WO2023134266A1 - 2-哌啶基或2-吡唑基取代的嘧啶化合物作为egfr抑制剂 - Google Patents

2-哌啶基或2-吡唑基取代的嘧啶化合物作为egfr抑制剂 Download PDF

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WO2023134266A1
WO2023134266A1 PCT/CN2022/128264 CN2022128264W WO2023134266A1 WO 2023134266 A1 WO2023134266 A1 WO 2023134266A1 CN 2022128264 W CN2022128264 W CN 2022128264W WO 2023134266 A1 WO2023134266 A1 WO 2023134266A1
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alkyl
haloalkyl
compound
pharmaceutically acceptable
hydrate
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French (fr)
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刘彬
高峰
原帅
赵卉
彭星哲
刘翀
邵宁
郭永起
吴勇勇
吴卓
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苏州浦合医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the field of medicine, in particular to pyrimidine compounds substituted by 2-piperidinyl or 2-pyrazolyl as EGFR inhibitors.
  • Lung cancer is one of the most common malignant tumors. There are about 1.6 million new cases of lung cancer each year in the world. It is divided into two types: small cell lung cancer and non-small cell lung cancer (NSCLC), of which non-small cell lung cancer accounts for about 85% of the total number of lung cancers. (Nature Reviews Disease Primers, 2015, 1, 15009). Epidermal growth factor receptor (EGFR) is the most common driver gene of non-small cell lung cancer. The positive rate reaches 17% in all non-small cell lung cancers, close to 30%-40% in domestic patients, and even higher in lung adenocarcinoma About 60%.
  • NSCLC non-small cell lung cancer
  • EGFR Epidermal growth factor receptor
  • EGFR is a transmembrane glycoprotein that belongs to the ErbB family of tyrosine kinase receptors. EGFR is abnormally activated by various mechanisms, such as receptor overexpression, mutation, ligand-dependent receptor dimerization, ligand-independent activation, and the sustained activation of its kinase activity initiates downstream signals of cell proliferation, differentiation, and survival conduction. Small molecule inhibitors of EGFR kinase can inhibit the activation of tyrosine kinase, inhibit the proliferation of tumor cells, promote the apoptosis of tumor cells and other biological effects, and are a hot area of lung cancer development.
  • Osimertinib is a drug developed for the first- and second-generation drug-resistant mutation EGFR (del19 or L858R) accompanied by T790M mutation. It has shown a very significant clinical effect, but as the treatment continues, patients will also appear drug resistance. In 2015 (Nature Medicine, 2015, 21, 560–562), the drug resistance data of 15 patients taking osimertinib were reported for the first time, among which the EGFR C797S mutation was one of the main mechanisms leading to drug resistance to osimertinib, accounting for about 40 %.
  • the first-generation EGFR inhibitor gefitinib gefitinib
  • the third-generation EGFR inhibitor osimertinib both produced good therapeutic effects in the first-line EGFR activating mutation population, but in subgroup analysis Among them, the benefit of the L858R population is much lower than that of the del19 population, with PFS of 14.4 and 21.4 months respectively (The new England journal of medicine, 2018, 378, 113-125).
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof thing:
  • Z is selected from CH or N
  • Ring A is a 4-8 membered heterocyclic group
  • Ring B selected from
  • R 1 and R 2 are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 and R 4 are independently selected from H, OR a , C 1-6 alkyl or C 1-6 haloalkyl;
  • R is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5 -6 membered heteroaryl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R 8 is selected from OR a , NR b R c , C 1-6 alkyl, -C 1-6 alkylene-C 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl , 4-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, which are optionally substituted by 1 or more R a ;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom they are connected to;
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, which also comprises other therapeutic agents.
  • the present invention provides the use of the compound of the present invention in the preparation of medicines for treating and/or preventing diseases mediated by EGFR protein and its mutants.
  • the present invention provides a method for treating and/or preventing diseases mediated by EGFR protein and its mutants in a subject, comprising administering the compound or the composition of the present invention to the subject.
  • the present invention provides the compound of the present invention or the composition of the present invention, which is used for treating and/or preventing diseases mediated by EGFR protein and its mutants.
  • C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 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.
  • C 1-6 alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl and C 1-2 alkyl are preferred. Examples of C 1-6 alkyl groups include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), t-butyl Base (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl ( C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 ).
  • C 1-6 alkyl also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead.
  • An alkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 2-6 alkenyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 alkenyl is preferred. Examples of C 2-6 alkenyl include: ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentenyl (C 5 ), hexenyl (C 6 ), and the like.
  • C alkenyl also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead.
  • An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 2-6 alkynyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Examples of C 2-6 alkynyl include, but are not limited to: ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • C2-6alkynyl also includes heteroalkynyl groups in which one or more (e.g., 1 , 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead.
  • An alkynyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 1-6 alkylene refers to a divalent group formed by removing another hydrogen of C 1-6 alkyl, and may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred.
  • the unsubstituted alkylene group includes but not limited to: methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene group (-CH 2 CH 2 CH 2 CH 2 -), pentylene group (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene group (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - ) ,etc.
  • alkylene groups substituted with one or more alkyl (methyl) groups include but are not limited to: substituted methylene groups (-CH(CH 3 )- , -C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2- ), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 ) -, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -), and the like.
  • C 0-6 alkylene refers to a chemical bond and the above-mentioned C 1-6 alkylene.
  • alkenylene groups eg, alkenylene groups substituted with one or more alkyl (methyl) groups
  • C 2-6 alkynylene refers to a divalent group formed by removing another hydrogen of a C 2-6 alkynyl, and may be substituted or unsubstituted. In some embodiments, C2-4 alkynylene is particularly preferred. Exemplary such alkynylene groups include, but are not limited to, ethynylene (-C ⁇ C-), substituted or unsubstituted propynylene (-C ⁇ CCH 2 -), and the like.
  • Halo or "halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • C 1-6 haloalkyl refers to the above-mentioned “C 1-6 alkyl", which is substituted with one or more halogen groups.
  • C 1-4 haloalkyl is particularly preferred, more preferably C 1-2 haloalkyl.
  • Exemplary haloalkyl groups include, but are not limited to: -CF 3 , -CH 2 F, -CHF 2 , -CHFCH 2 F, -CH 2 CHF 2 , -CF 2 CF 3 , -CCl 3 , -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.
  • a haloalkyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 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 5-7 cycloalkyl, C 3-6 cycloalkyl and C 3-5 cycloalkyl are particularly preferred, more preferably C 5-6 cycloalkyl. Cycloalkyl also includes ring systems wherein the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to indicate The number of carbons in the cycloalkyl system.
  • cycloalkyl groups include, but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene Cycloheptadienyl (C 7 ), Cycloheptadienyl (C 7 ), Cycloheptatrienyl (C 7 ), and the like. Cycloalkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 3-12 membered heterocyclyl refers to a 3 to 12 membered non-aromatic ring system group having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, Sulfur, boron, phosphorus and silicon.
  • the point of attachment can be a carbon or nitrogen atom, as valence permits.
  • 4-8 membered heterocyclyl is preferred, which is a 4 to 8 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5-8 membered Heterocyclyl, which is a 5 to 8 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3-8 membered heterocyclyl group having ring carbon atoms and 3 to 8 membered non-aromatic ring systems with 1 to 4 ring heteroatoms; preferably 3-6 membered heterocyclyl, which is a 3 to 6 membered nonaromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms; Preferred are 4-7 membered heterocyclic groups, which are 4 to 7 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; preferred 4-6 membered heterocyclic groups
  • Heterocyclyl also includes ring systems wherein the aforementioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or wherein the aforementioned heterocyclyl ring is fused to one or more aryl or Heteroaryl-fused ring systems wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridine, oxirane, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-diketone.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxasulfuranyl Oxazolidin-2-ones.
  • Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.
  • Exemplary 5-membered heterocyclyls (also referred to herein as 5,6-bicyclic heterocyclyls) fused to a C6 aryl ring include, but are not limited to: indolinyl, isoindolinyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like.
  • Exemplary 6-membered heterocyclyls (also referred to herein as 6,6 -bicyclic heterocyclyls) fused to a C aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.
  • a heterocyclyl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 6-10 aryl means a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having shared 6 or 10 ⁇ electrons) groups.
  • an aryl group has six ring carbon atoms ("C aryl”; eg, phenyl).
  • an aryl group has ten ring carbon atoms ("C 10 aryl”; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • Aryl also includes ring systems wherein the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system.
  • An aryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 5-14 membered heteroaryl means a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having 6, 10 or 14 ⁇ electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • the point of attachment can be a carbon or nitrogen atom, as valence permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems wherein the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said heteroaryl ring, in which case the carbon atoms Numbers continue to indicate the number of carbon atoms in the heteroaryl ring system.
  • 5-10 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms.
  • 5-9 membered heteroaryl is preferred, which is a 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms.
  • 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl.
  • 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 (eg, 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, pyridyl.
  • 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 tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.
  • Exemplary 5,6-bicyclic heteroaryls include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl , Benzisofuryl, Benzimidazolyl, Benzoxazolyl, Benzisoxazolyl, Benzoxadiazolyl, Benzthiazolyl, Benzisothiazolyl, Benzthiadiazolyl, Indenazinyl and Purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, multiplinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
  • a heteroaryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • Cycloalkylene is "cycloalkyl", “heterocyclyl”, “aryl” or “heteroaryl” as defined above A divalent group formed by the removal of another hydrogen and may be substituted or unsubstituted.
  • C 5-7 cycloalkylene refers to a divalent group formed by removing another hydrogen of C 5-7 cycloalkyl
  • 5-8 membered heterocyclylene refers to removing 5-8 A divalent group formed by another hydrogen of a membered heterocyclic group
  • C 6-10 arylene refers to a divalent group formed by removing another hydrogen of a C 6-10 aryl
  • 5-6 Heteroarylene refers to a divalent group formed by removing another hydrogen from a 5-6 membered heteroaryl.
  • Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, etc. are defined herein as optionally substituted groups.
  • Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are combined to form a heterocyclyl or Heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R groups group replacement;
  • Each of Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two Rcc groups are combined to form a heterocycle radical or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;
  • R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R groups;
  • Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R groups are combined to form a heterocyclyl or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R gg group substitution;
  • the term "pharmaceutically acceptable salt” refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention, which are suitable for use in contact with patient tissues within the scope of sound medical judgment without undue toxicity, Irritation, allergic effects, etc., commensurate with a reasonable benefit/risk ratio, are valid for their intended use, including, where possible, zwitterionic forms of the compounds of the invention.
  • Subjects for administration include, but are not limited to: human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adult, middle-aged adult or older adult)) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human", “patient” and “subject” are used interchangeably herein.
  • an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response.
  • an effective amount of a compound of the invention may vary depending on factors such as, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the condition of the subject. Age Health conditions and symptoms.
  • An effective amount includes a therapeutically effective amount and a prophylactically effective amount.
  • Combination and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent.
  • the compounds of the invention may be administered with the other therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together with the other therapeutic agent in a single unit dosage form.
  • the compound of the present invention refers to the following formula (I) compound (including sub-general formula, such as formula (II), formula (V-1) etc.), its pharmaceutically acceptable salt, enantiomer isomers, diastereoisomers, solvates, hydrates or isotopic modifications, and mixtures thereof.
  • the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound:
  • Z is selected from CH or N
  • Ring A is a 4-8 membered heterocyclic group
  • Ring B selected from
  • R 1 and R 2 are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 and R 4 are independently selected from H, OR a , C 1-6 alkyl or C 1-6 haloalkyl;
  • R is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from -C 0-6 alkylene-OR a , -C 0-6 alkylene-NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkane Base, 4-6 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R 8 is selected from -C 0-6 alkylene-OR a , -C 0-6 alkylene-NR b R c , C 1-6 alkyl, -C 1-6 alkylene-C 3-6 Cycloalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl, which is optionally replaced by 1 or more R a replaces;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl; or R b and R c Form a 4-7 membered heterocyclic group together with the nitrogen atom they are connected to;
  • X, Y, Z, ring A, ring B, L, R 1 -R 8 , R N , R a , R b and R c can be substituted by one or more deuterium atoms until completely Deuterium;
  • Z is CH; in another specific embodiment, Z is N.
  • the rings where X, Y and Z are located are selected from:
  • ring A is a 4-8 membered heterocyclyl; in another specific embodiment, ring A is selected from:
  • Ring B is In another specific embodiment, Ring B is In another specific embodiment, Ring B is In another specific embodiment, Ring B is
  • R 1 and R 2 are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; in another specific embodiment, one of R 1 and R 2 is Halogen, the other is selected from H, halogen or C 1-6 alkyl; In another specific embodiment, one of R 1 and R 2 is F, and the other is selected from H, F or Me; In another specific embodiment In the scheme, one of R1 and R2 is F and the other is H.
  • one of R 3 and R 4 is OR a , the other is selected from H or C 1-6 alkyl; in another specific embodiment, one of R 3 and R 4 is OH or OMe , the other selected from H or Me.
  • R is H ; in another specific embodiment, R is halogen; in another specific embodiment, R is C 1-6 alkyl; in another specific embodiment , R 5 is C 1-6 haloalkyl; In another specific embodiment, R 5 is selected from H or Me.
  • R 6 is -C 0-6 alkylene-OR a ; in another specific embodiment, R 6 is OR a ; in another specific embodiment, R 6 is -C 0 -6 alkylene-NR b R c ; In another specific embodiment, R 6 is NR b R c ; In another specific embodiment, R 6 is C 1-6 alkyl; In another specific embodiment In the scheme, R 6 is C 1-6 haloalkyl; In another specific embodiment, R 6 is C 3-6 cycloalkyl; In another specific embodiment, R 6 is 4-6 membered heterocyclyl ; In another specific embodiment, R 6 is C 6-10 aryl; In another specific embodiment, R 6 is 5-6 membered heteroaryl.
  • M is O; in another specific embodiment, M is NH.
  • R N is H; In another specific embodiment, R N is C 1-6 alkyl; In another specific embodiment, R N is C 1-6 haloalkyl; In another In one specific embodiment, R N and R 6 are connected to form C 1-6 alkylene; In another specific embodiment, RN and R 6 are connected to form C 2-6 alkenylene; In another specific embodiment In, R N and R 6 are connected to form a C 2-6 alkynylene group.
  • R 8 is -C 0-6 alkylene-OR a ; in another specific embodiment, R 8 is OR a ; in another specific embodiment, R 8 is -C 0 -6 alkylene-NR b R c ; In another specific embodiment, R 8 is NR b R c ; In another specific embodiment, R 8 is C 1-6 alkyl; In another specific embodiment In scheme, R 8 is -C 1-6 alkylene-C 3-6 cycloalkyl; In another specific embodiment, R 8 is C 1-6 haloalkyl; In another specific embodiment, R 8 is C 3-6 cycloalkyl; In another specific embodiment, R 8 is 4-6 membered heterocyclyl; In another specific embodiment, R 8 is C 6-10 aryl; In another specific embodiment, R 8 is C 6-10 aryl; In specific embodiments, R 8 is 5-6 membered heteroaryl.
  • any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments.
  • any technical scheme of X or any combination thereof can be combined with any technical scheme of Y, Z, ring A, ring B, L, R 5 , R 6 , etc., or any combination thereof.
  • the present invention intends to include the combination of all these technical solutions, which are not listed one by one due to space limitation.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrated Substances or solvates:
  • Z is selected from CH or N
  • Ring A is a 4-8 membered heterocyclic group
  • Ring B selected from
  • R 1 and R 2 are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 and R 4 are independently selected from H, OR a , C 1-6 alkyl or C 1-6 haloalkyl;
  • R is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5 -6 membered heteroaryl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R 8 is selected from OR a , NR b R c , C 1-6 alkyl, -C 1-6 alkylene-C 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl , 4-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, which are optionally substituted by 1 or more R a ;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom they are connected to;
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, Hydrates or solvates, wherein the rings where X, Y and Z are located are selected from:
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein ring A is selected from:
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein ring B is
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein ring B is
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein R 1 and R 2 one is halogen, another is selected from H, halogen or C 1-6 alkyl; Preferably, R 1 and R 2 One is F, another is selected from H, F or Me; preferably one of R1 and R2 is F and the other is H.
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein R 3 and R 4 one is OR a , the other is selected from H or C 1-6 alkyl; preferably, one of R 3 and R 4 is OH or OMe, the other is selected from From H or Me.
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein R 5 is selected from H or Me.
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, which has the following structure:
  • the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrated Substances or solvates:
  • Z is selected from CH or N
  • Ring A is a 4-8 membered heterocyclic group
  • R is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5 -6 membered heteroaryl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R 8 is selected from OR a , NR b R c , C 1-6 alkyl, -CH 2 -C 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 member Heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, which is optionally substituted by 1 or more R a ;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom to which they are attached.
  • the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrated Substances or solvates:
  • Ring A is a 4-8 membered heterocyclic group
  • R is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5 -6 membered heteroaryl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R 8 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5 -6 membered heteroaryl, which is optionally substituted by 1 or more R a ;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom to which they are attached.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • Ring A is selected from
  • R is selected from H or Me
  • R 6 is selected from Me, Et, Pr, CH 2 CF 3 , cyclopropyl, OH, NH 2 , NHMe, NMe 2 , furan-2-yl or pyridin-4-yl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R 8 is selected from Me, Et, Pr, CH 2 CF 3 , cyclopropyl, OH, NH 2 , NHMe, NMe 2 , pyran-4-yl, furan-2-yl or pyridin-4-yl;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom to which they are attached.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • Ring A is a 4-8 membered heterocyclic group
  • R 5 is H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R 8 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom to which they are attached.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • Ring A is a 4-8 membered heterocyclic group
  • R is selected from H or C 1-6 alkyl
  • R 6 is selected from NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 8 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or pyran-4-yl;
  • R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • Ring A is selected from
  • R 5 is H
  • R 6 is selected from Me or NH 2 ;
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R is selected from Me, Et, Pr, cyclopropyl or pyran-4-yl.
  • the present invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrated Substances or solvates:
  • Ring A is a 4-8 membered heterocyclic group
  • R 1 and R 2 are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 and R 4 are independently selected from H, OR a , C 1-6 alkyl or C 1-6 haloalkyl;
  • R is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5 -6 membered heteroaryl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom to which they are attached.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • Ring A is selected from
  • R 1 and R 2 are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 and R 4 are independently selected from H, OR a , C 1-6 alkyl or C 1-6 haloalkyl;
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5 -6 membered heteroaryl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom to which they are attached.
  • the present invention provides a compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
  • R 1 and R 2 are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 and R 4 are independently selected from H, OR a , C 1-6 alkyl or C 1-6 haloalkyl;
  • R is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5 -6 membered heteroaryl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom to which they are attached.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • R 1 and R 2 are halogen, and the other is selected from H, halogen or C 1-6 alkyl;
  • R 3 and R 4 is OR a , the other is selected from H or C 1-6 alkyl;
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 5-6 membered heteroaryl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom to which they are attached.
  • the present invention provides a compound of formula (VI), (VI-1) or (VI-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
  • M is O or NH
  • R 1 and R 2 are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3 and R 4 are independently selected from H, OR a , C 1-6 alkyl or C 1-6 haloalkyl;
  • R is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5 -6 membered heteroaryl;
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom they are connected to .
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • M is O or NH
  • R 1 and R 2 are halogen, and the other is selected from H, halogen or C 1-6 alkyl;
  • R 3 and R 4 is OR a , the other is selected from H or C 1-6 alkyl;
  • R is selected from H or C 1-6 alkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 5-6 membered heteroaryl;
  • RN is selected from H or C 1-6 alkyl
  • R N and R 6 are connected to form a C 1-6 alkylene group
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • M is O
  • R and R is F, and the other is selected from H, F or Me;
  • R3 and R4 is OH or OMe, and the other is selected from H or Me;
  • R is selected from H or Me
  • R 6 is selected from Me, Et, Pr, CH 2 CF 3 , cyclopropyl, NMe 2 , furan-2-yl or pyridin-4-yl;
  • RN is selected from H or Me
  • R N and R 6 are connected to form a C 1-4 alkylene group.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • M is O or NH
  • R and R is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl, and the other is H;
  • R 3 and R 4 is selected from OR a , C 1-6 alkyl or C 1-6 haloalkyl, and the other is H;
  • R is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5 -6 membered heteroaryl;
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom they are connected to .
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • M is O or NH
  • R 1 and R 2 are selected from halogen or C 1-6 alkyl, and the other is H;
  • R 3 and R 4 is OR a , and the other is H;
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl;
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • M is O
  • R and R is halogen (preferably F), the other is H;
  • R 3 and R 4 is OR a , and the other is H;
  • R is selected from H or C 1-4 alkyl
  • R 6 is selected from C 1-4 alkyl or C 1-4 haloalkyl
  • RN is selected from H, C 1-4 alkyl or C 1-4 haloalkyl; preferably C 1-4 alkyl;
  • R a is selected from H or C 1-4 alkyl.
  • the present invention provides a compound of formula (VII), (VII-1) or (VII-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
  • R is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5 -6 membered heteroaryl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R N and R 6 are connected to form C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R 8 is selected from OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5 -6 membered heteroaryl, which is optionally substituted by 1 or more R a ;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R b and R c form a 4-7 membered heterocyclic group together with the nitrogen atom to which they are attached.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • R is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl;
  • M is O or NH
  • RN is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 8 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic group, which is optionally substituted by 1 or more R a ;
  • R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • R is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • M is O or NH
  • R N is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R 8 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic group.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • R is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R N is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R 8 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compounds, of which:
  • R 5 is C 1-4 alkyl
  • R 6 is C 1-4 alkyl
  • R N is C 1-4 alkyl
  • R 8 is selected from C 1-4 alkyl or C 3-6 cycloalkyl.
  • the present invention provides a compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Said compound is selected from:
  • the compounds of the present invention may include one or more asymmetric centers, and thus may exist in various stereoisomeric forms, eg, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be individual enantiomers, diastereoisomers or geometric isomers (eg cis and trans isomers), or may be in the form of a mixture of stereoisomers, Racemic mixtures and mixtures enriched in one or more stereoisomers are included.
  • Isomers can be separated from mixtures by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be obtained by prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the compounds of the invention may also exist as tautomers.
  • a said compound is not limited to any particular tautomeric form, but is intended to encompass all tautomeric forms.
  • organic compounds may form complexes with solvents in which they react or from which they are precipitated or crystallized. These complexes are known as "solvates”. When the solvent is water, the complex is called a "hydrate”. The invention covers all solvates of the compounds of the invention.
  • solvate refers to a form of a compound, or a salt thereof, which is associated with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes both solution state solvates and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • hydrate refers to a compound that combines with water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined.
  • a hydrate of a compound can be represented, for example, by the general formula RxxH2O , where R is the compound, and x is a number greater than zero.
  • a given compound may form more than one hydrate type, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrates (R ⁇ 0.5H2 O)) and polyhydrates (x is a number greater than 1, eg, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
  • the compounds of the invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • the invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I), but with one or more atoms represented by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature replaced.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 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.
  • the compounds of the present invention their prodrugs and pharmaceutically acceptable salts of the compounds or the prodrugs containing the above-mentioned isotopes and/or other isotopes of other atoms all belong to the scope of the present invention.
  • Certain isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes (eg, 3H and14C ), are useful in drug and/or substrate tissue distribution assays. Tritium, ie3H , and carbon-14, ie14C isotopes are particularly preferred because of their ease of preparation and detection.
  • isotope-labeled compound of formula (I) of the present invention and its prodrug can generally be prepared in this way.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted in vivo to its active form having a medical effect, for example by hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, per intro This article serves as a reference.
  • the invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of a compound of the invention.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical composition comprises a prophylactically effective amount of a compound of the invention.
  • a pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- Block polymers, polyethylene glycol
  • kits eg, pharmaceutical packs.
  • kits can include a compound of the invention, another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packs or other suitable container).
  • first and second containers e.g., vials, ampoules, bottles, syringes, and/or dispersible packs or other suitable container.
  • provided kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent.
  • a compound of the invention and other therapeutic agent provided in a first container and a second container are combined to form a unit dosage form.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intracerebrospinal administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of the compound actually administered can be determined by the physician according to the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .
  • the compounds provided herein are administered to a subject at risk of developing the condition, typically on the advice and supervision of a physician, at dosage levels as described above.
  • Subjects at risk of developing a particular condition generally include those with a family history of the condition, or those determined by genetic testing or screening to be particularly susceptible to developing the condition.
  • Chronic administration refers to administering a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue administration indefinitely, For example, the rest of the subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within the therapeutic window.
  • compositions may be administered as a bolus injection, eg, in order to increase the concentration of the compound in the blood to effective levels.
  • the bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose provides slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., by IV intravenous infusion) ) can be delivered more rapidly, so that the concentration of the active ingredient in the blood rises rapidly to effective levels.
  • the pharmaceutical compositions may be administered as a continuous infusion, eg, by IV infusion, to provide a steady state concentration of the active ingredient in the subject's body. Additionally, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.
  • Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More usually, however, the compositions will be presented in unit dosage form for ease of precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions.
  • the compound will generally be a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the remainder being various components useful for forming the desired administration form. Carriers or excipients and processing aids.
  • a typical regimen is one to five oral dosages per day, especially two to four oral dosages, typically three oral dosages.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.
  • the transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injection dosage levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour from about 1 to about 120 hours, especially 24 to 96 hours.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be given in order to achieve adequate steady state levels.
  • the maximum total dose should not exceed approximately 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffering, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may comprise, for example, any of the following components, or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, peppermint, water Methyl sylate or orange flavoring.
  • binders such as microcrystalline cellulose, tragacanth, or gelatin
  • excipients such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound is typically a minor component, often from about 0.05 to 10% by weight, the remainder being injectable excipients and the like.
  • Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active ingredients When formulated in an ointment, the active ingredients are typically combined with a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream, with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art, and generally include other ingredients for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.
  • transdermal administration can be achieved using patches of the reservoir or porous membrane type, or various solid matrices.
  • compositions for oral administration, injection or topical administration are representative only. Other materials and processing techniques, etc. are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8, which is incorporated herein by reference.
  • the compounds of the invention may also be administered in sustained release form, or from a sustained release delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention also relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ -, and ⁇ -cyclodextrins composed of 6, 7, and 8 ⁇ -1,4-linked glucose units, respectively, optionally including a or multiple substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, eg, sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol. See, eg, U.S. 5,376,645.
  • the formulation includes hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the reagents used in the present invention are commercial reagents purchased directly or synthesized by common methods well known in the art.
  • Step 3 Dissolve 3-chloro-5-(prop-1-en-2yl)isoquinoline a1-4 (3.5g, 17.2mmol) in 50mL ethyl acetate, add platinum dioxide (0.78g , 3.4 mmol), reacted at room temperature under hydrogen atmosphere for 6 hours. The reaction solution was filtered, concentrated, and separated by column chromatography to obtain an oily intermediate a1-5 (2.1 g), yield: 54%, LC-MS: ESI-MS (m/z): 206.1 [M+H] + .
  • Step 1 Under ice bath and nitrogen protection, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate a2-1 (4.8g, 22mmol) and triethylamine (4.53g , 44mmol) was dissolved in 50mL of dichloromethane, and methanesulfonyl chloride (3.08g, 26mmol) was added dropwise, and the stirring was continued for 2 hours. 10 mL of saturated aqueous sodium bicarbonate solution was added to the reaction solution to quench the reaction, extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude compound a2-2 (6.24 g) was obtained, yield: 86%.
  • Step 2 Under the protection of nitrogen, the intermediate a2-2 (6.24g, 21mmol) of the previous step and sodium methyl mercaptide (20% aqueous solution) (15.0g, 42mmol) were dissolved in 50mL DMF, heated to 60°C and stirred for 12 hours , LC-MS detects that the reaction is complete. 200 mL of water was added to the system, extracted with ethyl acetate, washed with saturated brine, the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a colorless oil a2-3 (3.98 g), yield: 69%.
  • Step 3 Dissolve the above intermediate a2-3 (3.98g, 16mmol) in 200mL of dichloromethane, add the oxidant Oxone (50.1g, 81mmol), and react at room temperature for 48 hours. Stop the reaction, filter, and concentrate the filtrate to obtain compound a2-4 (4.18g), yield: 83%.
  • Step 4 Compound a2-4 (3.72g, 13mmol] was dissolved in 40mL of dichloromethane, trifluoroacetic acid (4.62g, 41mmol) was added dropwise, and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to obtain the crude product a2- 5 (1.95 g).
  • Step 5 Under the protection of nitrogen, mix the intermediate a2-5 (1.6g, 5.5mmol) and Cs 2 CO 3 (5.38g, 16.5mmol) in 25mL 1,4-dioxane, add Xantphos Pd G3 (520mg, 0.5mmol), heated to 100°C. Intermediate a1 (1.57g, 5.5mmol) was added to the reaction solution, and the reaction solution was continued to react at 100°C for 3 hours, the reaction was stopped, filtered, the filtrate was concentrated, and separated by flash column chromatography to obtain a yellow solid a2 (820mg) , Yield: 35%, LCMS: ESI-MS (m/z): 379.1 [M+H] + .
  • Step 2 Under the protection of nitrogen, the intermediate a4-1 (20mg, 0.042mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate a4-2 (40mg, 0.21mmol) and CuI (24mg, 0.12mmol) was mixed in 5mL DMF, heated to 90°C for 1 hour, and LC-MS monitored the completion of the reaction.
  • Step 2 Dissolve the above crude product a6-1 (50mg, 0.16mmol) in 3mL of dichloromethane, add HOBT (6mg, 0.047mmol), EDCI (36mg, 0.19mmol) and DIPEA (40mg, 0.31mmol), room temperature Stir for 1 hour. Aqueous ammonia (0.2 mL) was added to the reaction solution, and the reaction was continued at room temperature for 2 hours.
  • Step 1 Dissolve the raw material 1-(diphenylmethyl)-2,2-dimethylazetidin-3-one a7-1 (3.2g, 12.1mmol) in 50mL methanol under ice bath , sodium borohydride (912 mg, 24.1 mmol) was added, and the temperature was raised to 70° C. to react for 16 hours.
  • Step 2 Under ice bath, dissolve the intermediate a7-2 (1.0g, 3.74mmol) and triethylamine (605mg, 5.98mmol) in 20mL of dichloromethane, add methanesulfonyl chloride (554mg, 4.86mmol ), stirred at room temperature for 1 hour. Stop the reaction, add 50 mL of water to the system, extract with dichloromethane, and concentrate to obtain the crude product a7-3 (1.1 g), which is directly used in the next reaction.
  • Step 3 Dissolve methyl 2-methanesulfonylacetate a7-4 (745mg, 4.89mmol) in 20mL DMF under ice bath, add NaH (181mg, 4.52mmol, 60%), and stir the reaction solution at 0°C After 15 minutes, the crude product a7-3 (1.1 g) from the previous step was added to the system, and the temperature was raised to 80° C. to react for 16 hours.
  • Step 5 Under a hydrogen balloon atmosphere, dissolve the intermediate a7-6 (2200 mg, 0.64 mmol) in 12 mL of methanol, add 0.5 mL of trifluoroacetic acid and Pd(OH) 2 /C (20 mg), and react at room temperature for 16 Hour. Stop the reaction, filter, and concentrate under reduced pressure to obtain yellow trifluoroacetate a7-7 (150 mg), yield: 92%, LC-MS: ESI-MS (m/z): 178.2 [M+H] + .
  • Step 6 Under nitrogen protection, mix trifluoroacetic acid salt a7-7 (92mg, 0.31mmol), intermediate a1 (60mg, 0.21mmol) and Cs 2 CO 3 (171mg, 0.52mmol) in 3mL 1, Add XantPhos Pd G3 (65mg, 0.063mmol) to 4-dioxane, heat up to 100°C and react for 6 hours. Stop the reaction, filter, concentrate the filtrate, and separate by flash column chromatography to obtain a yellow solid a7 (35 mg), yield: 39%, LC-MS: ESI-MS (m/z): 381.1 [M+H] + .
  • Step 1 Dissolve dimethylphosphine oxide a8-1 (1.0g, 12.8mmol) in 20mL of anhydrous tetrahydrofuran at -20°C under nitrogen protection, add LDA (1M, 38.4mL) dropwise, and stir for 20 minutes Then, a tetrahydrofuran solution (10 mL) of intermediate a3-1 (5.72 g, 19.2 mmol) was added dropwise. After dropping, slowly rise to room temperature, and react at room temperature for 5 hours, then stop the reaction.
  • Step 2 Dissolve intermediate a8-2 (800 mg, 3.23 mmol) in 6 mL of dichloromethane, add 3 mL of trifluoroacetic acid, and stir overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain the crude product a8-3, which was directly used in the next reaction.
  • Step 3 Under nitrogen protection, mix trifluoroacetic acid salt a8-3, intermediate a1 (774mg, 2.7mmol) and Cs 2 CO 3 (2.66g, 8.2mmol) in 15mL 1,4-dioxane Add XantPhos Pd G3 (258mg, 0.27mmol) to the ring, heat up to 100°C and react for 16 hours. Stop the reaction, filter, concentrate the filtrate, and separate by flash column chromatography to obtain a yellow solid a8 (200 mg). LC-MS: ESI-MS (m/z): 351.0 [M+H] + .
  • Step 1 Dissolve activated zinc powder (0.6g, 9.16mmol) in 4mL DMA, raise the temperature to 65°C, add trimethylchlorosilane (0.13g, 0.13mL) and 1,2-dibromoethyl to the system dropwise Alkane (0.1mL, 1.3mmol), after dropping, continue to stir for 40 minutes.
  • a DMF solution (4 mL) of a10-2 (2.0 g, 7.06 mmol) was added dropwise to the reaction liquid, the reaction was continued for 30 minutes, cooled to room temperature, and set aside.
  • Step 2 Dissolve the intermediate a10-3 (200 mg, 0.85 mmol) in 4 mL of dichloromethane, add 1.5 mL of trifluoroacetic acid dropwise, react at room temperature for 3 hours, and stop the reaction. The solvent was distilled off under reduced pressure to obtain trifluoroacetic acid salt a10-4 (160 mg), yield 69%, LC-MS: ESI-MS (m/z): 135.1 [M+H] + .
  • Step 3 Under the protection of nitrogen, the trifluoroacetic acid salt a10-4 (31mg, 0.23mmol), the intermediate a1 (65mg, 0.23mmol) and Cs 2 CO 3 (223mg, 0.69mmol) were mixed in 3mL 1, Add XantPhos Pd G3 (22mg, 0.023mmol) to 4-dioxane, heat up to 100°C and react for 16 hours. Stop the reaction, filter, concentrate the filtrate, and separate by flash column chromatography to obtain a10 (50 mg) as a yellow solid. LC-MS: ESI-MS (m/z): 338.0 [M+H] + .
  • Step 2 Dissolve intermediate a11-2 (3.3 g, 13 mmol) in 40 mL of ethanol, add 20 mL of 1N aqueous NaOH solution, heat up to 80° C. for 2 hours, and stop the reaction.
  • the solvent ethanol was distilled off under reduced pressure, and the pH was adjusted to 3-4 with 1M hydrochloric acid.
  • Step 4 Under ice bath and nitrogen protection, dissolve NaH (420mg, 10.g mmol, 60%) in 10mL of anhydrous tetrahydrofuran, slowly add ethyl tert-butyl malonate a11-5 (1.96g, 10.5 mmol), after stirring for 30 minutes, a tetrahydrofuran solution (10 mL) of intermediate a11-4 (1.65 g, 5.24 mmol) was added, and stirring was continued for 2 hours under ice-cooling.
  • NaH 420mg, 10.g mmol, 60%
  • Step 5 Dissolve the intermediate a11-6 (780mg, 2.75mmol) in 10mL of ethanol, add DBU (1.23g, 8.22mmol), heat up to 80°C for 2 hours, and stop the reaction. Concentrate under reduced pressure to remove ethanol, add 1M hydrochloric acid to the reaction solution to adjust the pH to about 3, and precipitate a white solid, filter with suction, wash the filter cake with water, and dry to obtain intermediate a11-7 (440mg), yield: 61%, LC - MS: ESI-MS (m/z): 239.0 [M+H] + .
  • Step 6 Dissolve the above intermediate a11-7 (440mg, 1.67mmol) in 10mL DMF, add triethylamine (507mg, 5.02mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (718mg , 2.0mmol), reacted at room temperature for 2 hours, and stopped the reaction.
  • Step 7 Under nitrogen protection, mix intermediate a11-8 (210mg, 0.57mmol), intermediate a3-4 (140mg, 0.53mmol) and Cs 2 CO 3 (556mg, 1.71mmol) in 10mL 1,4 - Add Pd 2 (dba) 3 (52mg, 0.057mmol) and Xantphos (65mg, 0.113mmol) to dioxane, heat up to 60°C and react for 2 hours. Stop the reaction, filter, concentrate the filtrate, and separate by flash column chromatography to obtain white solid a11 (30mg), yield: 15%, LC-MS: ESI-MS (m/z): 370.0[M+H] + .
  • Step 1 Under nitrogen protection, the intermediate a1 (700mg, 2.46mmol), Pd 2 (dba) 3 (225mg, 0.25mmol), Xphos (234mg, 0.49mmol) and the newly prepared raw material a12-1 (4mL, 5.0mmol ) was dissolved in 4 mL of DMA, and the temperature was raised to 85° C. for 15 hours.
  • Step 2 Dissolve the above intermediate a12-2 (85 mg, 0.24 mmol) in 6 mL of dichloromethane, add 2 mL of trifluoroacetic acid dropwise, react at room temperature for 12 hours, and stop the reaction. The reaction solution was concentrated to obtain trifluoroacetate salt a12-3 (20 mg), yield: 30%, LC-MS: ESI-MS (m/z): 261.1 [M+H] + .
  • Step 3 Mix the above intermediate a12-3 (20mg, 0.08mmol) and K 2 CO 3 (43mg, 0.31mmol) in 5mL of acetonitrile, add 2-bromo-N-methylacetamide a12-4 (9mg , 0.061 mmol), reacted at room temperature for 3 hours, and stopped the reaction.
  • the intermediate a4-1 (50mg, 0.10mmol) was dissolved in 5mL DMF, Pd( tBuP ) 3 (16mg, 0.03mmol) and zinc cyanide (18mg, 0.16mmol) were added, and the temperature was raised to 100°C The reaction was carried out for 1 hour, and the reaction was completed by LC-MS monitoring.
  • Step 1 Under nitrogen protection, the intermediate a14-1 (1.0g, 6.11mmol), Pd 2 (dba) 3 (558mg, 0.61mmol), Xphos (581mg, 1.22mmol) and the newly prepared raw material a12-1 (8mL , 12.0mmol) was dissolved in 6mL of DMA, and the temperature was raised to 85°C for 12 hours.
  • Step 2 Dissolve the intermediate a14-2 (120 mg, 0.42 mmol) in 6 mL of dichloromethane, add 2 mL of trifluoroacetic acid dropwise, react at room temperature for 0.5 hours, and stop the reaction. The reaction solution was concentrated to obtain trifluoroacetate salt a14-3 (70 mg), yield: 91%, LC-MS: ESI-MS (m/z): 141.1 [M+H] + .
  • Step 3 Under the protection of nitrogen, the trifluoroacetic acid salt a14-3 (100mg, 0.71mmol), the intermediate a1 (203mg, 0.71mmol) and Cs 2 CO 3 (1162mg, 3.57mmol) were mixed in 10mL 1, Add XantPhos Pd G3 (68mg, 0.071mmol) to 4-dioxane, heat up to 100°C and react for 3 hours. Stop the reaction, filter, concentrate the filtrate, and separate by flash column chromatography to obtain a yellow solid a14 (70mg), yield: 26%, LC-MS: ESI-MS (m/z): 344.1[M+H] + .
  • Step 2 In an ice bath, dissolve the intermediate a15-1 (1.1g, 5.16mmol) of the previous step in 13mL of anhydrous tetrahydrofuran, add NaH (1.2g, 30.1mmol, 60%), and stir the reaction solution for 30 minutes.
  • CDI 2.5 g, 15.4 mmol was added to the reaction solution, the temperature was raised to room temperature, and the reaction was continued for 1 hour, and the reaction was completed by LC-MS monitoring.
  • Step 3 Dissolve the intermediate a15-2 (1.0g, 4.18mmol) and DIEA (530mg, 4.18mmol) in 15mL of acetonitrile, add POCl 3 (640mg, 4.18mmol), and raise the temperature of the reaction solution to 90°C React for 1 hour, stop the reaction, and cool to room temperature.
  • Step 4 Under ice bath, dissolve intermediate a3-4 (408mg, 1.55mmol), intermediate a15-3 (400mg, 1.55mmol) and DIEA (802mg, 6.19mmol) in 10mL of dichloromethane, under ice bath React for 1 hour. Stop the reaction, add 30 mL of water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and separate by flash column chromatography to obtain a white solid a15 (300 mg), yield: 47%, LC-MS: ESI- MS (m/z): 371.0 [M+H] + .
  • Step 1 Under nitrogen protection, compound a16-1 (304mg, 1.76mmol), intermediate a1 (500mg, 1.76mmol) and Cs 2 CO 3 (2.86g, 8.78mmol) were mixed in 10mL 1,4-dioxane Add XantPhos Pd G3 (166mg, 0.17mmol) to the ring, heat up to 100°C and react for 2 hours. Stop the reaction, filter, concentrate the filtrate, and separate by flash column chromatography to obtain a yellow solid a16-2 (400mg), yield: 55%, LC-MS: ESI-MS (m/z): 376.2[M+H] + .
  • Step 2 Under ice bath, dissolve the intermediate a16-2 (120mg, 0.32mmol) in 2mL of dichloromethane, add 0.5mL pyridine, slowly add 0.5mL trimethylsilyl trifluoromethanesulfonate, room temperature The reaction was carried out for 16 hours, and the reaction was monitored by LC-MS to complete.
  • Step 3 Dissolve the above intermediate a16-3 (21mg, 0.077mmol) and triethylamine (21mg, 0.21mmol) in 2mL of dichloromethane, add methanesulfonyl chloride (139 ⁇ L, 0.18mmol), and stir at room temperature 2 hours, stop the reaction. Add 10 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and separate by thin-layer chromatography to obtain a white solid a16 (20 mg), yield: 65%, LC-MS: ESI-MS (m/z): 354.0[M+H] + .
  • the intermediate a16 (40mg, 0.11mmol) was dissolved in 3mL DMF, NaH (6mg, 0.15mmol) and iodoethane (20mg, 0.13mmol) were added, and the temperature was raised to room temperature for 2 hours, LC-MS Monitor the reaction for completion.
  • Step 1 Under the protection of nitrogen, the raw material a25-1 (7.0g, 27.7mmol) and triethylamine (4.2g, 41.5mmol) were dissolved in 40mL of dichloromethane, and methylsulfonyl chloride (3.21g, 28.0mmol) was added , reacted at room temperature for 4 hours. The reaction was stopped, and the solvent was removed under reduced pressure to obtain the crude product a25-2 (10.8 g).
  • Step 2 Dissolve the above crude product a25-2 (10.8g) and raw material a25-3 (4.21g, 27.7mmol) in 30mL DMF, add NaH (1.11g, 27.7mmol), slowly raise the temperature to 80°C and react 12 Hours, LC-MS monitored the reaction to be complete. Add 100 mL of saturated saline solution to the system to quench the reaction, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product a25-4 (15 g).
  • Step 3 Dissolve the crude product a25-4 (15g) and LiCl (2.52g, 60.0mmol) in 40mL N,N-dimethylacetamide DMA, raise the temperature to 150°C for 2 hours, and stop the reaction. Add 100mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and separate by flash column chromatography to obtain a yellow solid a25-5 (6.42g). The total yield of three steps: 71% , LC-MS: ESI-MS (m/z): 330.1 [M+H] + .
  • Step 4 Under a hydrogen atmosphere (2atm), mix the intermediate a25-5 (6.42g, 19.5mmol) and Pd/C (1.28g, 20%) in 40mL methanol, add 2mL trifluoroacetic acid, at room temperature After 16 hours of reaction, the reaction was stopped. Filtration and concentration gave yellow oil a25 (4.5 g), which was directly used in the next reaction.
  • Step 1 In ice bath, under the protection of nitrogen, the raw material a28-1 (250mg, 1.45mmol) and triethylamine (294mg, 2.9mmol) were dissolved in 5mL DMF, and 3-chloropropylsulfonyl chloride a28-2 (282mg , 1.59mmol), after stirring for 30 minutes, NaH (174mg, 4.35mmol) was added, and the temperature was raised to room temperature for 12 hours to stop the reaction.
  • intermediate a40-1 was obtained. Operation steps: the intermediate 1-(3-chloro-5-isopropylisoquinolin-8-yl)-N-methylazetidine-3-amine a40-1 (10mg, 0.035mmol) and Triethylamine (11 mg, 0.11 mmol) was dissolved in 3 mL of dichloromethane, 1.0 mL of trifluoromethanesulfonic anhydride (20 mg, 0.07 mmol) in dichloromethane was added dropwise, and reacted at room temperature for 2 hours.
  • cis-3-fluoro-4-hydroxypiperidine-1-carboxylate tert-butyl ester b2 (800mg, 3.63mmol) was dissolved in 5mL 1,4-dioxane, and slowly added dropwise with 4M hydrogen chloride Dioxane solution (4.5 mL, 18.16 mmol) was reacted at room temperature for 2 hours, and the solvent was evaporated under reduced pressure to obtain compound b3-1 (210 mg), which was directly used in the next reaction.
  • intermediate a2 70mg, 0.185mmol
  • Cs 2 CO 3 180mg, 0.55mmol
  • intermediate b3 39mg, 0.185mmol
  • Pd was added 2 (dba) 3 CHCl 3 (56mg, 0.055mmol) and C-phos (24mg, 0.055mmol) were heated to 100°C for 12 hours, and the reaction was completed by LC-MS monitoring. After filtration, the filtrate was concentrated and separated by preparative HPLC chromatography to obtain yellow solid P1 (4.0 mg), yield: 4%, LCMS: ESI-MS (m/z): 555.0 [M+H] + .
  • intermediate a3 35mg, 0.10mmol
  • Cs 2 CO 3 48mg, 0.15mmol
  • intermediate b6 32mg, 0.12mmol
  • Pd was added 2 (dba) 3 CHCl 3 (10mg, 0.01mmol) and C-phos (4.5mg, 0.01mmol) were heated to 100°C for 12 hours, and the reaction was completed by LC-MS monitoring. After filtration, the filtrate was concentrated and separated by preparative HPLC chromatography to obtain yellow solid H1 (2.7mg), yield: 5%
  • intermediate a3 (9mg, 0.026mmol), Cs 2 CO 3 (17mg, 0.052mmol) and intermediate b8 (7mg, 0.026mmol) were mixed in 1.5mL 1,4-dioxane, added Pd 2 (dba) 3 CHCl 3 (81mg, 0.008mmol) and C-phos (3.0mg, 0.008mmol) were heated to 100°C for 20 hours, and the reaction was completed by LC-MS monitoring. After filtration, the filtrate was concentrated and separated by preparative HPLC chromatography to obtain yellow solid H3 (5.0 mg), yield: 44%, LCMS: ESI-MS (m/z): 437.3[M+H] + .
  • MSA Mobility Shift Assay
  • Conversion%_sample is the conversion rate reading of the sample
  • Conversion%_min is the average value of the negative control well, representing the conversion rate reading of the well without enzyme activity
  • Conversion%_max is the average value of the positive control well, representing the conversion rate reading of the well without compound inhibition.
  • the dose-effect curve was fitted using the log (inhibitor) vs. response-Variable slope of the analysis software GraphPad Prism 5, so as to obtain the IC 50 of each compound on the enzyme activity value.
  • Table 1 Compounds for EGFR (wild-type), EGFR (L858R), EGFR (L858R/C797S) and EGFR (L858R/T790M/C797S) inhibition test results
  • the molecule of the present invention has a good inhibitory effect on the drug-resistant mutation of osimertinib in EGFR, and has a weaker inhibitory effect on wild-type EGFR with high selectivity.
  • Promega CellTiter-Glo reagent was used to detect the effect of small molecule inhibitors on five Ba/F3 cell lines (Ba/F3-FL-EGFR, Ba/F3-FL-EGFR-L858R, Ba/F3-FL-EGFR-L858R-T790M- C797S, Ba/F3-TEL-EGFR-L858R-C797S and Ba/F3-FL-EGFR-del19-C797S) proliferation.
  • Cell lines were cultured in an incubator with culture conditions of 37 °C, 5% CO2 . Passage regularly, and take cells in logarithmic growth phase for plating. 95 ⁇ L of cell suspension was added to each well of the cell plate, and culture solution without cells (containing 0.1% DMSO) was added to the Min control well.
  • Compound detection cell plate dosing Take 5 ⁇ L of 20 ⁇ compound working solution and add it to the cell culture plate as shown in the table below. Add 5 ⁇ L of DMSO-cell culture solution mixture to the Max control, and the final concentration of DMSO is 0.1%. Add 5 ⁇ L of DMSO-cell culture medium mixture to the Max control. The final concentration of DMSO was 0.1%.
  • Inhibition Rate (Inh%) 100-(RLU Drug -RLU Min )/(RLU Max -RLU Min )*100%.
  • RLU Drug represents the relative luminescence unit of the cells added with the drug
  • RLU Min represents the luminescence unit of the culture medium
  • RLU Max represents the relative luminescence unit of the cells added with DMSO.
  • the inhibition rates corresponding to different concentrations of compounds were calculated in EXCEL, and then the GraphPad Prism software was used to draw the inhibition rate curve and calculate related parameters, including the maximum and minimum inhibition rates of cells, and IC 50 values.
  • the compound of the present invention has a good anti-proliferation effect on the L858R-related mutation in EGFR and the drug-resistant mutation of Osimertinib, weak inhibition on wild-type EGFR, and some compounds are significantly better than the control molecule.
  • Promega CellTiter-Glo reagent was used to detect the effects of small molecule inhibitors on three Ba/F3 cell lines (Ba/F3-FL-EGFR-del19, Ba/F3-FL-EGFR-del19-T790M, Ba/F3-FL-EGFR- del19-T790M-C797S) proliferation.
  • Cell lines were cultured in an incubator with culture conditions of 37 °C, 5% CO2 . Passage regularly, and take cells in logarithmic growth phase for plating. 95 ⁇ L of cell suspension was added to each well of the cell plate, and culture solution without cells (containing 0.1% DMSO) was added to the Min control well.
  • Compound detection cell plate dosing Take 5 ⁇ L of 20 ⁇ compound working solution and add it to the cell culture plate. Add 5 ⁇ L of DMSO-cell culture solution mixture to the Max control, and the final concentration of DMSO is 0.1%. Add 5 ⁇ L of DMSO-cell culture medium mixture to the Max control. The final concentration of DMSO was 0.1%.
  • Inhibition Rate (Inh%) 100-(RLU Drug -RLU Min )/(RLU Max -RLU Min )*100%.
  • RLU Drug represents the relative luminescence unit of the cells added with the drug
  • RLU Min represents the luminescence unit of the culture medium
  • RLU Max represents the relative luminescence unit of the cells added with DMSO.
  • the inhibition rates corresponding to different concentrations of compounds were calculated in EXCEL, and then the GraphPad Prism software was used to draw the inhibition rate curve and calculate related parameters, including the maximum and minimum inhibition rates of cells, and IC 50 values.
  • the compound to be tested is co-incubated with liver microsomes of different species with or without adding NADPH, the final concentration of the compound to be tested in the test system is 1 ⁇ M, and the final concentration of NADPH 1mM, the final concentration of liver microsomes is 0.5mg/ml. Detect the concentration of the compound in the incubation supernatant at different time points within 60 minutes and calculate the pharmacokinetic parameters (such as clearance rate Clint).
  • BaF3 (del19/T790M/C797S) tumor cells were cultured, and the tumor cells were inoculated into 6-8 week old female BALB/c nude mice (body weight about 20 g), and all mice were inoculated subcutaneously. Mice were raised in an SPF-grade experimental environment, and all mice had free access to commercially certified standard diets. When the average tumor volume of the mice grew to about 150 mm 3 , daily oral administration of the test compound was started. The dosage is: blank group vehicle (DMSO/Solutol/H 2 O, 5/10/85). The dosage of the administration group was 100mg/kg, twice a day; the dosage of the Osimertinib group was 25mg/kg, once a day.
  • Tumor volumes were measured with two-dimensional calipers three times a week, and animals were weighed daily. After 13 days of continuous administration, the inhibition rate (TGI/100%) was calculated according to the final tumor volume.
  • TGI blank group 0 3870 0% Osimertinib 25mg/kg, QD 3110 20% H12 100mg/kg $ , BID 1341 68% H23 100mg/kg $ , BID 28 103% P39a 100mg/kg, BID 945 79% P41a 100mg/kg, BID 693 85%
  • $ indicates that the dosage is 50mg/kg in the first 4 days and 100mg/kg from the 5th day.

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Abstract

一种2-哌啶基或2-吡唑基取代的嘧啶化合物，其为式(I)所示化合物或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物。包含所述化合物的药物组合物，及其在治疗EGFR蛋白及其突变体介导的疾病中的用途。

Description

2-哌啶基或2-吡唑基取代的嘧啶化合物作为EGFR抑制剂 技术领域
本发明属于医药领域，具体涉及2-哌啶基或2-吡唑基取代的嘧啶化合物作为EGFR抑制剂。
背景技术
肺癌是最常见的恶性肿瘤之一，全球每年新发肺癌病例数约160万，分为小细胞肺癌和非小细胞肺癌(NSCLC)两种类型，其中非小细胞肺癌约占肺癌总数的85％(Nature Reviews Disease Primers,2015,1,15009)。表皮生长因子受体(EGFR)是非小细胞肺癌最常见的驱动基因，在所有非小细胞肺癌中阳性率达到17％，在国内患者中接近30％～40％，在肺腺癌中更是高达约60％。
EGFR是一种跨膜糖蛋白，属于酪氨酸激酶受体的ErbB家族。EGFR被各种机制异常激活，如受体过表达、突变，配体依赖性受体二聚化、配体非依赖性激活，其激酶活性的持续激活启动了细胞增殖、分化和存活的下游信号传导。EGFR激酶的小分子抑制剂可以抑制酪氨酸激酶的活化，抑制肿瘤细胞的增殖、促进肿瘤细胞发生凋亡等生物学效应，是肺癌开发的热点领域。
奥希替尼(Osimertinib)是针对一二代药物耐药突变EGFR(del19或L858R)同时伴有T790M突变开发的药物，临床上显示非常显著的疗效，但随着治疗的持续，患者也会出现耐药性。2015年(Nature Medicine,2015,21,560–562)首次报道了15例服用奥希替尼患者的耐药数据，其中EGFR C797S突变是导致药物奥希替尼耐药的主要机制之一，约占40％。另外最新的文献报道显示，奥希替尼二线治疗后耐药患者中，有22-25％的比例为C797S突变(Nature Cancer,2021,377-391)。因此，开发针对C797S突变的新的小分子抑制剂，为患者提供更加安全有效的第四代EGFR抑制剂具有迫切的临床需求。
另一方面，虽然第一代EGFR抑制剂吉非替尼(gefitinib)和第三代EGFR抑制剂奥希替尼均在1线EGFR激活突变的人群中产生良好的治疗效果，但是在亚组分析中，L858R的人群获益远低于del19人群，PFS分别为14.4和21.4个月(The new England journal of medicine,2018,378,113-125)。
发明内容
在本发明中，我们使用临床上出现的L858R/C797S、L858R/T790M/C797S以及L858R等主要的突变类型，开展了酶学水平评价，并在构建的Ba/F3细胞水平上进行验证，最终发现了一系列具有较强生物学活性的新化学实体。
在一个方面，本发明提供了式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
Figure PCTCN2022128264-appb-000001
其中：
Figure PCTCN2022128264-appb-000002
表示
Figure PCTCN2022128264-appb-000003
或
Figure PCTCN2022128264-appb-000004
其中当
Figure PCTCN2022128264-appb-000005
为
Figure PCTCN2022128264-appb-000006
X选自CH或N，Y选自CH 2、C＝O或C＝S；当
Figure PCTCN2022128264-appb-000007
为
Figure PCTCN2022128264-appb-000008
时，X为C，Y为CH；
Z选自CH或N；
环A为4-8元杂环基；
环B选自
Figure PCTCN2022128264-appb-000009
L选自化学键、-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-、-C(＝O)-CH(R N)-、-CH(R N)-S(＝O)(＝M)-或-S(＝O)(＝M)-CH(R N)-；
R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 3和R 4独立地选自H、OR a、C 1-6烷基或C 1-6卤代烷基；
R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
R 7选自H、C 1-6烷基、C 1-6卤代烷基或-S(＝O)(＝M)-R 8；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R 8选自OR a、NR bR c、C 1-6烷基、-C 1-6亚烷基-C 3-6环烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基，其任选被1个或多个R a取代；
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基；
条件是，当L为-CH(R N)-S(＝O)(＝M)-，且X、Y和Z所在环为苯环时，B为
Figure PCTCN2022128264-appb-000010
在另一个方面，本发明提供了一种药物组合物，所述药物组合物含有本发明化合物，和任选地药学上可接受的赋形剂。
在另一个方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物，其还含有其它治疗剂。
在另一个方面，本发明提供了本发明化合物在制备用于治疗和/或预防EGFR蛋白及其突变体介导的疾病的药物中的用途。
在另一个方面，本发明提供了在受试者中治疗和/或预防EGFR蛋白及其突变体介导的疾病的方法，包括向所述受试者给药本发明化合物或本发明组合物。
在另一个方面，本发明提供了本发明化合物或本发明组合物，其用于治疗和/或预防EGFR蛋白及其突变体介导的疾病。
在具体实施方案中，所述EGFR突变体L858R突变体、del19突变体、T790M突变体、C797S突变体中的一种或多种；优选地，所述疾病选自肺癌、结肠癌、尿路上皮癌、乳腺癌、前列腺癌、脑癌、卵巢癌、胃癌、胰腺癌、头颈癌、膀胱癌和间皮瘤，优选非小细胞肺癌。
由随后的具体实施方案、实施例和权利要求，本发明的其它目的和优点将对于本领域技术人员显而易见。
定义
化学定义
下面更详细地描述具体官能团和化学术语的定义。
当列出数值范围时，既定包括每个值和在所述范围内的子范围。例如“C 1-6烷基”包括C 1、C 2、C 3、C 4、C 5、C 6、C 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和C 5-6烷基。
“C 1-6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团。在一些实施方案中，C 1-4烷基和C 1-2烷基是优选的。C 1-6烷基的例子包括：甲基(C 1)、乙基(C 2)、正丙基(C 3)、异丙基(C 3)、正丁基(C 4)、叔丁基(C 4)、仲丁基(C 4)、异丁基(C 4)、正戊基(C 5)、3-戊基(C 5)、戊基(C 5)、新戊基(C 5)、3-甲基-2-丁基(C 5)、叔戊基(C 5)和正己基(C 6)。术语“C 1-6烷基”还包括杂烷基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。常规烷基缩写包括：Me(-CH 3)、Et(-CH 2CH 3)、iPr(-CH(CH 3) 2)、nPr(-CH 2CH 2CH 3)、n-Bu(-CH 2CH 2CH 2CH 3)或i-Bu(-CH 2CH(CH 3) 2)。
“C 2-6烯基”是指具有2至6个碳原子和至少一个碳碳双键的直链或支链烃基团。在一些实施方案中，C 2-4烯基是优选的。C 2-6烯基的例子包括：乙烯基(C 2)、1-丙烯基(C 3)、2-丙烯基(C 3)、1-丁烯基(C 4)、2-丁烯基(C 4)、丁二烯基(C 4)、戊烯基(C 5)、戊二烯基(C 5)、己烯基(C 6)，等等。术语“C 2-6烯基”还包括杂烯基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烯基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C 2-6炔基”是指具有2至6个碳原子、至少一个碳-碳叁键以及任选地一个或多个碳-碳双键的直链或支链烃基团。在一些实施方案中，C 2-4炔基是优选的。C 2-6炔基的例子包括但不限于：乙炔基(C 2)、1-丙炔基(C 3)、2-丙炔基(C 3)、1-丁炔基(C 4)、2-丁炔基(C 4)，戊炔基(C 5)、己炔基(C 6)，等等。术语“C 2- 6炔基”还包括杂炔基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。炔基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C 1-6亚烷基”是指除去C 1-6烷基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C 1-4亚烷基、C 2-4亚烷基和C 1-3亚烷基是优选的。未取代的所述亚烷基包括但不限于：亚甲基(-CH 2-)、亚乙基(-CH 2CH 2-)、亚丙基(-CH 2CH 2CH 2-)、亚丁基(-CH 2CH 2CH 2CH 2-)、亚戊基(-CH 2CH 2CH 2CH 2CH 2-)、亚己基(-CH 2CH 2CH 2CH 2CH 2CH 2-)，等等。示例性的取代的所述亚烷基，例如，被一个或多个烷基(甲基)取代的所述亚烷基，包括但不限于：取代的亚甲基(-CH(CH 3)-、-C(CH 3) 2-)、取代的亚乙基(-CH(CH 3)CH 2-、-CH 2CH(CH 3)-、-C(CH 3) 2CH 2-、-CH 2C(CH 3) 2-)、取代的亚丙基(-CH(CH 3)CH 2CH 2-、-CH 2CH(CH 3)CH 2-、-CH 2CH 2CH(CH 3)-、-C(CH 3) 2CH 2CH 2-、-CH 2C(CH 3) 2CH 2-、-CH 2CH 2C(CH 3) 2-)，等等。
“C 0-6亚烷基”是指化学键和上述C 1-6亚烷基。
“C 2-6亚烯基”是指除去C 2-6烯基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C 2-4亚烯基是特别优选的。示例性的未取代的所述亚烯基包括但不限于：亚乙烯基(-CH＝CH-)和亚丙烯基(例如，-CH＝CHCH 2-、-CH 2-CH＝CH-)。示例性的取代的所述亚烯基，例如，被一个或多个烷基(甲基)取代的亚烯基，包括但不限于：取代的亚乙基(-C(CH 3)＝CH-、-CH＝C(CH 3)-)、取代的亚丙烯基(-C(CH 3)＝CHCH 2-、-CH＝C(CH 3)CH 2-、-CH＝CHCH(CH 3)-、-CH＝CHC(CH 3) 2-、-CH(CH 3)-CH＝CH-、-C(CH 3) 2-CH＝CH-、-CH 2-C(CH 3)＝CH-、-CH 2-CH＝C(CH 3)-)，等等。
“C 2-6亚炔基”是指除去C 2-6炔基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在 一些实施方案中，C 2-4亚炔基是特别优选的。示例性的所述亚炔基包括但不限于：亚乙炔基(-C≡C-)、取代或未取代的亚丙炔基(-C≡CCH 2-)，等等。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。
因此，“C 1-6卤代烷基”是指上述“C 1-6烷基”，其被一个或多个卤素基团取代。在一些实施方案中，C 1-4卤代烷基是特别优选的，更优选C 1-2卤代烷基。示例性的所述卤代烷基包括但不限于：-CF 3、-CH 2F、-CHF 2、-CHFCH 2F、-CH 2CHF 2、-CF 2CF 3、-CCl 3、-CH 2Cl、-CHCl 2、2,2,2-三氟-1,1-二甲基-乙基，等等。卤代烷基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。
“C 3-10环烷基”是指具有3至10个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，C 5-7环烷基、C 3-6环烷基和C 3-5环烷基是特别优选的，更优选C 5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在环烷基环上，且在这样的情况中，碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于：环丙基(C 3)、环丙烯基(C 3)、环丁基(C 4)、环丁烯基(C 4)、环戊基(C 5)、环戊烯基(C 5)、环己基(C 6)、环己烯基(C 6)、环已二烯基(C 6)、环庚基(C 7)、环庚烯基(C 7)、环庚二烯基(C 7)、环庚三烯基(C 7)，等等。环烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“3-12元杂环基”是指具有环碳原子和1至5个环杂原子的3至12元非芳香环系的基团，其中，每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中，只要化合价允许，连接点可为碳或氮原子。在一些实施方案中，优选4-8元杂环基，其为具有环碳原子和1至5个环杂原子的4至8元非芳香环系；在一些实施方案中，优选5-8元杂环基，其为具有环碳原子和1至5个环杂原子的5至8元非芳香环系；在一些实施方案中，优选3-8元杂环基，其为具有环碳原子和1至4个环杂原子的3至8元非芳香环系；优选3-6元杂环基，其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系；优选4-7元杂环基，其为具有环碳原子和1至3个环杂原子的4至7元非芳香环系；优选4-6元杂环基，其为具有环碳原子和1至3个环杂原子的4至6元非芳香环系；更优选5-6元杂环基，其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。杂环基还包括其中上述杂环基环与一个或多个环烷基稠合的环体系，其中连接点在环烷基环上，或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在杂环基环上；且在这样的情况下，环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环基包括但不限于：氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于：氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于：四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于：二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于：三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于：哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于：哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于：六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于：氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的与C 6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于：二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基，等等。示例性的与C 6芳基环稠合的6元杂环基(本文还指的是6,6-双环 杂环基)包括但不限于：四氢喹啉基、四氢异喹啉基，等等。杂环基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C 6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如，双环)4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中，芳基具有六个环碳原子(“C 6芳基”；例如，苯基)。在一些实施方案中，芳基具有十个环碳原子(“C 10芳基”；例如，萘基，例如，1-萘基和2-萘基)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述芳基环上，在这种情况下，碳原子的数目继续表示所述芳基环系统中的碳原子数目。芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“5-14元杂芳基”是指具有环碳原子和1-4个环杂原子的5-14元单环或双环的4n+2芳族环体系(例如，具有以环状排列共享的6、10或14个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述杂芳基环上，在这种情况下，碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中，5-10元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系。在一些实施方案中，5-9元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的5-9元单环或双环的4n+2芳族环体系。在另一些实施方案中，5-6元杂芳基是特别优选的，其为具有环碳原子和1-4个环杂原子的5-6元单环的4n+2芳族环体系。示例性的含有一个杂原子的5元杂芳基包括但不限于：吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于：咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于：三唑基、噁二唑基(例如，1,2,4-噁二唑基)和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于：四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于：吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于：哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于：三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于：氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于：吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于：萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。杂芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“亚环烷基”、“亚杂环基”、“亚芳基”或“亚杂芳基”为上述定义的“环烷基”、“杂环基”、“芳基”或“杂芳基”除去另一个氢而形成的二价基团，并且可以是取代或未取代的。例如，“C 5-7亚环烷基”是指去除C 5-7环烷基的另一个氢而形成的二价基团，“5-8元亚杂环基”是指去除5-8元杂环基的另一个氢而形成的二价基团，“C 6-10亚芳基”是指去除C 6-10芳基的另一个氢而形成的二价基团，“5-6元亚杂芳基”是指去除5-6元杂芳基的另一个氢而形成的二价基团。
本文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等为任选取代的基团。
示例性的碳原子上的取代基包括但不局限于：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-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、-CO 2H、-CHO、-C(OR cc) 2、-CO 2R aa、-OC(＝O)R aa、-OCO 2R aa、-C(＝O)N(R bb) 2、-OC(＝O)N(R bb) 2、-NR bbC(＝O)R aa、-NR bbCO 2R aa、-NR bbC(＝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 bbC(＝NR bb)N(R bb) 2、-C(＝O)NR bbSO 2R aa、-NR bbSO 2R aa、-SO 2N(R bb) 2、-SO 2R aa、-SO 2OR aa、-OSO 2R 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 bbP(＝O)(OR cc) 2、-NR bbP(＝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)、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代；
或者在碳原子上的两个偕氢被基团＝O、＝S、＝NN(R bb) 2、＝NNR bbC(＝O)R aa、＝NNR bbC(＝O)OR aa、＝NNR bbS(＝O) 2R aa、＝NR bb或＝NOR cc取代；
R aa的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个R aa基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代；
R bb的每个独立地选自：氢、-OH、-OR aa、-N(R cc) 2、-CN、-C(＝O)R aa、-C(＝O)N(R cc) 2、-CO 2R aa、-SO 2R aa、-C(＝NR cc)OR aa、-C(＝NR cc)N(R cc) 2、-SO 2N(R cc) 2、-SO 2R cc、-SO 2OR 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、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个R bb基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代；
R cc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个R cc基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代；
R dd的每个独立地选自：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-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、-CO 2H、-CO 2R ee、-OC(＝O)R ee、-OCO 2R ee、-C(＝O)N(R ff) 2、-OC(＝O)N(R ff) 2、-NR ffC(＝O)R ee、-NR ffCO 2R ee、-NR ffC(＝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 ffC(＝NR ff)N(R ff) 2、-NR ffSO 2R ee、-SO 2N(R ff) 2、-SO 2R ee、-SO 2OR ee、-OSO 2R 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) 2R ee、-P(＝O)(R ee) 2、-OP(＝O)(R ee) 2、-OP(＝O)(OR ee) 2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代，或者两个偕R dd取代基可结合以形成＝O或＝S；
R ee的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代；
R ff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个R ff基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代；
R gg的每个独立地是：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OC 1-6烷基、-ON(C 1-6烷基) 2、-N(C 1-6烷基) 2、-N(C 1-6烷基) 3 +X -、-NH(C 1-6烷基) 2 +X -、-NH 2(C 1-6烷基) +X -、-NH 3 +X -、-N(OC 1-6烷基)(C 1-6烷基)、-N(OH)(C 1-6烷基)、-NH(OH)、-SH、-SC 1-6烷基、-SS(C 1-6烷基)、-C(＝O)(C 1-6烷基)、-CO 2H、-CO 2(C 1-6烷基)、-OC(＝O)(C 1-6烷基)、-OCO 2(C 1-6烷基)、-C(＝O)NH 2、-C(＝O)N(C 1-6烷基) 2、- OC(＝O)NH(C 1-6烷基)、-NHC(＝O)(C 1-6烷基)、-N(C 1-6烷基)C(＝O)(C 1-6烷基)、-NHCO 2(C 1-6烷基)、-NHC(＝O)N(C 1-6烷基) 2、-NHC(＝O)NH(C 1-6烷基)、-NHC(＝O)NH 2、-C(＝NH)O(C 1-6烷基)、-OC(＝NH)(C 1- 6烷基)、-OC(＝NH)OC 1-6烷基、-C(＝NH)N(C 1-6烷基) 2、-C(＝NH)NH(C 1-6烷基)、-C(＝NH)NH 2、-OC(＝NH)N(C 1-6烷基) 2、-OC(NH)NH(C 1-6烷基)、-OC(NH)NH 2、-NHC(NH)N(C 1-6烷基) 2、-NHC(＝NH)NH 2、-NHSO 2(C 1-6烷基)、-SO 2N(C 1-6烷基) 2、-SO 2NH(C 1-6烷基)、-SO 2NH 2、-SO 2C 1-6烷基、-SO 2OC 1-6烷基、-OSO 2C 1-6烷基、-SOC 1-6烷基、-Si(C 1-6烷基) 3、-OSi(C 1-6烷基) 3、-C(＝S)N(C 1-6烷基) 2、C(＝S)NH(C 1-6烷基)、C(＝S)NH 2、-C(＝O)S(C 1-6烷基)、-C(＝S)SC 1-6烷基、-SC(＝S)SC 1-6烷基、-P(＝O) 2(C 1-6烷基)、-P(＝O)(C 1- 6烷基) 2、-OP(＝O)(C 1-6烷基) 2、-OP(＝O)(OC 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 7环烷基、C 6-C 10芳基、C 3-C 7杂环基、C 5-C 10杂芳基；或者两个偕R gg取代基可结合形成＝O或＝S；其中，X -为反离子。
示例性的氮原子上取代基包括但不局限于：氢、-OH、-OR aa、-N(R cc) 2、-CN、-C(＝O)R aa、-C(＝O)N(R cc) 2、-CO 2R aa、-SO 2R aa、-C(＝NR bb)R aa、-C(＝NR cc)OR aa、-C(＝NR cc)N(R cc) 2、-SO 2N(R cc) 2、-SO 2R cc、-SO 2OR 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、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者连接至氮原子的两个R cc基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代，且其中R aa、R bb、R cc和R dd如上所述。
其它定义
本文所用的术语“药学上可接受的盐”表示本发明化合物的那些羧酸盐、氨基酸加成盐，它们在可靠的医学判断范围内适用于与患者组织接触，不会产生不恰当的毒性、刺激作用、变态反应等，与合理的益处/风险比相称，就它们的预期应用而言是有效的，包括(可能的话)本发明化合物的两性离子形式。
给药的“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药代动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗有效量和预防有效量。
“组合”以及相关术语是指同时或依次给药本发明化合物和其它治疗剂。例如，本发明化合物可以与其它治疗剂以分开的单位剂型同时或依次给药，或与其它治疗剂一起在单一单位剂型中同时给药。
具体实施方案
本文中，“本发明化合物”指的是以下的式(I)化合物(包括子通式，例如式(II)、式(V-1)等)、其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，以及它们的混合物。
在一个实施方案中，本发明涉及式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
Figure PCTCN2022128264-appb-000011
其中：
Figure PCTCN2022128264-appb-000012
表示
Figure PCTCN2022128264-appb-000013
其中当
Figure PCTCN2022128264-appb-000014
为
Figure PCTCN2022128264-appb-000015
X选自CH或N，Y选自CH 2、C＝O或C＝S；当
Figure PCTCN2022128264-appb-000016
为
Figure PCTCN2022128264-appb-000017
时，X为C，Y为CH；
Z选自CH或N；
环A为4-8元杂环基；
环B选自
Figure PCTCN2022128264-appb-000018
L选自化学键、-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-、-C(＝O)-CH(R N)-、-CH(R N)-S(＝O)(＝M)-或-S(＝O)(＝M)-CH(R N)-；
R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 3和R 4独立地选自H、OR a、C 1-6烷基或C 1-6卤代烷基；
R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 6选自-C 0-6亚烷基-OR a、-C 0-6亚烷基-NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
R 7选自H、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR bR c、C 1-6烷基、C 1-6卤代烷基或-S(＝O)(＝M)-R 8；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R 8选自-C 0-6亚烷基-OR a、-C 0-6亚烷基-NR bR c、C 1-6烷基、-C 1-6亚烷基-C 3-6环烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基，其任选被1个或多个R a取代；
R a、R b和R c独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基；
其中X、Y、Z、环A、环B、L、R 1-R 8、R N、R a、R b和R c中的各基团定义可被一个或多个氘原子取代，直至完全氘代；
条件是，当L为-CH(R N)-S(＝O)(＝M)-，且X、Y和Z所在环为苯环时，B为
Figure PCTCN2022128264-appb-000019
X、Y、Z
在一个具体实施方案中，
Figure PCTCN2022128264-appb-000020
为
Figure PCTCN2022128264-appb-000021
X选自CH或N，Y选自CH 2、C＝O或C＝S，优选C＝O； 在另一个具体实施方案中，
Figure PCTCN2022128264-appb-000022
为
Figure PCTCN2022128264-appb-000023
X为C，Y为CH。
在一个具体实施方案中，Z为CH；在另一个具体实施方案中，Z为N。
在一个更具体的实施方案中，X、Y和Z所在的环选自：
Figure PCTCN2022128264-appb-000024
环A
在一个具体实施方案中，环A为4-8元杂环基；在另一个具体实施方案中，环A选自：
Figure PCTCN2022128264-appb-000025
环B
在一个具体实施方案中，环B为
Figure PCTCN2022128264-appb-000026
在另一个具体实施方案中，环B为
Figure PCTCN2022128264-appb-000027
在另一个具体实施方案中，环B为
Figure PCTCN2022128264-appb-000028
L
在一个具体实施方案中，L为化学键；在另一个具体实施方案中，L为-S(＝O)(＝M)-；在另一个具体实施方案中，L为-N(R N)-S(＝O)(＝M)-；在另一个具体实施方案中，L为-S(＝O)(＝M)-N(R N)-；在另一个具体实施方案中，L为-N(R N)-C(＝O)-；在另一个具体实施方案中，L为-C(＝O)-N(R N)-；在另一个具体实施方案中，L为-CH(R N)-C(＝O)-；在另一个具体实施方案中，L为-C(＝O)-CH(R N)-；在另一个具体实施方案中，L为-CH(R N)-S(＝O)(＝M)-；在另一个具体实施方案中，L为-S(＝O)(＝M)-CH(R N)-。
R 1、R 2、R 3和R 4
在一个具体实施方案中，R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；在另一个具体实施方案中，R 1和R 2之一为卤素，另一个选自H、卤素或C 1-6烷基；在另一个具体实施方案中，R 1和R 2之一为F，另一个选自H、F或Me；在另一个具体实施方案中，R 1和R 2之一为F，另一个为H。
在一个具体实施方案中，R 3和R 4之一为OR a，另一个选自H或C 1-6烷基；在另一个具体实施方案中，R 3和R 4之一为OH或OMe，另一个选自H或Me。
R 5
在一个具体实施方案中，R 5为H；在另一个具体实施方案中，R 5为卤素；在另一个具体实施方案中，R 5为C 1-6烷基；在另一个具体实施方案中，R 5为C 1-6卤代烷基；在另一个具体实施方案中，R 5选自H或Me。
R 6
在一个具体实施方案中，R 6为-C 0-6亚烷基-OR a；在另一个具体实施方案中，R 6为OR a；在另一个具体实施方案中，R 6为-C 0-6亚烷基-NR bR c；在另一个具体实施方案中，R 6为NR bR c；在另一个具体实施方案中，R 6为C 1-6烷基；在另一个具体实施方案中，R 6为C 1-6卤代烷基；在另一个具体实施方案中，R 6为C 3-6环烷基；在另一个具体实施方案中，R 6为4-6元杂环基；在另一个具体实施方案中，R 6为C 6-10芳基；在另一个具体实施方案中，R 6为5-6元杂芳基。
R 7
在一个具体实施方案中，R 7为H；在另一个具体实施方案中，R 7为-C 1-6亚烷基-CN；在另一个具体实施方案中，R 7为-C 1-6亚烷基-OR a；在另一个具体实施方案中，R 7为-C 1-6亚烷基-NR bR c；在另一个具体实施方案中，R 7为C 1-6烷基；在另一个具体实施方案中，R 7为C 1-6卤代烷基；在另一个具体实施方案中，R 7为-S(＝O)(＝M)-R 8。
M
在一个具体实施方案中，M为O；在另一个具体实施方案中，M为NH。
R N
在一个具体实施方案中，R N为H；在另一个具体实施方案中，R N为C 1-6烷基；在另一个具体实施方案中，R N为C 1-6卤代烷基；在另一个具体实施方案中，R N和R 6连接形成C 1-6亚烷基；在另一个具体实施方案中，R N和R 6连接形成C 2-6亚烯基；在另一个具体实施方案中，R N和R 6连接形成C 2-6亚炔基。
R 8
在一个具体实施方案中，R 8为-C 0-6亚烷基-OR a；在另一个具体实施方案中，R 8为OR a；在另一个具体实施方案中，R 8为-C 0-6亚烷基-NR bR c；在另一个具体实施方案中，R 8为NR bR c；在另一个具体实施方案中，R 8为C 1-6烷基；在另一个具体实施方案中，R 8为-C 1-6亚烷基-C 3-6环烷基；在另一个具体实施方案中，R 8为C 1-6卤代烷基；在另一个具体实施方案中，R 8为C 3-6环烷基；在另一个具体实施方案中，R 8为4-6元杂环基；在另一个具体实施方案中，R 8为C 6-10芳基；在另一个具体实施方案中，R 8为5-6元杂芳基。
以上任一具体实施方案中的任一技术方案或其任意组合，可以与其它具体实施方案中的任一技术方案或其任意组合进行组合。例如，X的任一技术方案或其任意组合，可以与Y、Z、环A、环B、L、R 5、R 6等的任一技术方案或其任意组合进行组合。本发明旨在包括所有这些技术方案的组合，限于篇幅，不再一一列出。
在更具体的实施方案中，本发明提供了式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
Figure PCTCN2022128264-appb-000029
其中：
Figure PCTCN2022128264-appb-000030
表示
Figure PCTCN2022128264-appb-000031
其中当
Figure PCTCN2022128264-appb-000032
为
Figure PCTCN2022128264-appb-000033
X选自CH或N，Y选自CH 2、C＝O或C＝S；当
Figure PCTCN2022128264-appb-000034
为
Figure PCTCN2022128264-appb-000035
时，X为C，Y为CH；
Z选自CH或N；
环A为4-8元杂环基；
环B选自
Figure PCTCN2022128264-appb-000036
L选自化学键、-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-、-C(＝O)-CH(R N)-、-CH(R N)-S(＝O)(＝M)-或-S(＝O)(＝M)-CH(R N)-；
R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 3和R 4独立地选自H、OR a、C 1-6烷基或C 1-6卤代烷基；
R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
R 7选自H、C 1-6烷基、C 1-6卤代烷基或-S(＝O)(＝M)-R 8；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R 8选自OR a、NR bR c、C 1-6烷基、-C 1-6亚烷基-C 3-6环烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基，其任选被1个或多个R a取代；
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基；
条件是，当L为-CH(R N)-S(＝O)(＝M)-，且X、Y和Z所在环为苯环时，B为
Figure PCTCN2022128264-appb-000037
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中X、Y和Z所在的环选自：
Figure PCTCN2022128264-appb-000038
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、 互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中环A选自：
Figure PCTCN2022128264-appb-000039
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中环B为
Figure PCTCN2022128264-appb-000040
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中环B为
Figure PCTCN2022128264-appb-000041
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-N(R N)-C(＝O)-、-CH(R N)-C(＝O)-或-CH(R N)-S(＝O)(＝M)-；优选地，L为-N(R N)-S(＝O)(＝M)-或-CH(R N)-S(＝O)(＝M)-。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中R 1和R 2之一为卤素，另一个选自H、卤素或C 1-6烷基；优选地，R 1和R 2之一为F，另一个选自H、F或Me；优选地，R 1和R 2之一为F，另一个为H。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中R 3和R 4之一为OR a，另一个选自H或C 1-6烷基；优选地，R 3和R 4之一为OH或OMe，另一个选自H或Me。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中R 5选自H或Me。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有以下结构：
Figure PCTCN2022128264-appb-000042
Figure PCTCN2022128264-appb-000043
其中各基团如上文所定义。
在更具体的实施方案中，本发明提供了式(II)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
Figure PCTCN2022128264-appb-000044
其中：
Figure PCTCN2022128264-appb-000045
表示
Figure PCTCN2022128264-appb-000046
其中当
Figure PCTCN2022128264-appb-000047
为
Figure PCTCN2022128264-appb-000048
X选自CH或N，Y选自CH 2、C＝O或C＝S；当
Figure PCTCN2022128264-appb-000049
为
Figure PCTCN2022128264-appb-000050
时，X为C，Y为CH；
Z选自CH或N；
环A为4-8元杂环基；
L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-、-C(＝O)-CH(R N)-、-CH(R N)-S(＝O)(＝M)-或-S(＝O)(＝M)-CH(R N)-；
R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
R 7选自H、C 1-6烷基、C 1-6卤代烷基或-S(＝O)(＝M)-R 8；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R 8选自OR a、NR bR c、C 1-6烷基、-CH 2-C 3-6环烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基，其任选被1个或多个R a取代；
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
在更具体的实施方案中，本发明提供了式(III)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
Figure PCTCN2022128264-appb-000051
其中：
环A为4-8元杂环基；
L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-、-C(＝O)-CH(R N)-、-CH(R N)-S(＝O)(＝M)-或-S(＝O)(＝M)-CH(R N)-；
R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
R 7选自H、C 1-6烷基、C 1-6卤代烷基或-S(＝O)(＝M)-R 8；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R 8选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基，其任选被1个或多个R a取代；
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
环A选自
Figure PCTCN2022128264-appb-000052
L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-、-C(＝O)-CH(R N)-、-CH(R N)-S(＝O)(＝M)-或-S(＝O)(＝M)-CH(R N)-；
R 5选自H或Me；
R 6选自Me、Et、Pr、CH 2CF 3、环丙基、OH、NH 2、NHMe、NMe 2、呋喃-2-基或吡啶-4-基；
R 7选自H、三氟乙基或-S(＝O)(＝M)-R 8；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R 8选自Me、Et、Pr、CH 2CF 3、环丙基、OH、NH 2、NHMe、NMe 2、吡喃-4-基、呋喃-2-基或吡啶-4-基；
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
环A为4-8元杂环基；
L选自-S(＝O)(＝M)-、-CH(R N)-C(＝O)-或-CH(R N)-S(＝O)(＝M)-；
R 5为H、C 1-6烷基或C 1-6卤代烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基；
R 7选自H、三氟乙基或-S(＝O)(＝M)-R 8；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R 8选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基；
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变 异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
环A为4-8元杂环基；
L选自-S(＝O)(＝M)-、-CH(R N)-C(＝O)-或-CH(R N)-S(＝O)(＝M)-；
R 5选自H或C 1-6烷基；
R 6选自NR bR c、C 1-6烷基或C 1-6卤代烷基；
R 7选自H、三氟乙基或-S(＝O)(＝M)-R 8；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
R 8选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或吡喃-4-基；
R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
环A选自
Figure PCTCN2022128264-appb-000053
L选自-S(＝O)(＝M)-、-CH(R N)-C(＝O)-或-CH(R N)-S(＝O)(＝M)-；
R 5为H；
R 6选自Me或NH 2；
R 7选自H或-S(＝O)(＝M)-R 8；
其中M为O；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
R 8选自Me、Et、Pr、环丙基或吡喃-4-基。
在更具体的实施方案中，本发明提供了式(IV)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
Figure PCTCN2022128264-appb-000054
其中：
环A为4-8元杂环基；
L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-或-C(＝O)-CH(R N)-；
R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 3和R 4独立地选自H、OR a、C 1-6烷基或C 1-6卤代烷基；
R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
环A选自
Figure PCTCN2022128264-appb-000055
L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-或-C(＝O)-CH(R N)-；
R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 3和R 4独立地选自H、OR a、C 1-6烷基或C 1-6卤代烷基；
R 5选自H、C 1-6烷基或C 1-6卤代烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
在更具体的实施方案中，本发明提供了式(V)、(V-1)或(V-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
Figure PCTCN2022128264-appb-000056
其中：
L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-或-C(＝O)-CH(R N)-；
R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 3和R 4独立地选自H、OR a、C 1-6烷基或C 1-6卤代烷基；
R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-N(R N)-C(＝O)-或-CH(R N)-C(＝O)-；
R 1和R 2之一为卤素，另一个选自H、卤素或C 1-6烷基；
R 3和R 4之一为OR a，另一个选自H或C 1-6烷基；
R 5选自H、C 1-6烷基或C 1-6卤代烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或5-6元杂芳基；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
在更具体的实施方案中，本发明提供了式(VI)、(VI-1)或(VI-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
Figure PCTCN2022128264-appb-000057
其中：
M为O或NH；
R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 3和R 4独立地选自H、OR a、C 1-6烷基或C 1-6卤代烷基；
R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
其中R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
M为O或NH；
R 1和R 2之一为卤素，另一个选自H、卤素或C 1-6烷基；
R 3和R 4之一为OR a，另一个选自H或C 1-6烷基；
R 5选自H或C 1-6烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或5-6元杂芳基；
R N选自H或C 1-6烷基；
或者R N和R 6连接形成C 1-6亚烷基；
其中R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
M为O；
R 1和R 2之一为F，另一个选自H、F或Me；
R 3和R 4之一为OH或OMe，另一个选自H或Me；
R 5选自H或Me；
R 6选自Me、Et、Pr、CH 2CF 3、环丙基、NMe 2、呋喃-2-基或吡啶-4-基；
R N选自H或Me；
或者R N和R 6连接形成C 1-4亚烷基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
M为O或NH；
R 1和R 2之一选自卤素、C 1-6烷基或C 1-6卤代烷基，另一个为H；
R 3和R 4之一选自OR a、C 1-6烷基或C 1-6卤代烷基，另一个为H；
R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
其中R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变 异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
M为O或NH；
R 1和R 2之一选自卤素或C 1-6烷基，另一个为H；
R 3和R 4之一为OR a，另一个为H；
R 5选自H、C 1-6烷基或C 1-6卤代烷基；
R 6选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
其中R a选自H、C 1-6烷基或C 1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
M为O；
R 1和R 2之一为卤素(优选F)，另一个为H；
R 3和R 4之一为OR a，另一个为H；
R 5选自H或C 1-4烷基；
R 6选自C 1-4烷基或C 1-4卤代烷基；
R N选自H、C 1-4烷基或C 1-4卤代烷基；优选C 1-4烷基；
其中R a选自H或C 1-4烷基。
在更具体的实施方案中，本发明提供了式(VII)、(VII-1)或(VII-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
Figure PCTCN2022128264-appb-000058
其中：
L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-、-C(＝O)-CH(R N)-、-CH(R N)-S(＝O)(＝M)-或-S(＝O)(＝M)-CH(R N)-；
R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
R 7选自H、C 1-6烷基、C 1-6卤代烷基或-S(＝O)(＝M)-R 8；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R 8选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基，其任选被1个或多个R a取代；
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
其中：
L选自-N(R N)-S(＝O)(＝M)-或-CH(R N)-S(＝O)(＝M)-；
R 5选自C 1-6烷基或C 1-6卤代烷基；
R 6选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基；
R 7为-S(＝O)(＝M)-R 8；
其中M为O或NH；
R N选自H、C 1-6烷基或C 1-6卤代烷基；
R 8选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基，其任选被1个或多个R a取代；
R a选自H、C 1-6烷基或C 1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
其中：
L选自-N(R N)-S(＝O)(＝M)-或-CH 2-S(＝O)(＝M)-；
R 5选自C 1-6烷基或C 1-6卤代烷基；
R 6选自C 1-6烷基或C 1-6卤代烷基；
R 7为-S(＝O)(＝M)-R 8；
其中M为O或NH；
R N选自C 1-6烷基或C 1-6卤代烷基；
R 8选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
其中：
L选自-N(R N)-S(＝O) 2-或-CH 2-S(＝O) 2-；
R 5选自C 1-6烷基或C 1-6卤代烷基；
R 6选自C 1-6烷基或C 1-6卤代烷基；
R 7为-S(＝O) 2-R 8；
其中R N选自C 1-6烷基或C 1-6卤代烷基；
R 8选自C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基。
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
其中：
L选自-N(R N)-S(＝O) 2-或-CH 2-S(＝O) 2-；
R 5为C 1-4烷基；
R 6为C 1-4烷基；
R 7为-S(＝O) 2-R 8；
其中R N为C 1-4烷基；
R 8选自C 1-4烷基或C 3-6环烷基。
在更具体的实施方案中，本发明提供了一种化合物，或其互变异构体、立体异构体、前药、晶型、 药学上可接受的盐、水合物或溶剂合物，其中所述化合物选自：
Figure PCTCN2022128264-appb-000059
Figure PCTCN2022128264-appb-000060
Figure PCTCN2022128264-appb-000061
Figure PCTCN2022128264-appb-000062
Figure PCTCN2022128264-appb-000063
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
本发明化合物还可能以互变异构体存在。在不同的互变异构形式存在的化合物，一个所述化合物并不局限于任何特定的互变异构体，而是旨在涵盖所有的互变异构形式。
本领域技术人员将理解，有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R×x H 2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R×0.5H 2O))和多水合物(x为大于1的数，例如，二水合物(R×2H 2O)和六水合物(R×6H 2O))。
本发明化合物可以是无定形或结晶形式(多晶型)。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、 光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
本发明还包括同位素标记的化合物(同位素变体)，它们等同于式(I)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如 3H和 14C)的那些可用于药物和/或底物组织分布测定。氚、即 3H和碳-14、即 14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即 2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，A.C.S.Symposium Series的Vol.14，Edward B.Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews(1996)19(2)115-130，每篇引入本文作为参考。
药物组合物和试剂盒
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的本发明化合物。在一些实施方案中，所述药物组合物包含治疗有效量的本发明化合物。在一些实施方案中，所述药物组合物包含预防有效量的本发明化合物。
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
给药
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉 内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。
实施例
本发明所采用的试剂为直接购买的商业化试剂或经本领域熟知的常用方法合成。
如下示例的具体反应路线或步骤为本发明所用，具体如下：
实施例1
关键中间体的制备
中间体a1的合成
Figure PCTCN2022128264-appb-000064
步骤1：-10℃下，氮气保护下，将3-氯异喹啉a1-1(3.5g,21.4mmol)溶于50mL三氟甲磺酸中，分批加入N-碘代丁二酰亚胺NIS(7.21g,32.1mmol)并继续搅拌4小时，TLC监测反应完成。向反应液中缓慢加入100mL氨水淬灭反应，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。残余物经柱层析分离(PE/EA＝100/1)，得到白色固体a1-2(4.1g)，收率：60％，LCMS：ESI-MS(m/z):289.8[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.95(s,1H),8.26(dd,J＝7.4,1.1Hz,1H),7.98-7.94(m,1H),7.93(d, J＝0.7Hz,1H),7.33(dd,J＝8.2,7.4Hz,1H).
步骤2：氮气保护下，将上步中间体a1-2(4.1g,14.2mmol)和K 2CO 3(5.87g,42.3mmol)混于110mL 1,4-二氧六环和水的混合液(v/v＝10/1)中，加入Pd(dppf)Cl 2(1.04g,1.42mmol)，升温至90℃。向该反应液中加入异丙烯基硼酸频哪醇酯a1-3(3.6g,21.2mmol)，该反应液继续在60℃下反应3小时。停止反应，过滤，滤液浓缩，向体系中加入50mL水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离，得到黄色固体a1-4(1.9g)，收率:53％，LC-MS:M+H +＝204.0。
1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.09(dd,J＝6.2,3.1Hz,1H),7.85(s,1H),7.68-7.65(m,2H),5.49(t,J＝1.6Hz,1H),5.03(s,1H),2.14(s,3H).
步骤3：将上步3-氯-5-(丙-1-烯-2基)异喹啉a1-4(3.5g,17.2mmol)溶于50mL乙酸乙酯中，加入二氧化铂(0.78g,3.4mmol)，氢气氛围下室温反应6小时。反应液过滤，浓缩，柱层析分离，得到油状中间体a1-5(2.1g)，收率：54％，LC-MS：ESI-MS(m/z):206.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ9.21(s,1H),8.12(s,1H),8.03(d,J＝8.1Hz,1H),7.76(d,J＝6.7Hz,1H),7.69(d,J＝7.9Hz,1H),3.76-3.65(m,1H),1.32(d,J＝6.8Hz,6H).
步骤4：-10℃下，氮气保护下，将上步中间体a1-5(1.8g,8.75mmol)溶于24mL浓硫酸中，分批加入N-溴代丁二酰亚胺NBS(2.02g,11.4mmol)并继续搅拌8小时，LC-MS监测反应完成。向反应液中缓慢加入200mL冰水淬灭反应，并用氨水调节pH至8左右，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。残余物经柱层析分离(PE/EA＝50/1)，得到白色固体a1(1.0g)，收率：36％，LCMS：ESI-MS(m/z):283.9[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ9.34(s,1H),8.22(s,1H),7.99(d,J＝7.9Hz,1H),7.66(d,J＝7.9Hz,1H),3.72(dt,J＝13.7,6.8Hz,1H),1.31(d,J＝6.8Hz,6H).
中间体a2的合成
Figure PCTCN2022128264-appb-000065
步骤1：冰浴、氮气保护下，将6-羟基-2-氮杂螺环[3.3]庚烷-2-羧酸叔丁酯a2-1(4.8g,22mmol)和三乙胺(4.53g，44mmol)溶于50mL二氯甲烷中，逐滴滴加甲基磺酰氯(3.08g,26mmol)，滴毕，继续搅拌2小时。向反应液中加入10mL饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，合并的有机层用无水硫酸钠干燥并浓缩。得到粗品化合物a2-2(6.24g)，收率：86％。
步骤2：氮气保护下，上步中间体a2-2(6.24g,21mmol)和甲硫醇钠(20％水溶液)(15.0g,42mmol)溶于50mL DMF中，升温至60℃下搅拌12小时，LC-MS检测反应完成。向体系加入200mL水，乙酸乙酯萃取，饱和食盐水洗涤，合并的有机层用无水硫酸钠干燥，过滤，浓缩，得到无色油状物a2-3(3.98g)，收率：69％。
步骤3：将上步中间体a2-3(3.98g,16mmol)溶于200mL二氯甲烷中，加入氧化剂Oxone(50.1g,81mmol)，室温下反应48小时。停止反应，过滤，滤液浓缩，得到化合物a2-4(4.18g)，收率：83％。
1H NMR(400MHz,CDCl 3)δ3.95(d,J＝5.7Hz,4H),3.72-3.52(m,1H),2.80(s,3H),2.76-2.65(m,2H),2.59-2.49(m,2H),1.43(s,9H).
步骤4：将化合物a2-4(3.72g,13mmol]溶于40mL二氯甲烷中，滴加三氟乙酸(4.62g,41mmol)，室温下搅拌2小时。减压蒸除溶剂，得到粗品a2-5(1.95g)。LCMS：ESI-MS(m/z):176.0[M+H] +。
步骤5：氮气保护下，将上步中间体a2-5(1.6g,5.5mmol)和Cs 2CO 3(5.38g,16.5mmol)混于25mL 1,4-二氧六环中，加入Xantphos Pd G3(520mg,0.5mmol)，升温至100℃。向该反应液中加入中间体a1(1.57g,5.5mmol)，该反应液继续在100℃下反应3小时，停止反应，过滤，滤液浓缩，flash柱层析分离，得到黄色固体a2(820mg)，收率:35％，LCMS：ESI-MS(m/z):379.1[M+H] +。
中间体a3，a5，a9的合成
Figure PCTCN2022128264-appb-000066
步骤1：氮气保护下，将[3-(碘甲基)氮杂环丁烷-1-基]甲酸叔丁酯a3-1(6.0g,16mmol)和甲硫醇钠(20％水溶液)(6.0g,16mmol)溶于50mL乙腈和水的混合液(v/v＝3/1)中，升温至60℃下搅拌12小时，LC-MS监测反应完成。向反应液中加水100mL，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到黄色油状物a3-2(2.43g)，收率：81％，LC-MS:[M+H] +＝162.0。
步骤2：氮气保护下，将上步油状物a3-2(2.43g,10mmol)溶于50mL二氯甲烷中，加入氧化剂Oxone(34.4g,56mmol)，室温下反应48小时，LC-MS监测反应完成。反应液过滤，滤液浓缩，得到白色固体a3-3(2.99g)，收率：95％，LC-MS:[M+H] +＝250.0。
步骤3：将上步中间体a3-3(2.99g,12mmol)溶于20mL二氯甲烷中，加入5mL三氟乙酸，室温下搅拌2小时。反应液减压浓缩，得到粗品a3-4，LC-MS:[M+H] +＝150.0。
步骤4：氮气保护下，将上步粗品a3-4(1.39g,5.27mmol)、中间体a1(500mg,1.76mmol)和Cs 2CO 3(2.86g,8.79mmol)混于10mL 1,4-二氧六环中，加入XantPhos Pd G3(167mg,0.18mmol)，升温至100℃下反应3小时。停止反应，过滤，滤液浓缩，flash柱层析分离，得到绿色固体a3(410mg)，收率:60％，LC-MS:M+H +＝353.0。
1H NMR(400MHz,CDCl 3)δ9.11(d,J＝0.5Hz,1H),7.84(s,1H),7.46(d,J＝8.0Hz,1H),6.52(d,J＝8.0Hz,1H),4.45(t,J＝7.5Hz,2H),4.02(dd,J＝7.6,5.3Hz,2H),3.50-3.40(m,4H),2.98(s,3H),1.33(d,J＝6.8Hz,6H)。
参照中间体a3的合成路线，采用类似的骨架结构，合成如下中间体。
Figure PCTCN2022128264-appb-000067
中间体a4的合成
Figure PCTCN2022128264-appb-000068
步骤1：将中间体a3(200mg,0.57mmol)溶于20mL DMF中，加入N-碘代丁二酰亚胺NIS(380mg,1.7mmol)，室温下反应2小时，LC-MS监测反应完成。向反应液中加入100mL水，乙酸乙酯萃取，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩，得到黄色固体a4-1(200mg)，收率:59％，LC-MS:M+H +＝478.9。
步骤2：氮气保护下，将上步中间体a4-1(20mg,0.042mmol)、2,2-二氟-2-(氟磺酰基)乙酸甲酯a4-2(40mg,0.21mmol)和CuI(24mg,0.12mmol)混于5mL DMF中，升温至90℃下反应1小时，LC-MS监测反应完成。向反应液加入50mL水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，柱层析分离(DCM/MeOH＝25/1)，得到黄色固体a4(15mg)，收率:77％，LC-MS:M+H +＝421.0。
中间体a6的合成
Figure PCTCN2022128264-appb-000069
步骤1：将2-(1-(3-氯-5-异丙基异喹啉-8-基)氮杂环丁烷-3-基)乙酸甲酯a5(120mg,0.36mmol)溶于6mL四氢呋喃和水(v/v＝5/1)的混合液中，加入一水合氢氧化锂(23mg,0.54mmol)，室温下搅拌12小时。停止反应，向反应液缓慢加入醋酸调节pH值至6左右，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品中间体a6-1(100mg)，收率：18％，LC-MS:ESI-MS(m/z):319.1[M+H] +。
步骤2：将上步粗品a6-1(50mg,0.16mmol)溶于3mL二氯甲烷中，加入HOBT(6mg,0.047mmol)、EDCI(36mg,0.19mmol)和DIPEA(40mg,0.31mmol)，室温下搅拌1小时。向反应液加入氨水0.2mL，室温下继续反应2小时。停止反应，向反应液加水20mL，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，薄层色谱分离，得到中间体a6(20mg)，收率：36％，LC-MS:ESI-MS(m/z):318.1[M+H] +。
中间体a7的合成
Figure PCTCN2022128264-appb-000070
步骤1：冰浴下，将原料1-(二苯基甲基)-2,2-二甲基氮杂环丁烷-3-酮a7-1(3.2g,12.1mmol)溶于50mL甲醇中，加入硼氢化钠(912mg,24.1mmol)，升温至70℃下反应16小时。停止反应，减压蒸除溶剂，向残留物中加入100mL水，乙酸乙酯萃取，有机相用盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离(PE/EA＝3/1)，得到白色固体a7-2(2.0g)，收率：59％，LC-MS：ESI-MS(m/z):268.1[M+H] +。1H NMR(400MHz,CDCl 3)δ7.46(dd,J＝18.3,7.4Hz,4H),7.24-7.08(m,6H),4.58(s,1H),4.05-3.95(m,1H),3.40-3.28(m,1H),2.72(dd,J＝7.7,5.9Hz,1H),1.69(d,J＝7.5Hz,1H),1.08(s,3H),1.01(s,3H).
步骤2：冰浴下，将上步中间体a7-2(1.0g,3.74mmol)和三乙胺(605mg,5.98mmol)溶于20mL二氯甲烷中，加入甲基磺酰氯(554mg,4.86mmol)，在室温下搅拌1小时。停止反应，向体系加入50mL水，二氯甲烷萃取，浓缩，得到粗品a7-3(1.1g)，直接用于下一步反应。
步骤3：冰浴下，将2-甲磺酰乙酸甲酯a7-4(745mg,4.89mmol)溶于20mL DMF中，加入NaH(181mg,4.52mmol,60％)，反应液在0℃下搅拌15分钟，向体系中加入上步粗品a7-3(1.1g)，升温至80℃下反应16小时。向体系加入50mL饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，有机相用盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离(DCM/MeOH＝20/1),得到白色固体a7-5(900mg)，收率：54％，LC-MS：ESI-MS(m/z):402.0[M+H] +。
步骤4：将上步中间体a7-5(900mg,2.24mmol)溶于20mL DMA中，加入LiCl(950mg,22.42mmol)，升温至150℃反应1小时。停止反应，向体系加入80mL水，乙酸乙酯萃取，有机相用盐水洗涤，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离(DCM/MeOH＝20/1),得到白色固体a7-6(200mg)，收率：27％，LC-MS：ESI-MS(m/z):344.0[M+H] +。
步骤5：氢气球氛围下，将上步中间体a7-6(2200mg,0.64mmol)溶于12mL甲醇中，加入0.5mL三氟乙酸和Pd(OH) 2/C(20mg)，室温下反应16小时。停止反应，过滤，减压浓缩，得到黄色三氟乙酸盐a7-7(150mg)，收率：92％，LC-MS：ESI-MS(m/z):178.2[M+H] +。
步骤6：氮气保护下，将上步三氟乙酸盐a7-7(92mg,0.31mmol)、中间体a1(60mg,0.21mmol)和Cs 2CO 3(171mg,0.52mmol)混于3mL 1,4-二氧六环中，加入XantPhos Pd G3(65mg,0.063mmol)，升温至100℃下反应6小时。停止反应，过滤，滤液浓缩，flash柱层析分离，得到黄色固体a7(35mg)，收率:39％，LC-MS：ESI-MS(m/z):381.1[M+H] +。
中间体a8的合成
Figure PCTCN2022128264-appb-000071
步骤1：-20℃下，氮气保护下，将二甲基氧化膦a8-1(1.0g,12.8mmol)溶于20mL无水四氢呋喃中，逐滴加入LDA(1M,38.4mL)，搅拌20分钟后，滴加中间体a3-1(5.72g,19.2mmol)的四氢呋喃溶液(10mL)。滴毕，缓慢升至室温，并在室温下反应5小时，停止反应。向体系中加入50mL饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离，得到棕色固体a8-2(0.8g)，收率：24％，LC-MS：ESI-MS(m/z):248.1[M+H] +。
步骤2：将中间体a8-2(800mg,3.23mmol)溶于6mL二氯甲烷中，加入3mL三氟乙酸，室温搅拌过夜。将反应液减压浓缩，得到粗品a8-3，直接用于下一步反应。LC-MS：ESI-MS(m/z):148.1[M+H] +。
步骤3：氮气保护下，将上步三氟乙酸盐a8-3、中间体a1(774mg,2.7mmol)和Cs 2CO 3(2.66g,8.2mmol)混于15mL 1,4-二氧六环中，加入XantPhos Pd G3(258mg,0.27mmol)，升温至100℃下反应16小时。停止反应，过滤，滤液浓缩，flash柱层析分离，得到黄色固体a8(200mg)，LC-MS：ESI-MS(m/z):351.0[M+H] +。
中间体a10，a17的合成
Figure PCTCN2022128264-appb-000072
步骤1：将活化锌粉(0.6g,9.16mmol)溶于4mL DMA中，升温至65℃，向体系中滴加三甲基氯硅烷(0.13g,0.13mL)和1,2-二溴乙烷(0.1mL,1.3mmol)，滴毕，继续搅拌40分钟。向反应液滴加a10-2(2.0g,7.06mmol)的DMF溶液(4mL)，继续反应30分钟，冷却至室温，备用。
氮气保护下，在另一反应瓶中，将3-碘吡啶a10-1(1.45g,7.1mmol)，Pd 2(dba) 3(647mg,0.71mmol)和Xphos(673mg,1.41mmol)溶于4mL DMA中，滴加上步配制的溶液，升温至85℃下反应16小时。停止反应，冷却至室温，将反应液倒入30mL冰水中，抽滤，滤饼用乙酸乙酯溶解，浓缩，flash柱层析分离(PE/EA＝1/1)得到化合物a10-3(200mg)，收率11％，LC-MS：ESI-MS(m/z):235.2[M+H] +。
步骤2：将中间体a10-3(200mg,0.85mmol)溶于4mL二氯甲烷中，滴加三氟乙酸1.5mL，室温下反应3小时，停止反应。减压蒸除溶剂，得到三氟乙酸盐a10-4(160mg)，收率69％，LC-MS：ESI-MS(m/z):135.1[M+H] +。
步骤3：氮气保护下，将上步三氟乙酸盐a10-4(31mg,0.23mmol)、中间体a1(65mg,0.23mmol)和Cs 2CO 3(223mg,0.69mmol)混于3mL 1,4-二氧六环中，加入XantPhos Pd G3(22mg,0.023mmol)，升温至100℃下反应16小时。停止反应，过滤，滤液浓缩，flash柱层析分离，得到黄色固体a10(50mg)，LC-MS：ESI-MS(m/z):338.0[M+H] +。
参照化合物a10的合成路线，采用类似的骨架结构，合成如下中间体。
Figure PCTCN2022128264-appb-000073
Figure PCTCN2022128264-appb-000074
中间体a11的合成
Figure PCTCN2022128264-appb-000075
步骤1：将4,6-二氯烟酸乙酯a11-1(3.0g，0.013mol)溶于50mL乙醇中，加入异丙胺(2.41g，0.040mol)，反应液在80℃下搅拌12小时，LC-MS监测反应完成。减压蒸除溶剂，残余物经柱层析分离(PE/EA＝10/1)，得到白色固体a11-2(3.31g)，收率：91％，LCMS：ESI-MS(m/z):243.1[M+H] +。
步骤2：将中间体a11-2(3.3g,13mmol)溶于40mL乙醇中，加入1N浓度的NaOH水溶液20mL，升温至80℃下反应2小时，停止反应。减压蒸馏除去溶剂乙醇，用1M浓度的盐酸调节pH至3-4，大量白色固体析出，抽滤，滤饼用水洗涤，干燥，得到白色固体a11-3(1.6g)，收率：50％，LC-MS：ESI-MS(m/z):215.0[M+H] +。
步骤3：将上步中间体a11-3(1.6g,7.48mmol)溶于30mL二氯甲烷中，加入苯并三氮唑(1.07g，8.99mmol)、EDCI(1.73g,8.99mmol)和HOBT(0.3g，2.2mmol)，室温下反应2小时，停止反应。向反应液加入50mL水，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，柱层析分离(PE/EA＝10/1)，得到油状物a11-4(1.65g)，收率：63％，LC-MS：ESI-MS(m/z):315.9[M+H] +。
步骤4：冰浴下，氮气保护下，将NaH(420mg,10.g mmol,60％)溶于10mL无水四氢呋喃中，缓慢加入丙二酸叔丁酯乙酯a11-5(1.96g，10.5mmol)，搅拌30分钟后，加入中间体a11-4(1.65g,5.24mmol)的四氢呋喃溶液(10mL)，冰浴下继续搅拌2小时。向反应液中加入30mL饱和氯化铵水溶液淬灭反应，经减压蒸馏除去四氢呋喃，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到粗品，粗品用二氯甲烷溶解，加入10mL三氟乙酸并在室温下搅拌2小时，反应完毕后加入20mL甲苯，经柱层析色谱分离(PE/EA＝10/1)，得到无色油状物a11-6(780mg)，收率：48％，LCMS：ESI-MS(m/z):285.1[M+H] +。
步骤5：将上步中间体a11-6(780mg,2.75mmol)溶于10mL乙醇中，加入DBU(1.23g，8.22mmol)，升温至80℃下反应2小时，停止反应。减压浓缩去除乙醇，向反应液加入1M浓度盐酸调节pH至3左右，析出白色固体，抽滤，滤饼用水洗涤，干燥，得到中间体a11-7(440mg)，收率：61％，LC-MS：ESI-MS(m/z):239.0[M+H] +。
步骤6：将上步中间体a11-7(440mg,1.67mmol)溶于10mL DMF中，加入三乙胺(507mg,5.02mmol)和N-苯基双(三氟甲烷磺酰基)亚胺(718mg,2.0mmol)，室温下反应2小时，停止反应。向反应 液中加入50mL水，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经薄层色谱分离(PE/EA＝3/1)，得到白色固体a11-8(620mg)，收率：90％，LCMS：ESI-MS(m/z):371.0[M+H]+。
步骤7：氮气保护下，将上步中间体a11-8(210mg,0.57mmol)、中间体a3-4(140mg,0.53mmol)和Cs 2CO 3(556mg,1.71mmol)混于10mL 1,4-二氧六环中，加入Pd 2(dba) 3(52mg,0.057mmol)和Xantphos(65mg,0.113mmol)，升温至60℃下反应2小时。停止反应，过滤，滤液浓缩，flash柱层析分离，得到白色固体a11(30mg)，收率：15％，LC-MS：ESI-MS(m/z):370.0[M+H] +。
中间体a12的合成
Figure PCTCN2022128264-appb-000076
步骤1：氮气保护下，将中间体a1(700mg,2.46mmol)，Pd 2(dba) 3(225mg,0.25mmol)，Xphos(234mg,0.49mmol)和新制备原料a12-1(4mL,5.0mmol)溶于4mL DMA中，升温至85℃下反应15小时。冷却至室温，将反应液倒入15mL冰水中，析出固体，抽滤，滤饼用乙酸乙酯溶解后过滤，浓缩，经flash柱层析分离(PE/EA＝1/1)得到黄色固体a12-2(280mg)，收率：29％，LC-MS：ESI-MS(m/z):361.1[M+H] +。
步骤2：将上步中间体a12-2(85mg,0.24mmol)溶于6mL二氯甲烷中，滴加2mL三氟乙酸，室温下反应12小时，停止反应。将反应液浓缩，得到三氟乙酸盐a12-3(20mg)，收率：30％，LC-MS：ESI-MS(m/z):261.1[M+H] +。
步骤3：将上步中间体a12-3(20mg,0.08mmol)和K 2CO 3(43mg,0.31mmol)混于5mL乙腈中，加入2-溴-N-甲基乙酰胺a12-4(9mg,0.061mmol)，室温下反应3小时，停止反应。向反应液加入20mL水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经flash柱层析分离(DCM/MeOH＝10/1)，得到白色固体a12(35mg)，收率：96％，LC-MS：ESI-MS(m/z):332.2[M+H] +。
中间体a13的合成
Figure PCTCN2022128264-appb-000077
氮气保护下，将中间体a4-1(50mg,0.10mmol)溶于5mL DMF中，加入Pd( tBuP) 3(16mg，0.03mmol)和氰化锌(18mg，0.16mmol)，升温至100℃下反应反应1小时，LC-MS监测反应完成。停止反应，向反应液中加入饱和碳酸氢钠水溶液30mL，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，薄层色谱分离，得到黄色固体a13(30mg)，收率：69％，LCMS：ESI-MS(m/z):378.0[M+H] +。
中间体a14的合成
Figure PCTCN2022128264-appb-000078
步骤1：氮气保护下，将中间体a14-1(1.0g,6.11mmol)，Pd 2(dba) 3(558mg,0.61mmol)，Xphos(581mg,1.22mmol)和新制备原料a12-1(8mL,12.0mmol)溶于6mL DMA中，升温至85℃下反应12小时。冷却至室温，将反应液倒入35mL冰水中，乙酸乙酯萃取，浓缩，经flash柱层析分离(PE/EA＝2/1)得到黄色固体a14-2(120mg)，收率：8％，LC-MS：ESI-MS(m/z):185.1[M-56] +。
步骤2：将上步中间体a14-2(120mg,0.42mmol)溶于6mL二氯甲烷中，滴加2mL三氟乙酸，室温下反应0.5小时，停止反应。将反应液浓缩，得到三氟乙酸盐a14-3(70mg)，收率：91％，LC-MS：ESI-MS(m/z):141.1[M+H] +。
步骤3：氮气保护下，将上步三氟乙酸盐a14-3(100mg,0.71mmol)、中间体a1(203mg,0.71mmol)和Cs 2CO 3(1162mg,3.57mmol)混于10mL 1,4-二氧六环中，加入XantPhos Pd G3(68mg,0.071mmol)，升温至100℃下反应3小时。停止反应，过滤，滤液浓缩，flash柱层析分离，得到黄色固体a14(70mg)，收率：26％，LC-MS：ESI-MS(m/z):344.1[M+H] +。
中间体a15的合成
Figure PCTCN2022128264-appb-000079
步骤1：冰浴下，将中间体a11-3(1.3g,6.10mmol)溶于13mL二氯甲烷中，滴加草酰氯(1.54g,12.1mmol)和3滴无水DMF，反应液搅拌1小时后，向反应液中滴加氨水12mL，升温至室温，继续反应1小时。向反应液加入30mL冰水淬灭反应，二氯甲烷萃取，浓缩，柱层析分离(PE/EA＝1/1)，得到白色固体a15-1(1.1g)，收率：85％。
1H NMR(400MHz,DMSO-d 6)δ8.72(d,J＝7.8Hz,1H),8.39(s,1H),8.07(s,1H),7.47(s,1H),6.69(s,1H),3.72-3.77(m,1H),1.16(d,J＝6.3Hz,6H).
步骤2：冰浴，将上步中间体a15-1(1.1g,5.16mmol)溶于13mL无水四氢呋喃中，加入NaH(1.2g,30.1mmol,60％)，反应液搅拌30分钟后，向反应液中加入CDI(2.5g,15.4mmol)，升温至室温，继续反应1小时，LC-MS监测反应完成。向反应液加入50mL冰水，二氯甲烷萃取，浓缩，柱层析分离(PE/EA＝1/1)，得到白色固体a15-2(1.0g)，收率：81％，LC-MS：ESI-MS(m/z):240.0[M+H] +。
步骤3：将上步中间体a15-2(1.0g,4.18mmol)和DIEA(530mg,4.18mmol)溶于15mL乙腈中，加入POCl 3(640mg,4.18mmol)，将反应液升温至90℃下反应1小时，停止反应，冷却至室温。将反应液倒入40mL冰水中，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，柱层析分离(PE/EA＝5/1)，得 到白色固体a15-3(700mg)，收率：65％，LC-MS：ESI-MS(m/z):258.0[M+H] +。
步骤4：冰浴下，将中间体a3-4(408mg,1.55mmol)、中间体a15-3(400mg,1.55mmol)和DIEA(802mg,6.19mmol)溶于10mL二氯甲烷中，冰浴下反应1小时。停止反应，向反应液加水30mL，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离，得到白色固体a15(300mg)，收率：47％，LC-MS：ESI-MS(m/z):371.0[M+H] +。
中间体a16，a18-a22，a24，a27，a29，a31，a34，a36-a38的合成
Figure PCTCN2022128264-appb-000080
步骤1：氮气保护下，将化合物a16-1(304mg,1.76mmol)、中间体a1(500mg,1.76mmol)和Cs 2CO 3(2.86g,8.78mmol)混于10mL 1,4-二氧六环中，加入XantPhos Pd G3(166mg,0.17mmol)，升温至100℃下反应2小时。停止反应，过滤，滤液浓缩，flash柱层析分离，得到黄色固体a16-2(400mg)，收率：55％，LC-MS：ESI-MS(m/z):376.2[M+H] +。
步骤2：冰浴下，将上步中间体a16-2(120mg,0.32mmol)溶于2mL二氯甲烷中，加入0.5mL吡啶，缓慢加入0.5mL三氟甲磺酸三甲基硅酯，室温下反应16小时，LC-MS监测反应完成。向体系中加入30mL饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，有机相合并，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，薄层色谱分离，得到黄色固体a16-3(75mg)，收率：77％，LC-MS：ESI-MS(m/z):276.2[M+H] +。
步骤3：将上步中间体a16-3(21mg,0.077mmol)和三乙胺(21mg,0.21mmol)溶于2mL二氯甲烷中，加入甲基磺酰氯(139μL,0.18mmol)，室温下搅拌2小时，停止反应。向反应液中加入10mL冰水，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，薄层色谱分离，得到白色固体a16(20mg)，收率：65％，LC-MS：ESI-MS(m/z):354.0[M+H] +。
参照中间体a16的合成路线，采用类似的骨架结构，合成如下中间体。
Figure PCTCN2022128264-appb-000081
Figure PCTCN2022128264-appb-000082
中间体a23，a30，a32，a33，a35，a39，a41的合成
Figure PCTCN2022128264-appb-000083
冰浴下，将中间体a16(40mg,0.11mmol)溶于3mL DMF中，加入NaH(6mg,0.15mmol)和碘乙 烷(20mg,0.13mmol)，升温至室温下反应2小时，LC-MS监测反应完成。向体系中加入30mL饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，有机相合并，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析色谱分离，得到黄色固体a23(40mg)，收率：84％，LC-MS：ESI-MS(m/z):382.1[M+H] +。
参照中间体a23的合成路线，采用类似的骨架结构，合成如下中间体。
Figure PCTCN2022128264-appb-000084
中间体a25,a42的合成
Figure PCTCN2022128264-appb-000085
步骤1：氮气保护下，将原料a25-1(7.0g,27.7mmol)和三乙胺(4.2g,41.5mmol)溶于40mL二氯甲烷中，加入甲基磺酰氯(3.21g,28.0mmol)，室温下反应4小时。停止反应，减压整除溶剂，得到粗品a25-2(10.8g)。
步骤2：将上步粗品a25-2(10.8g)和原料a25-3(4.21g,27.7mmol)溶于30mL DMF中，加入NaH(1.11g,27.7mmol)，缓慢升温至80℃下反应12小时，LC-MS监测反应完成。向体系中加入100mL 饱和食盐水溶液淬灭反应，二氯甲烷萃取，有机相合并，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到粗品a25-4(15g)。LC-MS：ESI-MS(m/z):388.3[M+H] +。
步骤3：将上步粗品a25-4(15g)和LiCl(2.52g,60.0mmol)溶于40mL N,N-二甲基乙酰胺DMA中，升温至150℃下反应2小时，停止反应。向反应液中加入100mL冰水，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，flash柱层析色谱分离，得到黄色固体a25-5(6.42g)，三步总收率：71％，LC-MS：ESI-MS(m/z):330.1[M+H] +。
步骤4：氢气氛围下(2atm)，将上步中间体a25-5(6.42g,19.5mmol)和Pd/C(1.28g,20％)混于40mL甲醇中，加入2mL三氟乙酸，室温下反应16小时，停止反应。过滤，浓缩，得到黄色油状物a25(4.5g)，直接用于下一步反应。LC-MS：ESI-MS(m/z):164.2[M+H] +。
参照中间体a25的合成路线，采用类似的骨架结构，合成如下中间体。
Figure PCTCN2022128264-appb-000086
中间体a26,a43的合成
Figure PCTCN2022128264-appb-000087
氮气保护下，将中间体a25(2.0g,12.3mmol)、中间体a1(3.47g,12.3mmol)和Cs 2CO 3(8.01g,24.6mmol)混于80mL 1,4-二氧六环中，加入XantPhos Pd G3(1.14g,1.2mmol)，升温至100℃下反应6小时。停止反应，过滤，滤液浓缩，flash柱层析分离，得到棕色固体a26(970mg)，收率:23％，LC-MS:M+H +＝367.3。
参照中间体a26的合成路线，采用类似的骨架结构，合成如下中间体。
Figure PCTCN2022128264-appb-000088
中间体a28的合成
Figure PCTCN2022128264-appb-000089
步骤1：冰浴，氮气保护下，将原料a28-1(250mg,1.45mmol)和三乙胺(294mg,2.9mmol)溶于5mL DMF中，加入3-氯丙基磺酰氯a28-2(282mg,1.59mmol)，搅拌30分钟后，加入NaH(174mg,4.35mmol)，升温至室温反应12小时，停止反应。向体系中加入30mL饱和NH 4Cl水溶液，乙酸乙 酯萃取，无水硫酸钠干燥，过滤，浓缩，得到粗品a28-3(380mg)，收率:83％，LC-MS:M+Na +＝299.0。
步骤2：将上步中间体a28-3(220mg,0.72mmol)溶于7mL二氯甲烷中，加入3mL三氟乙酸，室温反应2小时，停止反应。减压蒸除溶剂，加入10mL水，冻干，得到白色固体a28-4(150mg)，收率:65％，LC-MS:M+H +＝177.1。
步骤3：氮气保护下，将中间体三氟乙酸盐a28-4(100mg,0.34mmol)、中间体a1(212mg,0.75mmol)和Cs 2CO 3(332mg,1.02mmol)混于10mL 1,4-二氧六环中，加入XantPhos Pd G3(35mg,0.034mmol)，升温至100℃下反应3小时。停止反应，过滤，滤液浓缩，flash柱层析分离，得到黄色固体a28(50mg)，收率:35％，LC-MS:M+H +＝380.1。
中间体a40的合成
Figure PCTCN2022128264-appb-000090
参照中间体a16的合成路线，得到中间体a40-1。操作步骤：将中间体1-(3-氯-5-异丙基异喹啉-8-基)-N-甲基氮杂环丁烷-3-胺a40-1(10mg，0.035mmol)和三乙胺(11mg，0.11mmol)溶于3mL二氯甲烷中，滴加三氟甲磺酸酐(20mg，0.07mmol)的二氯甲烷溶液1.0mL，室温下反应2小时。向体系中加入30mL饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经薄层色谱分离(DCM/MeOH,10/1)，得到淡黄色固体a40(15mg)，收率：93％，LC-MS:M+H +＝422.1。
中间体b1,b2的合成
Figure PCTCN2022128264-appb-000091
冰浴、氮气保护下，将原料3-氟-4-氧代哌啶-1-羧酸叔丁酯中间体b1-1(3.0g,14.0mmol)溶于50mL乙醇中，加入硼氢化钠(0.78g,21.0mmol)，升温至室温下反应4小时，LC-MS监测反应完成。向反应液中加入50mL饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，flash柱层析分离(PE/EA＝2/1)，得到反式中间体b1和顺式中间体b2(2.52g)，收率:90％，LCMS:ESI-MS(m/z):164.0[M-55] +。
中间体b3-b5,b10-b12，x1，x2的合成
Figure PCTCN2022128264-appb-000092
氮气保护下，将顺式3-氟-4-羟基哌啶-1-羧酸叔丁酯b2(800mg，3.63mmol)溶于5mL 1,4-二氧六环中，缓慢滴加4M氯化氢的二氧六环溶液(4.5mL,18.16mmol)，室温下反应2小时，减压蒸除溶剂，得到化合物b3-1(210mg)，直接用于下一步反应。
将顺式3-氟哌啶-4-醇盐酸盐b3-1(840mg,5.4mmol)、2-氯嘧啶-4-胺b3-2(700mg,5.4mmol)和三乙胺(1.63g,16.2mmol)溶于20mL异丙醇中，反应体系在110℃下封管反应18小时。冷却至室温，反应液减压浓缩，柱层析分离(DCM/MeOH＝21/1)得到黄色固体顺式b3(200mg)，收率：16％，LC-MS:ESI-MS(m/z):283.9[M+H] +。
参照化合物b3的合成路线，采用类似的骨架结构，合成如下中间体。
Figure PCTCN2022128264-appb-000093
Figure PCTCN2022128264-appb-000094
中间体b6-b8的合成
Figure PCTCN2022128264-appb-000095
冰浴下，将原料4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑b6-1(200mg,1.03mmol)溶于2mL DMF中，加入60％NaH(82mg,2.06mmol)，搅拌1小时后，加入环丙烷磺酰氯(217mg，1.54mmol)，升至室温并继续搅拌5小时。向反应液中加入30mL冰水淬灭反应，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到粗品b6-2，直接用于下一步的反应。LCMS：ESI-MS(m/z):299.1[M+H] +。
氮气保护下，将上步粗品b6-2(288mg,0.58mmol)、2-氯嘧啶-4-胺b3-2(50mg,0.39mmol)和Cs 2CO 3(252mg,0.77mmol)混于6mL 1,4-二氧六环和水的混合液(v/v＝5/1)中，加入Pd(dppf)Cl 2(57mg,0.077mmol)，升温至100℃下反应6小时，LC-MS监测反应完成。过滤，滤液中加入20mL水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离(PE/EA＝2/1)，得到化合物b6(30mg)，收率:27％，LCMS：ESI-MS(m/z):266.0[M+H] +。
参照化合物b6的合成路线，采用类似的骨架结构，合成如下中间体。
Figure PCTCN2022128264-appb-000096
Figure PCTCN2022128264-appb-000097
中间体b9，x3,x4的合成
Figure PCTCN2022128264-appb-000098
冰浴下，将顺式中间体b2(600mg,2.72mmol)溶于6mL无水四氢呋喃中，加入NaH(131mg,3.3mmol)，滴加碘甲烷(426mg,3.0mmol)，升温至室温反应3小时。向体系中加入20mL冰水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，flash柱层析分离(PE/EA＝5/1)，得到淡黄色固体b9-1(600mg)，收率：94％，LCMS：ESI-MS(m/z):134.0[M-55] +。
氮气保护下，将顺式中间体b9-1(600mg，2.56mmol)溶于5mL二氯甲烷中，缓慢滴加2mL三氟乙酸，室温下反应2小时，减压蒸除溶剂，得到化合物b9-2(340mg)，直接用于下一步反应。
将顺式三氟乙酸盐b9-2(340mg,1.37mmol)、2-氯嘧啶-4-胺b3-2(125mg,0.96mmol)和碳酸铯(896mg,2.72mmol)混于8mL DMF中，反应体系在100℃下反应1小时。冷却至室温，向体系中加入30mL水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，柱层析分离(EtOAc)得到白色固体顺式b9(200mg)，收率：65％，LC-MS:ESI-MS(m/z):227.1[M+H] +。
参照化合物b9的合成路线，采用类似的骨架结构，合成如下中间体。
Figure PCTCN2022128264-appb-000099
实施例2
目标分子P1-P5，P7-P9，P11-P19，P21-P51的制备
Figure PCTCN2022128264-appb-000100
氮气保护下，将中间体a2(70mg,0.185mmol)，Cs 2CO 3(180mg,0.55mmol)和中间体b3(39mg,0.185mmol)混于2mL 1,4-二氧六环中，加入Pd 2(dba) 3CHCl 3(56mg,0.055mmol)和C-phos(24mg,0.055mmol)，升温至100℃下反应12小时，LC-MS监测反应完成。过滤，滤液浓缩，HPLC制备色谱分离，得到黄色固体P1(4.0mg)，收率:4％，LCMS：ESI-MS(m/z):555.0[M+H] +。
1HNMR(400MHz,DMSO-d 6)δ9.87(s,1H),9.00(s,1H),8.60(s,1H),7.95(d,J＝5.7Hz,1H),7.36(d,J＝8.0Hz,1H),6.41(d,J＝5.7Hz,1H),6.34(d,J＝8.1Hz,1H),5.11(d,J＝5.1Hz,1H),4.74-4.58(m,1H),4.58-4.52(m,1H),4.38-4.30(m,1H),4.17(s,2H),4.08(s,J＝6.7Hz,2H),3.93-3.76(m,2H),3.59-3.40(m,2H),2.87(s,3H),2.64-2.53(m,4H),1.72-1.64(m,2H),1.25(dd,J＝6.7,4.6Hz,6H).
参照化合物P1的合成路线，采用类似的骨架结构，合成如下目标分子(除非单独声明，否则化合物为顺式构型cis)。
Figure PCTCN2022128264-appb-000101
Figure PCTCN2022128264-appb-000102
Figure PCTCN2022128264-appb-000103
Figure PCTCN2022128264-appb-000104
Figure PCTCN2022128264-appb-000105
Figure PCTCN2022128264-appb-000106
Figure PCTCN2022128264-appb-000107
Figure PCTCN2022128264-appb-000108
Figure PCTCN2022128264-appb-000109
Figure PCTCN2022128264-appb-000110
Figure PCTCN2022128264-appb-000111
Figure PCTCN2022128264-appb-000112
实施例3
目标分子P6的制备
Figure PCTCN2022128264-appb-000113
将2-氯-8-甲氧基喹唑啉P6-1(2.0g,10.3mmol)溶于50mL乙腈中，加入N-溴代丁二酰亚胺(3.67g,20.6mmol)，室温下搅拌2小时，LC-MS监测反应完成。减压蒸除溶剂，向体系加水100mL，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离(PE/EA＝1/10)，得到5-溴-2-氯-8-甲氧基喹唑啉P6-2(2.85g)，收率：80％，LCMS：ESI-MS(m/z):272.9[M+H] +。
1H NMR(400MHz,CDCl 3)δ9.54(s,1H),7.78(d,J＝8.4Hz,1H),7.15(d,J＝8.4Hz,1H),4.08(s,3H).
将上步中间体P6-2(2.0g,10.3mmol)溶于30mL二氯甲烷中，加入三溴化硼(2.74g,10.9mmol)，室温下反应12小时，LC-MS监测反应完成。向反应液中缓慢加入饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离(DCM/MeOH＝20/1)，得到2,5-二溴-8-羟基喹唑啉P6-3(2.8g)，收率：81％，LCMS：ESI-MS(m/z):302.8[M+H] +。
将上步中间体P6-3(2.8g,9.2mmol)溶于1M浓度的46mL氯化氢的1,4-二氧六环溶液中，室温 下反应1小时，LC-MS监测反应完成。反应液减压浓缩，向反应液中缓慢加入饱和碳酸氢钠水溶液调节ph至8左右，二氯甲烷萃取，无水硫酸钠干燥，过滤，减压浓缩，得到粗品P6-4(2.7g)，LCMS：ESI-MS(m/z):258.8[M+H] +。
将上步粗品P6-4(2.7g)和DIEA(2.7g,20.8mmol)溶于30mL二氯甲烷中，加入N-苯基双三氟甲基磺酰胺P6-5(5.57g，15.6mmol)，室温下反应12小时，LC-MS监测反应完成。反应液减压浓缩，向反应液中加入100mL水，二氯甲烷萃取，无水硫酸钠干燥，过滤，减压浓缩，经柱层析分离(PE/EA＝1/1)，得到化合物P6-6(3.2g)，收率：71％，LCMS：ESI-MS(m/z):392.8[M+H] +。
氮气保护下，将上步中间体P6-6(1.0g,2.6mmol)，K 2CO 3(706mg,5.2mmol)和异丙烯基硼酸频那醇酯a1-3(515mg,3.1mmol)溶于11mL 1,4-二氧六环和水的混合溶液(v/v＝10/1)中，加入Pd(dppf)Cl 2(187mg,0.25mmol)，升温至45℃下反应2小时，LC-MS监测反应完成。过滤，滤液浓缩，柱层析色谱分离(PE/EA＝10/1)，得到棕色油状物P6-7(100mg)，收率:8％，LCMS：ESI-MS(m/z):282.8[M+H] +。
将上步中间体P6-7(100mg,0.21mmol)和Cs 2CO 3(649mg,0.63mmol)溶于5mL DMF中，加入1-(4-氨基吡啶-2-基)哌啶-4-醇P6-8(49mg,0.25mmol)，升温至110℃反应12小时，LC-MS监测反应完成。冷却至室温，向反应液加入50mL水，二氯甲烷萃取，无水硫酸钠干燥，过滤，减压浓缩，经柱层析分离(DCM/MeOH＝20/1)，得到化合物P6-9(40mg)，收率：39％，LCMS：ESI-MS(m/z):439.7[M+H] +。
氮气保护下，将上步中间体P6-9(40mg,0.091mmol)，Cs 2CO 3(89mg,0.27mmol)和中间体a3-4(36mg,0.14mmol)溶于2mL 1,4-二氧六环中，加入XantPhos PdG3(17mg,0.018mmol)，升温至100℃下反应6小时，LC-MS监测反应完成。过滤，滤液浓缩，HPLC制备色谱分离，得到黄色固体P6-10(30mg)，收率:59％，LCMS：ESI-MS(m/z):509.1[M+H] +。
将上步中间体P6-10(20mg,0.04mmol)溶于5mL乙酸乙酯中，加入二氧化铂(45mg,0.19mmol)，氢气氛围下室温反应6小时。反应液过滤，浓缩，HPLC制备色谱分离，得到目标化合物P6(1.0mg)，收率：5％，LC-MS：ESI-MS(m/z):510.9[M+H] +。
实施例4
Figure PCTCN2022128264-appb-000114
氮气保护下，将中间体a5(100mg,0.30mmol)，Cs 2CO 3(196mg,0.60mmol)和中间体b3cis(64mg,0.30mmol)混于3mL 1,4-二氧六环中，加入Pd 2(dba) 3CHCl 3(31mg,0.03mmol)，升温至100℃下反应16小时，LC-MS监测反应完成。过滤，滤液浓缩，flash柱层析分离(DCM/MeOH＝10/1)，得到黄色固体P10-1(100mg)，收率:59％，LCMS：ESI-MS(m/z):508.9[M+H] +。
将上步中间体P10-1(100mg,0.60mmol)溶于1mL四氢呋喃中，加入3N LiOH水溶液(0.5mL)，室温下反应3小时。停止反应，反应液减压浓缩，向体系加入醋酸调节pH至6左右，加水10mL，乙酸乙酯萃取，减压浓缩，得到粗品P10-2(50mg)，收率：23％，LCMS：ESI-MS(m/z):495.1[M+ H] +。
将粗品P10-1(10mg,0.039mmol)和二甲胺四氢呋喃溶液(1mL,1M)溶于1mL DMF中，加入DIEA(16mg,0.12mmol)和HATU(3.0mg,0.06mmol)，室温下搅拌16小时。向体系加入5mL水，乙酸乙酯萃取，减压浓缩，经薄层色谱分离，得到化合物P10(1.5mg)，收率：24％。[顺式构型cis]
1H NMR(400MHz,DMSO-d 6)δ9.08(s,1H),8.41(s,1H),7.92(d,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),6.39(d,J＝8.2Hz,1H),6.33(d,J＝6.3Hz,1H),4.86(s,1H),4.66-4.56(m,1H),4.32-4.40(m,3H),3.89-4.00(m,1H),3.85-3.89(m,2H),3.57-3.65(m,2H),3.45-3.50(m,1H),3.10(s,3H),3.09-3.13(m,3H),2.89(s,3H),2.60(d,J＝6.0Hz,2H),1.84-1.90(m,1H),1.80-1.82(m,1H),1.33(dd,J＝6.7,4.5Hz,6H).
参照化合物P10的合成路线，采用类似的骨架结构，合成如下目标分子(除非单独声明，否则化合物为顺式构型cis)。
Figure PCTCN2022128264-appb-000115
实施例5
目标分子H1-H2，H4-H5，H12，H23，H25，H33-H34的制备
Figure PCTCN2022128264-appb-000116
氮气保护下，将中间体a3(35mg,0.10mmol)，Cs 2CO 3(48mg,0.15mmol)和中间体b6(32mg,0.12mmol)混于3mL 1,4-二氧六环中，加入Pd 2(dba) 3CHCl 3(10mg,0.01mmol)和C-phos(4.5mg,0.01mmol)，升温至100℃下反应12小时，LC-MS监测反应完成。过滤，滤液浓缩，HPLC制备色谱分离，得到黄色固体H1(2.7mg)，收率:5％，LCMS：ESI-MS(m/z):582.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ10.37(d,J＝8.4Hz,1H),9.10(s,1H),8.77(s,1H),8.70(s,1H),8.51(s,1H),8.43(d,J＝5.9Hz,1H),7.45(d,J＝8.0Hz,1H),7.25(s,1H),6.45(d,J＝8.1Hz,1H),4.41(t,J＝7.7Hz,2H),3.98(t,J＝6.9Hz,2H),3.64-3.52(m,3H),3.31-3.23(m,2H),3.02(s,3H),1.37(d,J＝6.8Hz,6H),1.30(ddd,J＝21.4,16.3,9.3Hz,4H).
参照化合物H1的合成路线，采用类似的骨架结构，合成如下目标分子。
Figure PCTCN2022128264-appb-000117
Figure PCTCN2022128264-appb-000118
Figure PCTCN2022128264-appb-000119
实施例6
目标分子H3，H6-H11，H13-H22，H24，H26-H32的制备
Figure PCTCN2022128264-appb-000120
氮气保护下，将中间体a3(9mg,0.026mmol)，Cs 2CO 3(17mg,0.052mmol)和中间体b8(7mg,0.026mmol)混于1.5mL 1,4-二氧六环中，加入Pd 2(dba) 3CHCl 3(81mg,0.008mmol)和C-phos(3.0mg,0.008mmol)，升温至100℃下反应20小时，LC-MS监测反应完成。过滤，滤液浓缩，HPLC制备色谱分离，得到黄色固体H3(5.0mg)，收率:44％，LCMS：ESI-MS(m/z):437.3[M+H] +。
冰浴下，将化合物H3(5mg,0.011mmol)溶于1.5mL二氯甲烷中，加入三乙胺(3mg,0.021mmol)和正丙基磺酰氯(3mg,0.021mmol)，升温至室温下反应1小时，停止反应。向反应液中加入10mL水，乙酸乙酯萃取，浓缩，HPLC制备色谱分离，得到化合物H6(2.1mg)，LCMS：ESI-MS(m/z):584.0[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.11(s,1H),8.77(s,1H),8.70(s,1H),8.53(s,1H),8.44(d,J＝5.9Hz,1H),7.46(d,J＝8.0Hz,1H),7.25(bs,1H),6.45(d,J＝8.1Hz,1H),4.43-4.39(m,2H),3.98-3.82(m,2H),3.586-3.52(m,2H),3.60-3.57(m,3H),3.29-3.26(m,1H),3.02(s,3H),1.64-1.58(m,2H),1.38(d,J＝6.8Hz,6H),0.96-0.90(m,3H).
参照化合物H6的合成路线，采用类似的骨架结构，合成如下目标分子。
Figure PCTCN2022128264-appb-000121
Figure PCTCN2022128264-appb-000122
Figure PCTCN2022128264-appb-000123
Figure PCTCN2022128264-appb-000124
Figure PCTCN2022128264-appb-000125
实施例7
本发明化合物对于激酶EGFR活性抑制效果：
利用MSA(Mobility Shift Assay)方法检测小分子抑制剂对EGFR野生型及其突变体(EGFR wt、EGFR-L858R、EGFR-L858R-T790M-C797S、EGFR-L858R-C797S)激酶活性的影响。
在化合物孔和阳性对照Max孔分别加10μL的2.5倍终浓度的激酶溶液；在阴性对照Min孔中加10μl的1×激酶缓冲液。1000rpm离心30秒，反应板振荡混匀后室温孵育10分钟。用1×激酶缓冲液配制5/3倍终浓度的ATP和激酶底物的混合溶液。加入15μL的5/3倍终浓度的ATP和底物的混合溶液，起始反应。将384孔板1000rpm离心30秒，振荡混匀后室温孵育相应时间。加入30μL终止检测液停止激酶反应，1000rpm离心30秒，振荡混匀。用Caliper EZ Reader读取转化率。
计算公式：
Figure PCTCN2022128264-appb-000126
其中：Conversion％_sample是样品的转化率读数；Conversion％_min是阴性对照孔均值，代表没有酶活孔的转化率读数；Conversion％_max是阳性对照孔均值，代表没有化合物抑制孔的转化率读数。
拟合量效曲线：
以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC 50值。
计算公式是Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))
表1：化合物对于EGFR(wild-type)、EGFR(L858R)、EGFR(L858R/C797S)和EGFR(L858R/T790M/C797S)抑制实验结果
Figure PCTCN2022128264-appb-000127
Figure PCTCN2022128264-appb-000128
N.D.＝未测试
以上结果表明，本发明分子对于EGFR中奥希替尼的耐药突变具有良好的抑制效果，且对野生型EGFR抑制较弱，选择性高。
Figure PCTCN2022128264-appb-000129
(对照A；WO2021133809)
实施例8
利用Promega CellTiter-Glo试剂检测小分子抑制剂对5株Ba/F3细胞系(Ba/F3-FL-EGFR、Ba/F3-FL-EGFR-L858R、Ba/F3-FL-EGFR-L858R-T790M-C797S、Ba/F3-TEL-EGFR-L858R-C797S和Ba/F3-FL-EGFR-del19-C797S)增殖的影响。
将细胞系在培养条件37℃，5％CO 2的培养箱中进行培养。定期传代，取处于对数生长期的细胞用于铺板。在细胞板中每孔加入95μL细胞悬液，在Min对照孔中加入不含细胞(含0.1％DMSO)的培养液。化合物检测细胞板加药：取5μL的20×化合物工作液按下表所示加入到细胞培养板中。在Max对照中加入5μL DMSO-细胞培养液混合液，DMSO终浓度为0.1％。在Max对照中加入5μL DMSO-细胞培养液混合液。DMSO终浓度为0.1％。
待测化合物加入到下表
1×化合物溶液 C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10
浓度(μM) 10.0000 2.5000 0.6250 0.1563 0.0391 0.0098 0.0024 0.00061 0.00015 10.0000
C1至C9(μL) 5 5 5 5 5 5 5 5 5 5
培养液(μL) 95 95 95 95 95 95 95 95 95 95
将培养板在37℃,5％CO 2培养箱中培养72小时。CellTiter-Glo发光法细胞活性检测。数据分析：
细胞增殖抑制率(Inhibition Rate)数据采用下列公式来处理：
Inhibition Rate(Inh％)＝100-(RLU Drug-RLU Min)/(RLU Max-RLU Min)*100％。
其中：RLU Drug表示加入药物的细胞相对发光单位，RLU Min表示培养液的发光单位，RLU Max表示 加入DMSO的细胞相对发光单位。
在EXCEL中计算不同浓度化合物对应的抑制率，然后用GraphPad Prism软件作抑制率曲线图并计算相关参数，参数包括细胞最大和最小抑制率，IC 50值。
表2：代表化合物对于BaF3细胞转染激酶EGFRwt，EGFR(L858R)，EGFR(L858R/C797S)，EGFR(L858R/T790M/C797S)和EGFR(del19/C797S)抗增殖抑制效果
Figure PCTCN2022128264-appb-000130
Figure PCTCN2022128264-appb-000131
N.D.＝未测试
以上结果表明，本发明化合物对于EGFR中的L858R的相关突变以及Osimertinib的耐药突变具有良好的抗增殖效果，对于野生型EGFR抑制较弱，且部分化合物显著优于对照分子。
实施例9
利用Promega CellTiter-Glo试剂检测小分子抑制剂对3株Ba/F3细胞系(Ba/F3-FL-EGFR-del19、Ba/F3-FL-EGFR-del19-T790M、Ba/F3-FL-EGFR-del19-T790M-C797S)增殖的影响。
将细胞系在培养条件37℃，5％CO 2的培养箱中进行培养。定期传代，取处于对数生长期的细胞用于铺板。在细胞板中每孔加入95μL细胞悬液，在Min对照孔中加入不含细胞(含0.1％DMSO)的培养液。化合物检测细胞板加药：取5μL的20×化合物工作液加入到细胞培养板中。在Max对照中加入5μL DMSO-细胞培养液混合液，DMSO终浓度为0.1％。在Max对照中加入5μL DMSO-细胞培养液混合液。DMSO终浓度为0.1％。
将培养板在37℃,5％CO 2培养箱中培养72小时。CellTiter-Glo发光法细胞活性检测。数据分析：
细胞增殖抑制率(Inhibition Rate)数据采用下列公式来处理：
Inhibition Rate(Inh％)＝100-(RLU Drug-RLU Min)/(RLU Max-RLU Min)*100％。
其中：RLU Drug表示加入药物的细胞相对发光单位，RLU Min表示培养液的发光单位，RLU Max表示加入DMSO的细胞相对发光单位。
在EXCEL中计算不同浓度化合物对应的抑制率，然后用GraphPad Prism软件作抑制率曲线图并计算相关参数，参数包括细胞最大和最小抑制率，IC 50值。
表3：代表化合物对于BaF3细胞转染激酶EGFR(del19)，EGFR(del19/T790M)和EGFR(del19/T790M/C797S)抗增殖抑制效果
Figure PCTCN2022128264-appb-000132
Figure PCTCN2022128264-appb-000133
以上结果表明，本发明化合物对于EGFR中的del19的相关突变以及Osimertinib的耐药突变具有良好的抗增殖效果。
实施例10：
化合物的肝微粒体稳定性实验。具体如下：
对本发明化合物进行肝微粒体稳定性试验研究，将待测化合物在加入或不加入NADPH情况下与不同种属的肝微粒体进行共孵育，试验体系中待测化合物终浓度为1μM，NADPH终浓度为1mM，肝微粒体终浓度为0.5mg/ml。检测60分钟内不同时间点孵育上清中的化合物浓度并计算药代动力学参数(例如清除率Clint)。
该结果表明本发明分子具有较好的代谢稳定性(尤其在人体中，具有较好的代谢稳定性)。
Figure PCTCN2022128264-appb-000134
实施例11：
BALB/c裸鼠体内药效实验。具体如下：
培养BaF3(del19/T790M/C797S)的肿瘤细胞，将该肿瘤细胞接种到6-8周的雌性BALB/c裸鼠中(体重约20g左右)，所有小鼠皮下接种。小鼠培养于SPF级实验环境中，所有小鼠可自由获取商业认证的标准饮食。当小鼠平均肿瘤体积成长到150mm 3左右时，将试验化合物开始每日口服给药。给药剂量为：空白组溶媒(DMSO/Solutol/H 2O,5/10/85)。给药组剂量为100mg/kg，每日两次；其中Osimertinib组给药剂量为25mg/kg，每日一次。肿瘤体积一周三次用二维卡尺测量，每天动物称重。连续给药13天后，根据最终肿瘤体积计算抑制率(TGI/100％)。体积计算公式为：V＝1/2a*b 2，a代表肿瘤长径，b代表肿瘤短径。
受试药物 给药剂量 肿瘤体积(mm 3) TGI
空白组 0 3870 0％
Osimertinib 25mg/kg,QD 3110 20％
H12 100mg/kg $,BID 1341 68％
H23 100mg/kg $,BID 28 103％
P39a 100mg/kg,BID 945 79％
P41a 100mg/kg,BID 693 85％
$表示前4天给药剂量为50mg/kg，第5天开始为100mg/kg。
该结果表明本发明分子具有较好体内药效，对于osimertinib耐药的肿瘤细胞具有优异的抑制效果，能够克服耐药，带来临床获益。

Claims (37)

  1. 式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
    Figure PCTCN2022128264-appb-100001
    其中：
    Figure PCTCN2022128264-appb-100002
    表示
    Figure PCTCN2022128264-appb-100003
    其中当
    Figure PCTCN2022128264-appb-100004
    为
    Figure PCTCN2022128264-appb-100005
    X选自CH或N，Y选自CH 2、C＝O或C＝S；当
    Figure PCTCN2022128264-appb-100006
    为
    Figure PCTCN2022128264-appb-100007
    时，X为C，Y为CH；
    Z选自CH或N；
    环A为4-8元杂环基；
    环B选自
    Figure PCTCN2022128264-appb-100008
    L选自化学键、-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-、-C(＝O)-CH(R N)-、-CH(R N)-S(＝O)(＝M)-或-S(＝O)(＝M)-CH(R N)-；
    R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 3和R 4独立地选自H、OR a、C 1-6烷基或C 1-6卤代烷基；
    R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 6选自-C 0-6亚烷基-OR a、-C 0-6亚烷基-NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
    R 7选自H、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR bR c、C 1-6烷基、C 1-6卤代烷基或-S(＝O)(＝M)-R 8；
    其中M为O或NH；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    R 8选自-C 0-6亚烷基-OR a、-C 0-6亚烷基-NR bR c、C 1-6烷基、-C 1-6亚烷基-C 3-6环烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基，其任选被1个或多个R a取代；
    R a、R b和R c独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基；
    其中X、Y、Z、环A、环B、L、R 1-R 8、R N、R a、R b和R c中的各基团定义可被一个或多个氘原子取代，直至完全氘代；
    条件是，当L为-CH(R N)-S(＝O)(＝M)-，且X、Y和Z所在环为苯环时，B为
    Figure PCTCN2022128264-appb-100009
  2. 权利要求1的式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中X、Y和Z所在的环选自：
    Figure PCTCN2022128264-appb-100010
  3. 权利要求1或2的式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中环A选自：
    Figure PCTCN2022128264-appb-100011
  4. 权利要求1-3中任一项的式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中环B为
    Figure PCTCN2022128264-appb-100012
  5. 权利要求1-3中任一项的式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中环B为
    Figure PCTCN2022128264-appb-100013
  6. 权利要求1-5中任一项的式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-N(R N)-C(＝O)-、-CH(R N)-C(＝O)-或-CH(R N)-S(＝O)(＝M)-；优选地，L为-N(R N)-S(＝O)(＝M)-或-CH(R N)-S(＝O)(＝M)-。
  7. 权利要求1-6中任一项的式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中R 1和R 2之一为卤素，另一个选自H、卤素或C 1- 6烷基；优选地，R 1和R 2之一为F，另一个选自H、F或Me；优选地，R 1和R 2之一为F，另一个为H。
  8. 权利要求1-7中任一项的式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中R 3和R 4之一为OR a，另一个选自H或C 1-6烷基；优选地，R 3和R 4之一为OH或OMe，另一个选自H或Me。
  9. 权利要求1-8中任一项的式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中R 5选自H或Me。
  10. 权利要求1-9中任一项的式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有以下结构：
    Figure PCTCN2022128264-appb-100014
    Figure PCTCN2022128264-appb-100015
    其中各基团如权利要求1-9中任一项所定义。
  11. 权利要求10的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(II)化合物：
    Figure PCTCN2022128264-appb-100016
    其中：
    Figure PCTCN2022128264-appb-100017
    表示
    Figure PCTCN2022128264-appb-100018
    其中当
    Figure PCTCN2022128264-appb-100019
    为
    Figure PCTCN2022128264-appb-100020
    X选自CH或N，Y选自CH 2、C＝O或C＝S；当
    Figure PCTCN2022128264-appb-100021
    为
    Figure PCTCN2022128264-appb-100022
    时，X为C，Y为CH；
    Z选自CH或N；
    环A为4-8元杂环基；
    L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-、-C(＝O)-CH(R N)-、-CH(R N)-S(＝O)(＝M)-或-S(＝O)(＝M)-CH(R N)-；
    R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
    R 7选自H、C 1-6烷基、C 1-6卤代烷基或-S(＝O)(＝M)-R 8；
    其中M为O或NH；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    R 8选自OR a、NR bR c、C 1-6烷基、-CH 2-C 3-6环烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基，其任选被1个或多个R a取代；
    R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
  12. 权利要求10的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(III)化合物：
    Figure PCTCN2022128264-appb-100023
    其中：
    环A为4-8元杂环基；
    L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-、-C(＝O)-CH(R N)-、-CH(R N)-S(＝O)(＝M)-或-S(＝O)(＝M)-CH(R N)-；
    R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
    R 7选自H、C 1-6烷基、C 1-6卤代烷基或-S(＝O)(＝M)-R 8；
    其中M为O或NH；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    R 8选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基，其任选被1个或多个R a取代；
    R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
  13. 权利要求12的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    环A选自
    Figure PCTCN2022128264-appb-100024
    L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-、-C(＝O)-CH(R N)-、-CH(R N)-S(＝O)(＝M)-或-S(＝O)(＝M)-CH(R N)-；
    R 5选自H或Me；
    R 6选自Me、Et、Pr、CH 2CF 3、环丙基、OH、NH 2、NHMe、NMe 2、呋喃-2-基或吡啶-4-基；
    R 7选自H、三氟乙基或-S(＝O)(＝M)-R 8；
    其中M为O或NH；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    R 8选自Me、Et、Pr、CH 2CF 3、环丙基、OH、NH 2、NHMe、NMe 2、吡喃-4-基、呋喃-2-基或吡啶-4-基；
    R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
  14. 权利要求12的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前 药、多晶型、水合物或溶剂合物，其中：
    环A为4-8元杂环基；
    L选自-S(＝O)(＝M)-、-CH(R N)-C(＝O)-或-CH(R N)-S(＝O)(＝M)-；
    R 5为H、C 1-6烷基或C 1-6卤代烷基；
    R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基；
    R 7选自H、三氟乙基或-S(＝O)(＝M)-R 8；
    其中M为O或NH；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    R 8选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基；
    R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
  15. 权利要求12的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    环A为4-8元杂环基；
    L选自-S(＝O)(＝M)-、-CH(R N)-C(＝O)-或-CH(R N)-S(＝O)(＝M)-；
    R 5选自H或C 1-6烷基；
    R 6选自NR bR c、C 1-6烷基或C 1-6卤代烷基；
    R 7选自H、三氟乙基或-S(＝O)(＝M)-R 8；
    其中M为O或NH；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    R 8选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或吡喃-4-基；
    R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基。
  16. 权利要求12的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    环A选自
    Figure PCTCN2022128264-appb-100025
    L选自-S(＝O)(＝M)-、-CH(R N)-C(＝O)-或-CH(R N)-S(＝O)(＝M)-；
    R 5为H；
    R 6选自Me或NH 2；
    R 7选自H或-S(＝O)(＝M)-R 8；
    其中M为O；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    R 8选自Me、Et、Pr、环丙基或吡喃-4-基。
  17. 权利要求10的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(IV)化合物：
    Figure PCTCN2022128264-appb-100026
    其中：
    环A为4-8元杂环基；
    L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-或-C(＝O)-CH(R N)-；
    R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 3和R 4独立地选自H、OR a、C 1-6烷基或C 1-6卤代烷基；
    R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
    其中M为O或NH；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
  18. 权利要求17的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    环A选自
    Figure PCTCN2022128264-appb-100027
    L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-或-C(＝O)-CH(R N)-；
    R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 3和R 4独立地选自H、OR a、C 1-6烷基或C 1-6卤代烷基；
    R 5选自H、C 1-6烷基或C 1-6卤代烷基；
    R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
    其中M为O或NH；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
  19. 权利要求10的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(V)、(V-1)或(V-2)化合物：
    Figure PCTCN2022128264-appb-100028
    其中：
    L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-或-C(＝O)-CH(R N)-；
    R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 3和R 4独立地选自H、OR a、C 1-6烷基或C 1-6卤代烷基；
    R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
    其中M为O或NH；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
  20. 权利要求19的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-N(R N)-C(＝O)-或-CH(R N)-C(＝O)-；
    R 1和R 2之一为卤素，另一个选自H、卤素或C 1-6烷基；
    R 3和R 4之一为OR a，另一个选自H或C 1-6烷基；
    R 5选自H、C 1-6烷基或C 1-6卤代烷基；
    R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或5-6元杂芳基；
    其中M为O或NH；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
  21. 权利要求10的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前 药、多晶型、水合物或溶剂合物，其为式(VI)、(VI-1)或(VI-2)化合物：
    Figure PCTCN2022128264-appb-100029
    其中：
    M为O或NH；
    R 1和R 2独立地选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 3和R 4独立地选自H、OR a、C 1-6烷基或C 1-6卤代烷基；
    R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    其中R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
  22. 权利要求21的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    M为O或NH；
    R 1和R 2之一为卤素，另一个选自H、卤素或C 1-6烷基；
    R 3和R 4之一为OR a，另一个选自H或C 1-6烷基；
    R 5选自H或C 1-6烷基；
    R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或5-6元杂芳基；
    R N选自H或C 1-6烷基；
    或者R N和R 6连接形成C 1-6亚烷基；
    其中R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基。
  23. 权利要求21的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    M为O；
    R 1和R 2之一为F，另一个选自H、F或Me；
    R 3和R 4之一为OH或OMe，另一个选自H或Me；
    R 5选自H或Me；
    R 6选自Me、Et、Pr、CH 2CF 3、环丙基、NMe 2、呋喃-2-基或吡啶-4-基；
    R N选自H或Me；
    或者R N和R 6连接形成C 1-4亚烷基。
  24. 权利要求21的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    M为O或NH；
    R 1和R 2之一选自卤素、C 1-6烷基或C 1-6卤代烷基，另一个为H；
    R 3和R 4之一选自OR a、C 1-6烷基或C 1-6卤代烷基，另一个为H；
    R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    其中R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
  25. 权利要求21的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    M为O或NH；
    R 1和R 2之一选自卤素或C 1-6烷基，另一个为H；
    R 3和R 4之一为OR a，另一个为H；
    R 5选自H、C 1-6烷基或C 1-6卤代烷基；
    R 6选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    其中R a选自H、C 1-6烷基或C 1-6卤代烷基。
  26. 权利要求21的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    M为O；
    R 1和R 2之一为卤素(优选F)，另一个为H；
    R 3和R 4之一为OR a，另一个为H；
    R 5选自H或C 1-4烷基；
    R 6选自C 1-4烷基或C 1-4卤代烷基；
    R N选自H、C 1-4烷基或C 1-4卤代烷基；优选C 1-4烷基；
    其中R a选自H或C 1-4烷基。
  27. 权利要求10的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(VII)、(VII-1)或(VII-2)化合物：
    Figure PCTCN2022128264-appb-100030
    其中：
    L选自-S(＝O)(＝M)-、-N(R N)-S(＝O)(＝M)-、-S(＝O)(＝M)-N(R N)-、-N(R N)-C(＝O)-、-C(＝O)-N(R N)-、-CH(R N)-C(＝O)-、-C(＝O)-CH(R N)-、-CH(R N)-S(＝O)(＝M)-或-S(＝O)(＝M)-CH(R N)-；
    R 5选自H、卤素、C 1-6烷基或C 1-6卤代烷基；
    R 6选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基；
    R 7选自H、C 1-6烷基、C 1-6卤代烷基或-S(＝O)(＝M)-R 8；
    其中M为O或NH；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    或者R N和R 6连接形成C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    R 8选自OR a、NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环基、C 6-10芳基或5-6元杂芳基，其任选被1个或多个R a取代；
    R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基；或者R b和R c与它们连接的氮原子一起形成4-7元杂环基。
  28. 权利要求27的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    其中：
    L选自-N(R N)-S(＝O)(＝M)-或-CH(R N)-S(＝O)(＝M)-；
    R 5选自C 1-6烷基或C 1-6卤代烷基；
    R 6选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基；
    R 7为-S(＝O)(＝M)-R 8；
    其中M为O或NH；
    R N选自H、C 1-6烷基或C 1-6卤代烷基；
    R 8选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基，其任选被1个或多个R a取代；
    R a选自H、C 1-6烷基或C 1-6卤代烷基。
  29. 权利要求27的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    其中：
    L选自-N(R N)-S(＝O)(＝M)-或-CH 2-S(＝O)(＝M)-；
    R 5选自C 1-6烷基或C 1-6卤代烷基；
    R 6选自C 1-6烷基或C 1-6卤代烷基；
    R 7为-S(＝O)(＝M)-R 8；
    其中M为O或NH；
    R N选自C 1-6烷基或C 1-6卤代烷基；
    R 8选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基或4-6元杂环基。
  30. 权利要求27的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    其中：
    L选自-N(R N)-S(＝O) 2-或-CH 2-S(＝O) 2-；
    R 5选自C 1-6烷基或C 1-6卤代烷基；
    R 6选自C 1-6烷基或C 1-6卤代烷基；
    R 7为-S(＝O) 2-R 8；
    其中R N选自C 1-6烷基或C 1-6卤代烷基；
    R 8选自C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基。
  31. 权利要求27的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：
    其中：
    L选自-N(R N)-S(＝O) 2-或-CH 2-S(＝O) 2-；
    R 5为C 1-4烷基；
    R 6为C 1-4烷基；
    R 7为-S(＝O) 2-R 8；
    其中R N为C 1-4烷基；
    R 8选自C 1-4烷基或C 3-6环烷基。
  32. 化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物选自：
    Figure PCTCN2022128264-appb-100031
    Figure PCTCN2022128264-appb-100032
    Figure PCTCN2022128264-appb-100033
    Figure PCTCN2022128264-appb-100034
    Figure PCTCN2022128264-appb-100035
    Figure PCTCN2022128264-appb-100036
  33. 药物组合物，其含有权利要求1-32中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，和药学上可接受的赋形剂；优选地，其还含有其它治疗剂。
  34. 权利要求1-32中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体在制备用于治疗和/或预防EGFR蛋白及其突变体介导的疾病的药物中的用途。
  35. 一种在受试者中治疗和/或预防EGFR蛋白及其突变体介导的疾病的方法，所述方法包括向所述受试者给药权利要求1-32中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体或权利要求33的药物组合物。
  36. 权利要求1-32中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体或权利要求33的药物组合物，其用于治疗和/或预防EGFR蛋白及其突变体介导的疾病。
  37. 权利要求34的用途或权利要求35的方法或权利要求36的化合物或组合物的用途，其中所述EGFR突变体选自L858R突变体、del19突变体、T790M突变体、C797S突变体中的一种或多种；优选地，所述疾病选自肺癌、结肠癌、尿路上皮癌、乳腺癌、前列腺癌、脑癌、卵巢癌、胃癌、胰腺癌、头颈癌、膀胱癌和间皮瘤，优选非小细胞肺癌。
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