1H), 5.14 (d, J = 10.9 Hz, 1H), 4.80 – 4.40 (m, 3H), 4.23 (d, J = 7.4 Hz,1H), 3.94 (s, 2H), 3.53 – 3.34 (m, 3H), 2.97 (d, J = 2.8 Hz, 3H), 2.85 (d, J= 3.1 Hz, 3H), 1.45 (dd, J = 6.0, 3.5 Hz, 3H).

[0166] Example 3

[0167] Preparation of target molecule P2

[0168]

[0169] Procedure: Under a hydrogen atmosphere, compound P1 (10 mg, 0.02 mmol) was dissolved in 2 mL of ethyl acetate, and PtO2 (10 mg) was added. After stirring for 5 minutes, the mixture was reacted at room temperature under hydrogen (1 atm) for 5 hours. The reaction was then stopped, filtered, and the solvent was removed by vacuum distillation. The crude product was separated by HPLC column chromatography (column: XBridge Prep Shield RP18 OBD Column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; retention time: 11 min) to obtain compound P2 (1.7 mg), yield: 17%, LCMS: ESI–MS (m / z): 549 [M +H) + .

[0170] 1H NMR (300 MHz, DMSO-d6) δ 10.08 (d, J = 19.5 Hz, 1H), 9.07 (d, J =4.5 Hz, 1H), 8.82 – 8.59 (m, 1H), 8.33 (dd, J = 6.3, 3.4 Hz, 1H), 7.96 – 7.69(m, 1H), 7.26 (dd, J = 13.9, 7.6 Hz, 1H), 6.77 – 6.51 (m, 2H), 5.71 (dd, J =82.8, 7.0 Hz, 1H), 5.46 – 4.99 (m, 1H), 4.66 (d, J = 7.4 Hz, 1H), 4.52 – 4.39(m, 1H), 4.20 (d, J = 7.1 Hz, 1H), 3.88 (q, J = 7.3 Hz, 1H), 3.48 (d, J = 4.8Hz, 3H), 2.94 (d, J = 3.1 Hz, 2H), 2.81 (d, J = 2.3 Hz, 3H), 2.04 (d, J = 9.4Hz, 1H), 1.41 (dd, J = 5.8, 2.6 Hz, 3H), 1.32 (s, 2H), 1.22 (s, 3H).

[0171] Example 4

[0172] The effects of small molecule inhibitors on the proliferation of three Ba / F3 cell lines (Ba / F3-EGFR-del19, Ba / F3-FL-EGFR, and Ba / F3-EGFR-del19-T790M-C797S) were detected using Promega CellTiter-Glo reagent.

[0173] (Ba / F3-EGFR-del19, Ba / F3-EGFR-del19-T790M-C797S) Culture medium: 1640 medium, 10% FBS, Glutamax and penicillin-streptomycin.

[0174] (Ba / F3-FL-EGFR) culture medium: 1640 medium, 10% FBS, Glutamax, 100 ng / mL EGF and penicillin-streptomycin.

[0175] 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%.

[0176] 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:

[0177] Cell proliferation inhibition rate data were processed using the following formula:

[0178] Inhibition Rate(Inh%)=100- (RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100%.

[0179] 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.

[0180] 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.

[0181] Table 1: Antiproliferative inhibitory effects of representative compounds on wild-type EGFR (wt), mutant EGFR (del19), and mutant EGFR (del19 / T790M / C797S) transfected EGFR in BaF3 cells.

[0182] P1 3416 325 809 P2 5778 540 1403

[0183] ND = Untested

[0184] The above results demonstrate that the molecule of this invention exhibits good anti-proliferative effects against osimertinib-resistant cell lines (containing the C797S mutation), reflecting the effectiveness of this invention in addressing osimertinib-resistant tumors. It also shows good inhibitory effects on the EGFR mutant primary cell line (EGFR del19), with weaker inhibition against wild-type cells, demonstrating the high selectivity of the molecule of this invention.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from: 、 。 2. A pharmaceutical composition comprising a compound of any one of claims 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

3. Use of any compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing EGFR kinase-mediated diseases.

4. The use of claim 3, wherein the EGFR kinase-mediated disease is cancer, and the cancer is selected from: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma.

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