WO2022042331A1 - 杂环化合物及其制备方法和用途 - Google Patents

杂环化合物及其制备方法和用途 Download PDF

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Publication number
WO2022042331A1
WO2022042331A1 PCT/CN2021/112400 CN2021112400W WO2022042331A1 WO 2022042331 A1 WO2022042331 A1 WO 2022042331A1 CN 2021112400 W CN2021112400 W CN 2021112400W WO 2022042331 A1 WO2022042331 A1 WO 2022042331A1
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Prior art keywords
alkyl
cycloalkyl
compound
membered heterocycloalkyl
halogen
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PCT/CN2021/112400
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English (en)
French (fr)
Inventor
田强
易磊
王波
王太津
刘谦
陈慧萍
杨禹
宋宏梅
薛彤彤
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN202180058539.0A priority Critical patent/CN116113418A/zh
Publication of WO2022042331A1 publication Critical patent/WO2022042331A1/zh

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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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 medicinal chemistry, and particularly relates to a substituted pyrazine compound used as a SHP2 (src homology 2 domain containing phosphotyrosine phosphatase 2) inhibitor, its preparation method, pharmaceutical composition and its use in the treatment of SHP2 enzyme-related diseases ( Also referred to herein as "SHP2 phosphatase related diseases” or “SHP2 related diseases”).
  • SHP2 src homology 2 domain containing phosphotyrosine phosphatase 2
  • SHP2 phosphatase related diseases also referred to herein as "SHP2 phosphatase related diseases” or "SHP2 related diseases”
  • SHP2 a protein tyrosine phosphatase encoded by the gene PTPN11, is an intracellular non-receptor member of the PTP family, which catalyzes protein tyrosine dephosphorylation.
  • SHP2 has two N-terminal SH2 (Src homology 2) domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-rich proline group and a tyrosine phosphorylation site end tail. These two SH2 domains control the subcellular localization and functional regulation of SHP2. In the inactive state, SHP2 is in an autoinhibited state, and the interaction of N-SH2 and PTP inhibits phosphatase activity.
  • cytokines or inflammatory factors such as platelet-derived growth factor (PDGF) and FGF
  • PDGF platelet-derived growth factor
  • FGF fibroblast growth factor
  • phosphorylation of tyrosine residues Tyr542, Tyr580 combined with N-SH2
  • SHP2 is widely expressed in the human body and participates in multiple signaling pathways such as Ras-Erk, PI3K-Akt, Jak-Stat, Met, FGFR, EGFR and NF-kB, thereby regulating cell proliferation, differentiation, migration, apoptosis and other physiological functions .
  • Activating mutants of SHP2 are associated with various diseases, such as Noonan syndrome, breast cancer, and melanoma.
  • Overexpression of SHP2 increases the risk of cancers such as chronic myeloid leukemia, mastocytosis, glioblastoma, lung cancer, and breast cancer, suggesting that SHP2 has a broad role in different types of cancer and at different stages of cancer development. Therefore, there is a need for SHP2 phosphatase inhibitor compounds and the treatment of cancer and other diseases with these compounds.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N- Oxides, isotopically labeled compounds, metabolites or prodrugs:
  • L 1 is selected from single bond and -S-;
  • Ring B is selected from 5-10 membered heteroaromatic rings and 5-6 membered heterocycles
  • Ring C is a 4-16-membered nitrogen-containing heterocycle
  • n are each independently selected from 0, 1 and 2.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof compounds, solvates, N-oxides, isotopically-labeled compounds, metabolites or prodrugs and one or more pharmaceutically acceptable carriers.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N- Use of oxides, isotopically-labeled compounds, metabolites or prodrugs or the pharmaceutical compositions of the present invention in the preparation of medicaments for preventing or treating SHP2 phosphatase-related diseases.
  • the present invention provides a method for preventing or treating a SHP2 phosphatase-related disease, the method comprising administering to an individual in need thereof a compound of formula (I) or a pharmaceutically acceptable
  • a compound of formula (I) or a pharmaceutically acceptable The salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically-labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the present invention.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N- Oxides, isotopically-labeled compounds, metabolites or prodrugs or the pharmaceutical compositions of the present invention are used for preventing or treating SHP2 phosphatase-related diseases.
  • the SHP2 phosphatase-related disease is a disease sensitive or responsive to SHP2 phosphatase inhibition.
  • the SHP2 phosphatase-related disease is a tumor-like disorder, including but not limited to solid and hematological malignancies.
  • the SHP2 phosphatase-related disease is lung cancer or esophageal cancer.
  • the present invention further provides compounds of formula (I) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopes thereof
  • Labeled compounds, metabolites or prodrugs or the pharmaceutical compositions of the present invention are used in combination with additional therapeutic methods for the prevention or treatment of SHP2 phosphatase-related diseases, including but not limited to: radiation therapy, chemotherapy therapy, immunotherapy, or a combination thereof.
  • the present invention provides a method for the preparation of a compound of formula (I), said method comprising the steps of:
  • the compound of formula S-1 is coupled with the compound of formula S-3 to generate the compound of formula BM-1;
  • LG 1 and LG 2 each independently represent a leaving group
  • X represents sulfur or a single bond
  • R x represents H or a leaving group
  • Ring A, Ring B, Ring C, L 1 , R 1 , R 2 , R 3 , R 4 , m and n are as defined above.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N- Oxides, isotopically labeled compounds, metabolites or prodrugs:
  • L 1 is selected from single bond and -S-;
  • Ring B is selected from 5-10 membered heteroaromatic rings and 5-6 membered heterocycles
  • Ring C is a 4-16-membered nitrogen-containing heterocycle
  • n are each independently selected from 0, 1 and 2.
  • the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, or N-oxide thereof.
  • ring D is selected from C 3-6 carbocycles and 3-6 membered heterocycles
  • p, q are each independently selected from 0, 1 and 2;
  • L 1 , Ring B, Ring C, R 1 , R 2 , R 3 , R 4 , m and n are as defined in Formula I.
  • ring B is a 6-9 membered heteroaromatic ring or a 5-6 membered heterocyclic ring.
  • ring B is a 6-membered heteroaromatic ring, a 9-membered heteroaromatic ring or a 6-membered heterocyclic ring.
  • ring B is pyrazinyl, pyrimidinone or 9-membered heteroaromatic ring.
  • ring B is pyrazinyl, pyrazolopyrazinyl or imidazopyrimidyl.
  • each R 2 is independently selected from hydrogen, C 1-6 alkyl, -CH 2 -OH, oxo and amino.
  • each R 2 is independently selected from hydrogen, C 1-6 alkyl, -CH 2 -OH and amino.
  • each R2 is independently selected from hydrogen, methyl, -CH2 - OH, and amino.
  • each R 2 is independently selected from hydrogen, methyl, ethyl, -CH 2 F, -CH 2 CHF 2 and -CH 2 CH 2 F.
  • ring B is a 6-9 membered heteroaromatic ring or a 5-6 membered heterocycloalkyl
  • ring B is a 6-membered heteroaromatic ring, a 9-membered heteroaromatic ring or a 6-membered heterocyclic ring;
  • ring B is pyrazinyl, pyrimidinone or 9-membered heteroaromatic ring
  • ring B is pyrazinyl, pyrimidinone or 9-membered heteroaromatic ring
  • Each R 2 is independently selected from hydrogen, C 1-6 alkyl, -CH 2 -OH, oxo and amino.
  • ring B is pyrazinyl, pyrazolopyrazinyl or imidazopyrimidyl
  • Each R 2 is independently selected from hydrogen, C 1-6 alkyl, -CH 2 -OH, and amino.
  • R 2 is as defined in formula I.
  • Ring B is
  • R2 is selected from hydrogen , methyl, ethyl , -CH2F , -CH2CHF2 and -CH2CH2F .
  • R2 is selected from hydrogen , methyl, ethyl , -CH2F , -CH2CHF2 and -CH2CH2F .
  • the present invention provides compounds of formula (II-1) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N- Oxides, isotopically labeled compounds, metabolites or prodrugs:
  • Ring D is selected from C 3-6 carbocycle and 4-6 membered heterocycle
  • L 1 , Ring C, R 1 , R 2 , R 3 , R 4 , m and n are as defined in general formula I
  • U , V, W, R5, R5 ' , p and q are as defined in general formula II.
  • each R 2 is independently selected from hydrogen, C 1-6 alkyl, -CH 2 -OH, oxo and amino.
  • each R 2 is independently selected from hydrogen, C 1-6 alkyl, -CH 2 -OH and amino.
  • the present invention provides compounds of formula (II-1a) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N- Oxides, isotopically labeled compounds, metabolites or prodrugs:
  • ring D is selected from C 3-6 carbocycle and 4-6 membered heterocycle
  • L 1 , ring C, R 1 , R 3 , R 4 and m are as defined in general formula I
  • U, V, W, R 5 , R 5' , p and q are as defined in general formula II.
  • ring D is a 4-membered oxygen-containing heterocycle
  • R 6 is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, each of said alkyl, cycloalkyl, heterocycloalkyl is optionally selected by one or more selected from hydroxyl, halogen, cyano Substituent substitution of base, -O-(C 1-6 alkyl);
  • the present invention provides compounds of formula (II-1) or (II-1a), wherein Ring D is a 4-membered oxygen-containing heterocycle, preferably, Ring D is
  • R 6 is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, each of said alkyl, cycloalkyl, heterocycloalkyl is optionally selected by one or more selected from hydroxyl, halogen, cyano Substituents of -O-(C 1-6 alkyl) groups.
  • R 6 is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, each of said alkyl, cycloalkyl, heterocycloalkyl is optionally selected by one or more selected from hydroxyl, halogen, cyano Substituents of -O-(C 1-6 alkyl) groups.
  • the present invention provides compounds of formula (II-1) or (II-1a) wherein Ring D is W is -O-, U is -N(R 6 )-, V is -CH 2 -;
  • R 6 is selected from hydrogen, C 1-3 alkyl and C 3-6 cycloalkyl, each of said alkyl, cycloalkyl, heterocycloalkyl is optionally selected by one or more selected from hydroxyl, halogen, cyano Substituents of -O-(C 1-6 alkyl) groups.
  • the present invention provides compounds of formula (II-1) or (II-1a) wherein Ring D is W is -O-, U is -N(R 6 )-, V is -CH 2 -; R 6 is selected from hydrogen and C 1-3 alkyl.
  • the present invention provides compounds of formula (II-1-1) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • X 1 is selected from -O-, -CH 2 - and -N(R 8 )-;
  • y is selected from 0, 1, 2 and 3;
  • Rings D, U, V, W, L 1 , R 1 , R 5 , R 5′ , m, p and q are as defined in general formula II.
  • X 1 is -O-.
  • the present invention provides a compound of formula (II-1-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • E is selected from 3-6 membered heterocycle, C 3-6 carbocycle, benzene ring and 5-6 membered heteroaromatic ring;
  • Ring F is a C 3-6 cycloalkyl; the cycloalkyl is optionally substituted by one or more selected from the group consisting of hydroxy, halogen, cyano, amino, -O-(C 1-6 alkyl), -O- Substituent substitution of (halogenated C 1-6 alkyl) and -O-(3-6 membered heterocycloalkyl);
  • z is selected from 0, 1, 2 or 3;
  • Rings D, U, V, W, L 1 , R 1 , R 5 , R 5′ , m, p and q are as defined in general formula II.
  • the present invention provides a compound of formula (II-1-2a) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • X is selected from -CH- and -N-;
  • X 2 , R 9 , z, ring D, U, V, W, L 1 , R 1 , R 5 , R 5′ , m, p and q are as defined in general formula II-1-2.
  • the present invention provides a compound of formula (II-1-2a) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, In N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • X 2 is -O- and -CH 2 -;
  • X 3 is selected from -CH- and -N-;
  • R 9 are each independently selected from hydrogen and halogen
  • z is selected from 0, 1, 2 and 3;
  • Rings D, U, V, W, L 1 , R 1 , R 5 , R 5′ , m, p and q are as defined in general formula II.
  • the present invention provides a compound of formula (II-1b-1) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • X 1 is selected from -O-, -CH 2 - and -N(R 8 )-;
  • y 0, 1, 2 or 3;
  • Rings D, U, V, W, L 1 , R 1 , R 5 , R 5′ , m, p and q are as defined in general formula II.
  • X 1 is -O-.
  • the present invention provides compounds of formula (II-1b-2) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • X is selected from -CH- and -N-;
  • Ring F is a C 3-6 cycloalkyl; the cycloalkyl is optionally substituted by one or more selected from the group consisting of hydroxy, halogen, cyano, amino, -O-(C 1-6 alkyl), -O- Substituent substitution of (halogenated C 1-6 alkyl) and -O-(3-6 membered heterocycloalkyl);
  • z is selected from 0, 1, 2 or 3;
  • Rings D, U, V, W, L 1 , R 1 , R 5 , R 5′ , m, p and q are as defined in general formula II.
  • the present invention provides a compound of formula (II-2-1) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • X 1 is selected from -O-, -CH 2 - and -N(R 8 )-;
  • y is selected from 0, 1, 2 and 3;
  • Rings D, U, V, W, L 1 , R 1 , R 5 , R 5′ , m, p and q are as defined in general formula II.
  • X 1 is -O-.
  • the present invention provides compounds of formula (II-2-2) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • X is selected from -CH- and -N-;
  • Ring F is a C 3-6 cycloalkyl; the cycloalkyl is optionally substituted by one or more selected from the group consisting of hydroxy, halogen, cyano, amino, -O-(C 1-6 alkyl), -O- Substituent substitution of (halogenated C 1-6 alkyl) and -O-(3-6 membered heterocycloalkyl);
  • z is selected from 0, 1, 2 or 3;
  • Rings D, U, V, W, L 1 , R 1 , R 5 , R 5′ , m, p and q are as defined in general formula II.
  • the present invention provides formula (II), formula (II-1), formula (II-1a), formula (II-1-1), formula (II-1-2), formula (II) Among the compounds of -1-2a), formula (II-1b-1), formula (II-1b-2), formula (II-2-1) and formula (II-2-2),
  • R 6 and R 6 ′ are as defined in general formula II-1a.
  • R 6 and R 6 ′ are as defined in general formula II-1a.
  • the present invention provides formula (I), formula (II), formula (II-1), formula (II-1a), formula (II-1-1), formula (II-1-2) ), formula (II-1-2a), formula (II-1b-1), formula (II-1b-2), formula (II-2-1), formula (II-2-2) in the compound,
  • R 1 , R 5 , and R 5' are each independently selected from hydrogen and C 1-6 alkyl; the alkyl is optionally surrounded by one or more selected from hydroxy, halogen, cyano, and -O-(C 1 -6 alkyl) substituents.
  • the present invention provides formula (I), formula (II), formula (II-1), formula (II-1a), formula (II-1-1), formula (II-1-2) ), formula (II-1-2a), formula (II-1b-1), formula (II-1b-2), formula (II-2-1), formula (II-2-2) in the compound, R 1 , R 5 and R 5' are each independently selected from hydrogen and methyl.
  • Ring C is a 5-15 membered nitrogen-containing heterocycle
  • the present invention provides in compounds of formula (I), formula (II), formula (II-1), formula (II-1a):
  • Ring C is a 6-14 membered nitrogen-containing heterocycle
  • the present invention provides in compounds of formula (I), formula (II), formula (II-1), formula (II-1a):
  • Ring C is a 6-14 membered nitrogen-containing heterocycle
  • R 3 and R 4 are each independently selected from hydrogen, amino, C 1-6 alkyl, -C 1-6 alkyl-C 3-6 cycloalkyl, -C 1-6 alkyl-3-6 membered hetero Cycloalkyl, each of said alkyl, cycloalkyl, heterocycloalkyl is optionally selected by one or more (eg: 1, 2, 3 or 4) selected from hydroxy, halogen, amino, cyano, - Substituent substitution of O-(C 1-6 alkyl), -O-(halogenated C 1-6 alkyl) and C 3-6 cycloalkyl.
  • the present invention provides in compounds of formula (I), formula (II), formula (II-1), formula (II-1a):
  • Ring C is a 6-14 membered nitrogen-containing heterocycle
  • R 3 and R 4 are each independently selected from hydrogen, halogen, amino, C 1-6 alkyl, -C 1-6 alkyl-C 3-6 cycloalkyl, -C 1-6 alkyl-3-6 Membered heterocycloalkyl, each of said alkyl, cycloalkyl, heterocycloalkyl is optionally selected by one or more (eg: 1, 2, 3 or 4) selected from hydroxy, halogen, amino, cyano , -O-(C 1-6 alkyl), -O-(halogenated C 1-6 alkyl) and C 3-6 cycloalkyl substituents.
  • the present invention provides in compounds of formula (I), formula (II), formula (II-1), formula (II-1a):
  • Ring C is a 6-14 membered nitrogen-containing heterocycle
  • R 3 , R 4 are each independently selected from hydrogen, halogen, amino and C 1-6 alkyl optionally substituted with one or more (eg 1, 2, 3 or 4) amino groups.
  • the present invention provides in compounds of formula (I), formula (II), formula (II-1), formula (II-1a):
  • Ring C is a 6-14 membered nitrogen-containing heterocycle
  • R 3 and R 4 are each independently selected from hydrogen, -F, -NH 2 , -CH(NH 2 )CH 3 , -CH 2 F, -CH 2 OCH 3 , -CH 2 OCH 2 F, - CH2OCHF2 , and -CH3 .
  • R 3 , R 4 are each independently selected from hydrogen, -F, -NH 2 , -CH(NH 2 )CH 3 and -CH 3 .
  • L 1 is -S-
  • X 1 is selected from -O- and -CH 2 -;
  • Ring D is selected from
  • U is -N(R 6 )-
  • R 6 is selected from hydrogen and C 1-3 alkyl
  • Each R 7 is independently selected from C 1-6 alkyl and amino; or any two R 7 and the carbon atoms to which they are commonly attached form a 3-6 membered cycloalkyl;
  • L 1 is -S-
  • X 2 is selected from -O- and -CH 2 -;
  • X 3 is selected from -CH- and -N-;
  • Ring D is selected from
  • U is -N(R 6 )-
  • R 6 is selected from hydrogen and C 1-3 alkyl
  • R 9 are each independently selected from hydrogen and halogen
  • the present invention provides compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopically labeled compounds, metabolites thereof or a prodrug, wherein the compound is selected from:
  • the present invention provides compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopically labeled compounds, metabolites thereof or a prodrug, wherein the compound is selected from:
  • Yet another aspect of the present invention also relates to a method for the preparation of the compound of the present invention, the method comprising:
  • the compound of formula S-1 is coupled with the compound of formula S-3 to generate the compound of formula BM-1;
  • LG 1 and LG 2 each independently represent a leaving group, such as a halogen or a C 1-6 alkyl sulfonate group optionally substituted with a halogen (eg, a triflate); in addition, LG 2 can also be hydroxyl;
  • X represents sulfur or a single bond
  • R x represents H or a leaving group
  • Ring A, Ring B, Ring C, L 1 , R 1 , R 2 , R 3 , R 4 , m and n are as defined above.
  • LG 1 represents a halogen, such as iodine or bromine
  • LG 2 represents halogen (eg, bromine or chlorine) or hydroxy
  • X represents sulfur
  • Rx is selected from the group consisting of H, sodium, potassium, boronic acid, boronic ester, substituted silicon, substituted metal, and C1-6 alkyl optionally substituted with halogen Sulfonate group. In a more preferred embodiment, Rx is H.
  • the starting materials for the preparation method of the present invention can be obtained from commercial sources or can be prepared according to known methods.
  • compositions, formulations and kits are provided.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the compounds defined above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (e.g. hydrate), N-oxide, isotopically-labeled compound, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.
  • a further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, the method comprising adding any compound as defined above or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof.
  • the conformers, polymorphs, solvates, N-oxides, isotopically-labeled compounds, metabolites or prodrugs, or mixtures thereof, are combined with one or more pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).
  • the pharmaceutical composition can be administered in any form so long as it achieves prevention, alleviation, prevention or cure of symptoms in human or animal patients.
  • various suitable dosage forms can be prepared according to the route of administration.
  • the pharmaceutical composition can be formulated into any orally acceptable formulation, including but not limited to tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions and oral emulsions Wait.
  • the pharmaceutical compositions When administered transdermally or topically, the pharmaceutical compositions may be formulated in a suitable ointment, lotion or liniment in which the active ingredient may be suspended or dissolved in one or more carriers.
  • Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or liniments include, but are not limited to: minerals Oil, sorbitan monostearate, Tween 60, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical composition can also be administered in the form of injections, including injection solutions, sterile powders for injections and concentrated solutions for injections.
  • useful vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils can also be employed as a solvent or suspending medium, such as mono- or diglycerides.
  • the administration of the compounds or pharmaceutical compositions of the present invention may be combined with additional methods of treatment.
  • the additional treatment method may be selected from, but is not limited to, radiation therapy, chemotherapy therapy, immunotherapy, or a combination thereof.
  • Administration of the compounds or pharmaceutical compositions of the present invention may be before, during, or after the performance of the additional method of treatment.
  • the implementation of the additional treatment method and the administration of the compound or pharmaceutical composition of the present invention may be performed simultaneously, or in close connection with one another, or may be performed at a time interval. Adjustment.
  • Another aspect of the present invention also relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising any of the compounds defined above, a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate thereof compounds, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or mixtures thereof as active ingredients, or pharmaceutical compositions of the present invention.
  • the formulation is in the form of a solid, semisolid, liquid, or gaseous formulation.
  • a further object of the present invention is to provide an article of manufacture, eg in the form of a kit.
  • Article of manufacture as used herein is intended to include, but not be limited to, kits and packages.
  • the article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition in the first container, wherein the composition comprises: a first therapeutic agent comprising: any compound as defined above or a pharmaceutically acceptable compound thereof acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or mixtures thereof; and ( c) An optional package insert stating that the pharmaceutical composition can be used to treat a neoplastic disorder (as defined above).
  • the first container is a container for containing a pharmaceutical composition. This container can be used for preparation, storage, transportation and/or individual/bulk sale.
  • the first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (eg, for cream preparations), or any other container for preparing, containing, storing, or dispensing a pharmaceutical product.
  • the second container is the container for holding the first container and optional package insert.
  • the second container include, but are not limited to, boxes (eg, carton or plastic), boxes, cartons, bags (eg, paper or plastic), pouches, and sacks.
  • the package insert may be physically adhered to the exterior of the first container via cable ties, glue, staples, or other means of attachment, or it may be placed inside the second container without contact with the Any physical tool to which the first container is attached.
  • the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferred that the package insert is physically attached via cable ties, glue, staples or other means of attachment. Alternatively, it may abut or contact the exterior of the second container without physical adhesion.
  • the package insert is a trademark, label, sign, etc., which lists information related to the pharmaceutical composition located in the first container.
  • the information listed is generally at the discretion of the regulatory agency (eg, the US Food and Drug Administration) that governs the region in which the article of manufacture is to be marketed.
  • the package insert specifically lists the indications for which the pharmaceutical composition is approved.
  • the package insert can be made of any material from which the information contained in or on it can be read.
  • the package insert is a printable material (eg, paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) on which the desired information can be formed (eg, printed or applied).
  • the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopes, thereof Use of the labeled compound, metabolite or prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating SHP2-related diseases.
  • Another object of the present invention is to provide a method for preventing or treating SHP2 enzyme-related diseases, the method comprising administering to an individual in need thereof an effective amount of any compound as defined above or a pharmaceutically acceptable salt or ester thereof , stereoisomers, tautomers, polymorphs, solvates, N-oxides, metabolites or prodrugs, or mixtures thereof, or pharmaceutical compositions of the present invention.
  • the SHP2 enzyme-related disease is a disease sensitive or responsive to SHP2 enzyme inhibition.
  • the SHP2 enzyme-related disease is a neoplastic disorder, including but not limited to solid and hematological malignancies.
  • the tumor-like disorders include, but are not limited to, breast cancer, colorectal cancer, colon cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and bronchioloalveolar cancer) and prostate cancer, and cholangiocarcinoma , bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovarian, pancreatic, skin, testicular, thyroid, uterine, cervical and vulvar cancers, and leukemia ( Including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML), multiple myeloma and lymphoma.
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • the disease is cancer.
  • the compounds of the present invention may be used in combination with chemoradiotherapy or immunotherapy to prevent or treat cancer.
  • Dosage regimens can be adjusted to provide the optimal desired response.
  • a single bolus injection, bolus injection, and/or continuous infusion may be administered, among others.
  • several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses.
  • the dose of treatment will vary, depending upon considerations such as: age, sex, and general health of the patient to be treated; frequency of treatment and nature of effect desired; degree of tissue damage; duration; and other variables that can be adjusted by individual physicians.
  • the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition.
  • the amount and schedule of administration of the pharmaceutical composition can be readily determined by one of ordinary skill in the clinical arts.
  • the composition or compound of the present invention may be administered in divided doses 4 times a day to once every 3 days, and the dose may be, for example, 0.01 to 1000 mg/time.
  • the required dose can be administered in one or more doses to obtain the desired result.
  • the pharmaceutical compositions according to the present invention may also be provided in unit dosage form.
  • the present invention provides a new type of highly active SHP2 inhibitor, which can achieve at least one of the following technical effects:
  • concentrations are by weight and ratios (including percentages) are by molarity.
  • one (species) or more (species) may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (species) or more (species).
  • the expression “ C1-6” should be understood to encompass any sub - range therein and each point value, eg , C2-5 , C3-4 , C1-2 , C1-3 , C1-4 , C 1 - 5 etc., and C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , etc.
  • the expression “ C3-10 " should also be interpreted in a similar manner, eg, can encompass any sub - range and point value subsumed therein , eg , C3-9 , C6-9 , C6-8 , C6- 7 , C7-10 , C7-9 , C7-8 , C8-9 , etc.
  • the expression "3-10 yuan” should be understood to cover any sub-range therein and each point value, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan Yuan, 3-9 Yuan, 4-5 Yuan, 4-6 Yuan, 4-7 Yuan, 4-8 Yuan, 5-7 Yuan, 5-8 Yuan, 6-7 Yuan, etc. and 3, 4, 5, 6 , 7, 8, 9, 10 yuan, etc.
  • the expression "5-10 yuan” should also be understood in a similar manner, for example, can cover any sub-range and point value contained therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5- 9 yuan, 5-10 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 6-10 yuan, 7-8 yuan, etc. and 5, 6, 7, 8, 9, 10 yuan, etc.
  • alkyl refers to a saturated straight or branched chain hydrocarbon group.
  • C1-6 alkyl refers to a saturated straight or branched chain hydrocarbon group having 1-6 carbon atoms (eg, 1, 2, 3, 4, 5, or 6 carbon atoms).
  • C 1-6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo- Amyl or n-hexyl, etc.
  • alkylene refers to a saturated straight or branched chain divalent hydrocarbon group.
  • C 1-6 alkylene refers to a saturated linear or branched divalent hydrocarbon radical having 1-6 carbon atoms. Including but not limited to methylene, ethylene, propylene or butylene and the like.
  • cycloalkyl refers to a saturated or partially saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring; for example, a monocyclic ring such as cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene; or bicyclic rings, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.).
  • C3-12cycloalkyl refers to a cycloalkyl group having 3-12 ring carbon
  • heterocycloalkyl or “heterocycle” refers to a saturated or partially saturated non-aromatic cyclic group containing at least one ring member which is a heteroatom selected from N, O, P and S, preferably , the number of the heteroatoms is 1, 2, 3 or 4.
  • ring member which is a heteroatom selected from N, O, P and S, preferably , the number of the heteroatoms is 1, 2, 3 or 4.
  • 3-8 membered, 3-6 membered heterocycloalkyl include, but are not limited to, oxiranyl, oxocyclobutanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, and the like.
  • fused ring system refers to a polycyclic structure formed by two or more (eg 3, 4 or 5) carbocyclic or heterocyclic rings sharing ring edges, the carbocyclic rings including Cycloalkyl and aryl, the heterocycle includes heteroaryl and heterocycloalkyl.
  • the condensed ring system includes but is not limited to: condensed ring system formed by cycloalkyl and cycloalkyl, condensed ring system formed by cycloalkyl and heterocycloalkyl, condensed ring formed by cycloalkyl and aromatic ring Ring system, fused ring system formed by cycloalkyl and heteroaromatic ring, fused ring system formed by heterocycloalkyl and heteroaromatic ring, fused ring system formed by heterocycloalkyl and aromatic ring, heteroaromatic ring and Condensed ring system formed by heteroaromatic ring, condensed ring system formed by heteroaromatic ring and aromatic ring, etc.
  • halo or halogen group, used herein alone or in combination with other groups, means F, Cl, Br or I.
  • haloalkyl refers to an alkyl group as described above wherein one or more hydrogen atoms are replaced by halogen.
  • haloC1-6 alkyl refers to a C1-6 alkyl optionally substituted with one or more (eg, 1-3) halogens. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different, and may be located on the same or different C atoms.
  • haloalkyl groups are eg -CH2F , -CHF2 , -CF3 , -CCl3 , -C2F5 , -C2Cl5 , -CH2CF3 , -CH2Cl or -CH2CH 2 CF 3 etc.
  • nitrogen-containing heterocycle refers to a saturated or partially unsaturated ring having, for example, 4-16 (suitably 4-12, more suitably 4-10) ring atoms.
  • Saturated monocyclic or polycyclic ring systems eg 4-15 membered, 4-12 membered, 4-10 membered
  • at least one ring atom is N, optionally containing one or more (eg 1 or 2) heteroatoms selected from N, O, P and S, and the remaining ring atoms are C.
  • the polycyclic ring system may be a fused ring system, a bridged ring system or a spiro ring system.
  • the individual rings in the ring system may be saturated or unsaturated (ie having one or more double and/or triple bonds within the ring), non-aromatic ring systems, or aromatic ring systems (eg aromatic or heteroaromatic ring).
  • Examples include but are not limited to:
  • aryl or "aromatic ring”, as used herein, alone or in combination with other groups, refers to an all-carbon monocyclic or fused ring polycyclic (eg bicyclic) aromatic group having a conjugated pi electron system or aromatic rings.
  • C6-10 aryl refers to an aromatic group containing 6-10 carbon atoms. Examples include, but are not limited to, phenyl, naphthyl, and the like.
  • heteroaryl or “heteroaromatic ring,” as used herein, alone or in combination with other groups, refers to an aromatic ring having a conjugated pi electron system in which one or more (eg, 1, 2, or 3 ) ring atoms are heteroatoms selected from N, O, P and S, and the remaining ring atoms are C.
  • Heteroaryl groups or heteroaromatic rings can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl group may contain 5-12 (eg 5, 6, 7, 8, 9, 10, 11 or 12) ring atoms, especially 5, 6, 9, 10 ring atoms .
  • heteroaryl groups are thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl oxazolyl, thiadiazolyl, etc.; the term also covers instances where a heteroaryl or heteroaryl ring may optionally be further fused to an aryl, or heteroaryl ring, to form a fused ring system. Examples include but are not limited to:
  • Non-limiting examples of spiroheterocyclyl include:
  • hydroxy means -OH.
  • cyano means -CN.
  • amino means -NH2 .
  • substituted and “substituted” mean that one or more (eg, one, two, three, or four) hydrogens on the designated atom have been replaced by a selection from the designated group, provided that no more than the designated The normal valences of the specified atoms in the present case and the substitutions form stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent may be (1) unsubstituted, or (2) substituted. If an atom or group is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on that atom or group may be independently selected, optional substituents alternative. If substituents are described as being “independently selected from” or “each independently is”, then each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
  • R group such as, but not limited to, R 2 and/or R z
  • R 2 and/or R z the difference between each R are selected independently, either the same or different. The same is true for the choice of numerical values such as g, n.
  • the point of attachment of a substituent can be from any suitable position on the substituent.
  • alkyl or aryl or any of their prefix roots appear in the name of a substituent, by themselves or as part of another substituent, unless otherwise stated, they should be construed to include the above “Alkyl” and “aryl” limitations are given.
  • the number of carbon atoms specified eg, C 1-6 ) shall independently refer to the number of carbon atoms in the alkyl moiety or the number of carbon atoms in the alkyl moiety of the larger substituent with alkyl as its prefix root.
  • the present invention also includes all pharmaceutically acceptable isotopically-labeled compounds that are identical to the compounds of the present invention, except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature or atomic substitution of mass numbers.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (eg, deuterium (2H), tritium ( 3H )); isotopes of carbon (eg, 13C and14C ); chlorine isotopes (eg 37 Cl); isotopes of iodine (eg 125 I); isotopes of nitrogen (eg 13 N and 15 N); isotopes of oxygen (eg 17 O and 18 O); isotopes of phosphorus (eg 32 P); and Isotopes of sulfur (eg 34 S).
  • isotopes of hydrogen eg, deuterium (2H), tritium ( 3H )
  • isotopes of carbon eg, 13C and14C
  • chlorine isotopes eg 37 Cl
  • isotopes of iodine eg 125 I
  • isotopes of nitrogen eg 13 N and 15 N
  • stereoisomer refers to isomers formed due to at least one asymmetric center. In compounds having one or more (eg, one, two, three or four) asymmetric centers, it may give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual of diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • Solid lines may be used in this article solid wedge or virtual wedge
  • the carbon-carbon bonds of the compounds of the present invention are depicted.
  • the use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, a specific enantiomer, racemic mixture, etc.).
  • the use of real or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomer exists.
  • real and imaginary wedges are used to define relative, rather than absolute, stereochemistry.
  • the compounds of the present invention may exist as stereoisomers (which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereomers).
  • the present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present invention may exist in free form for use in therapy, or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can be directly Or indirectly provide a compound of formula (I) or a metabolite thereof. Accordingly, references herein to "compounds of the present invention" are also intended to encompass the various derivative forms of the compounds described above.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate/carbonate, glucoheptonate, gluconate, nitrate, palmitate and others like Salt.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, magnesium, and other similar salts.
  • esters means esters derived from the compounds described herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the invention in free acid or alcohol form) .
  • the compounds of the present invention may themselves also be esters.
  • the compounds of the present invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the present invention comprise a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides.
  • nitrogen-containing heterocycles capable of forming N-oxides.
  • tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines.
  • peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA)
  • hydrogen peroxide alkyl Hydrogen peroxides such as t-butyl hydroperoxide
  • sodium perborate and dioxiranes such as dimethyldioxirane
  • metabolites of the compounds of the present invention ie substances formed in the body upon administration of the compounds of the present invention. Metabolites of compounds can be identified by techniques well known in the art, and their activities can be characterized by experimental methods. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like, of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by methods of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity when administered into or onto the body can be converted into compounds of the invention having the desired activity, for example, by hydrolytic cleavage.
  • prodrugs will be functional derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as “pro-moiety (eg as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" Prepared by substituting appropriate functional groups present in the compounds of the present invention.
  • the present invention also encompasses compounds of the present invention that contain protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be accomplished with conventional protecting groups, such as those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 2006, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • the present invention also encompasses methods of making the compounds described herein. It will be appreciated that the compounds of the present invention can be synthesized using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials employed and suitable for effecting the transformation.
  • active ingredient refers to a chemical entity that is effective in treating one or more symptoms of a target disorder or condition.
  • an effective amount refers to an amount of active ingredient which, upon administration, will achieve the desired effect to the extent that it is administered, such as a relief from the condition being treated. one or more symptoms or to prevent the occurrence of a disorder or its symptoms.
  • treating means reversing, alleviating the progression of one or more symptoms of the disorder or condition to which such term is applied, or such disorder or condition.
  • prevention refers to inhibiting and delaying the onset of a disease, including not only prevention before the disease develops, but also prevention of the recurrence of the disease after treatment.
  • an “individual” as used herein includes a human or non-human animal.
  • exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein).
  • Non-human animals in the present invention include all vertebrates such as non-mammals (eg birds, amphibians, reptiles) and mammals such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs) , cats, cows, pigs, etc.).
  • MS Mass Spectrometry
  • HPLC High Performance Liquid Chromatography
  • Thin-layer chromatography was used for purification using GF 254 (0.4-0.5nm) silica gel plates produced in Yantai.
  • the monitoring of the reaction adopts thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), and the developing solvent systems used include but are not limited to: dichloromethane and methanol system, n-hexane and ethyl acetate system and petroleum In the ether and ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, or by adding triethylamine and the like.
  • TLC thin layer chromatography
  • LC-MS liquid chromatography-mass spectrometry
  • Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase.
  • the eluent system includes but is not limited to dichloromethane and methanol system and n-hexane and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.
  • reaction temperature is room temperature (20°C to 30°C).
  • reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company, Nanjing Yaoshi Technology or Shanghai Shuya Pharmaceutical Technology.
  • A-1 (1.40 g, 5.66 mmol) was dissolved in acetonitrile (20 mL) and water (10 mL), cooled to 0 °C, NaIO 4 (1.82 g, 8.49 mmol) and RuCl 3 ⁇ H 2 O (12.76 mg, 56.61 mmol) were added umol), reacted at 0 °C for 1 hour, LCMS detected the reaction and added sodium thiosulfate solution to the reaction solution, extracted with ethyl acetate, combined the organic phases, dried and concentrated to obtain crude product A-2 (1.33g), It was used directly in the next reaction.
  • the fourth step the preparation of 1-(((2-bromopyridin-3-yl)oxy)methyl)cyclobutan-1-amine (compound A-4)
  • A-3 (780 mg, 2.18 mmol) was dissolved in DCM (6 mL), TFA (3 mL) was added, the reaction was carried out at 25°C for 1 hour, the reaction solution was concentrated, the crude product was dissolved in DCM, and saturated sodium bicarbonate solution was added to adjust the pH to 9 , extracted with dichloromethane, the organic phases were combined, dried and concentrated to give crude product A-4 (550 mg), which was directly used in the next reaction.
  • Step 5 Preparation of 2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine] (Compound A-5)
  • A-4 (550 mg, 2.14 mmol) was dissolved in dioxane (10 mL), cesium carbonate (2.09 g, 6.42 mmol), Xantphos (123.77 mg, 213.90 umol) and Pd 2 (dba) 3 (97.94 mg, 106.95umol), heated to 100 °C after nitrogen replacement, reacted for 2 hours, LCMS detected the reaction and added water to the reaction solution, extracted with ethyl acetate, combined the organic phases, dried and concentrated, and purified by thin layer chromatography to obtain A-5 (300 mg, 79% yield).
  • A-5 (300 mg, 1.70 mmol) was dissolved in THF (3 mL), cooled to 0 °C, sodium hydride (204.30 mg, 5.11 mmol, 60% purity) was added, and methyl iodide (362.47 g) was added dropwise after the reaction at 0 °C for half an hour. mg, 2.55 mmol), heated to 25 ° C, reacted for 1 hour, LCMS detected the completion of the reaction, added water to the reaction solution, extracted with ethyl acetate, combined the organic phases, dried and concentrated, and purified by thin layer chromatography to obtain A- 6 (180 mg, 55% yield).
  • A-6 (160 mg, 841.04 umol) was dissolved in THF (5 mL), cooled to -78 °C, n-butyllithium (2.5M n-hexane solution, 1.35 mL) was added dropwise, the temperature was raised to 0 °C, and after 1 hour of reaction, The temperature was lowered to -78°C, a THF solution (0.5mL) of iodine (426.92mg, 1.68mmol) was added dropwise, the temperature was raised to 25°C, and the reaction was carried out for 1 hour.
  • reaction droplets were added to saturated ammonium chloride solution, Extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium sulfite solution, dried and concentrated, and purified by thin layer chromatography to obtain A-7 (208 mg, yield 78%).
  • Step 9 4'-methyl-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-8'- Preparation of Thiophenol (Compound IM-1)
  • the first step 6-bromo-3-((3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl )-5-methylpyrazine-2-carboxylate ethyl ester (B-2) preparation
  • Compound IM-4 was synthesized using a method similar to that described in the first step of the intermediate IM-3 synthesis step, except that D-0 was used in this step instead of C-0 in the first step of the IM-3 synthesis step.
  • Compound IM-5 was synthesized by a method similar to that described in steps 8 to 9 in the preparation of intermediate IM-1.
  • IM-6 2'H,4'H-spiro[oxetane-3,3'-pyrido[3,2-b][1,4]oxazine]-8'-thiophenol (compound Preparation of IM-6)
  • IM-6 was synthesized according to the corresponding analogous methods of Intermediate Preparation Example IM-1 and Intermediate Preparation Example IM-5.
  • Step 2 ((3S,4S)-8-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b ] Preparation of tert-butyl pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (compound IM-25)
  • IM-2 (40mg, 87.46umol), IM-1 (27mg, 121.45umol), cuprous iodide (17mg, 89.26umol), 1,10-phenanthroline (16mg, 88.79umol), potassium phosphate ( 56 mg, 263.82 umol) was added to dioxane (2 mL), and the temperature was raised to 100 ° C after nitrogen replacement, and the reaction was carried out for 1.5 hours. After the reaction was detected by LCMS, ethyl acetate was added to the reaction solution, filtered, and the filtrate was concentrated. Purification by thin layer chromatography gave 1-1 (30 mg, 57% yield).
  • the first step 6-chloro-3-((4'-methyl-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4 ]oxazine]-8'-yl)thio)pyrazin-2-amine (compound 3-1) preparation
  • the crude compound TME8 was synthesized by a method similar to that described in the first and second steps in Example 1, except that IM-4 was used in the first step instead of IM-2 in the first step of Example 1. Purification by thin layer chromatography gave compound TME8.
  • C-1 and IM-5 were respectively used to replace IM-2 and IM-1 in the first step of Example 1 to synthesize compound 5-1.
  • the third step (6-((2'H,4'H-spiro[cyclobutane-1,3'-pyridine[3,2-b][1,4]oxazine]-8'-yl) thio)-3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)methanol ( Preparation of compound TMC4)
  • the crude product of TMC4 was synthesized with reference to the second step of Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMC4 (42 mg, yield). rate 80%).
  • the crude product of TMC3 was synthesized by a similar method with reference to Example 5, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMC3.
  • the crude product of TMC33 was synthesized by a similar method with reference to Example 5, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMC33.
  • a crude product of compound TMC34 was synthesized using a method similar to that described in Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to give compound TMC34 as trifluoroacetic acid salt.
  • a crude product of compound TMC19 was synthesized using a method similar to that described in Example 5, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous ammonium bicarbonate solution) to give compound TMC19.
  • Example 11 (S)-1'-(5-((2'H,4'H-spiro[oxetane-3,3'-pyrido[3,2-b][1,4 ]oxazin]-8'-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine (compound TMA19).
  • a crude product of compound TMA19 was synthesized using a method similar to that described in Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to afford compound TMA19 as the trifluoroacetic acid salt.
  • the crude product of TMC1 was synthesized by a similar method with reference to Example 5, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMC1.
  • the crude product of compound TMA3 was synthesized by a method similar to Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMA3.
  • a crude product of compound TMD19 was synthesized using a method similar to that described in Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to give compound TMD19 as trifluoroacetic acid salt.
  • a crude product of compound TMD20 was synthesized using a method similar to that described in Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to give compound TMD20 as trifluoroacetic acid salt.
  • a crude product of compound TMD3 was synthesized using a method similar to that described in Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to give compound TMD3 as the trifluoroacetic acid salt.
  • Example 17 (S)-1'-(5-((2'H,4'H-spiro[cyclobutane-3,3'-pyrido[3,2-b][1,4]oxa Preparation of oxazin]-8'-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine (compound TMA20).
  • a crude product of compound TMA20 was synthesized using a method similar to that described in Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to give compound TMA20 as the trifluoroacetic acid salt.
  • Step 2 (3S,4S)-8-(5-((2'H,4'H-spiro[1,3'-pyrido[3,2-b][1,4]oxazine]- Preparation of 8'-yl)thio)-6-aminopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (compound TMB4)
  • a crude product of compound TMB20 was synthesized using a method similar to that described in Example 18, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous ammonium bicarbonate solution) to give compound TMB20.
  • the crude product of compound TMC36 was synthesized by a method similar to Example 5, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMC36.
  • the crude product of compound TMA33 was synthesized by a method similar to Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMA33.
  • the crude product of compound TMC37 was synthesized by a method similar to Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMC37.
  • Example 23 (6-((2'H,4'H-spiro[oxetane-3,3'-pyrido[3,2-b][1,4]oxazine]-8' Preparation of -yl)thio)-3-(4-amino-8-azabispiro[2.1.55.23]dodec-8-yl)pyrazin-2-yl)methanol (compound TMC38)
  • the crude product of compound TMC38 was synthesized by a method similar to Example 5, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMC38.
  • the crude product of compound TMA34 was synthesized by a method similar to Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous ammonium bicarbonate solution) to obtain compound TMA34.
  • IM-18 (25 mg, 54.30 ⁇ mol), IM-6 (17.11 mg, 81.46 ⁇ mol), potassium phosphate (23.03 mg, 108.61 ⁇ mol), Xantphos (3.14 mg, 5.43 ⁇ mol) and Pd 2 (dba) 3 (4.97 mg , 5.43 ⁇ mol) was added to dioxane (3 mL), and the temperature was raised to 100 ° C after nitrogen replacement, and the reaction was carried out for 3 hours. After the LCMS detection was completed, ethyl acetate was added to the reaction solution, filtered, and the filtrate was concentrated. After purification by layer chromatography, compound 25-1 (10 mg, yield 31%) was obtained.
  • the crude product of compound TMC39 was synthesized by a method similar to Example 5, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous ammonium bicarbonate solution) to obtain compound TMC39.
  • the crude product of compound TMD33 was synthesized by a method similar to Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMD33.
  • the crude product of compound TMB33 was synthesized by a method similar to Example 18, and the crude product was purified by thin layer chromatography to obtain TMB33.
  • the crude product of compound TMB34 was synthesized by the method similar to Example 18, and the crude product was purified by thin layer chromatography to obtain TMB34.
  • the crude product of compound TMA36 was synthesized by a method similar to Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMA36.
  • the crude product of compound TMD34 was synthesized by a method similar to Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMD34.
  • the crude compound TMB35 was synthesized using a method similar to that described in the second step of Example 18, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to give compound TMB35 in trifluoroacetic acid Salt.
  • the crude product of compound TMF1 was synthesized by a method similar to Example 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution) to obtain the trifluoroacetic acid salt of compound TMF1.
  • the crude product of compound TMC40 was synthesized by a method similar to Example 5, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous ammonium bicarbonate solution) to obtain compound TMC40.
  • Test Example 1 SHP2 (protein phosphatase) in vitro enzymatic activity inhibition test
  • Phosphatase Recombinant full-length human PTPN11(SHP2), Active(SignalChem)
  • Buffer system 60 mM Hepes pH7.2; 75 mM NaCl; 75 mM KCl; 0.05% P-20; 1 mM EDTA; 5 mM DTT
  • Compound incubation and action time with enzymes and activating peptides 60 minutes at room temperature
  • Enzyme and substrate reaction time 30 minutes at room temperature
  • Microplate reader parameters BMG PHERAstar Fluorescence, excitation wavelength 340nm, emission wavelength 450nm
  • the mixture of the test compound and phosphatase SHP2 was incubated with the activating peptide IRS-1 in the buffer system for 60 minutes at room temperature, and the substrate DiFMUP was added to initiate the reaction. After incubation at room temperature for 30 minutes, the reaction was terminated by the addition of bpv, and the reaction plate was placed in the enzyme The fluorescence value of each well in the plate was read by the end-point method.
  • the vehicle group (containing 0.5nM SHP2, 200 ⁇ M DiFMUP, 0.5 ⁇ M IRS-1, 160 ⁇ M bpv, 0.05%DMSO) was used as the negative control, and the reaction buffer group (200 ⁇ M DiFMUP, 0.5 ⁇ M IRS-1, 160 ⁇ M bpv, 0.05%DMSO) was the blank
  • the curve was fitted according to a four parameter model and the median inhibitory concentration ( IC50 ) of the compound was calculated.
  • Example IC50 (nM) Example IC50 (nM) Example 1 6.30 Example 18 9.90 Example 2 2.60 Example 19 4.80 Example 3 6.70 Example 20 4.80 Example 5 2.70 Example 22 3.64 Example 6 6.59 Example 24 2.50 Example 7 7.20 Example 25 3.90
  • Example 8 3.20 Example 26 5.95 Example 9 7.30 Example 27 4.33 Example 10 4.50 Example 28 7.19 Example 11 1.60 Example 29 4.51 Example 12 4.60 Example 30 2.79 Example 13 10.90 Example 31 1.80 Example 14 3.40 Example 32 5.36 Example 15 5.90 Example 33 4.33 Example 16 1.70 Example 34 3.48 Example 17 1.90 Example 35 7.40
  • the compounds of the present invention exhibited significant inhibitory activity.
  • Test Example 2 Inhibitory test of compound on proliferation activity of KYSE-520 cells (human esophageal squamous cell carcinoma cells)
  • Kit Name/Manufacturer Luminescent Cell Viability Assay, Promega
  • Cells were cultured in medium containing 10% fetal bovine serum and placed at 37°C under 5% CO2 culture conditions. An appropriate amount of cells was plated into a 96-well plate and cultured overnight in an incubator to allow the cells to adhere to the wall. The next day, the medium was removed, complete medium containing pre-diluted compounds was added, and the cells were incubated at 37°C for 5 days. On the fifth day, the detection reagent CellTiter-GLo was added to each well, and the relative luminescence unit (RLU) of each well was detected by chemiluminescence.
  • RLU relative luminescence unit
  • the inhibitory activity of the compounds on the proliferation of KYSE-520 was determined as described above, and the results are shown in Table 2.
  • Example IC50 ( ⁇ M) Example IC50 ( ⁇ M) Example 2 0.12 Example 19 0.075 Example 6 0.12 Example 20 0.075 Example 7 0.27 Example 22 0.046 Example 8 0.038 Example 25 0.21 Example 10 0.016 Example 28 0.08 Example 11 0.017 Example 29 0.04 Example 12 0.35 Example 30 0.28 Example 14 0.06 Example 31 0.038 Example 17 0.064 Example 32 0.16
  • the compounds of the present invention have strong cell proliferation inhibitory activity against KYSE-520.
  • Test Example 3 Inhibitory test of compound on proliferation activity of NCI-H358 cells (human non-small cell lung cancer cells)
  • Kit Name/Manufacturer Luminescent Cell Viability Assay, Promega
  • the cells were cultured in a medium containing 10% fetal bovine serum at 37°C under 5% CO2 culture conditions. An appropriate amount of cells was plated into a 96-well plate and cultured overnight in an incubator to allow the cells to adhere to the wall. The next day, the medium was removed, complete medium containing pre-diluted compounds was added, and the cells were incubated at 37°C for 5 days. On the fifth day, the detection reagent CellTiter-GLo was added to each well, and the relative luminescence unit (RLU) of each well was detected by chemiluminescence.
  • RLU relative luminescence unit
  • the background was obtained using the group without cells and compound, and the group with cells without compound was used as the vehicle group.
  • Example IC50 ( ⁇ M) Example IC50 ( ⁇ M) Example 2 0.039 Example 22 0.015 Example 6 0.049 Example 25 0.039 Example 10 0.0076 Example 28 0.019 Example 11 0.0096 Example 29 0.0094 Example 19 0.008 Example 31 0.045 Example 20 0.008 Example 32 0.026

Abstract

本发明涉及杂环化合物及其制备方法和用途。具体地，本发明涉及式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、其制备方法、包含其的药物组合物及其在预防和治疗相关疾病中的用途。

Description

杂环化合物及其制备方法和用途 技术领域
本发明属于药物化学领域，并且具体地涉及一种用作SHP2(src homology 2 domain containing phosphotyrosine phosphatase 2)抑制剂的取代吡嗪化合物、其制备方法、药物组合物及其在治疗SHP2酶相关疾病(在本文中也称作“SHP2磷酸酶相关疾病”或“SHP2相关疾病”)中的用途。
背景技术
SHP2是一种由基因PTPN11编码的蛋白酪氨酸磷酸酶，是PTP家族胞内非受体型成员，其催化蛋白质酪氨酸去磷酸化反应。SHP2具有两个N末端SH2(Src homology 2)结构域(N-SH2和C-SH2)、催化结构域(PTP)和一个富含脯氨酸基团和酪氨酸磷酸化位点的C-末端尾巴。这两个SH2结构域控制SHP2的亚细胞定位和功能调节。在未激活状态下，SHP2处于自抑制状态，N-SH2与PTP相互结合抑制了磷酸酶活性。然而在生长因子、细胞因子或炎症因子，如血小板源性生长因子(platelet derived growth factor，PDGF)和FGF等刺激下，磷酸化酪氨酸残基Tyr542，Tyr580，与N-SH2结合，PTP结构域的催化活性位点暴露，进而解除自抑制状态，激活了SHP2的PTP活性，从而引发由酪氨酸磷酸化所启动的信号传导级联反应。
SHP2在人体中广泛表达，参与Ras-Erk,PI3K-Akt,Jak-Stat,Met,FGFR,EGFR和NF-kB等等多条信号通路，进而调节细胞增殖、分化、迁移、凋亡等生理学功能。SHP2的激活突变体与多种疾病的发生相关，如努南综合征(Noonan syndrome)、乳腺癌、黑色素瘤。SHP2的过表达会增加慢性粒细胞白血病、肥大细胞增多症、恶性胶质瘤、肺癌和乳腺癌等癌症的风险，提示SHP2在不同类型癌症及癌症的不同发展阶段中有广泛的作用。因此，有必要使用SHP2磷酸酶抑制剂化合物和用这些化合物治疗癌症和其他疾病。
目前已发现嘧啶酮类、吡嗪类、羧酸类、醌类、喹啉类和吲哚类等化合物具有抑制SHP2活性的功能(例如，见WO2018013597A1)，但本领域仍然亟需新的SHP2抑制剂，特别是具有高活性以及其他优异性质的SHP2抑制剂。我们研究发现一类吡嗪化合物具有较高的SHP2酶抑制活性，展示出良好的应用前景。
发明概述
在本发明的实施方案中，本发明提供式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2021112400-appb-000001
其中，
L 1选自单键和-S-；
环A选自9-12元螺杂环，其任选地被一个或多个(例如1、2、3或4个)选自氢、卤素、氰基、羟基、氧代基、氨基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-O-C 1-6烷基、-C(＝O)-NH-C 1-6烷基、-NH-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基和-S(＝O) 2-C 3-6环烷基的取代基取代；所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代；
各R 1独立地选自氢、卤素、氰基、羟基、氨基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3- 6环烷基、3-6元杂环烷基、-NH-C(＝O)-O-C 1-6烷基；所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代；
环B选自5-10元杂芳环和5-6元杂环；
各R 2独立地选自氢、卤素、C 1-6烷基、氧代基、氨基、氰基、-C(＝O)-NH 2、-NH-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基；所述烷基、环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代；
环C为4-16元含氮杂环；
R 3、R 4各自独立地选自氢、氨基、卤素、氰基、羟基、氧代基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 2-6烯基、-C 2-6炔基、C 5-10芳基、C 5-10杂芳基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、-S(＝O) 2-(3-6元杂环烷基)、-NH-C(＝O)-C 1-6烷基、-C(＝O)-NH 2和-C(＝O)-NH-C 1-6烷基；所述烷基、环烷基、杂环烷基、烯基、炔基、芳基、杂芳基各自任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)、-O-(3-6元杂环烷基)、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、C 2-6烯烃、C 2-6炔烃、氧代基、C 3-6环烷基和3-6元杂环烷基的取代基取代；
m、n各自独立地选自0、1和2。
在本发明的实施方案中，本发明提供一种药物组合物，其包含式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以及一种或多种药学上可接受的载体。
在本发明的实施方案中，本发明提供式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物在制备用于预防或治疗SHP2磷酸酶相关疾病的药物中的用途。
在本发明的实施方案中，本发明提供一种用于预防或治疗SHP2磷酸酶相关疾病的方法，所述方法包括向有此需要的个体给药式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物。
在本发明的实施方案中，本发明提供式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物，用于预防或治疗SHP2磷酸酶相关疾病。
在本发明的优选实施方案中，所述SHP2磷酸酶相关疾病为对SHP2磷酸酶抑制敏感或有响应的疾病。在本发明的优选实施方案中，所述SHP2磷酸酶相关疾病为肿瘤类病症，包括但不限于实体和血液恶性肿瘤。
在本发明的优选实施方案中，所述SHP2磷酸酶相关疾病为肺癌或食管癌。
在本发明的实施方案中，本发明进一步提供式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物与另外的治疗方法组合用于预防或治疗SHP2磷酸酶相关疾病的方法，所述另外的治疗方法包括但不限于：放射疗法、化疗疗法，免疫疗法或其组合。
在本发明的实施方案中，本发明提供式(I)的化合物的制备方法，所述方法包括以下步骤：
方法A：
1.使式S-1的化合物与式S-2的化合物发生缩合或者取代反应以生成式AM-1的化合物；
Figure PCTCN2021112400-appb-000002
2.使式AM-1的化合物与式S-3的化合物发生偶联反应，随后进行脱保护和/或功能基团转化生成式(I)的化合物；
Figure PCTCN2021112400-appb-000003
方法B：
1.使式S-1的化合物与式S-3的化合物发生偶联反应以生成式BM-1的化合物；
Figure PCTCN2021112400-appb-000004
2.使式BM-1的化合物与式S-2的化合物发生取代或者偶联反应，随后进行脱保护和/或功能基团转化生成式(I)的化合物；
Figure PCTCN2021112400-appb-000005
其中，LG 1和LG 2各自独立地表示离去基团；
X表示硫或者单键；
R x表示H或离去基团；
环A、环B、环C、L 1、R 1、R 2、R 3、R 4、m和n如上文所定义。
发明详述
本发明的化合物
在本发明的实施方案中，本发明提供式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2021112400-appb-000006
其中，
L 1选自单键和-S-；
环A选自9-12元螺杂环，其任选地被一个或多个(例如1、2、3或4个)选自氢、卤素、氰基、羟基、氧代基、氨基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-O-C 1-6烷基、-C(＝O)-NH-C 1-6烷基、-NH-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基和-S(＝O) 2-C 3-6环烷基的取代基取代；所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代；
各R 1独立地选自氢、卤素、氰基、羟基、氨基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3- 6环烷基、3-6元杂环烷基、-NH-C(＝O)-O-C 1-6烷基；所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代；
环B选自5-10元杂芳环和5-6元杂环；
各R 2独立地选自氢、卤素、C 1-6烷基、氧代基、氨基、氰基、-C(＝O)-NH 2、-NH-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基；所述烷基、环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代；
环C为4-16元含氮杂环；
R 3、R 4各自独立地选自氢、氨基、卤素、氰基、羟基、氧代基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 2-6烯基、-C 2-6炔基、C 5-10芳基、C 5-10杂芳基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、-S(＝O) 2-(3-6元杂环烷基)、-NH-C(＝O)-C 1-6烷基、-C(＝O)-NH 2和-C(＝O)-NH-C 1-6烷基；所述烷基、环烷基、杂环烷基、烯基、炔基、芳基、杂芳基各自任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)、-O-(3-6元杂环烷基)、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、C 2-6烯烃、C 2-6炔烃、氧代基、C 3-6环烷基和3-6元杂环烷基的取代基取代；
m、n各自独立地选自0、1和2。
在部分实施方案中，本发明提供式(II)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2021112400-appb-000007
其中，环D选自C 3-6碳环和3-6元杂环；
R 5、R 5'各自独立地选自氢、卤素、氰基、羟基、氧代基、氨基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-O-C 1-6烷基、-C(＝O)-NH-C 1-6烷基、-NH-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基和-S(＝O) 2-C 3-6环烷基；所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代；
U、V、W各自独立地选自单键、-CH 2-、-O-、-N(R 6)-、-CH 2O-、-OCH 2-、-CH 2N(R 6)-、-N(R 6)CH 2-、-C(＝O)-、-C(＝O)N(R 6)-、-N(R 6)C(＝O)-、-C(＝O)O-和-OC(＝O)-；
R 6选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-O-C 1-6烷基，所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)的取代基取代；
p、q各自独立地选自0、1和2；
L 1、环B、环C、R 1、R 2、R 3、R 4、m和n如通式I中所定义。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，环B为6-9元杂芳环或5-6元杂环。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，环B为6元杂芳环、9元杂芳环或6元杂环。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，环B为吡嗪基、嘧啶酮基或9元杂芳环。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，环B为吡嗪基、吡唑并吡嗪基或咪唑并嘧啶基。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，各R 2独立地选自氢、卤素、C 1-6烷基、氧代基、氨基、氰基、-C(＝O)-NH 2；所述烷基各自任选地被一个或多个选自氢、羟基、卤素、氰基的取代基取代。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，各R 2独立地选自氢、C 1-6烷基、-CH 2-OH、-CH 2F、-CH 2CHF 2、-CH 2CH 2F、-C(＝O)-NH 2、氧代基、氨基；
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，各R 2独立地选自氢、C 1-6烷基、-CH 2-OH、氧代基和氨基。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，各R 2独立地选自氢、C 1-6烷基、-CH 2-OH和氨基。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，各R 2独立地选自氢、甲基、-CH 2-OH和氨基。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，各R 2独立地选自氢、甲基、乙基、- CH 2F、-CH 2CHF 2和-CH 2CH 2F。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，环B为6-9元杂芳环或5-6元杂环烷基；
各R 2独立地选自氢、卤素、C 1-6烷基、氧代基、氨基、氰基和-C(＝O)-NH 2；所述的烷基任选地被一个或多个选自羟基、卤素、氰基的取代基所取代。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，环B为6元杂芳环、9元杂芳环或6元杂环；
各R 2独立地选自氢、卤素、C 1-6烷基、氧代基、氨基、氰基和-C(＝O)-NH 2；所述的烷基任选地被一个或多个选自羟基、卤素、氰基的取代基所取代。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，环B为吡嗪基、嘧啶酮基或9元杂芳环；
各R 2独立地选自氢、C 1-6烷基、-CH 2-OH、-CH 2F、-CH 2CHF 2、-CH 2CH 2F、-C(＝O)-NH 2、氧代基和氨基。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，环B为吡嗪基、嘧啶酮基或9元杂芳环；
各R 2独立地选自氢、C 1-6烷基、-CH 2-OH、氧代基和氨基。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，环B为吡嗪基、吡唑并吡嗪基或咪唑并嘧啶基；
各R 2独立地选自氢、C 1-6烷基、-CH 2-OH和氨基。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，
Figure PCTCN2021112400-appb-000008
选自：
Figure PCTCN2021112400-appb-000009
R 2如通式I中所定义。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，
Figure PCTCN2021112400-appb-000010
环B为
Figure PCTCN2021112400-appb-000011
Figure PCTCN2021112400-appb-000012
R 2选自氢、甲基、乙基、-CH 2F、-CH 2CHF 2和-CH 2CH 2F。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，
Figure PCTCN2021112400-appb-000013
为
Figure PCTCN2021112400-appb-000014
Figure PCTCN2021112400-appb-000015
R 2选自氢、甲基、乙基、-CH 2F、-CH 2CHF 2和-CH 2CH 2F。
在部分实施方案中，本发明提供的式(I)或式(II)化合物中，
Figure PCTCN2021112400-appb-000016
为
Figure PCTCN2021112400-appb-000017
Figure PCTCN2021112400-appb-000018
在部分实施方案中，本发明提供式(II-1)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2021112400-appb-000019
其中，环D选自C 3-6碳环和4-6元杂环，L 1、环C、R 1、R 2、R 3、R 4、m和n如通式I中所定义，U、V、W、R 5、R 5'、p和q如通式II中所定义。
在部分实施方案中，本发明提供的式(II-1)化合物中，各R 2独立地选自氢、卤素、C 1-6烷基、氧代基、氨基、氰基和-C(＝O)-NH 2；所述烷基各自任选地被一个或多个选自羟基、卤素、氰基的取代基取代。
在部分实施方案中，本发明提供的式(II-1)化合物中，各R 2独立地选自氢、C 1-6烷基、-CH 2-OH、-CH 2F、-CH 2CHF 2、-CH 2CH 2F、-C(＝O)-NH 2、氧代基和氨基。
在部分实施方案中，本发明提供的式(II-1)化合物中，各R 2独立地选自氢、C 1-6烷基、-CH 2-OH、氧代基和氨基。
在部分实施方案中，本发明提供的式(II-1)化合物中，各R 2独立地选自氢、C 1-6烷基、-CH 2-OH和氨基。
在部分实施方案中，本发明提供式(II-1a)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2021112400-appb-000020
其中，环D选自C 3-6碳环和4-6元杂环，L 1、环C、R 1、R 3、R 4和m如通式I所定义，U、V、 W、R 5、R 5'、p和q如通式II中所定义。
在部分实施方案中，本发明提供的式(II-1)或(II-1a)的化合物中，环D为4元含氧杂环、
Figure PCTCN2021112400-appb-000021
Figure PCTCN2021112400-appb-000022
W为-O-，U为-N(R 6)-,V为-CH 2-；或者W为-N(R 6)-，U为-N(R 6)-，V为-C(＝O)-；
R 6选自氢、C 1-3烷基、C 3-6环烷基，所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)的取代基取代；
R 6'选自C 1-3烷基、C 3-6环烷基、3-6元杂环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-O-C 1-6烷基、-C(＝O)-NH-C 1-6烷基、-S(＝O) 2-C 1-6烷基和-S(＝O) 2-C 3-6环烷基；所述的烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代。
在部分实施方案中，本发明提供式(II-1)或(II-1a)的化合物中，环D为4元含氧杂环，优选地，环D为
Figure PCTCN2021112400-appb-000023
W为-O-，U为-N(R 6)-,V为-CH 2-；或者W为-N(R 6)-，U为-N(R 6)-，V为-C(＝O)-；
R 6选自氢、C 1-3烷基、C 3-6环烷基，所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)的取代基取代。
在部分实施方案中，本发明提供的式(II-1)或(II-1a)的化合物中，环D为
Figure PCTCN2021112400-appb-000024
W为-O-，U为-N(R 6)-，V为-CH 2-；或者W为-N(R 6)-，U为-N(R 6)-，V为-C(＝O)-；
R 6选自氢、C 1-3烷基、C 3-6环烷基，所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)的取代基取代。
在部分实施方案中，本发明提供式(II-1)或(II-1a)的化合物中，环D为
Figure PCTCN2021112400-appb-000025
W为-O-，U为-N(R 6)-，V为-CH 2-；
R 6'选自C 1-3烷基、C 3-6环烷基、3-6元杂环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-O-C 1-6烷基、-C(＝O)-NH-C 1-6烷基、-S(＝O) 2-C 1-6烷基和-S(＝O) 2-C 3-6环烷基；所述的烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代；
R 6选自氢、C 1-3烷基和C 3-6环烷基，所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)的取代基取代。
在部分实施方案中，本发明提供式(II-1)或(II-1a)的化合物中，环D为
Figure PCTCN2021112400-appb-000026
W为-O-，U为-N(R 6)-,V为-CH 2-；R 6选自氢和C 1-3烷基。
在部分实施方案中，本发明提供式(II-1-1)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2021112400-appb-000027
其中，X 1选自-O-、-CH 2-和-N(R 8)-；
各R 7独立地选自C 1-6烷基和氨基，所述C 1-6烷基任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)、C 3-6环烷基、3-6元杂环烷基、-O-(卤代C 1-6烷基)、-S(＝O) 2-C 1-6烷基、氧代基的取代基取代；或者任意两个R 7和它们共同相连的碳原子形成3-6元环烷基或3-6元杂环烷基；
R 8选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基和-S(＝O) 2-(3-6元杂环烷基)；所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、氧代基、-O-(C 1-6烷基)、C 2-6烯烃和C 2-6炔烃取代基取代；
y选自0、1、2和3；
环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如通式II中所定义。
在部分实施方案中，本发明提供的式(II-1-1)的化合物中，X 1为-O-。
在部分实施方案中，本发明提供式(II-1-2)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2021112400-appb-000028
其中，E选自3-6元杂环、C 3-6碳环、苯环和5-6元杂芳环；
R 9各自独立地选自氢、氨基、卤素、氰基、羟基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 2-6烯基、-C 2-6炔基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、-NH-C(＝O)-C 1-6烷基、-C(＝O)-NH 2、-C(＝O)-NH-C 1-6烷基；所述烷基、环烷基、杂环烷基、烯基、炔基、芳基、杂芳基各自任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)、-O-(3-6元杂环烷基)、C 2-6烯烃、C 2-6炔烃、羰基、C 3-6环烷基、3-6元杂环烷基的取代基取代；
X 2选自-O-、-CH 2-、-N(R 8)-、-C(＝O)和
Figure PCTCN2021112400-appb-000029
环F为C 3-6环烷基；所述环烷基任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)和-O-(3-6元杂环烷基)的取代基取代；
R 8选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基和-S(＝O) 2-(3-6元杂环烷基)；其中所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、氧代基、-O-(C 1-6烷基)、C 2-6烯烃和C 2-6炔烃取代基取代；
z选自0、1、2或3；
环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如通式II中所定义。
在部分实施方案中，本发明提供式(II-1-2a)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2021112400-appb-000030
其中，X 3选自-CH-和-N-；
X 2、R 9、z、环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如通式II-1-2中所定义。
在部分实施方案中，本发明提供式(II-1-2a)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药中：
X 2为-O-和-CH 2-；
X 3选自-CH-和-N-；
R 9各自独立地选自氢和卤素；
z选自0、1、2和3；
环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如通式II中所定义。
在部分实施方案中，本发明提供式(II-1b-1)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2021112400-appb-000031
其中，X 1选自-O-、-CH 2-和-N(R 8)-；
各R 7独立地选自C 1-6烷基和氨基，所述C 1-6烷基任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)、C 3-6环烷基、3-6元杂环烷基、-O-(卤代C 1-6烷基)、-S(＝O) 2-C 1-6烷基、氧代基的取代基取代；或者任意两个R 7和它们共同相连的碳原子形成3-6元环烷基或3-6元杂环烷基；
R 8选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基和-S(＝O) 2-(3-6元杂环烷基)；其中所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、氧代基、-O-(C 1-6烷基)、C 2-6烯烃和C 2-6炔烃取代基取代；
y为0、1、2或3；
环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如通式II中所定义。
在部分实施方案中，本发明提供的式(II-1b-1)的化合物中，X 1为-O-。
在部分实施方案中，本发明提供式(II-1b-2)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2021112400-appb-000032
其中，X 3选自-CH-和-N-；
R 9各自独立地选自氢、氨基、卤素、氰基、羟基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 2-6烯基、-C 2-6炔基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、-NH-C(＝O)-C 1-6烷基、-C(＝O)-NH 2、-C(＝O)-NH-C 1-6烷基；所述烷基、环烷基、杂环烷基、烯基、炔基、芳基、杂芳基各自任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)、-O-(3-6元杂环烷基)、C 2-6烯烃、C 2-6炔烃、羰基、C 3-6环烷基、3-6元杂环烷基的取代基取代；
X 2选自-O-、-CH 2-、-N(R 8)-、-C(＝O)和
Figure PCTCN2021112400-appb-000033
环F为C 3-6环烷基；所述环烷基任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)和-O-(3-6元杂环烷基)的取代基取代；
R 8选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基和-S(＝O) 2-(3-6元杂环烷基)；其中所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、氧代基、-O-(C 1-6烷基)、C 2-6烯烃和C 2-6炔烃取代基取代；
z选自0、1、2或3；
环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如通式II中所定义。
在部分实施方案中，本发明提供式(II-2-1)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2021112400-appb-000034
其中，X 1选自-O-、-CH 2-和-N(R 8)-；
各R 7独立地选自C 1-6烷基和氨基，所述C 1-6烷基任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)、C 3-6环烷基、3-6元杂环烷基、-O-(卤代C 1-6烷基)、-S(＝O) 2-C 1-6烷基、氧代基的取代基取代；或者任意两个R 7和它们共同相连的碳原子形成3-6元环烷基或3-6元杂环烷基；
R 8选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基和-S(＝O) 2-(3-6元杂环烷基)；所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、氧代基、-O-(C 1-6烷基)、C 2-6烯烃和C 2-6炔烃取代基取代；
y选自0、1、2和3；
环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如通式II中所定义。
在部分实施方案中，本发明提供的式(II-2-1)的化合物中，X 1为-O-。
在部分实施方案中，本发明提供式(II-2-2)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2021112400-appb-000035
其中，X 3选自-CH-和-N-；
R 9各自独立地选自氢、氨基、卤素、氰基、羟基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 2-6烯基、-C 2-6炔基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、-NH-C(＝O)-C 1-6烷基、-C(＝O)-NH 2、-C(＝O)-NH-C 1-6烷基；所述烷基、环烷基、杂环烷基、烯基、炔基、芳基、杂芳基各自任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)、-O-(3-6元杂环烷基)、C 2-6烯烃、C 2-6炔烃、羰基、C 3-6环烷基、3-6元杂环烷基的取代基取代；
X 2选自-O-、-CH 2-、-N(R 8)-、-C(＝O)和
Figure PCTCN2021112400-appb-000036
环F为C 3-6环烷基；所述环烷基任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)和-O-(3-6元杂环烷基)的取代基取代；
R 8选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基和-S(＝O) 2-(3-6元杂环烷基)；其中所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、氧代基、-O-(C 1-6烷基)、C 2-6烯烃和C 2-6炔烃取代基取代；
z选自0、1、2或3；
环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如通式II中所定义。
在部分实施方案中，本发明提供的式(II)、式(II-1)、式(II-1a)、式(II-1-1)、式(II-1-2)、式(II-1-2a)、式(II-1b-1)、式(II-1b-2)、式(II-2-1)、式(II-2-2)的化合物中，
Figure PCTCN2021112400-appb-000037
选自：
Figure PCTCN2021112400-appb-000038
优选地，
Figure PCTCN2021112400-appb-000039
选自：
Figure PCTCN2021112400-appb-000040
其中R 6和R 6’如通式II-1a中所定义。
优选地，
Figure PCTCN2021112400-appb-000041
选自：
Figure PCTCN2021112400-appb-000042
其中R 6和R 6’如通式II-1a中所定义。
在部分实施方案中，本发明提供的式(I)、式(II)、式(II-1)、式(II-1a)、式(II-1-1)、式(II-1-2)、式(II-1-2a)、式(II-1b-1)、式(II-1b-2)、式(II-2-1)、式(II-2-2)的化合物中，R 1、R 5和R 5'各自独立地选自氢和C 1-6烷基；所述烷基任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代。
在部分实施方案中，本发明提供的式(I)、式(II)、式(II-1)、式(II-1a)、式(II-1-1)、式(II-1-2)、式(II-1-2a)、式(II-1b-1)、式(II-1b-2)、式(II-2-1)、式(II-2-2)的化合物中，R 1、R 5和R 5'各自独立地选自氢和甲基。
在部分实施方案中，本发明提供的式(I)、式(II)、式(II-1)、式(II-1a)的化合物中：
环C为5-15元含氮杂环；
R 3、R 4各自独立地选自氢、氨基、卤素、氰基、羟基、氧代基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 2-6烯基、-C 2-6炔基、C 5-10芳基、C 5-10杂芳基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、-S(＝O) 2-(3-6元杂环烷基)、-NH-C(＝O)-C 1-6烷基、-C(＝O)-NH 2和-C(＝O)-NH-C 1-6烷基；所述烷基、环烷基、杂环烷基、烯基、炔基、芳基、杂芳基各自任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)、-O-(3-6元杂环烷基)、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、C 2-6烯烃、C 2-6炔烃、氧代基、C 3-6环烷基、3-6元杂环烷基的取代基取代。
在部分实施方案中，本发明提供式(I)、式(II)、式(II-1)、式(II-1a)的化合物中：
环C为6-14元含氮杂环；
R 3、R 4各自独立地选自氢、卤素、氨基、C 1-6烷基、-C 1-6烷基-C 3-6环烷基、-C 1-6烷基-3-6元杂环烷基、-C(＝O)-C 1-6烷基和-S(＝O) 2-C 1-6烷基，所述烷基、环烷基、杂环烷基各自任选地被一个或多个(例如：1、2、3或4个)选自羟基、卤素、氨基、氰基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)、C 3- 6环烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、C 2-6烯烃和C 2-6炔烃的取代基取代。
在部分实施方案中，本发明提供式(I)、式(II)、式(II-1)、式(II-1a)的化合物中：
环C为6-14元含氮杂环；
R 3、R 4各自独立地选自氢、氨基、C 1-6烷基、-C 1-6烷基-C 3-6环烷基、-C 1-6烷基-3-6元杂环烷基，所述烷基、环烷基、杂环烷基各自任选地被一个或多个(例如：1、2、3或4个)选自羟基、卤素、氨基、氰基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)和C 3-6环烷基的取代基取代。
在部分实施方案中，本发明提供式(I)、式(II)、式(II-1)、式(II-1a)的化合物中：
环C为6-14元含氮杂环；
R 3、R 4各自独立地选自氢、卤素、氨基、C 1-6烷基、-C 1-6烷基-C 3-6环烷基、-C 1-6烷基-3-6元杂环烷基，所述烷基、环烷基、杂环烷基各自任选地被一个或多个(例如：1、2、3或4个)选自羟基、卤素、氨基、氰基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)和C 3-6环烷基的取代基取代。
在部分实施方案中，本发明提供式(I)、式(II)、式(II-1)、式(II-1a)的化合物中：
环C为6-14元含氮杂环；
R 3、R 4各自独立地选自氢、卤素、氨基和C 1-6烷基，所述烷基任选地被一个或多个(例如：1、2、3或4个)氨基取代。
在部分实施方案中，本发明提供式(I)、式(II)、式(II-1)、式(II-1a)的化合物中：
环C为6-14元含氮杂环；
R 3、R 4各自独立地选自氢、-F、-NH 2、-CH 2NH 2、-CH 3、-CH(NH 2)CH 3、-CH(NH 2)CH 2OCH 3、-CH(NH 2)CH 2F、-CH(NH 2)CH 2CN、-CH(NH 2)CH(CH 3)OCH 3、-CH(NH 2)CH(CH 3)OH、-CH(NH 2)C(CH 3) 2OCH 3、-CH(NH 2)CH 2OCHF 2、-CH(NH 2)CH 2S(＝O) 2CH 3、-CH 2F、-CH 2OCH 3、-CH 2OCH 2F、-CH 2OCHF 2、
Figure PCTCN2021112400-appb-000043
优选地，R 3、R 4各自独立地选自氢、-F、-NH 2、-CH(NH 2)CH 3、-CH 2F、-CH 2OCH 3、-CH 2OCH 2F、-CH 2OCHF 2、和-CH 3。
优选地，R 3、R 4各自独立地选自氢、-F、-NH 2、-CH(NH 2)CH 3和-CH 3。
在部分实施方案中，本发明提供的式(I)、式(II)、式(II-1)、式(II-1a)的化合物中：
Figure PCTCN2021112400-appb-000044
选自：
Figure PCTCN2021112400-appb-000045
在部分实施方案中，本发明提供的式(I)、式(II)、式(II-1)、式(II-1a)的化合物中：
Figure PCTCN2021112400-appb-000046
选自：
Figure PCTCN2021112400-appb-000047
在部分实施方案中，本发明提供的式(II-1-1)、式(II-1b-1)、(II-2-1)的化合物中，
L 1为-S-；
X 1选自-O-和-CH 2-；
环D选自
Figure PCTCN2021112400-appb-000048
W选自-O-、-OCH 2-、-N(R 6)-和-N(R 6)C(＝O)-；
U为-N(R 6)-；
V选自-CH 2-和-C(＝O)-；
R 6选自氢和C 1-3烷基；
m、p、q为0；
各R 7独立地选自C 1-6烷基和氨基；或者任意两个R 7和它们共同相连的的碳原子形成3-6元环烷基；
y为2。
在部分实施方案中，本发明提供的式(II-1-2a)、式(II-1b-2)、(II-2-2)的化合物中，
L 1为-S-；
X 2选自-O-和-CH 2-；
X 3选自-CH-和-N-；
环D选自
Figure PCTCN2021112400-appb-000049
W选自-O-、-OCH 2-、-N(R 6)-和-N(R 6)C(＝O)-；
U为-N(R 6)-；
V选自-CH 2-和-C(＝O)-；
R 6选自氢和C 1-3烷基；
m、p、q为0；
R 9各自独立地选自氢和卤素；
z为1。
本领域技术人员应当理解，本发明涵盖对各个实施方案进行任意组合所得的化合物。由一个实施方案中的技术特征或优选技术特征与另外的实施方案中的技术特征或优选技术特征组合得到的实施方案也包括在本发明的范围内。
在一些优选的实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：
Figure PCTCN2021112400-appb-000050
Figure PCTCN2021112400-appb-000051
Figure PCTCN2021112400-appb-000052
Figure PCTCN2021112400-appb-000053
Figure PCTCN2021112400-appb-000054
Figure PCTCN2021112400-appb-000055
Figure PCTCN2021112400-appb-000056
Figure PCTCN2021112400-appb-000057
Figure PCTCN2021112400-appb-000058
在一些优选的实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：
Figure PCTCN2021112400-appb-000059
Figure PCTCN2021112400-appb-000060
制备方法
本发明的又一方面还涉及本发明的化合物的制备方法，所述方法包括：
方法A：
1.使式S-1的化合物与式S-2的化合物发生缩合或者取代反应以生成式AM-1的化合物；
Figure PCTCN2021112400-appb-000061
2.使式AM-1的化合物与式S-3的化合物发生偶联反应，随后进行脱保护和/或功能基团转化生成式(I)的化合物；
Figure PCTCN2021112400-appb-000062
方法B：
1.使式S-1的化合物与式S-3的化合物发生偶联反应以生成式BM-1的化合物；
Figure PCTCN2021112400-appb-000063
2.使式BM-1的化合物与式S-2的化合物发生取代或者偶联反应，随后进行脱保护和/或功能基团转化生成式(I)的化合物；
Figure PCTCN2021112400-appb-000064
其中，LG 1和LG 2各自独立地表示离去基团，例如卤素或者任选地被卤素取代的C 1-6烷基磺酸酯基(例如三氟甲磺酸酯基)；另外，LG 2也可以为羟基；
X表示硫或者单键；
R x表示H或离去基团；
环A、环B、环C、L 1、R 1、R 2、R 3、R 4、m和n如上文所定义。
在一些优选的实施方案中，LG 1表示卤素，如碘或溴；
在一些优选的实施方案中，LG 2表示卤素(如溴或氯)或者羟基；
在一些优选的实施方案中，X表示硫；
在一些优选的实施方案中，R x选自H、钠、钾、硼酸基、硼酸酯基、取代的硅基、取代的金属基团和任选地被卤素取代的C 1-6烷基磺酸酯基。在更优选的实施方案中，R x为H。
本发明制备方法的起始原料可来自商业来源或可按照已知方法制备。
本领域技术人员应当理解，根据期望获得的产物结构，可适当地调整反应步骤的顺序，以及增加或省略保护/脱保护反应步骤。
药物组合物、制剂和试剂盒
本发明还提供一种药物组合物，其包含上文定义的任意化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物(例如水合物)、N-氧化物、同位素标记的化合物、代谢物或前药以及一种或多种药学上可接受的载体。
本发明的进一步的目的在于提供一种制备本发明的药物组合物的方法，所述方法包括将上文定义的任意化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、或者它们的混合物与一种或多种药学上可接受的载体组合。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(2005)中所述。
药物组合物可以以任意形式施用，只要其实现预防、减轻、防止或者治愈人类或动物患者的症状。例如，可根据给药途径制成各种适宜的剂型。
当口服用药时，所述药物组合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊剂、颗粒剂、丸剂、糖浆剂、口服溶液剂、口服混悬剂和口服乳剂等。
当经皮或局部施用时，所述药物组合物可制成适当的软膏、洗剂或搽剂形式，其中活性成分可 以悬混或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂或搽剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、2-辛基十二烷醇、苄醇和水。
所述药物组合物还可以注射剂形式用药，包括注射液、注射用无菌粉末与注射用浓溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
在另一些实施方案中，本发明的化合物或药物组合物的施用可以与另外的治疗方法组合。所述另外的治疗方法可以选自，但不限于：放射疗法、化疗疗法、免疫疗法，或其组合。可以是在另外的治疗方法实施前、实施期间或实施后施用本发明的化合物或药物组合物。另外的治疗方法的实施与本发明的化合物或药物组合物的施用可以同时进行，也可以前后紧密连接地进行，也可以相隔一段时间进行，其施用的方式与顺序可以根据具体治疗情况进行选择和调整。
本发明的另一方面还涉及一种药物制剂，其包含上文定义的任意化合物、其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、或它们的混合物作为活性成分，或者本发明的药物组合物。在一些实施方案中，所述制剂的形式为固体制剂、半固体制剂、液体制剂或气态制剂。
本发明的进一步的目的在于提供一种制品，例如以试剂盒形式提供。本文所用的制品意图包括但不限于药盒和包装。本发明的制品包含：(a)第一容器；(b)位于第一容器中的药物组合物，其中所述组合物包含：第一治疗剂，包括：上文定义的任意化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、或者它们的混合物；和(c)任选存在的包装说明书，其说明所述药物组合物可用于治疗肿瘤病症(如前文所定义)。
所述第一容器为用于容纳药物组合物的容器。此容器可用于制备、储存、运输和/或独立/批量销售。第一容器意图涵盖瓶、罐、小瓶、烧瓶、注射器、管(例如用于乳膏制品)，或者用于制备、容纳、储存或分配药物产品的任何其它容器。
所述第二容器为用于容纳所述第一容器和任选包装说明书的容器。所述第二容器的实例包括但不限于盒(例如纸盒或塑料盒)、箱、纸箱、袋(例如纸袋或塑料袋)、小袋和粗布袋。所述包装说明书可经由扎带、胶水、U形钉或别的粘附方式物理粘附于所述第一容器的外部，或者其可放在所述第二容器的内部，而无需与所述第一容器粘附的任何物理工具。或者，所述包装说明书位于所述第二容器的外面。当位于所述第二容器的外面时，优选的是所述包装说明书经由扎带、胶水、U形钉或别的粘附方式物理粘附。或者，其可邻接或接触所述第二容器的外部，而无需物理粘附。
所述包装说明书为商标、标签、标示等，其列举了与位于所述第一容器内的药物组合物相关的信息。所列出的信息通常由管辖待销售所述制品的区域的管理机构(例如美国食品与药品管理局)决定。优选所述包装说明书具体列出了所述药物组合物获准用于的适应症。所述包装说明书可由任何材料制成，可从所述材料上读取包含于其中或其上的信息。优选所述包装说明书为可印刷材料(例如纸、塑料、卡纸板、箔、胶粘纸或塑料等)，其上可形成(例如印刷或施涂)所需信息。
治疗方法和用途
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物在制备用于预防或治疗SHP2相关疾病的药物中的用途。
本发明的另一目的在于提供一种预防或治疗SHP2酶相关疾病的方法，所述方法包括向有此需要的个体给药有效量的上文定义的任意化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、代谢物或前药、或者它们的混合物，或者本发明的药物组合物。
根据本发明的一些实施方案，所述的SHP2酶相关疾病为对SHP2酶抑制敏感或有响应的疾病。
在进一步的实施方案中，所述SHP2酶相关疾病为肿瘤类病症，包括但不限于实体和血液恶性肿瘤。在进一步的实施方案中，所述肿瘤类病症包括但不限于乳腺癌、结肠直肠癌、结肠癌、肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌)和前列腺癌，以及胆管癌、骨癌、膀胱癌、头颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、宫颈癌和外阴癌，以及白血病(包括慢性淋巴细胞性白血病(CLL)、急性淋巴细胞性白血病(ALL)和慢性骨髓性白血病(CML))、多发性骨髓瘤和淋巴瘤。
在一些优选的实施方案中，所述疾病为癌症。
在进一步优选的实施方案中，本发明的化合物可以与放化疗或免疫疗法联用以预防或治疗癌症。
可调整给药方案以提供最佳所需响应。例如，以注射剂形式用药时，可给药单次推注、团注和/或连续输注，等等。例如，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。一般地，治疗的剂量是变化的，这取决于所考虑的事项，例如：待治疗患者的年龄、性别和一般健康状况；治疗的频率和想要的效果的性质；组织损伤的程度；症状的持续时间；以及可由各个医师调整的其它变量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。可以通过临床领域的普通技术人员容易地确定所述药物组合物的施用量和施用方案。例如，本发明的组合物或化合物可以以分剂量每天4次至每3天给药1次，给药量可以是例如0.01～1000mg/次。可以以一次或多次施用需要的剂量，以获得需要达到的结果。也可以以单位剂量形式提供根据本发明的药物组合物。
有益效果
本发明提供一类新型的高活性SHP2抑制剂，能够实现下述至少一种技术效果：
(1)对SHP2酶的高抑制活性。
(2)优异的物理化学性质(例如溶解度、物理和/或化学稳定性)。
(3)优异的药物代谢动力学性质(例如良好的生物利用度、合适的半衰期和作用持续时间)。
(4)优异的安全性(较低的毒性和/或较少的副作用，较宽的治疗窗)等。
一般术语和定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的，且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解，上述术语如“包括”涵盖“由…组成”的含义。
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
除非另有声明，浓度以重量计，比例(包括百分比)以摩尔量计。
术语“一个(种)或多个(种)”或者类似的表述“至少一个(种)”可以表示例如1、2、3、4、5、6、7、8、9、10个(种)或更多个(种)。
当公开了数值范围的下限和上限时，落入该范围中的任何数值和任何包括的范围都被具体公开。特别地，本文公开的值的每个取值范围(以形式“约a至b”，或同等的，“大约a至b”，或同等的，“约a-b”)，应理解为表示涵盖于较宽范围中的每个数值和范围。
例如，表述“C 1- 6”应理解为涵盖其中的任意亚范围以及每个点值，例如C 2- 5、C 3- 4、C 1- 2、C 1- 3、C 1- 4、C 1- 5等，以及C 1、C 2、C 3、C 4、C 5、C 6等。例如，表述“C 3- 10”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如C 3- 9、C 6- 9、C 6- 8、C 6- 7、C 7- 10、C 7- 9、C 7- 8、C 8- 9等以及C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10等。又例如，表述“3-10元”应理解为涵盖其中的任意亚范围以及的每个点值，例如3-4元、3-5元、3-6元、3-7元、3-8元、3-9元、4-5元、4-6元、4-7元、4-8元、5-7元、5-8元、6-7元等以及3、4、5、6、7、8、9、10元等。还例如，表述“5-10元”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如5-6元、5-7元、5-8元、5-9元、5-10元、6-7元、6-8元、6-9元、6-10元、7-8元等以及5、6、7、8、9、10元等。
术语“烷基”，在本文中单独或与其他基团组合使用时，指饱和的直链或支链烃基。如本文中所使用，术语“C 1-6烷基”指具有1-6个碳原子(例如1、2、3、4、5或6个碳原子)的饱和直链或支链烃基。例如“C 1-6烷基”可以是甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基等。
术语“亚烷基”指饱和的直链或支链的二价烃基。例如，如本文中所使用，术语“C 1-6亚烷基”指具有1-6个碳原子饱和的直链或支链的二价烃基。包括但不限于亚甲基、亚乙基、亚丙基或亚丁基等。
术语“环烷基”，在本文中单独或与其他基团组合使用时，指饱和的或者部分饱和的非芳族单环或多环(诸如双环)烃环；例如单环，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环丁烯、环戊烯、环己烯；或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚 基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)。例如，术语“C 3-12环烷基”指具有3-12个环碳原子(如3、4、5、6、7、8、9或10个)的环烷基。
术语“杂环烷基”或“杂环”是指含有至少一个环成员为选自N、O、P和S的杂原子的饱和或部分饱和的不具有芳香性的环状基团，优选地，所述杂原子的个数为1、2、3或4个。例如3-8元、3-6元杂环烷基。具体的实例包括但不限于环氧乙烷基、氧代环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基、高哌嗪基等。
术语“稠合环系(稠环)”是指由两个或两个以上(例如3、4或5个)碳环或杂环以共有环边而形成的多环结构，所述碳环包括环烷基和芳基，所述杂环包括杂芳环和杂环烷基。所述稠合环系包括但不限于：环烷基与环烷基形成的稠合环系、环烷基与杂环烷基形成的稠合环系、环烷基与芳环形成的稠合环系、环烷基与杂芳环形成的稠合环系、杂环烷基与杂芳环形成的稠合环系、杂环烷基与芳环形成的稠合环系、杂芳环与杂芳环形成的稠合环系、杂芳环与芳环形成的稠合环系等。
术语“卤代”或“卤素”基团，在本文中单独或与其他基团组合使用时，表示F、Cl、Br或I。
术语“卤代烷基”，在本文中单独或与其他基团组合使用时，指上文所述的烷基，其中一个或多个氢原子被卤素代替。例如，术语“卤代C 1-6烷基”指任选地被一个或多个(如1-3个)卤素取代的C 1-6烷基。本领域技术人员应当理解，当卤素取代基多于一个时，卤素可以相同也可以不同，并且可以位于相同或不同的C原子上。卤代烷基的实例有例如-CH 2F、-CHF 2、-CF 3、-CCl 3、-C 2F 5、-C 2Cl 5、-CH 2CF 3、-CH 2Cl或-CH 2CH 2CF 3等。
术语“含氮杂环”或(“含氮杂环基”)，指具有例如4-16个(适合地具有4-12个，更适合地具有4-10个)环原子的饱和或部分不饱和的单环或多环体系(例如4-15元、4-12元、4-10元)，其中至少一个环原子是N，还任选地含有一个或多个(例如1或2个)选自N、O、P和S的杂原子，且其余环原子是C。所述多环体系可以是稠合环系、桥环体系或螺环体系。该环体系中的单个环可以是饱和或不饱和的(即在环内具有一个或多个双键和/或三键)非芳香族环系，也可以是芳香族环系(例如芳环或杂芳环)。所述的“含氮杂环”任选地被一个或多个本文所述的取代基所取代，例如取代基选自任选地被取代的C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、-S(＝O) 2-(3-6元杂环烷基)等。该术语还涵盖这样的情况，其中的C原子可以被(＝O)取代和/或环上的S原子可以被1个或2个(＝O)取代。
实例包括但不限于：
Figure PCTCN2021112400-appb-000065
术语“芳基”或“芳环”，在本文中单独或与其他基团组合使用时，指具有共轭π电子系统的全碳单环或稠合环多环(如双环)芳族基团或芳族环。如本文中所使用，术语“C 6-10芳基”指含有6-10个碳原子的芳族基团。其实例包括但不限于苯基和萘基等。
术语“杂芳基”或“杂芳环”，在本文中单独或与其他基团组合使用时，指具有共轭π电子系统的芳族环，其中一个或多个(如1、2或3个)环原子是选自N、O、P和S的杂原子，其余的环原子为C。杂芳基或杂芳环可以用环原子的数目表征。例如，5-12元杂芳基可以含有5-12个(例如5、6、7、8、9、10、11或12个)环原子，特别是含有5、6、9、10个环原子。例如，杂芳基的实例有噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、吡嗪基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等；该术语还涵盖这样的情况，杂芳基或杂芳环可任选地进一步稠合于芳基、或杂芳基环上，形成稠合环系。实例包括但不限于：
Figure PCTCN2021112400-appb-000066
等。
术语“螺杂环”或“螺杂环基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其含 有至少一个选自N、O、S、C(＝O)、S(＝O)、S(＝O) 2的杂原子，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。例如为6至12元，7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环、双螺杂环或多螺杂环。例如为3元/7元、4元/6元、5元/6元或6元/6元单螺环烷基。
螺杂环基的非限制性实例包括：
Figure PCTCN2021112400-appb-000067
术语“羟基”表示-OH。
术语“氰基”表示-CN。
术语“氨基”表示-NH 2。
术语“取代”和“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地…被取代”，则取代基可(1)未被取代，或(2)被取代。如果某个原子或基团被描述为任选地被取代基列表中的一个或多个取代，则该原子或基团上的一个或多个氢可被独立地选择的、任选的取代基替代。如果取代基被描述为“独立地选自”或“各自独立地为”，则各取代基互相独立地加以选择。因此，各取代基可与另一(其他)取代基相同或不同。例如，某个取代基或取代位置或者不同的取代基或取代位置具有可能相同或不同符号指代的R基团(例如但不限于R 2和/或R z)的选择时，各个R之间独立地加以选择，即可以相同也可以不同。关于数值如g、n的选择也是如此。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
每当术语“烷基”或“芳基”或其前缀词根中的任一个出现在取代基的名称中时，除非另有说明，其本身或作为另一取代基的一部分，应解释为包括上面给出的“烷基”和“芳基”的限制。所指定的碳原子数(例如，C l-6)应独立地指烷基部分中的碳原子数或其中烷基作为其前缀根的较大取代基的烷基部分中的碳原子数。
术语“氧代”或“＝O”是指其与其相连的碳原子一起形成C＝O。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘( 2H)、氚( 3H))；碳的同位素(例如 13C及 14C)；氯的同位素(例如 37Cl)；碘的同位素(例如 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 34S)。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本发明的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本文中可使用实线
Figure PCTCN2021112400-appb-000068
实楔形
Figure PCTCN2021112400-appb-000069
或虚楔形
Figure PCTCN2021112400-appb-000070
描绘本发明的化合物的碳-碳键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物可以以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本文中使用
Figure PCTCN2021112400-appb-000071
表示该化学键表示该处化学键可以为单键或者双键。
本发明还涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供式(I)的化合物或其代谢物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括盐酸盐、乙酸盐、天冬氨酸盐、苯甲酸盐、碳酸氢盐/碳酸盐、葡庚糖酸盐、葡糖酸盐、硝酸盐、棕榈酸盐及其它类似的盐。适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、镁盐及其它类似的盐。适合的盐的综述参见例如“Remington′s Pharmaceutical Sciences”，Mack Publishing Company,Easton,Pa.,(2005)；和“药用盐手册：性质、选择和应用”(Handbook of Pharmaceutical Salts：Properties,Selection,and Use)，Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本文所描述的化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物。本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(mCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist,Comprehensive Organic Synthesis,vol.7,pp 748-750(A.R.Katritzky和A.J.Boulton,Eds.,Academic Press)；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry,vol.22,pp 390-392(A.R.Katritzky和A.J.Boulton,Eds.,Academic Press)。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过试验的方法进行表征。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,2006中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
本发明还涵盖本文所述化合物的制备方法。应当理解，本发明的化合物可使用下文描述的方法以及合成有机化学领域中已知的合成方法或本领域技术人员所了解的其变化形式来合成。优选方法包括(但不限于)下文所述那些。反应可在适于所使用的试剂和材料且适合于实现转化的溶剂或溶剂混合物中进行。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标 病症或病况的一种或多种症状。
如本文中所使用的术语“有效量”(例如“治疗有效量”或“预防有效量”)指给药后会在一定程度上实现预期效果的活性成分的量，例如缓解所治疗病症的一种或多种症状或预防病症或其症状的出现。
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻这样的术语所应用的病症或病况或者这样的病症或病况的一种或多种症状的进展。
术语“预防”指抑制和延迟疾病的发作，不仅包括在发展疾病之前的预防，还包括在治疗后预防疾病的复发。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
实施例
以下列举实施例和试验例，进而详细地说明本发明，但它们不限制本发明的范围，另外在不脱离本发明的范围下可进行变化。
质谱(MS)的测定使用Agilent(ESI)质谱仪，生产商：Agilent，型号：Agilent 6120B。
制备高效液相色谱法(HPLC)使用岛津LC-8A制备液相色谱仪(YMC,ODS,250×20mm色谱柱)。
薄层色谱法纯化采用烟台产GF 254(0.4～0.5nm)硅胶板。
反应的监测采用薄层色谱法(TLC)或液相色谱质谱联用(LC-MS)，使用的展开剂体系包括但不限于：二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系和石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，或者加入三乙胺等进行调节。
柱色谱法一般使用青岛海洋200～300目硅胶为固定相。洗脱剂体系包括但不限于二氯甲烷和甲醇体系以及正己烷和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺等进行调节。
如实施例中无特殊说明，则反应的温度为室温(20℃～30℃)。
除非特别指明，实施例中所使用的试剂购自Acros Organics、Aldrich Chemical Company、南京药石科技或者上海书亚医药科技等公司。
本文中所使用的缩写具有以下含义：
Figure PCTCN2021112400-appb-000072
Figure PCTCN2021112400-appb-000073
中间体的制备
IM-1：4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-硫酚(化合物IM-1)的制备
Figure PCTCN2021112400-appb-000074
第一步：7-氧杂-6-硫杂-5-氮杂螺[3.4]辛烷-5-羧酸叔丁酯6-氧化物(化合物A-1)的制备
将氯化亚砜(1.77g,14.91mmol)溶于乙腈(30mL)，降温至-40℃，滴加入A-0(1.20g,5.96mmol)的乙腈溶液(2mL)，10分钟后滴加入吡啶(1.65g,20.87mmol)，于-40℃反应1小时后缓慢升温至0℃。LCMS检测反应完成后向反应液中加入1N盐酸(20mL)，用乙酸乙酯萃取，合并有机相，加入饱和碳酸氢钠溶液(20mL)萃取，将有机相合并，干燥浓缩，得粗品A-1(1.40g)，其直接用于下一步反应。
第二步：7-氧杂-6-硫杂-5-氮杂螺[3.4]辛烷-5-羧酸叔丁酯6,6-二氧化物(化合物A-2)的制备
将A-1(1.40g,5.66mmol)溶于乙腈(20mL)和水(10mL)，降温至0℃，加入NaIO 4(1.82g,8.49mmol)和RuCl 3·H 2O(12.76mg,56.61umol)，于0℃反应1小时，LCMS检测反应完成后向反应液中加入硫代硫酸钠溶液，用乙酸乙酯萃取，将有机相合并，干燥浓缩，得粗品A-2(1.33g)，其直接用于下一步反应。
第三步：(1-(((2-溴吡啶-3-基)氧基)甲基)环丁基)氨基甲酸叔丁酯(化合物A-3)的制备
将2-溴吡啶-3-酚(700mg,4.02mmol)溶于DMF(30mL)，加入A-2(1.33g,5.05mmol)和碳酸铯(4.00g,12.28mmol)，于微波反应器中加热至80℃，反应2.5小时，LCMS检测反应完成后向反应液中加入水，用3N盐酸调节至pH＝5，用乙酸乙酯萃取，将有机相合并，干燥浓缩，经薄层色谱纯化得A-3(1.4g,收率97％)。
第四步：1-(((2-溴吡啶-3-基)氧基)甲基)环丁-1-胺(化合物A-4)的制备
将A-3(780mg,2.18mmol)溶于DCM(6mL)，加入TFA(3mL)，于25℃反应1小时，将反应液浓缩，粗品溶于DCM，加入饱和碳酸氢钠溶液调节pH到9，用二氯甲烷萃取，将有机相合并，干燥浓缩，得粗品A-4(550mg)，其直接用于下一步反应。
第五步：2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪](化合物A-5)的制备
将A-4(550mg,2.14mmol)溶于二氧六环(10mL)，加入碳酸铯(2.09g,6.42mmol)、Xantphos(123.77mg,213.90umol)和Pd 2(dba) 3(97.94mg,106.95umol)，氮气置换后加热至100℃，反应2小时，LCMS检测反应完成后向反应液加入水，用乙酸乙酯萃取，将有机相合并，干燥浓缩，经薄层色谱纯化得A-5(300mg,收率79％)。
第六步：4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪](化合物A-6)的制备
将A-5(300mg,1.70mmol)溶于THF(3mL)，降温至0℃，加入氢化钠(204.30mg,5.11mmol,60％purity)，于0℃反应半小时后滴加入碘甲烷(362.47mg,2.55mmol)，升温至25℃，反应1小时，LCMS检测反应完成后向反应液中加入水，用乙酸乙酯萃取，将有机相合并，干燥浓缩，经薄层色谱纯化纯化得A-6(180mg,收率55％)。
第七步：8'-碘-4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪](化合物A-7)的制备
将A-6(160mg,841.04umol)溶于THF(5mL)，降温至-78℃，滴加入正丁基锂(2.5M正己烷溶液,1.35mL)，升至0℃，反应1小时后，降温至-78℃，滴加入碘(426.92mg,1.68mmol)的THF 溶液(0.5mL)，升温至25℃，反应1小时，LCMS检测反应完成后将反应液滴加入饱和氯化铵溶液中，用乙酸乙酯萃取，将有机相合并，经饱和亚硫酸钠溶液洗涤，干燥浓缩，经薄层色谱纯化纯化得A-7(208mg,收率78％)。
第八步：3-(((4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)丙酸2-乙基己酯(化合物A-8)的制备将A-7(208mg,657.94umol)溶于二氧六环(5mL)，加入DIPEA(255.10mg,1.97mmol)、Xantphos(19.03mg,32.90umol)、Pd 2(dba) 3(30.12mg,32.90umol)和3-巯基丙酸2-乙基己酯(215.50mg,986.91umol)，氮气置换后于微波反应器中升温至90℃，反应2小时，LCMS检测反应完成后，将反应液过滤，用乙酸乙酯洗涤，将滤液浓缩，经薄层色谱纯化纯化得A-8(220mg,收率82％)。
第九步：4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-硫酚(化合物IM-1)的制备
将A-8(50mg,122.98umol)溶于THF(1mL)，加入乙醇钠(50.21mg,147.57umol,20％乙醇溶液)，于25℃反应半小时，TLC检测反应完成后将反应液浓缩，复溶于水，用3N盐酸溶液调节至pH＝5，加入二氯甲烷萃取，将有机相合并，干燥浓缩得粗品IM-1(27mg)，其直接用于下一步反应。
IM-2:((3S,4S)-8-(5-溴-3-(羟甲基)-6-甲基吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯(化合物IM-2)的制备
Figure PCTCN2021112400-appb-000075
第一步:6-溴-3-((3S,4S)-4-(叔丁氧羰基氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-甲基吡嗪-2-羧酸乙酯(B-2)的制备
将化合物B-0(200mg,766.07umol)、DMF(4mL)、化合物B-1(195.60mg,804.37umol)、BOP(312.74mg,1.53mmol)和DIPEA(594.04mg,4.60mmol)混合后，升温至40℃，反应2小时。反应结束后，加入二碳酸二叔丁酯(250.79mg,1.15mmol)，继续反应2小时。加入水和乙酸乙酯进行萃取，将有机相用饱和食盐水洗涤，用无水硫酸钠干燥，浓缩，得到粗品。粗品经薄层色谱纯化，得到化合物B-2(290mg,收率73％)。
第二步：((3S,4S)-8-(5-溴-3-(羟甲基)-6-甲基吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯(化合物IM-2)的制备
将B-2(100mg,194.77umol)溶于MeOH(2mL)，降温至0℃，加入氯化钙(216.16mg,1.95mmol)和硼氢化钠(73.69mg,1.95mmol)，升温至25℃，反应半小时，TLC检测反应完成后向反应液中加入饱和氯化铵溶液，用乙酸乙酯萃取，将有机相合并，干燥浓缩，经薄层色谱纯化纯化得IM-2(45mg,收率49％)。
IM-3:((3S,4S)-8-(5-溴-3-(羟甲基)吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯(化合物IM-3)的制备
Figure PCTCN2021112400-appb-000076
第一步：6-溴-3-((3S,4S)-4-(叔丁氧羰基氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)吡嗪-2-羧酸甲酯(化合物C-1)的制备：
将化合物C-0(120.0mg,0.41mmol)、化合物B-1(103.54mg,0.43mmol)、DIPEA(314.46mg,2.43mmol)加入到NMP(3mL)中，于25℃反应12小时。然后向反应液中加入二碳酸二叔丁酯(177.01mg,811.04umol)，于25℃继续反应2小时。加入水和乙酸乙酯，萃取产品，将有机相用饱和食盐水 洗涤，用无水硫酸钠干燥，浓缩，得到粗品，粗品经薄层色谱法纯化，得到化合物C-1(162mg,收率82％)。
第二步：((3S,4S)-8-(5-溴-3-(羟甲基)吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯(化合物IM-3)的制备：
将化合物C-1(60mg,0.12mmol)溶于二氯甲烷(2mL)中，于-25℃缓慢加入DIBAL-H(1M的己烷溶液,0.84mL)，保温反应1小时。反应完成后，向反应液中加入二氯甲烷(10mL)和饱和酒石酸钾钠水溶液(5mL)，搅拌2小时，萃取产品，将有机相用无水硫酸钠干燥，过滤，浓缩滤液，得到粗品，粗品经薄层色谱法纯化，得到化合物IM-3(40mg,收率71％)。
IM-4:((3S,4S)-8-(8-溴咪唑并[1,2-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯(化合物IM-4)的制备
Figure PCTCN2021112400-appb-000077
除在本步骤中使用D-0代替IM-3合成步骤中第一步的C-0外，采用与中间体IM-3合成步骤第一步所描述的类似方法合成化合物IM-4。
IM-5：2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-硫酚(化合物IM-5)的制备
Figure PCTCN2021112400-appb-000078
第一步：(1-(((2-氟吡啶-3-基)氧基)甲基)环丁基)氨基甲酸叔丁酯(化合物E-1)的制备
参照中间体IM-1制备例第三步类似的方法合成化合物E-1。第二步：(1-(((2-氟-4-碘吡啶-3-基)氧基)甲基)环丁基)氨基甲酸叔丁酯(化合物E-2)的制备
将E-0(2.7g,9.11mmol)溶于THF(100mL)，降温至-78℃，滴加入LDA(2M的四氢呋喃溶液,11mL)，于-78℃反应2.5小时后滴加入碘(6.94g,27.33mmol)的THF(100mL)溶液，于-78℃反应0.5小时；LCMS检测反应完成后将反应液中加入饱和氯化铵溶液中，加入硫代硫酸钠溶液，用乙酸乙酯萃取，将有机相合并，干燥浓缩，经柱层析纯化得到化合物E-1(3g,收率78％)。
第三步：1-((2-氟-4-碘吡啶-3-基)氧基)甲基)环丁烷-1-胺(化合物E-3)的制备
将E-1(100mg,236.84umol)溶于DCM(1mL)，加入三氟乙酸(0.5mL)，于25℃反应0.5小时；LCMS检测反应完成后，将反应液浓缩，得到粗品化合物E-3(100mg,收率97％)，其直接用于下一步反应。
第四步：8'-碘-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪](化合物E-4)的制备
将E-3(100mg,229.28μmol)溶于NMP(1mL)，加入磷酸钾(194.68mg,917.14μmol)，加热至110℃，反应0.5小时，LCMS检测反应完成后将反应液加入水中，固体析出，过滤，将固体收集后溶于乙酸乙酯，用水洗，用饱和食盐水洗，将有机相合并干燥浓缩，得粗品化合物E-4(63mg,收率91％)，其直接用于下一步反应。
第五步至第六步：2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-硫酚(化合物IM-5)的制备
参照中间体制备IM-1中第八步至第九步所描述的类似方法合成化合物IM-5。
IM-6：2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-硫酚(化合物IM-6)的制备
Figure PCTCN2021112400-appb-000079
参照中间体制备例IM-1及中间体制备例IM-5的相对应的类似方法合成IM-6。
IM-7：4',5'-二氢-2'H-螺[环丙烷-1,3'-吡啶并[3,2-b][1,4]氧氮杂环庚烷]-9'-硫酚的制备(化合物IM-7)的制备
Figure PCTCN2021112400-appb-000080
第一步：1-(((2-氟吡啶-3-基)氧基)甲基)环丙基)甲基)氨基甲酸叔丁酯(化合物G-2)的制备
将G-1(50mg,0.25mmol)、2-氟-吡啶-3-酚(28.10mg,0.25mmol)溶于四氢呋喃(5mL)中，氮气保护下加入三苯基膦(97.74mg,0.37mmol)和DIAD(75.35mg,0.37mmol)，于25℃反应2小时。反应完毕后，加水稀释后，用乙酸乙酯萃取。将有机相合并，干燥浓缩，粗品经硅胶柱色谱纯化得到淡黄色油状化合物G-2(1.2g,收率78％)。
第二步至第六步：4',5'-二氢-2'H-螺[环丙烷-1,3'-吡啶并[3,2-b][1,4]氧氮杂环庚烷]-9'-硫酚(化合物IM-7)的制备参照中间体制备例IM-5第二步至第六步类似方法合成IM-7。
IM-8：2',3'-二氢-5'H-螺[环丙烷-1,4'-吡啶并[3,2-b][1,4]氧氮杂环庚烷]-9'-硫酚的制备(化合物IM-7)的制备
Figure PCTCN2021112400-appb-000081
参照中间体制备例IM-7类似方法合成化合物IM-8。参照中间体制备例IM-2或IM-3的方法合成如下中间体：
Figure PCTCN2021112400-appb-000082
IM-25：((3S,4S)-8-(3-溴-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯(化合物IM-25)的制备
Figure PCTCN2021112400-appb-000083
第一步：3-溴-6-氯-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡嗪(化合物I-2)的制备
将化合物I-1(4.00g,17.13mmol)和四氢呋喃(20mL)加入到50毫升单口瓶中，冷却到0℃，慢慢加入氢化钠(2.06g,51.4mmol,60％wt)。在该温度下搅拌30分钟后加入2-(三甲基硅烷基)乙氧基甲基氯(8.57g,51.40mmol)，在0℃反应1小时后升温到室温，反应1小时。反应完毕后向反应液中慢慢加入适量的饱和氯化铵淬灭反应，然后加入DCM充分搅拌后分液，将水相用DCM萃取，合并有机相，并用水萃洗两次，将有机相经无水硫酸钠干燥后过滤，浓缩滤液得到棕色粘稠状粗品，粗品经硅胶柱色谱纯化后得到化合物I-2(5.28g,收率84.73％)
第二步：((3S,4S)-8-(3-溴-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯(化合物IM-25)的制备
将化合物I-2(1g,2.75mmol)和B-1(802.30mg,3.30mmol)溶解在N,N-二甲基乙酰胺(10mL)和水(2mL)中，加入碳酸钾(1.90g,13.75mmol)，在100℃反应2小时。反应完毕后加入二碳酸二叔丁酯(899.06mg,4.12mmol)，继续反应1小时。反应完毕后加水稀释，用乙酸乙酯萃取，将有机相干燥后浓缩得到粗品，粗品经硅胶柱色谱纯化得到化合物IM-25(1.07g,收率61.9％)。
实施例1：(3-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-甲基-6-((4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)甲醇(化合物TMD8)的制备
Figure PCTCN2021112400-appb-000084
第一步：((3S,4S)-8-(3-(羟甲基)-6-甲基-5-((4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯(化合物1-1)的制备
将IM-2(40mg,87.46umol)、IM-1(27mg,121.45umol)、碘化亚铜(17mg,89.26umol)、1,10-邻菲咯啉(16mg,88.79umol)、磷酸钾(56mg,263.82umol)加入到二氧六环(2mL)中，氮气置换后升温至100℃，反应1.5小时，LCMS检测反应完成后，向反应液中加入乙酸乙酯，过滤，将滤液浓缩，经薄层色谱纯化得1-1(30mg,收率57％)。
第二步：(3-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-甲基-6-((4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)甲醇(化合物TMD8)的制备
将1-1(30mg,50.10umol)溶于DCM(1mL)，加入TFA(0.3mL)，于25℃反应半小时，LCMS检测反应完成后，将反应液浓缩，得到粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的甲酸水溶液)纯化得到化合物TMD8(5mg,收率19％)。
MS m/z(ESI):499.2[M+H] +
1H NMR(400MHz,DMSO)δ8.22(s,1H),8.19(s,1H),7.52(d,J＝5.2Hz,1H),6.03(d,J＝5.6Hz,1H),4.49(s,2H),4.20(s,2H),4.15–4.04(m,1H),3.71(d,J＝8.4Hz,1H),3.68–3.57(m,2H),3.54(d,J＝8.4Hz,1H), 3.24–3.12(m,2H),3.09(s,3H),3.05(d,J＝5.2Hz,1H),2.57–2.42(m,2H),1.93–1.46(m,8H),1.12(d,J＝6.4Hz,3H).
实施例2：(3-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-6-((4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)甲醇(化合物TMC8)的制备
Figure PCTCN2021112400-appb-000085
除在第一步中使用IM-3代替实施例1的第一步中的IM-2外，采用与实施例1中第一步至第二步所描述的类似方法合成化合物TMC8的粗品，粗品经薄层色谱纯化得到化合物TMC8。
MS m/z(ESI):513.2[M+H] +
1H NMR(400MHz,DMSO)δ7.48(d,J＝5.6Hz,1H),5.83(d,J＝5.2Hz,1H),5.35(s,1H),4.44(d,J＝3.6Hz,2H),4.20(s,2H),4.12–3.97(m,1H),3.65(d,J＝8.4Hz,2H),3.68–3.52(m,2H),3.49(d,J＝8.4Hz,2H),3.28–3.11(m,2H),3.09(s,3H),2.89(d,J＝4.8Hz,1H),2.57–2.42(m,2H),2.39(s,3H),1.93–1.37(m,8H),1.08(d,J＝6.4Hz,3H).
实施例3：(3S,4S)-8-(6-氨基-5-((4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-胺(化合物TMB8)的制备
Figure PCTCN2021112400-appb-000086
第一步：6-氯-3-((4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-胺(化合物3-1)的制备
除在第一步中使用3-溴-6-氯吡嗪-2-胺代替实施例1的第一步中的IM-2外，采用与实施例1中第一步所描述的类似方法合成化合物中间体3-1。
第二步：(3S,4S)-8-(6-氨基-5-((4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-胺(化合物TMB8)的制备
将3-1(20mg,57.17umol)、B-1(28mg,115.14umol)和DIPEA(59.11mg,457.35umol)于微波反应器中升温至100℃，反应5hr,LCMS检测反应完成后，将反应液浓缩，经薄层色谱纯化得到TMB8(6mg,收率20％)。
MS m/z(ESI):484.2[M+H] +
1H NMR(400MHz,DMSO)δ7.59(s,1H),7.45(d,J＝5.6Hz,1H),6.05(s,2H),5.73(d,J＝5.6Hz,1H),4.21(s,2H),4.11–4.01(m,1H),3.87–3.75(m,2H),3.66(d,J＝8.8Hz,1H),3.48(d,J＝8.8Hz,1H),3.41–3.23(m,2H),3.07(s,3H),2.89(d,J＝5.2Hz,1H),2.55–2.42(m,2H),1.91–1.39(m,8H),1.07(d,J＝6.4Hz,3H).
实施例4：(3S,4S)-3-甲基-8-(8-((4'-甲基-2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)咪唑并[1,2-c]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸-4-胺(化合物TME8)的制备
Figure PCTCN2021112400-appb-000087
除在第一步中使用IM-4代替实施例1的第一步中的IM-2外，采用与实施例1中第一步和第二步所描述的类似方法合成化合物TME8粗品，粗品经薄层色谱法纯化得到化合物TME8。
MS m/z(ESI):508.2[M+H] +
1H NMR(400MHz,CD 3OD)δ7.96(s,1H),7.80(d,J＝1.6Hz,1H),7.54(d,J＝1.6Hz,1H),7.31(d,J＝5.6Hz,1H),5.81(d,J＝5.6Hz,1H),4.33–4.15(m,3H),3.90(d,J＝8.8Hz,1H),3.87–3.78(m,2H),3.75(d,J＝8.8Hz,1H),3.43–3.25(m,2H),3.13(s,3H),3.09(d,J＝4.8Hz,1H),2.67–2.47(m,2H),2.12–1.68(m,8H),1.24(d,J＝6.4Hz,3H).
实施例5：(6-((2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)吡嗪-2-基)甲醇(化合物TMC4)的制备
Figure PCTCN2021112400-appb-000088
第一步：6-((2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-((3S,4S)-4-((叔丁氧羰基)氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)吡嗪-2-羧酸甲酯(化合物5-1)的制备
参照实施例1第一步类似的方法，分别采用c-1和IM-5代替实施例1第一步中的IM-2和IM-1，合成化合物5-1。
第二步：((3S,4S)-8-(5-((2'H,4'H-螺[1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-(羟甲基)吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯(化合物5-2)的制备将5-1(170mg,0.27mmol)溶于乙醇(5mL)，加入氯化钙(461.88mg,4.16mmol)和硼氢化钠(104.96mg,2.77mmol)，于25℃反应20分钟；TLC检测反应完成后，向反应液中加入饱和氯化铵溶液和饱和食盐水，用乙酸乙酯萃取，将有机相合并干燥浓缩，粗品经薄层色谱法纯化得到5-2(50mg,收率30％)。
第三步：(6-((2'H,4'H-螺[环丁烷-1,3'-吡啶[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)吡嗪-2-基)甲醇(化合物TMC4)的制备
参照实施例1第二步的方法合成TMC4的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化得到化合物TMC4的三氟乙酸盐(42mg,收率80％)。
MS m/z(ESI):485.2[M+H] +
1H NMR(400MHz,DMSO)δ8.53(s,1H),8.30(s,1H),7.95(s,3H),7.45(d,J＝5.6Hz,1H),6.13(d,J＝5.6Hz,1H),5.53(br,1H),4.51(s,2H),4.30–4.14(m,3H),3.86(d,J＝9.2Hz,1H),3.86–3.72(m,2H),3.69(d,J＝8.8Hz,1H),3.47–3.39(m,1H),3.15–2.97(m,2H),2.31–2.16(m,2H),2.12–1.99(m,2H),1.95–1.68(m,5H),1.60(d,J＝13.2Hz,1H),1.22(d,J＝6.4Hz,3H).
实施例6：(6-((2'H,4'H-螺[氧杂环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)吡嗪-2-基)甲醇(化合物TMC3)的制备
Figure PCTCN2021112400-appb-000089
参照实施例5类似方法合成TMC3粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化得到化合物TMC3的三氟乙酸盐。
MS m/z(ESI):487.2[M+H] +
1H NMR(400MHz,DMSO)δ8.58(s,1H),8.28(s,1H),7.97(s,3H),7.49(d,J＝6.0Hz,1H),6.13(d,J＝6.0Hz,1H),4.67(d,J＝6.4Hz,2H),4.50(s,2H),4.48(d,J＝6.8Hz,2H),4.42(s,2H),4.25–4.17(m,1H),3.86(d,J＝8.8Hz,1H),3.83–3.71(m,2H),3.69(d,J＝8.8Hz,1H),3.49–3.35(m,1H),3.13–2.97(m,2H),1.95–1.51(m,4H),1.22(d,J＝6.4Hz,3H).
实施例7：(3-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-6-((4',5'-二氢-2'H-螺[环丙烷-1,3'-吡啶并[3,2-b][1,4]氧氮杂环庚烷]-9'-基)硫基)吡嗪-2-基)甲醇(化合物TMC33)的制备
Figure PCTCN2021112400-appb-000090
参照实施例5类似方法合成TMC33粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化得到化合物TMC33的三氟乙酸盐。
MS m/z(ESI):485.2[M+H] +
1H NMR(400MHz,DMSO)δ8.26(s,1H),8.21(s,3H),7.52(d,J＝5.6Hz,1H),6.17(t,J＝3.6Hz,1H),6.01(d,J＝5.6Hz,1H),4.51(s,2H),4.14-4.08(m,1H),3.88(s,2H),3.73(d,J＝8.8Hz,1H),3.70-3.59(m,2H),3.56(d,J＝8.8Hz,1H),3.23-3.12(m,2H),3.09-3.06(m,3H),1.87-1.71(m,2H),1.65-1.54(m,2H),1.13(d,J＝6.4Hz,3H),0.54(d,J＝5.6Hz,4H).
实施例8：(R)-(6-((2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-基)甲醇(化合物TMC34)的制备
Figure PCTCN2021112400-appb-000091
采用与实施例1所描述的类似方法合成化合物TMC34的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMC34的三氟乙酸盐。
MS m/z(ESI):519.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.34(s,1H),7.53(d,J＝7.2Hz,1H),7.43–7.39(m,1H),7.34(d,J＝6.4Hz,1H),7.08–7.04(m,1H),6.99(d,J＝8.4Hz,1H),6.39(d,J＝6.4Hz,1H),4.70(s,2H),4.66(s,1H),4.30(s,2H),4.10–4.07(m,1H),3.89–3.86(m,1H),3.54–3.42(m,2H),2.42–2.31(m,2H),2.25–2.22(m,3H),2.10–2.07(m,1H),2.00–1.89(m,4H).
实施例9：(6-((2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-(4-(1-氨基乙基)-4-甲基 哌啶-1-基)吡嗪-2-基)甲醇(化合物TMC35)的制备
Figure PCTCN2021112400-appb-000092
采用与实施例1所描述的类似方法，将实施例1第一步中的IM1和IM2分别替换为IM-5和IM-11，合成化合物TMC35的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMC35的三氟乙酸盐。
MS m/z(ESI):457.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.71(br,3H),7.46–7.44(m,,1H),6.11–6.10(m,1H),4.50(s,2H),4.21(s,2H),3.80–3.74(m,2H),3.19–3.11(m,3H),2.26–2.22(m,2H),2.08–2.04(s,2H),1.84–1.74(m,2H),1.64–1.54(m,3H),1.44–1.40(m,1H),1.14(d,J＝6.8Hz,3H),1.01(s,3H).
实施例10：((S)-(6-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)吡嗪-2-基)甲醇(化合物TMC19)的制备
Figure PCTCN2021112400-appb-000093
采用与实施例5所描述的类似方法合成化合物TMC19的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的碳酸氢铵水溶液)纯化得到化合物TMC19。
MS m/z(ESI):519.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),7.82(s,1H),7.54–7.41(m,2H),7.33–7.24(m,2H),6.04(d,J＝5.6Hz,1H),5.50(br,1H),4.63(d,J＝6.4Hz,2H),4.52(s,2H),4.45(d,J＝6.4Hz,2H),4.34(s,2H),4.25(s,1H),3.93–3.75(m,2H),3.21–3.06(m,14.3Hz,3H),2.89(d,J＝16.0Hz,1H),1.93–1.77(m,2H),1.58–1.39(m,2H).
实施例11：(S)-1'-(5-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺(化合物TMA19)的制备。
Figure PCTCN2021112400-appb-000094
采用与实施例1所描述的类似方法合成化合物TMA19的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMA19的三氟乙酸盐。
MS m/z(ESI):489.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.30(s,1H),8.24(brs,3H),7.51(d,J＝7.2Hz,1H),7.46(m, 1H),7.41–7.30(m,3H),6.01(m,1H),4.69(d,J＝6.4Hz,2H),4.50(d,J＝6.4Hz,2H),4.44(s,2H),4.41–4.33(m,2H),4.31–4.26(m,1H),3.32–3.22(m,2H),3.22–3.15(m,1H),3.05(d,J＝16.3Hz,1H),1.79–1.67(m,2H),1.60–1.50(m,2H).
实施例12：(3-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-6-((2',3'-二氢-5'H-螺[环丙烷-1,4'-吡啶并[3,2-b][1,4]氧氮杂环庚烷]-9'-基)硫基)吡嗪-2-基)甲醇(化合物TMC1)的制备
Figure PCTCN2021112400-appb-000095
参照实施例5类似方法合成TMC1粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化得到化合物TMC1的三氟乙酸盐。
MS m/z(ESI):485.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.34(s,1H),7.95(s,3H),7.54(d,J＝6.0Hz,1H),7.09-6.89(m,1H),6.14(d,J＝6.0Hz,1H),4.52(s,2H),4.30-4.27(m,2H),4.23-4.17(m,1H),3.87-3.74(m,3H),3.70(d,J＝8.8Hz,1H),3.47-3.39(m,1H),3.13-3.02(m,2H),2.00(t,J＝6.0Hz,2H),1.88-1.82(m,2H),1.77-1.71(m,1H),1.64-1.57(m,1H),1.22(d,J＝6.4Hz,3H),0.86-0.80(m,2H),0.67-0.63(m,2H).
实施例13：(3S,4S)-8-(5-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-胺(化合物TMA3)的制备
Figure PCTCN2021112400-appb-000096
采用实施例1类似的方法合成化合物TMA3的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMA3的三氟乙酸盐。
MS m/z(ESI):457.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.63(brs,1H),8.50(d,J＝1.2Hz,1H),8.29(d,J＝1.2Hz,1H),7.98(brs,3H),7.46(d,J＝5.6Hz,1H),5.97(d,J＝5.6Hz,1H),4.67(d,J＝6.8Hz,2H),4.48(d,J＝6.8Hz,2H),4.44(s,2H),4.30–4.15(m,3H),3.90(d,J＝8.8Hz,1H),3.69(d,J＝8.8Hz,1H),3.47–3.37(m,1H),3.25–3.09(m,2H),1.85–1.55(m,4H),1.21(d,J＝6.8Hz,3H).
实施例14：(S)-(6-(((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-甲基吡嗪-2-基)甲醇(化合物TMD19)的制备
Figure PCTCN2021112400-appb-000097
采用与实施例1所描述的类似方法合成化合物TMD19的粗品，粗品经HPLC(流动相A：乙腈， 流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMD19的三氟乙酸盐。
MS m/z(ESI):533.2[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.24(br,3H),8.16–8.06(m,1H),7.52-7.51(m,1H),7.45(d,J＝5.6Hz,1H),7.36–7.32(m,2H),5.91(d,J＝5.6Hz,1H),4.65(d,J＝6.4Hz,2H),4.48–4.38(m,5H),3.95–3.91(m,1H),3.84–3.81(m,1H),3.42–3.35(m,2H),3.23–3.12(m,3H),3.02–2.98(m,1H),2.42(s,3H),1.89–1.79(m,2H),1.62–1.52(m,2H).
实施例15：(S)-(6-(((2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-甲基吡嗪-2-基)甲醇(化合物TMD20)的制备
Figure PCTCN2021112400-appb-000098
采用与实施例1所描述的类似方法合成化合物TMD20的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMD20的三氟乙酸盐。
MS m/z(ESI):531.2[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.67(br,1H),8.28(s 3H),7.52(m,1H),7.44(d,J＝5.6Hz,1H),7.41–7.28(m,3H),5.97(d,J＝5.6Hz,1H),5.45(br,1H),4.49(s,2H),4.43–4.40(m,1H),4.23–4.20(m,2H),3.98–3.94(m,1H),3.88–3.85(m,1H),3.24–3.12(m,3H),3.03–3.99(m,1H),2.43(s,3H),2.26–2.24(m,2H),2.09–2.04(m,2H),1.89–1.75(m,4H),1.61–1.52(m,2H).
实施例16：(6-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-甲基吡嗪-2-基)甲醇(化合物TMD3)的制备
Figure PCTCN2021112400-appb-000099
采用与实施例1所描述的类似方法合成化合物TMD3的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMD3的三氟乙酸盐。
MS m/z(ESI):501.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.46(br,1H),7.94(s,3H),7.46(d,J＝5.6Hz,1H),5.94(d,J＝5.6Hz,1H),4.67(d,J＝6.4Hz,2H),4.49-4.46(m,4H),4.41(s,2H),4.22-4.20(m,1H),3.90-3.79(m,3H),3.69(d,J＝8.8Hz,1H),3.47-3.40(m,1H),3.10-2.99(m,2H),2.41(s,3H),1.89-1.81(m,2H),1.76-1.71(m,1H),1.64-1.57(m,1H),1.21(d,J＝6.4Hz,3H).
实施例17：(S)-1'-(5-((2'H,4'H-螺[环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺(化合物TMA20)的制备。
Figure PCTCN2021112400-appb-000100
采用与实施例1所描述的类似方法合成化合物TMA20的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMA20的三氟乙酸盐。
MS m/z(ESI):487.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.31(s,1H),8.25(s,3H),7.51(d,J＝7.2Hz,1H),7.43(d,J＝6.0Hz,1H),7.40–7.34(m,2H),7.34–7.30(m,1H),5.97(d,J＝6.0Hz,1H),4.44–4.35(m,2H),4.31–4.25(m,1H),4.20(s,2H),4.32–4.24(m,2H),3.19(d,J＝16.2Hz,1H),3.03(d,J＝16.2Hz,1H),2.28–2.18(m,2H),2.10–2.03(m,2H),1.85–1.70(m,4H),1.60–1.60(m,2H).
实施例18：(3S,4S)-8-(5-((2'H,4'H-螺[1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-6-氨基吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-胺(化合物TMB4)的制备
Figure PCTCN2021112400-appb-000101
第一步：3-((2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-6-氯吡嗪-2-胺(化合物21-1)的制备
将E-4(100mg,0.33mmol)溶于二氧六环(3mL)，加入DIPEA(128.34mg,0.99mmol,164.11)、Xantphos(19.15mg,0.033mmol)和Pd 2(dba) 3(15.16mg,0.016mmol)和3-氨基-5-氯吡嗪-2-硫醇钠(80mg,0.43mmol)，经氮气置换后升温至110℃，反应3小时；反应完成后，将反应液经硅藻土过滤，用乙酸乙酯洗涤，将滤液浓缩，经薄层色谱法纯化得到18-1(60mg,收率53％)。
第二步：(3S,4S)-8-(5-((2'H,4'H-螺[1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-6-氨基吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-胺(化合物TMB4)的制备
将18-1(20mg,59.56μmol)溶于DMF(1mL)，加入(3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-胺二盐酸盐(21.72mg,89.34μmol)和DIPEA(61.58mg,476.46μmol)，加热至100℃，反应8小时；反应完成后将反应液浓缩，经薄层色谱法纯化得到TMB4(6mg，收率20％)。
MS m/z(ESI):470.2[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.24(s,1H),7.60(s,1H),7.34(d,J＝5.6Hz,1H),7.18(s,1H),6.07(s,1H),5.68(d,J＝5.6Hz,1H),4.14–4.02(m,3H),3.94–3.82(m,2H),3.70(d,J＝8.0Hz,2H),3.51(d,J＝8.0Hz,2H),3.03–2.95(m,1H),2.20–1.97(m,4H),1.81–1.42(m,6H),1.10(d,J＝6.4Hz,3H).
实施例19：(S)-1'-(5-((2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-6-氨基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺(化合物TMB20)的制备
Figure PCTCN2021112400-appb-000102
采用与实施例18所描述的类似方法合成化合物TMB20的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的碳酸氢铵水溶液)纯化，得到化合物TMB20。
MS m/z(ESI):502.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ9.08(br,1H),8.30(s,3H),7.70(s,1H),7.52-7.48(m,2H),7.41–7.28(m,3H),6.29(s,2H),5.94(d,J＝6.4Hz,1H),4.44–4.36(m,1H),4.35–4.17(m,4H),3.25–3.08(m,3H),3.02(d,J＝16.4Hz,1H),2.35–2.20(m,2H),2.15–2.05(m,2H),1.92–1.62(m,4H),1.58–1.44(m,2H).
实施例20：(R)-(6-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-(3-氨基-5-氟-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-基)甲醇(化合物TMC36)的制备
Figure PCTCN2021112400-appb-000103
采用实施例5类似的方法合成化合物TMC36的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMC36的三氟乙酸盐。
MS m/z(ESI):539.0[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.69(brs,3H),8.32(s,1H),7.50(d,J＝6.0Hz,1H),7.44(dd,J＝8.0,2.8Hz,1H),7.21(td,J＝9.2,2.8Hz,1H),7.00(dd,J＝8.8,4.0Hz,1H),6.19(d,J＝6.0Hz,1H),4.76–4.70(m,1H),4.68(d,J＝6.4Hz,2H),4.55(s,2H),4.48(d,J＝6.4Hz,2H),4.45(s,2H),4.10–4.01(m,1H),3.95–3.85(m,1H),3.40–3.20(m,2H),2.26–2.12(m,1H),2.06–1.90(m,2H),1.88–1.78(m,1H).
实施例21：(R)-1'-(5-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)-5-氟-3H-螺[苯并呋喃-2,4'-哌啶]-3-胺(化合物TMA33)的制备
Figure PCTCN2021112400-appb-000104
采用实施例1类似的方法合成化合物TMA33的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMA33的三氟乙酸盐。
MS m/z(ESI):509.0[M+H] +
1H NMR(400MHz,CD 3OD)δ8.42(d,J＝1.2Hz,1H),8.32(d,J＝1.2Hz,1H),7.40(d,J＝6.8Hz,1H),7.30 (dd,J＝8.0,2.8Hz,1H),7.16(td,J＝8.8,2.8Hz,1H),6.98(dd,J＝9.2,4.0Hz,1H),6.27(d,J＝6.4Hz,1H),4.82(d,J＝7.2Hz,2H),4.67(s,2H),4.62(d,J＝7.2Hz,2H),4.58(s,2H),4.48–4.40(m,1H),3.55–3.40(m,2H),2.15–1.80(m,4H).
实施例22：(R)-(3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-6-((2',4'-二氢螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)甲醇(化合物TMC37)的制备
Figure PCTCN2021112400-appb-000105
采用实施例1类似的方法合成化合物TMC37的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMC37的三氟乙酸盐。
MS m/z(ESI):521.0[M+H] +
1H-NMR(400MHz,DMSO-d 6):δ8.45(s,3H),8.29(s,1H),8.12(br,1H),7.56(d,J＝7.2Hz,1H),7.48(d,J＝5.6Hz,1H),7.41–7.34(m,1H),7.07–6.96(m,2H),6.11(d,J＝5.2Hz,1H),4.74–4.68(m,1H),4.65(d,J＝6.4Hz,2H),4.55(s,2H),4.46(d,J＝6.4Hz,2H),4.38(s,2H),4.08–4.00(m,1H),3.91–3.82(m,1H),3.60–3.22(m,2H),2.20–1.75(m,4H).
实施例23：(6-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-(4-氨基-8-氮杂双螺[2.1.55.23]十二烷-8-基)吡嗪-2-基)甲醇(化合物TMC38)的制备
Figure PCTCN2021112400-appb-000106
采用实施例5类似的方法合成化合物TMC38的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMC38的三氟乙酸盐。
MS m/z(ESI):497.0[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.41(brs,1H),8.26(s,1H),7.75(brs,3H),7.48(d,J＝6.0Hz,1H),6.09(d,J＝5.6Hz,1H),4.65(d,J＝6.4Hz,2H),4.50(s,2H),4.47(d,J＝6.4Hz,2H),4.40(s,2H),3.77–3.66(m,2H),3.32–3.08(m,2H),2.91–2.82(m,1H),2.04–2.18(m,6H),1.64–1.50(m,2H),1.02–0.90(m,1H),0.84–0.74(m,1H),0.64–0.44(m,2H).
实施例24：(S)-1'-(5-((2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)-5,7-二氢螺[环戊烯并[b]吡啶-6,4'-哌啶]-5-胺(化合物TMA34)的制备
Figure PCTCN2021112400-appb-000107
采用实施例1类似的方法合成化合物TMA34的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的碳酸氢铵水溶液)纯化，得到化合物TMA34。
MS m/z(ESI):488.0[M+H] +
1H NMR(400MHz,CD 3OD)δ8.36(d,J＝4.8Hz,1H),8.29(d,J＝2.8Hz,1H),8.24(d,J＝1.6Hz,1H),7.83(d,J＝7.2Hz,1H),7.31(d,J＝5.2Hz,1H),7.27(dd,J＝7.6,4.8Hz,1H),5.95(d,J＝5.6Hz,1H),4.42–4.30(m,2H),4.11(s,2H),4.06(s,1H),3.40–3.20(m,2H),2.95(d,J＝16.4Hz,1H),2.28–2.15(m,4H),1.95–1.75(m,4H),1.71–1.61(m,1H),1.50–1.40(m,1H).
实施例25：(S)-1'-(5-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)-5,7-二氢螺[环戊烯并[b]吡啶-6,4'-哌啶]-5-胺(化合物TMA35)的制备
Figure PCTCN2021112400-appb-000108
第一步：(1'-(5-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)-5,7-二氢螺[环戊烯并[b]吡啶-6,4'-哌啶]-5-基)氨基甲酸叔丁酯(化合物25-1)的制备
将IM-18(25mg,54.30μmol)、IM-6(17.11mg,81.46μmol)、磷酸钾(23.03mg,108.61μmol)、Xantphos(3.14mg,5.43μmol)和Pd 2(dba) 3(4.97mg,5.43μmol)加入到二氧六环(3mL)中，氮气置换后升温至100℃，反应3小时，LCMS检测反应完成后，向反应液中加入乙酸乙酯，过滤，将滤液浓缩，经薄层色谱纯化得化合物25-1(10mg,收率31％)。
第二步：(S)-1'-(5-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)-5,7-二氢螺[环戊烯并[b]吡啶-6,4'-哌啶]-5-胺(化合物TMA35)的制备
将25-1(8mg,13.57μmol)用TFA(0.5mL)和DCM(2.5mL)溶解，于25℃反应2小时，LCMS监测反应完全后，减压浓缩,残留物经HPLC(流动相A：乙腈，流动相B：0.05％的碳酸氢铵水溶液)纯化，得到化合物TMA35(1.72mg,收率25％)。
MS m/z(ESI):490.0[M+H] +
1H NMR(400MHz,CD 3OD)δ8.42(d,J＝4.8Hz,1H),8.31(d,J＝1.6Hz,1H),8.25(d,J＝1.2Hz,1H),7.87(d,J＝7.6Hz,1H),7.38(d,J＝5.6Hz,1H),7.31(dd,J＝7.6,5.2Hz,1H),6.00(d,J＝5.6Hz,1H),4.74(d,J＝6.8Hz,2H),4.56(d,J＝6.8Hz,2H),4.46–4.30(m,4H),4.21(s,1H),3.40–3.20(m,2H),3.05(d,J＝16.8Hz,1H),1.94–1.78(m,2H),1.71–1.51(m,2H).
实施例26：(R)-(6-((2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-(3-氨基-3H-螺[呋喃并[2,3-b]吡啶-2,4'-哌啶]-1'-基)吡嗪-2-基)甲醇(化合物TMC39)的制备
Figure PCTCN2021112400-appb-000109
采用实施例5类似的方法合成化合物TMC39的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的碳酸氢铵水溶液)纯化，得到化合物TMC39。
MS m/z(ESI):519.9[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.23(s,1H),7.99(dd,J＝4.8,1.2Hz,1H),7.71(d,J＝6.8Hz,1H),7.41(d,J＝5.6Hz,1H),7.31(s,1H),6.90(dd,J＝7.2,5.6Hz,1H),6.01(d,J＝5.2Hz,1H),5.49(t,J＝6.0Hz,1H),4.53(d,J＝6.0Hz,2H),4.13(s,1H),4.07(s,2H),3.92–3.72(m,2H),3.45–3.23(m,2H),2.25–1.63(m,10H).
实施例27：(R)-(6-(((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-5-甲基吡嗪-2-基)甲醇(化合物TMD33的制备
Figure PCTCN2021112400-appb-000110
采用实施例1类似的方法合成化合物TMD33的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMD33的三氟乙酸盐。
MS m/z(ESI):535.0[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.45(s,3H),8.40(br,1H),7.55(d,J＝7.2Hz,1H),7.45(d,J＝6.0Hz,1H),7.38–7.34(m,1H),7.04–6.95(m,2H),5.97(d,J＝5.6Hz,1H),4.71–4.70(m,1H),4.66(d,J＝6.4Hz,2H),4.52–4.43(m,4H),4.40(s,2H),4.09–4.06(m,1H),3.93–3.89(m,1H),3.35–3.25(m,2H),2.42(s,3H),2.18–2.11(m,1H),2.02–1.87(m,2H),1.79–1.76(m,1H).
实施例28：(S)-1'-(5-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-6-氨基吡嗪-2-基)-5,7-二氢螺[环戊烯并[b]吡啶-6,4’-哌啶]-5-胺(化合物TMB33)的制备
Figure PCTCN2021112400-appb-000111
采用实施例18类似的方法合成化合物TMB33的粗品，粗品经薄层色谱法纯化得TMB33。
MS m/z(ESI):505.1[M+H] +
1H-NMR(400MHz,DMSO-d 6):δ8.31(d,J＝5.2Hz,1H),7.70(s,1H),7.65(d,J＝7.2Hz,1H),7.62(s,1H),7.41(d,J＝5.2Hz,1H),7.17(dd,J＝5.2,7.2Hz,1H),6.08(s,2H),5.75(d,J＝5.2Hz,1H),4.61(d,J＝6.4Hz,2H),4.45(d,J＝6.4Hz,2H),4.34(s,2H),4.24–4.17(m,2H),3.89(s,1H),3.17–3.08(m,3H),2.74(d,J＝16.8Hz,1H),1.80–1.60(m,2H),1.54–1.50(m,1H),1.12–1.09(m,1H).
实施例29：(S)-1'-(5-((2'H,4'H-螺[环丁烷-1,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-6-氨基吡嗪-2-基)-5,7-二氢螺[环戊烯并[b]吡啶-6,4’-哌啶]-5-胺(化合物TMB34)的制备。
Figure PCTCN2021112400-appb-000112
采用实施例18类似的方法合成化合物TMB34的粗品，粗品经薄层色谱法纯化得TMB34。
MS m/z(ESI):503.1[M+H] +
1H-NMR(400MHz,DMSO-d 6):δ8.31(d,J＝5.2Hz,1H),7.64(d,J＝7.2Hz,1H),7.62(s,1H),7.35(d,J＝5.2Hz,1H),7.19–7.15(m,2H),6.06(s,2H),5.70(d,J＝5.2Hz,1H),4.20–4.16(d,J＝6.4Hz,2H),4.07(s,2H),3.88(s,1H),3.17–3.07(m,3H),2.74(d,J＝16.8Hz,1H),2.18–1.98(m,4H),1.79–1.63(m,3H),1.52(d,J＝13.6Hz,1H),1.10(d,J＝13.6Hz,1H).
实施例30：(S)-1'-(8-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊烯并[b]吡啶-6,4'-哌啶]-5-胺(化合物TME33)的制备
Figure PCTCN2021112400-appb-000113
采用实施例1类似的方法合成化合物TME33的粗品，粗品经薄层色谱法纯化得到化合物TME33。MS m/z(ESI):529.0[M+H] +
1H-NMR(400MHz,DMSO-d 6):δ8.42–8.38(m,1H),7.99(s,1H),7.84(d,J＝1.6Hz,1H),7.79–7.74(m,2H),7.59(d,J＝1.6Hz,1H),7.34(d,J＝5.2Hz,1H),7.29–7.21(m,1H),5.79(d,J＝5.2Hz,1H),4.66(d,J＝6.4Hz,2H),4.49(d,J＝6.0Hz,2H),4.41(s,2H),4.12(s,1H),3.99–3.90(m,2H),3.45–3.25(m,2H),3.18(d,J＝16.8Hz,1H),2.89(d,J＝16.4Hz,1H),2.06–1.94(m,2H),1.69–1.60(m,1H),1.43–1.33(m,1H).
实施例31：(R)-1'-(5-(((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-胺(化合物TMA36)的制备
Figure PCTCN2021112400-appb-000114
采用实施例1类似的方法合成化合物TMA36的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMA36的三氟乙酸盐。
MS m/z(ESI):491.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.56(d,J＝1.2Hz,1H),8.43(s,3H),8.32(d,J＝1.2Hz,1H),8.24(br,1H),7.56(d,J＝7.6Hz,1H),7.45(d,J＝5.6Hz,1H),7.40–7.36(m,1H),7.05–6.99(m,2H),5.95(d,J＝6.0Hz,1H),4.68–4.67(m,1H),4.65(d,J＝6.4Hz,2H),4.55–4.52(m,1H),4.47(d,J＝6.4Hz,2H),4.40(s,2H),4.37–4.36(m,1H),3.40–3.28(m,2H),2.03–1.98(m,2H),1.82–1.77(m,2H).
实施例32：(S)-(6-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基-3-(5-氨基-5,7-二氢螺[环戊烯并[b]吡啶-6,4'-哌啶]-1'-基)-5-甲基吡嗪-2-基)甲醇(化合物TMD34)的制备
Figure PCTCN2021112400-appb-000115
采用实施例1类似的方法合成化合物TMD34的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMD34的三氟乙酸盐。
MS m/z(ESI):534.0[M+H] +
1H-NMR(400MHz,DMSO-d 6):δ8.90(br,1H),8.57-8.52(m,1H),8.42(s,3H),7.93(d,J＝7.6Hz,1H),7.49(d,J＝6.4Hz,1H),7.40–7.34(m,1H),6.02(d,J＝6.0Hz,1H),4.69(d,J＝6.4Hz,2H),4.56–4.44(m,7H),4.05–3.85(m,2H),3.30–3.15(m,3H),3.09(d,J＝16.8Hz,1H),2.43(s,3H),1.94–1.80(m,2H),1.68–1.50(m,2H).
实施例33：(R)-1'-(5-(((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-6-氨基吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-胺(化合物TMB35)的制备
Figure PCTCN2021112400-appb-000116
采用与实施例18第二步所描述的类似方法合成化合物TMB35粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMB35的三氟乙酸盐。
MS m/z(ESI):506.0[M+H] +
1H NMR(400MHz,CD 3OD)δ7.60(s,1H),7.40–7.36(m,2H),7.20–7.16(m,1H),6.90–6.86(m,1H),6.79(d,J＝8.0Hz,1H),5.95(d,J＝5.2Hz,1H),4.74(d,J＝6.8Hz,2H),4.61(br,2H),4.58(d,J＝7.2Hz,2H),4.43–4.40(m,3H),4.32–4.29(m,1H),4.10(s,1H),3.44–3.37(m,2H),1.96–1.92(m,2H),1.82–1.79(m,2H).
实施例34：(3S,4S)-8-(3-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-1H-吡唑并[3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-胺(化合物TMF1)的制备
Figure PCTCN2021112400-appb-000117
采用实施例1类似的方法合成化合物TMF1的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的三氟乙酸水溶液)纯化，得到化合物TMF1的三氟乙酸盐。
MS m/z(ESI):497.2[M+H] +
1H NMR(400MHz,DMSO-d 6)δ13.82(s,1H),8.49(s,1H),7.97–7.93(m,3H),7.38–7.35(m,1H),5.87–5.82(m,1H),4.71–4.67(m,2H),4.55–4.47(m,3H),4.34–4.17(m,4H),3.90(d,J＝8.8Hz,1H),3.71(d,J＝8.8Hz,1H),3.41(t,J＝4.8Hz,1H),3.26–3.17(m,2H),1.81–1.72(m,3H),1.61–1.58(m,1H),1.21(d,J＝6.4Hz,3H).
实施例35：(S)-(6-((2'H,4'H-螺[氧杂环丁烷-3,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-基)硫基)-3-(5-氨基-5,7-二氢螺[环戊烯并[b]吡啶-6,4'-哌啶]-1'-基)吡嗪-2-基)甲醇(化合物TMC40)的制备
Figure PCTCN2021112400-appb-000118
采用实施例5类似的方法合成化合物TMC40的粗品，粗品经HPLC(流动相A：乙腈，流动相B：0.05％的碳酸氢铵水溶液)纯化，得到化合物TMC40。
MS m/z(ESI):520.0[M+H] +
1H-NMR(400MHz,DMSO-d 6):δ9.16(br,1H),8.55(d,J＝7.6Hz,1H),8.49(s,3H),8.32(s,1H),7.95(d,J＝7.6Hz,1H),7.52(d,J＝6.4Hz,1H),7.39–7.34(m,1H),6.21(d,J＝6.4Hz,1H),4.70(d,J＝6.4Hz,2H),4.54–4.42(m,7H),4.03–3.84(m,2H),3.31–3.08(m,4H),1.95–1.82(m,2H),1.70–1.50(m,2H).
生物学实施例
试验例1：SHP2(蛋白磷酸酶)体外酶学活性抑制试验
试验系统：
磷酸酶：Recombinant full-length human PTPN11(SHP2),Active(SignalChem)
底物：6,8-Difluoro-4-methylumbelliferyl phosphate(DiFMUP)(Invitrogen)
激活肽：IRS1_pY1172(dPEG8)pY1222(BPS Bioscience)
终止试剂：bpv(phen)(Abcam)
试验参数：
SHP2浓度：0.5nM；DiFMUP浓度：200μM；IRS-1浓度：0.5μM；bpv：160μM
缓冲液体系：60mM Hepes pH7.2；75mM NaCl；75mM KCl；0.05％P-20；1mM EDTA；5mM DTT化合物孵育及与酶和激活肽作用时间：室温60分钟
酶与底物反应时间：室温30分钟
酶标仪参数：BMG PHERAstar Fluorescence，激发波长340nm，发射波长450nm
试验步骤：
将待测化合物和磷酸酶SHP2的混合物与激活肽IRS-1在缓冲液体系下室温孵育60分钟，加入底物DiFMUP启动反应，室温孵育30分钟后，加入bpv终止反应，将反应板放入酶标仪中，采用终点法读取板中各孔的荧光值。
数据处理：
以溶媒组(含0.5nM SHP2,200μM DiFMUP,0.5μM IRS-1,160μM bpv,0.05％DMSO)为阴性对照、反应缓冲液组(200μM DiFMUP,0.5μM IRS-1,160μM bpv,0.05％DMSO)为空白对照，计算各浓度组的相对抑制活性，抑制率＝100％-(测试组的荧光值-空白组的荧光值)/(溶媒组的荧光值-空白组的荧光值)*100％。按照四参数模型拟合曲线，计算化合物的半数抑制浓度(IC 50)。
试验结果：
按照上述方法测定化合物对SHP2活性的抑制，结果如表1中所示。
表1.SHP2酶活抑制试验结果
实施例 IC 50(nM) 实施例 IC 50(nM)
实施例1 6.30 实施例18 9.90
实施例2 2.60 实施例19 4.80
实施例3 6.70 实施例20 4.80
实施例5 2.70 实施例22 3.64
实施例6 6.59 实施例24 2.50
实施例7 7.20 实施例25 3.90
实施例8 3.20 实施例26 5.95
实施例9 7.30 实施例27 4.33
实施例10 4.50 实施例28 7.19
实施例11 1.60 实施例29 4.51
实施例12 4.60 实施例30 2.79
实施例13 10.90 实施例31 1.80
实施例14 3.40 实施例32 5.36
实施例15 5.90 实施例33 4.33
实施例16 1.70 实施例34 3.48
实施例17 1.90 实施例35 7.40
结论：
在SHP2酶学活性抑制试验中，本发明的化合物表现出显著的抑制活性。
试验例2：化合物对KYSE-520细胞(人食管鳞癌细胞)增殖活性抑制试验
试验系统：
细胞名称/制造商：KYSE-520/JCRB Cell Bank
试剂盒名称/制造商：
Figure PCTCN2021112400-appb-000119
Luminescent Cell Viability Assay,Promega
试验参数：
细胞数量：1500细胞/孔
铺板培养基：KYSE-520:1640+10％FBS
加药培养基：KYSE-520:1640+10％FBS
化合物孵育条件：37℃，5％CO 2
孵育时间：5d
检测温度：RT
BMG PHERAstar FS Luminescent
试验步骤：
将细胞培养在含有10％胎牛血清的培养基中，放置在37℃，5％CO 2培养条件下进行培养。向96孔板中铺入适量细胞，培养箱中过夜培养，使细胞附着贴壁。次日，移除培养基，加入含有预先稀释化合物的完全培养基，37℃孵育5d。第五天向每孔中加入检测试剂CellTiter-GLo，化学发光检测各孔的相对发光单位(RLU)。
数据处理：
利用不含细胞的培养基的CellTiter-Glo获得背景值。细胞活率＝(样品RLU-背景RLU)/(溶媒RLU-背景RLU)×100％，最大抑制率＝100％-细胞活率 最大浓度，按照四参数模型拟合曲线，计算化合物的半数抑制浓度(IC 50)。
试验结果：
按照上述方法测定化合物对KYSE-520增殖的抑制活性，结果如表2中所示。
表2.化合物对KYSE-520细胞增殖活性抑制结果
实施例 IC 50(μM) 实施例 IC 50(μM)
实施例2 0.12 实施例19 0.075
实施例6 0.12 实施例20 0.075
实施例7 0.27 实施例22 0.046
实施例8 0.038 实施例25 0.21
实施例10 0.016 实施例28 0.08
实施例11 0.017 实施例29 0.04
实施例12 0.35 实施例30 0.28
实施例14 0.06 实施例31 0.038
实施例17 0.064 实施例32 0.16
结论：
本发明的化合物对KYSE-520具有较强的细胞增殖抑制活性。
试验例3：化合物对NCI-H358细胞(人非小细胞肺癌细胞)增殖活性抑制试验
试验系统：
细胞名称/制造商：NCI-H358/JCRB Cell Bank
试剂盒名称/制造商：
Figure PCTCN2021112400-appb-000120
Luminescent Cell Viability Assay,Promega
试验参数：
细胞数量：1500细胞/孔
铺板培养基：NCI-H358:1640+10％FBS
加药培养基：NCI-H358:1640+10％FBS
化合物孵育条件：37℃，5％CO 2
孵育时间：5d
检测温度：RT
BMG PHERAstar FS Luminescent
试验步骤：
将细胞培养在含有10％胎牛血清的培养基中，放置在37℃，5％CO2培养条件下进行培养。向96孔板中铺入适量细胞，培养箱中过夜培养，使细胞附着贴壁。次日，移除培养基，加入含有预先稀释化合物的完全培养基，37℃孵育5d。第五天向每孔中加入检测试剂CellTiter-GLo，化学发光检测各孔的相对发光单位(RLU)。
数据处理：
利用不含细胞和化合物的组获得背景，含有细胞不含化合物的组作为溶媒组。细胞活率＝(样品RLU-背景RLU)/(溶媒RLU-背景RLU)×100％，最大抑制率＝100％-细胞活率 最大浓度，按照四参数模型拟合曲线，计算化合物的半数抑制浓度(IC 50)。
试验结果：
按照上述方法测定化合物对NCI-H358增殖的抑制活性，结果如表3中所示。
表3.化合物对NCI-H358细胞增殖活性抑制结果
实施例 IC 50(μM) 实施例 IC 50(μM)
实施例2 0.039 实施例22 0.015
实施例6 0.049 实施例25 0.039
实施例10 0.0076 实施例28 0.019
实施例11 0.0096 实施例29 0.0094
实施例19 0.008 实施例31 0.045
实施例20 0.008 实施例32 0.026
上述实施例不以任何方式限定本申请的方案。除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (19)

  1. 一种具有式(I)结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
    Figure PCTCN2021112400-appb-100001
    其中，
    L 1选自单键和-S-；
    环A选自9-12元螺杂环，其任选地被一个或多个(例如1、2、3或4个)选自氢、卤素、氰基、羟基、氧代基、氨基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-O-C 1-6烷基、-C(＝O)-NH-C 1-6烷基、-NH-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基和-S(＝O) 2-C 3-6环烷基的取代基取代；所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代；
    各R 1独立地选自氢、卤素、氰基、羟基、氨基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3- 6环烷基、3-6元杂环烷基、-NH-C(＝O)-O-C 1-6烷基；所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代；
    环B选自5-10元杂芳环和5-6元杂环；
    各R 2独立地选自氢、卤素、C 1-6烷基、氧代基、氨基、氰基、-C(＝O)-NH 2、-NH-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基；所述烷基、环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代；
    环C为4-16元含氮杂环；
    R 3、R 4各自独立地选自氢、氨基、卤素、氰基、羟基、氧代基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 2-6烯基、-C 2-6炔基、C 5-10芳基、C 5-10杂芳基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、-S(＝O) 2-(3-6元杂环烷基)、-NH-C(＝O)-C 1-6烷基、-C(＝O)-NH 2和-C(＝O)-NH-C 1-6烷基；所述烷基、环烷基、杂环烷基、烯基、炔基、芳基、杂芳基各自任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)、-O-(3-6元杂环烷基)、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、C 2-6烯烃、C 2-6炔烃、氧代基、C 3-6环烷基和3-6元杂环烷基的取代基取代；
    m、n各自独立地选自0、1和2。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其具有式(II)所示结构：
    Figure PCTCN2021112400-appb-100002
    其中，环D选自C 3-6碳环和3-6元杂环；
    R 5、R 5'各自独立地选自氢、卤素、氰基、羟基、氧代基、氨基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-O-C 1-6烷基、-C(＝O)-NH-C 1-6烷 基、-NH-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基和-S(＝O) 2-C 3-6环烷基；所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代；
    U、V、W各自独立地选自单键、-CH 2-、-O-、-N(R 6)-、-CH 2O-、-OCH 2-、-CH 2N(R 6)-、-N(R 6)CH 2-、-C(＝O)-、-C(＝O)N(R 6)-、-N(R 6)C(＝O)-、-C(＝O)O-和-OC(＝O)-；
    R 6选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-O-C 1-6烷基，所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)的取代基取代；
    p、q各自独立地选自0、1和2；
    L 1、环B、环C、R 1、R 2、R 3、R 4、m和n如权利要求1所定义。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，
    环B为6-9元杂芳环或5-6元杂环；
    各R 2独立地选自氢、卤素、C 1-6烷基、氧代基、氨基、氰基和-C(＝O)-NH 2；所述的烷基任选地被一个或多个选自羟基、卤素、氰基的取代基所取代；
    优选地，环B为吡嗪基、嘧啶酮基或9元杂芳环；
    各R 2独立地选自氢、C 1-6烷基、-CH 2-OH、-CH 2F、-CH 2CHF 2、-CH 2CH 2F、-C(＝O)-NH 2、氧代基和氨基。
  4. 根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其具有式(II-1)所示结构：
    Figure PCTCN2021112400-appb-100003
    其中，环D选自C 3-6碳环和4-6元杂环，L 1、环C、R 1、R 2、R 3、R 4、m和n如权利要求1所定义，U、V、W、R 5、R 5'、p和q如权利要求2所定义。
  5. 根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其具有式(II-1a)所示结构：
    Figure PCTCN2021112400-appb-100004
    其中，环D选自C 3-6碳环和4-6元杂环，L 1、环C、R 1、R 3、R 4和m和如权利要求1所定义，U、V、W、R 5、R 5'、p和q如权利要求2所定义。
  6. 根据权利要求4或5所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，
    环D为4元含氧杂环、
    Figure PCTCN2021112400-appb-100005
    W为-O-，U为-N(R 6)-,V为-CH 2-；
    R 6选自氢、C 1-3烷基、C 3-6环烷基，所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)的取代基取代；
    R 6'选自C 1-3烷基、C 3-6环烷基、3-6元杂环烷基、-C(＝O)-C 1-6烷基、-C(＝O)-O-C 1-6烷基、-C(＝O)-NH-C 1-6烷基、-S(＝O) 2-C 1-6烷基和-S(＝O) 2-C 3-6环烷基；所述的烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基和-O-(C 1-6烷基)的取代基取代。
  7. 根据权利要求5所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其具有式(II-1-1)所示结构：
    Figure PCTCN2021112400-appb-100006
    其中，X 1选自-O-、-CH 2-和-N(R 8)-；
    各R 7独立地选自C 1-6烷基和氨基，所述C 1-6烷基任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)、C 3-6环烷基、3-6元杂环烷基、-O-(卤代C 1-6烷基)、-S(＝O) 2-C 1-6烷基、氧代基的取代基取代；或者任意两个R 7和它们共同相连的碳原子形成3-6元环烷基或3-6元杂环烷基；
    R 8选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基和-S(＝O) 2-(3-6元杂环烷基)；其中所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、氧代基、-O-(C 1-6烷基)、C 2-6烯烃和C 2-6炔烃取代基取代；
    y为0、1、2或3；
    环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如权利要求2所定义。
  8. 根据权利要求5所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其具有式(II-1-2)所示结构：
    Figure PCTCN2021112400-appb-100007
    其中，E选自3-6元杂环、3-6元碳环、苯环和5-6元杂芳环；
    R 9各自独立地选自氢、氨基、卤素、氰基、羟基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 2-6烯基、-C 2-6炔基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、-NH-C(＝O)-C 1-6烷基、-C(＝O)-NH 2、-C(＝O)-NH-C 1-6烷基；所述烷基、环烷基、杂环烷基、烯基、炔基、芳基、杂芳基各自任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)、-O-(3-6元杂环烷基)、C 2-6烯烃、C 2-6炔烃、羰基、C 3-6环烷基、3-6元杂环烷基的取代基取代；
    X 2选自-O-、-CH 2-、-N(R 8)-、-C(＝O)和
    Figure PCTCN2021112400-appb-100008
    环F为C 3-6环烷基；所述环烷基任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)和-O-(3-6元杂环烷基)的取代基取代；
    R 8选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基和-S(＝O) 2-(3-6元杂环烷基)；其中所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、氧代基、-O-(C 1-6烷基)、C 2-6烯烃和C 2-6炔烃取代基取代；
    z选自0、1、2或3；
    环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如权利要求2所定义。
  9. 根据权利要求8所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其具有式(II-1-2a)所示结构：
    Figure PCTCN2021112400-appb-100009
    其中，X 3选自-CH-和-N-；
    X 2、R 9、z、环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如权利要求8所定义。
  10. 根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其具有式(II-1b-1)所示结构：
    Figure PCTCN2021112400-appb-100010
    其中，X 1选自-O-、-CH 2-和-N(R 8)-；
    各R 7独立地选自C 1-6烷基和氨基，所述C 1-6烷基任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)、C 3-6环烷基、3-6元杂环烷基、-O-(卤代C 1-6烷基)、-S(＝O) 2-C 1-6烷基、氧代基的取代基取代；或者任意两个R 7和它们共同相连的碳原子形成3-6元环烷基或3-6元杂环烷基；
    R 8选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基和-S(＝O) 2-(3-6元杂环烷基)；其中所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、氧代基、-O-(C 1-6烷基)、C 2-6烯烃和C 2-6炔烃取代基取代；
    y为0、1、2或3；
    环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如权利要求2所定义。
  11. 根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其具有式(II-1b-2)所示结构：
    Figure PCTCN2021112400-appb-100011
    其中，X 3选自-CH-和-N-；
    R 9各自独立地选自氢、氨基、卤素、氰基、羟基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 2-6烯基、-C 2-6炔基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、-NH-C(＝O)-C 1-6烷基、-C(＝O)-NH 2、-C(＝O)-NH-C 1-6烷基；所述烷基、环烷基、杂环烷基、烯基、炔基、芳基、杂芳基各自任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)、-O-(3-6元杂环烷基)、C 2-6烯烃、C 2-6炔烃、羰基、C 3-6环烷基、3-6元杂环烷基的取代基取代；
    X 2选自-O-、-CH 2-、-N(R 8)-、-C(＝O)和
    Figure PCTCN2021112400-appb-100012
    环F为C 3-6环烷基；所述环烷基任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)和-O-(3-6元杂环烷基)的取代基取代；
    R 8选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基和-S(＝O) 2-(3-6元杂环烷基)；其中所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、氧代基、-O-(C 1-6烷基)、C 2-6烯烃和C 2-6炔烃取代基取代；
    z选自0、1、2或3；
    环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如权利要求2所定义。
  12. 根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其具有式(II-2-1)所示结构：
    Figure PCTCN2021112400-appb-100013
    其中，X 1选自-O-、-CH 2-和-N(R 8)-；
    各R 7独立地选自C 1-6烷基和氨基，所述C 1-6烷基任选地被一个或多个选自羟基、卤素、氰基、-O-(C 1-6烷基)、C 3-6环烷基、3-6元杂环烷基、-O-(卤代C 1-6烷基)、-S(＝O) 2-C 1-6烷基、氧代基的取代基取代；或者任意两个R 7和它们共同相连的碳原子形成3-6元环烷基或3-6元杂环烷基；
    R 8选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基和-S(＝O) 2-(3-6元杂环烷基)；其中所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、氧代基、-O-(C 1-6烷基)、C 2-6烯烃和C 2-6炔烃取代基取代；
    y为0、1、2或3；
    环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如权利要求2所定义。
  13. 根据权利要求根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其具有式(II-2-2)所示结构：
    Figure PCTCN2021112400-appb-100014
    其中，X 3选自-CH-和-N-；
    R 9各自独立地选自氢、氨基、卤素、氰基、羟基、-O-(C 1-6烷基)、-O-(C 3-6环烷基)、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 2-6烯基、-C 2-6炔基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基、-NH-C(＝O)-C 1-6烷基、-C(＝O)-NH 2、-C(＝O)-NH-C 1-6烷基；所述烷基、环烷基、杂环烷基、烯基、炔基、芳基、杂芳基各自任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)、-O-(3-6元杂环烷基)、C 2-6烯烃、C 2-6炔烃、羰基、C 3-6环烷基、3-6元杂环烷基的取代基取代；
    X 2选自-O-、-CH 2-、-N(R 8)-、-C(＝O)和
    Figure PCTCN2021112400-appb-100015
    环F为C 3-6环烷基；所述环烷基任选地被一个或多个选自羟基、卤素、氰基、氨基、-O-(C 1-6烷基)、-O-(卤代C 1-6烷基)和-O-(3-6元杂环烷基)的取代基取代；
    R 8选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-C 1-6亚烷基-C 3-6环烷基、-C 1-6亚烷基-(3-6元杂环烷基)、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-(3-6元杂环烷基)、-C(＝O)-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 3-6环烷基和-S(＝O) 2-(3-6元杂环烷基)；其中所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自羟基、卤素、氰基、氧代基、-O-(C 1-6烷基)、C 2-6烯烃和C 2-6炔烃取代基取代；
    z选自0、1、2或3；
    环D、U、V、W、L 1、R 1、R 5、R 5'、m、p和q如权利要求2所定义。
  14. 根据权利要求1至13任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，
    Figure PCTCN2021112400-appb-100016
    选自：
    Figure PCTCN2021112400-appb-100017
    其中，R 6和R 6'如权利要求6所定义。
  15. 化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，所述化合物选自：
    Figure PCTCN2021112400-appb-100018
    Figure PCTCN2021112400-appb-100019
    Figure PCTCN2021112400-appb-100020
    Figure PCTCN2021112400-appb-100021
    Figure PCTCN2021112400-appb-100022
    Figure PCTCN2021112400-appb-100023
    Figure PCTCN2021112400-appb-100024
    Figure PCTCN2021112400-appb-100025
    Figure PCTCN2021112400-appb-100026
  16. 根据权利要求1所述化合物的制备方法，其包括下列步骤：
    方法A：
    步骤1.使式S-1的化合物与式S-2的化合物发生缩合或者取代反应以生成式AM-1的化合物；
    Figure PCTCN2021112400-appb-100027
    步骤2.使式AM-1的化合物与式S-3的化合物发生偶联反应，随后进行脱保护和/或功能基团转化生成式(I)的化合物；
    Figure PCTCN2021112400-appb-100028
    或者，
    方法B：
    步骤1.使式S-1的化合物与式S-3的化合物发生偶联反应以生成式BM-1的化合物；
    Figure PCTCN2021112400-appb-100029
    步骤2.使式BM-1的化合物与式S-2的化合物发生取代或者偶联反应，随后进行脱保护和/或功能基团转化生成式(I)的化合物；
    Figure PCTCN2021112400-appb-100030
    其中，LG 1和LG 2各自独立地为离去基团，优选地为卤素或者任选地被卤素取代的C 1-6烷基磺酸酯基；
    X为硫或者单键；
    R x为H或离去基团；
    环A、环B、环C、L 1、R 1、R 2、R 3、R 4、m和n如权利要求1所定义。
  17. 一种药物组合物，其包含根据权利要求1至15中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，以及药学上可接受的载体。
  18. 根据权利要求1至15中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者根据权利要求17所述的药物组合物在制备用于预防和/或治疗SHP2磷酸酶相关疾病的药物中的用途；优选地，所述SHP2磷酸酶相关疾病为肿瘤类病症；优选地，所述SHP2磷酸酶相关疾病为癌症。
  19. 一种预防和/或治疗SHP2磷酸酶相关疾病的方法，其包括向有此需要的个体给药有效量的权利要求1至15中任一项所述的化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，或者权利要求17所述的药物组合物；优选地，所述SHP2磷酸酶相关疾病为肿瘤类病症；优选地，所述SHP2磷酸酶相关疾病为癌症。
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022235866A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2022235870A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors for the treatment of cancer
WO2022235864A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
WO2023169170A1 (zh) * 2022-03-10 2023-09-14 捷思英达控股有限公司 作为shp2抑制剂的杂环化合物、包括该杂环化合物的组合物、及其使用方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018013597A1 (en) * 2016-07-12 2018-01-18 Revolution Medicines, Inc. 2,5-disubstituted 3-methyl pyrazines and 2,5,6-trisubstituted 3-methyl pyrazines as allosteric shp2 inhibitors
WO2020061103A1 (en) * 2018-09-18 2020-03-26 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as src homology-2 phosphatase inhibitors
CN111153899A (zh) * 2018-11-08 2020-05-15 四川科伦博泰生物医药股份有限公司 一种取代吡啶化合物、其制备方法和用途
CN111484491A (zh) * 2019-01-25 2020-08-04 四川科伦博泰生物医药股份有限公司 取代吡啶并环化合物、其制备方法和用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018013597A1 (en) * 2016-07-12 2018-01-18 Revolution Medicines, Inc. 2,5-disubstituted 3-methyl pyrazines and 2,5,6-trisubstituted 3-methyl pyrazines as allosteric shp2 inhibitors
CN109983001A (zh) * 2016-07-12 2019-07-05 锐新医药公司 作为变构shp2抑制剂的2,5-双取代型3-甲基吡嗪及2,5,6-三取代型3-甲基吡嗪
WO2020061103A1 (en) * 2018-09-18 2020-03-26 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as src homology-2 phosphatase inhibitors
WO2020061101A1 (en) * 2018-09-18 2020-03-26 Nikang Therapeutics, Inc. Tri-substituted heteroaryl derivatives as src homology-2 phosphatase inhibitors
CN111153899A (zh) * 2018-11-08 2020-05-15 四川科伦博泰生物医药股份有限公司 一种取代吡啶化合物、其制备方法和用途
CN111484491A (zh) * 2019-01-25 2020-08-04 四川科伦博泰生物医药股份有限公司 取代吡啶并环化合物、其制备方法和用途

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022235866A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2022235870A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors for the treatment of cancer
WO2022235864A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
WO2023169170A1 (zh) * 2022-03-10 2023-09-14 捷思英达控股有限公司 作为shp2抑制剂的杂环化合物、包括该杂环化合物的组合物、及其使用方法

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