WO2024067675A1 - Fused ring kif18a inhibitor compound, pharmaceutical composition, and preparation method therefor and use thereof - Google Patents

Fused ring kif18a inhibitor compound, pharmaceutical composition, and preparation method therefor and use thereof Download PDF

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WO2024067675A1
WO2024067675A1 PCT/CN2023/121929 CN2023121929W WO2024067675A1 WO 2024067675 A1 WO2024067675 A1 WO 2024067675A1 CN 2023121929 W CN2023121929 W CN 2023121929W WO 2024067675 A1 WO2024067675 A1 WO 2024067675A1
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ring
alkyl
alkoxy
cyano
compound
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PCT/CN2023/121929
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French (fr)
Chinese (zh)
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陆标
杨方龙
张辰
王思勤
金磊
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长春金赛药业有限责任公司
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • patent application number 202211217025.8 filed with the State Intellectual Property Office of China on September 30, 2022, entitled “Fused-ring KIF18A inhibitor compounds, pharmaceutical compositions, preparation methods and applications thereof”;
  • patent application number 202211406766.0 filed with the State Intellectual Property Office of China on November 10, 2022, entitled “Fused-ring KIF18A inhibitor compounds, pharmaceutical compositions, preparation methods and applications thereof”;
  • the present invention belongs to the field of medicine, and specifically relates to a condensed-ring KIF18A inhibitor compound, a pharmaceutical composition, and a preparation method and application thereof.
  • Cancer is one of the most serious diseases affecting human health, with mortality and morbidity often ranking among the highest among all diseases.
  • quality of life of some patients has been greatly improved with the continuous development and progress of medical technology and drug research and development, there are still more unmet clinical needs in the search for effective treatment or cure drugs for different cancers, and more new targets will provide new possibilities for future cancer drug research and development.
  • Cancer cells experience unregulated cell proliferation due to damage or loss of one or more genes that regulate the cell cycle.
  • Various kinases and kinesins have been identified as playing key roles in cell cycle and mitosis regulation and progression in both normally dividing cells and cancer cells.
  • Kinesin molecules are motor proteins that use intracellular microtubules as tracks, also known as molecular motors, which can convert ATP energy into mechanical energy. In eukaryotic cells, they are closely related to cell mitosis and meiosis, the growth and development of tissues and organs, and the development and signal transduction of neurons. Kinesin members share a relatively conserved motor domain.
  • the kinesin family is roughly divided into three categories: N-type kinesin, that is, the amino (-NH 2 ) terminal region of the protein polypeptide chain has a motor domain; M-type kinesin, that is, the middle region has a motor domain; C-type kinesin, that is, the carboxyl (-COOH) terminal region has a motor domain.
  • Chromosomal instability is a hallmark of cancer and is caused by errors in chromosome segregation during mitosis.
  • Targeting chromosomal instability is an emerging therapeutic strategy in drug development.
  • KIF18A is a member of the N-type Kinesin-8 kinesin family and has been shown to play a role in maintaining the integrity of the bipolar spindle and promoting the viability of cancer cells with chromosomal instability.
  • Mitosis is an effective intervention point, and many anti-mitotic drugs are used in the clinical treatment of human cancers. The most widely used microtubule inhibitor, it can both stabilize microtubules and prevent microtubule assembly. Current anti-mitotic drugs have the limitation of a narrow therapeutic window, and these problems need to be addressed by the development of new targets.
  • tubulin inhibitors are widely used as standard treatments for a variety of human cancer types, these drugs have collateral damage to normal cells, including bone marrow suppression and neurotoxicity. Since KIF18A may not be essential in normal diploid somatic cells (KIF18A knockout mice are viable but have reproductive defects, indicating that KIF18A is not an essential gene for normal somatic cell division), targeting KIF18A may significantly reduce its toxicity, which is conducive to improving the therapeutic safety window of tubulin-targeted drugs in the clinic.
  • KIF18A protein is highly expressed in a variety of tumors, including colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer, and ovarian cancer.
  • KIF18A plays a key role in the occurrence, development, and metastasis of breast cancer, and its high expression indicates a poor prognosis in patients.
  • KIF18A is required for the proliferation of chromosomal instability cells derived from triple-negative breast cancer or colorectal cancer, but KIF18A is not required in diploid cells. Knockout of the KIF18A gene can cause infertility in male mice, but female mice are not affected.
  • KIF18A mRNA expression is significantly associated with higher tumor grade and larger tumors in breast cancer patients, and KIF18A is an independent predictor of lymph node metastasis in breast cancer, with a risk coefficient of 3.2.
  • inhibiting KIF18A expression not only affects the key function of KIF18A in cell mitosis, but also reduces cancer cell migration by stabilizing leading-edge microtubules, ultimately leading to the inactivation of the PI3K-AKT signaling pathway and inducing cell apoptosis.
  • KIF18A protein inhibitors may be a new breakthrough in cancer drugs.
  • the present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound:
  • A is selected from unsubstituted or optionally substituted by one, two or more Ra or a fused ring group 1;
  • the fused ring group 1 comprises two, three or four rings independently selected from a saturated or partially unsaturated C 3-14 carbocyclic ring, a C 6-14 aromatic ring, a 5-14 membered heteroaromatic ring, or a 3-14 membered heterocyclic ring;
  • each Ra is the same or different and is independently selected from H, OH, halogen, cyano, NH 2 , NO 2 , the following groups which are unsubstituted or optionally substituted by one, two or more Ra1 : C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl; or two Ras attached to the same ring carbon atom together with the carbon atom to which they are attached form a saturated or partially unsaturated C 3-14 carbocyclic ring; each Ra1 is the same or different and is independently selected from H, OH, hal
  • X1 , X2 , X3 are the same or different and are independently selected from N or CR0 ;
  • R0 is selected from H, halogen, cyano, C1-12 alkyl, halogenated C1-12 alkyl, cyano C1-12 alkyl, C1-12 alkoxy, halogenated C1-12 alkoxy, cyano C1-12 alkoxy;
  • R b is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R b : C 1-12 alkyl, halogenated C 1-12 alkyl, cyano C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, cyano C 1-12 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylthio, 3-14 membered heterocyclyl; each R b is the same or different and is independently selected from halogen, cyano, C 1-12 alkyl, halogenated C 1-12 alkyl, cyano C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, cyano C 1-12 alkoxy ;
  • Ring G is selected from a fused ring group 2 which is unsubstituted or optionally substituted by one, two or more Rgs , and the fused ring group 2 is formed by condensing ring G1 and ring G2 ;
  • ring G1 is selected from a C6-14 aromatic ring, a 5-14 membered heteroaromatic ring, and a 3-14 membered heterocyclic ring;
  • ring G2 is selected from a C3-14 carbocyclic ring, a C6-14 aromatic ring, a 5-14 membered heteroaromatic ring, and a 3-14 membered heterocyclic ring;
  • M and E are preferably attached to ring G1 ;
  • each Rg is the same or different and is independently selected from halogen, cyano, C1-12 alkyl, halogenated C1-12 alkyl, cyano C1-12 alkyl, C1-12 alkoxy, halogenated C1-12 alkoxy, and
  • Re1 , Re2 , Re3 , Re4 , Re5 , Re6 , and Re7 are the same or different and are independently selected from H, C1-12 alkyl, C1-12 alkoxy , hydroxyC1-12 alkyl, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, cyanoC1-12 alkyl, cyanoC1-12 alkoxy, C3-12 cycloalkyl, 3-14 membered heterocyclyl , and C1-12 alkoxy- C1-12 alkyl;
  • M is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R m : C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-14 membered heterocyclyl; each R m is the same or different and independently selected from halogen, cyano, C 1-12 alkyl, halo C 1-12 alkyl, cyano C 1-12 alkyl, C 1-12 alkoxy, cyano C 1-12 alkoxy.
  • A is selected from unsubstituted or optionally substituted with one, two or more Ra or a fused ring group 1;
  • the fused ring group 1 comprises two, three or four rings independently selected from a saturated or partially unsaturated C 3-8 carbocyclic ring, a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring, or a 3-8 membered heterocyclic ring;
  • each Ra is the same or different and independently selected from H, OH, halogen, cyano, NH 2 , NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, cyano C 1-6 alkyl, cyano C 1-6 alkoxy , or C 3-8 cycloalkyl -C 1-6 alkoxy; or, two Ras attached to the same ring carbon atom together with the carbon atom to which they are attached form
  • A is selected from
  • T is selected from CH 2 , CH, NH, NR a or O;
  • Z is selected from CH 2 , CH, NH, NR a or O;
  • X is selected from N or CH
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • p and q are independently selected from 0, 1, 2, and 3, and p and q are not 0 at the same time;
  • r and s are independently selected from 0, 1, 2, and 3, and r and s are not 0 at the same time.
  • X 1 and X 2 are the same or different and are independently selected from N or CR 0 .
  • X 1 and X 2 are the same or different and are independently selected from N or CH.
  • X 2 and X 3 are not N at the same time.
  • X3 when X1 and X2 are N, X3 is CR0 ; when X1 is N or CR0 and X2 is CR0 , X3 is N or CR0 ; when X1 is N or CR0 and X2 is N, X3 is CR0 ; R0 is selected from H, halogen, C1-6 alkyl;
  • X3 when X1 and X2 are N, X3 is CR0 ; when X1 is N or CH and X2 is CH, X3 is N or CR0 ; when X1 is CH and X2 is N, X3 is CR0 ; when X1 is N and X2 is CR0 , X3 is N; R0 is selected from H, C1-6 alkyl;
  • B is selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, 3-8 membered heterocyclyl, halogenated 3-8 membered heterocyclyl.
  • B is selected from a halogenated 6-membered N-containing heterocyclic group; for example, a halogenated piperidinyl group.
  • B is selected from
  • A is selected from unsubstituted or optionally substituted with one, two or more Ra Or a fused ring group 1;
  • the fused ring group 1 is composed of two, three, four or more rings selected from a benzene ring, a pyridine ring, an imidazole ring, a piperazine ring, a dihydropyridine ring, a tetrahydropyridine ring, a dihydropyrrole ring, a tetrahydropyrrole ring, a dihydropyran ring, a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, and a cycloheptene ring.
  • A is selected from the following groups which are unsubstituted or optionally substituted with one, two or more Ra :
  • each Ra is the same or different and is independently selected from H, OH, F, Cl, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclopropylmethoxy; or, two Ras attached to the same ring carbon atom together with the carbon atom to which they are attached form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, or a cycloheptane ring.
  • A is selected from
  • ring G is selected from a fused ring group 2 which is unsubstituted or optionally substituted by one, two or more R g , and the fused ring group 2 is formed by condensing ring G 1 and ring G 2 ;
  • ring G 1 is selected from a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring, and a 5-10 membered heterocyclic ring;
  • ring G 2 is selected from a C 3-10 carbocyclic ring, a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring, and a 3-10 membered heterocyclic ring;
  • ring G1 is selected from a cyclopentene ring, a cyclohexene ring, a dihydrofuran ring, a dihydropyran ring, an imidazole ring, a triazole ring, a benzene ring, a pyridine ring, a dihydropyridine ring, a pyrrole ring, a pyrazole ring, a furan ring, and a thiophene ring; preferably a benzene ring or a pyridine ring.
  • ring G2 is selected from a cyclopentene ring, a cyclohexene ring, a dihydrofuran ring, a dihydropyran ring, an imidazole ring, a triazole ring, a benzene ring, a pyridine ring, a pyrrole ring, a pyrazole ring, a furan ring, a thiophene ring, and a methylimidazole ring.
  • ring G is selected from
  • Re1 , Re2 , Re3 are the same or different and are independently selected from H, C1-6 alkyl, hydroxyC1-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxy, cyanoC1-6 alkyl, cyanoC1-6 alkoxy, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C1-6 alkoxy- C1-6 alkyl; each Re is the same or different and are independently selected from OH, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, cyanoC1-6 alkyl, cyanoC1-6 alk
  • E is selected from
  • M is selected from C 3-8 cycloalkyl, C 3-8 cycloalkenyl or nitrogen-containing 3-8 membered heterocyclyl which is unsubstituted or optionally substituted by one, two or more R m ; each R m is the same or different and is independently selected from H, halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy, cyano C 1-6 alkoxy; or, two R m connected to the same ring carbon atom together with the carbon atom to which they are connected form a saturated or partially unsaturated C 3-8 carbocyclic ring;
  • M is selected from unsubstituted or optionally substituted with one, two or more R m
  • the compound represented by formula (I) is selected from the following structures:
  • A, M, E, Ring G, Ring G 1 , and Ring G 2 are independently defined as described herein, Represents a carbon-carbon single bond or a carbon-carbon double bond.
  • the compound represented by formula (I) has the following structure:
  • B, M, E, ring G, X, Z, T, X 1 , X 2 , X 3 , Ra , n, p, q, r, and s are independently defined as described herein.
  • the compound represented by formula (I) has the following structure:
  • the compound represented by formula (I) has the following structure:
  • ring G 1 and ring G 2 are independently defined as described herein.
  • the compound represented by formula (I) has the following structure:
  • a and ring G2 independently have the definitions described herein.
  • the compound represented by formula (I) has the following structure:
  • the compound represented by formula (I) has the following structure:
  • ring G 2 , X 1 , X 2 , and X 3 are independently as defined herein.
  • the compound represented by formula (I) is selected from the following structures:
  • the present invention also provides a method for preparing the compound represented by formula (I), comprising the following steps:
  • A, E, M and ring G are independently defined as above; L is selected from halogen, such as Cl, Br, I; and Q is selected from halogen, such as F, Cl, Br.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • the present invention also provides a method for treating tumor diseases, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the compounds represented by formula (I), its racemates, stereoisomers, tautomers, isotope-labeled substances, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof.
  • the present invention also provides a method for treating tumor diseases, comprising administering to a patient an effective amount of the above-mentioned pharmaceutical composition for prevention or treatment.
  • the tumor diseases include colorectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer and ovarian cancer.
  • the patient comprises a mammal, preferably a human.
  • the present invention also provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or at least one of its prodrug compounds for treating tumor diseases, or a pharmaceutical composition thereof.
  • the present invention also provides the use of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof in the preparation of a drug.
  • the use may be use in preparing a medicament for treating KIF18A-mediated disorders and/or diseases, such as use in preparing a KIF18A inhibitor drug.
  • the disease is, for example, cancer, including colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.
  • the compound of the present invention has a good KIF18A inhibitory effect.
  • the compound can regulate KIF18A protein alone or by forming a binding complex with microtubules, so as to treat KIF18A-mediated disorders and/or diseases, such as tumor diseases, and to prepare drugs for such disorders or diseases.
  • the present invention creatively obtains a class of novel structural compounds through structural optimization, which not only have good KIF18A inhibitory effect and OVCAR-3 in vitro cell activity, but also have significantly improved physicochemical properties (solubility, permeability), and significantly improved OVCAR-3 in vivo efficacy.
  • FIG1 is a line graph showing the effects of compound 9 of the present invention on tumor volume and body weight of mice in an OVCAR-3 mouse xenograft tumor model.
  • the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein.
  • the numerical range "1-14" is equivalent to recording each integer value in the numerical range "1-14", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14.
  • C 1-12 alkyl is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms
  • C 1-8 alkyl means straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms
  • C 1-6 alkyl means straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.
  • C 3-12 cycloalkyl is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, preferably a "C 3-10 cycloalkyl", more preferably a "C 3-8 cycloalkyl".
  • C 3-12 cycloalkyl is understood to mean a saturated monovalent monocyclic, bicyclic (such as bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
  • the C 3-12 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group, such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonanyl, 2,6-diaza
  • C 3-12 cycloalkenyl is understood to mean a monovalent monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic olefin containing a carbon-carbon double bond, which has 3 to 12 carbon atoms, preferably a "C 3-10 cycloalkenyl", more preferably a "C 3-8 cycloalkenyl", which may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
  • the C 3-12 cycloalkenyl may be a monocyclic hydrocarbon group, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, or a bicyclic hydrocarbon group such as spiro[2.5]oct-5-enyl, spiro[3.5]non-6-enyl, spiro[4.5]dec-7-enyl.
  • C 6-14 aryl is understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a single aromatic ring or multiple aromatic rings condensed together, preferably "C 6-10 aryl”.
  • C 6-14 aryl is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring (“C 6-14 aryl") having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6-20 aryl When the C 6-20 aryl is substituted, it may be mono
  • 5-14 membered heteroaryl is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-10 membered heteroaryl".
  • heteroaryl is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, furthermore, may be benzo-fused.
  • Heteroaryl also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring.
  • Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3- , 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnoliny
  • Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
  • the 5-14 membered heteroaryl group When the 5-14 membered heteroaryl group is connected to other groups to form the compound of the present invention, it can be a carbon atom on the 5-14 membered heteroaryl ring connected to other groups, or it can be a heteroatom on the 5-14 membered heteroaryl ring connected to other groups.
  • the 5-14 membered heteroaryl group When the 5-14 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted.
  • substitution site for example, a hydrogen atom connected to a carbon atom on a heteroaryl ring may be substituted, or a hydrogen atom connected to a heteroatom on a heteroaryl ring may be substituted.
  • 3-14 membered heterocyclyl refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) 2 -.
  • the heterocyclyl may be selected from "3-10 membered heterocyclyl".
  • the term "3-10 membered heterocyclyl” means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N.
  • the heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present).
  • the heterocyclic group can include fused or bridged rings and spirocyclic rings.
  • the heterocyclic group can include, but is not limited to: 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl.
  • the heterocyclic group can be benzo-fused.
  • the heterocyclic group can be bicyclic, such as, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta [c] pyrrole -2 (1H) -yl ring, or 5,6-membered bicyclic rings, such as hexahydropyrrolo [1,2-a] pyrazine -2 (1H) -yl ring.
  • the heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.
  • the carbon atom on the 3-14 membered heterocyclic group may be connected with other groups, or the heterocyclic atom on the 3-14 membered heterocyclic group may be connected with other groups.
  • the 3-14 membered heterocyclic group is selected from piperazinyl
  • the nitrogen atom on the piperazinyl may be connected with other groups.
  • the 3-14 membered heterocyclic group is selected from piperidinyl
  • the nitrogen atom on the piperidinyl ring and the carbon atom on the para position thereof may be connected with other groups.
  • spirocyclic refers to a ring system in which two rings share one ring-forming atom.
  • fused ring refers to a ring system in which two rings share two ring atoms.
  • bridged ring refers to a ring system in which two rings share three or more ring atoms.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • Halo means substituted with one or more halogens.
  • connection site 1 When ring G is selected from When the substituent is substituted with , it has three connection sites. Generally speaking, the three connection sites can be connected to A, M, and E in the general structure respectively. For example, the connection position 1 is connected to A, the connection position 2 is connected to M, and the connection position 3 is connected to E.
  • the same explanation as above shall apply.
  • Ra when A is selected from unsubstituted or optionally substituted with one, two or more Ra
  • X 1 can be located at any position on the ring where X 1 is located.
  • Ra when X 1 is CH, Ra can replace the H on X 1 to form CR a .
  • the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form a base addition salt; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form an inner salt.
  • an acidic center e.g., a carboxyl group
  • a basic center e.g., an amino group
  • the compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • the amount of the polar solvent, in particular water may be present in a stoichiometric or non-stoichiometric ratio.
  • the compounds of the present invention may be chiral, and therefore various enantiomeric forms may exist. Thus, these compounds may exist in racemic form or optically active form.
  • the compounds of the present invention encompass isomers or mixtures, racemates in which each chiral carbon is in R or S configuration.
  • the compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolution agent.
  • suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in R and S forms.
  • Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel.
  • Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane/isopropanol/acetonitrile.
  • the corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.
  • terapéuticaally effective amount refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition.
  • Preventing disease e.g., preventing a disease,
  • McLaughlin's acid (compound 1-3) (4947.77 mg, 34.329 mmol, 1 eq) was added to a solution of 2-bromo-4-fluoro-5-methoxybenzaldehyde (8 g, 34.329 mmol, 1 eq) in formic acid (10 mL) at room temperature, followed by dropwise addition of triethylamine (14.32 mL, 102.987 mmol, 3 eq). The reaction solution was heated to 100 °C and stirred for 10 hours.
  • trifluoromethanesulfonic acid (3.19 mL, 36.090 mmol, 5 eq) was added dropwise to a solution of 3-(2-bromo-4-fluoro-5-methoxyphenyl)propanoic acid (2.0 g, 7.218 mmol, 1 eq) in 1,2-dichloroethane (12 mL) at room temperature.
  • the reaction solution was heated to 80°C and microwaved for 1 hour.
  • the reaction mixture was quenched with water at room temperature, extracted with dichloromethane (3 ⁇ 60 mL), and the organic phases were combined, backwashed with saturated brine (1 ⁇ 60 mL), and dried over anhydrous sodium sulfate.
  • triethylsilane (3.74 mL, 23.160 mmol, 3 eq) was added to a solution of 4-bromo-6-fluoro-7-methoxy-2,3-dihydroindene-1-one (2 g, 7.720 mmol, 1 eq) in trifluoroacetic acid (8.80 mL) at 0 ° C.
  • the reaction mixture was then heated and stirred at 50 ° C for 16 hours, and the reaction system was monitored by thin layer chromatography.
  • the reaction mixture was quenched with water at room temperature.
  • the reaction mixture was extracted with ethyl acetate (3 ⁇ 60 mL).
  • reaction solution was heated to 80°C and carbon monoxide was introduced for 1 hour.
  • the reaction mixture was quenched with water at room temperature and extracted with ethyl acetate (3 ⁇ 10 mL).
  • the organic phases were combined, backwashed with saturated brine (1 ⁇ 10 mL), and dried over anhydrous sodium sulfate.
  • the resulting mixture was filtered and the filtrate was concentrated under reduced pressure.
  • the resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (10:1) to give methyl 7-bromo-5-fluoro-2,3-dihydro-1H-indene-4-carboxylate (400 mg, 44.32%).
  • Lithium hydroxide (131.54 mg, 5.493 mmol, 3 eq) was added to a solution of 7-bromo-5-fluoro-2,3-dihydro-1H-indene-4-carboxylic acid methyl ester (500 mg, 1.831 mmol, 1 eq) in tetrahydrofuran/water (4 mL, 3/1, v/v) at room temperature.
  • the reaction mixture was stirred at room temperature for 16 hours, and the reaction mixture was diluted with water at room temperature and acidified to pH 5-6 with 1 mol/L hydrochloric acid solution.
  • the reaction mixture was extracted with ethyl acetate (3 ⁇ 30 mL).
  • reaction solution was cooled to room temperature and quenched with water.
  • the reaction mixture was extracted with ethyl acetate (3 ⁇ 30 mL). The organic phases were combined, backwashed with saturated brine (1 ⁇ 30 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure.
  • the reaction solution was heated to 100 ° C and heated for 1 hour.
  • the reaction solution was cooled to room temperature and the reaction mixture was quenched with water at room temperature.
  • the reaction mixture was extracted with ethyl acetate (3 ⁇ 10 mL).
  • the organic phases were combined, backwashed with saturated brine (1 ⁇ 10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by high-performance liquid chromatography under the following conditions (chromatographic column specifications: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL/min; elution gradient: 48% B to 80% B, 80% B within 8 min; detection wavelength: UV 220 nm; retention time (minutes): 7.88). Compound 1 (21.93 mg, 44.81%) was obtained.
  • the first step is the synthesis of 7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-5-fluoro-2,3-dihydro-1H-indene-4-carboxamide (compound 9-2):
  • N-methylimidazole (475.38 mg, 5.790 mmol, 10 eq) was added to a solution of 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine (197.37 mg, 0.868 mmol, 1.5 eq), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (649.81 mg, 2.316 mmol, 4 eq) and 7-bromo-5-fluoro-2,3-dihydro-1H-indene-4-carboxylic acid (150 mg, 0.579 mmol, 1.00 eq) in dichloromethane (7.5 mL) at room temperature.
  • reaction solution was heated to 60°C and stirred for 1 hour.
  • the reaction solution was cooled to room temperature and extracted with dichloromethane (3 ⁇ 50 mL).
  • the organic phases were combined, backwashed with saturated brine (1 ⁇ 50 mL), and dried over anhydrous sodium sulfate.
  • the resulting mixture was filtered and the filtrate was concentrated under reduced pressure.
  • reaction solution was cooled to room temperature and extracted with ethyl acetate (3 ⁇ 50 mL). The organic phases were combined, backwashed with saturated brine (3 ⁇ 50 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure.
  • reaction solution was heated to 100°C and stirred for 1 hour.
  • the reaction solution was cooled to room temperature and extracted with ethyl acetate (3 ⁇ 10 mL).
  • the organic phases were combined, backwashed with saturated brine (1 ⁇ 10 mL), and dried over anhydrous sodium sulfate.
  • the resulting mixture was filtered and the filtrate was concentrated under reduced pressure.
  • the crude product was purified by preparative high performance liquid phase to obtain 5- ⁇ 6-azaspiro[2.5]octan-6-yl ⁇ -N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (8.8 mg, 17.98%).
  • reaction solution was cooled to room temperature and extracted with ethyl acetate (3 ⁇ 10 mL). The organic phases were combined, backwashed with saturated brine (1 ⁇ 10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (3:1) to give 5-(6-azaspiro[2.5]octan-6-yl)-7-bromo-2,3-dihydro-1H-indene-4-carboxylic acid (30 mg, 53.11%).
  • 6-(4,4-difluoropiperidin-1-yl)pyridin-2-amine (9.13 mg, 0.044 mmol, 1.5 eq), tetramethyl chlorouronium hexafluorophosphate (64.09 mg, 0.228 mmol, 4 eq), and N-methylimidazole (46.88 mg, 0.570 mmol, 10 eq) were added to a solution of 5-(6-azaspiro[2.5]octan-6-yl)-7-bromo-2,3-dihydro-1H-indene-4-carboxylic acid (20 mg, 0.057 mmol, 1 eq) in dichloromethane (1 mL) at room temperature.
  • the reaction solution was heated to 80°C for 1 hour.
  • the reaction solution was cooled to room temperature and extracted with dichloromethane (3 ⁇ 10 mL).
  • the organic phases were combined, backwashed with saturated brine (1 ⁇ 10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure.
  • reaction solution was heated to 100°C and stirred for 1 hour.
  • the reaction solution was cooled to room temperature and extracted with ethyl acetate (3 ⁇ 10mL).
  • the organic phases were combined, backwashed with saturated brine (1 ⁇ 10mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by high-performance liquid chromatography under the following conditions (chromatographic column kinete 5 ⁇ m EVO C18, 30mm*150mm, mobile phase A: water (10mm ol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60mL/min, elution gradient: 40% B to 75% B in 8min; 254nm; Rt: 6.9min), to obtain 5-(6-azaspiro[2.5]octan-6-yl)-N-[6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (2.79mg, 10.29%).
  • N,N,N,N-tetramethylchloroformamidine hexafluorophosphate 80.11 mg, 0.284 mmol, 4 eq
  • N-methylimidazole 58.60 mg, 0.710 mmol, 10 eq
  • 5- ⁇ 6-azaspiro[2.5]octan-6-yl ⁇ -7-bromo-2,3-dihydro-1H-indene-4-carboxylic acid 25 mg, 0.071 mmol, 1 eq
  • 6-(4,4-difluoropiperidin-1-yl)pyrazin-2-amine 18.35 mg, 0.085 mmol, 1.2 eq
  • dichloromethane 5 mL
  • reaction solution was heated to 80°C and stirred for 1 hour.
  • the reaction solution was cooled to room temperature and extracted with ethyl acetate (3 ⁇ 5 mL).
  • the organic phases were combined, backwashed with saturated brine (1 ⁇ 10 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure.
  • reaction solution was cooled to room temperature and extracted with ethyl acetate (3 ⁇ 5mL). The organic phases were combined, backwashed with saturated sodium chloride solution (2 ⁇ 5mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure.
  • the first step is the synthesis of 5-(6-azaspiro[2.5]octane-6-yl)-7-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-4-yl]-2,3-dihydro-1H-indene-4-carboxamide (compound 27-2):
  • N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate 80.11 mg, 0.284 mmol, 4 eq
  • 1-methylimidazole 58.60 mg, 0.710 mmol, 10 eq
  • 5-(6-azaspiro[2.5]octan-6-yl)-7-bromo-2,3-dihydro-1H-indene-4-carboxylic acid 25 mg, 0.071 mmol, 1 eq
  • 2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-4-amine 18.15 mg, 0.078 mmol, 1.1 eq) in dichloromethane (2 mL) at room temperature.
  • the mixture was heated to 60°C and stirred for 1 hour.
  • the reaction mixture was diluted with water (10 mL). Extracted with dichloromethane (3 ⁇ 10 mL). The organic phases were combined, backwashed with saturated brine (1 ⁇ 10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure.
  • bicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine 5.69 mg, 0.011 mmol, 0.2eq
  • (methanesulfonic acid ⁇ bicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine ⁇ (2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) (4.89 mg, 0.005 mmol, 0.1eq) were added.
  • the crude product was purified by high-performance liquid chromatography under the following conditions: Chromatography column specifications: XBridge BEH Shield RP18 5 ⁇ m, 30mm*150mm; Mobile phase A: water (10mm ol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL/min; elution gradient: 50% B to 75% B in 8min; 254nm; Rt: 6.9min.
  • the first step is the synthesis of 5- ⁇ 6-azaspiro[2.5]octane-6-yl ⁇ -7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (compound 28-2):
  • 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-amine 23.77 mg, 0.103 mmol, 1.2 eq
  • tetramethylchloroformamidine hexafluorophosphate 96.13 mg, 0.344 mmol, 4 eq
  • N-methylimidazole 70.33 mg, 0.860 mmol, 10 eq
  • reaction solution was cooled to room temperature and extracted with ethyl acetate (3 ⁇ 20 mL). The organic phases were combined, backwashed with saturated brine (1 ⁇ 20 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure.
  • reaction solution was heated to 100°C and stirred for 1 hour.
  • the reaction solution was cooled to room temperature, extracted with ethyl acetate (3 ⁇ 10mL), the organic phases were combined, backwashed with saturated brine (2 ⁇ 10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Phase B acetonitrile; flow rate: 60 mL/min; elution gradient: 60% B to 85% B in 8 min, detection wavelength: 220 nm; retention time (min): 7.8.
  • reaction solution was cooled to room temperature, quenched with water, and the reaction mixture was extracted with ethyl acetate (3 ⁇ 80 mL). The organic phases were combined, backwashed with saturated brine (2 ⁇ 80 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (3:1) to obtain methyl 5,7-dichloroimidazo[1,2-a]pyridine-8-carboxylate (1.5 g, 67.65%)
  • Lithium hydroxide (199.37 mg, 8.325 mmol, 3 eq) was added to a mixed solution of 5,7-dichloroimidazo[1,2-a]pyridine-8-carboxylic acid methyl ester (680 mg, 2.775 mmol, 1 eq) in water (5 mL) and tetrahydrofuran (5 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours.
  • the reaction mixture was acidified to pH 6 with 1N hydrochloric acid solution.
  • the resulting mixture was concentrated to give crude 5,7-dichloroimidazo[1,2-a]pyridine-8-carboxylic acid (1.2 g).
  • 6-(4,4-difluoropiperidin-1-yl)-4-methylpyrimidin-2-amine (944.33 mg, 4.156 mmol, 1.2 eq)
  • N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate 3886.32 mg, 13.852 mmol, 4 eq
  • N-methylimidazole 2843.13 mg, 34.630 mmol, 10 eq
  • 6-azaspiro[2.5]octane 34.99 mg, 0.315 mmol, 1.5 eq
  • triethylamine 63.69 mg, 0.630 mmol, 3 eq
  • ethyl 2-[(7-chloro-8- ⁇ [2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]carbamoyl ⁇ imidazo[1,2-a]pyridin-5-yl)sulfamoyl]ethyl acetate 120 mg, 0.210 mmol, 1 eq
  • reaction solution was heated to 100°C and stirred for 2 days.
  • the reaction solution was cooled to room temperature and the reaction mixture was extracted with ethyl acetate (3 ⁇ 20 mL). The organic phases were combined, backwashed with saturated brine (2 ⁇ 20 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure.
  • lithium aluminum hydride (5.28 mg, 0.140 mmol, 1.5 eq) was added to a solution of ethyl 2-[(7- ⁇ 6-azaspiro[2.5]octane-6-yl ⁇ -8- ⁇ [2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]carbamoyl ⁇ imidazo[1,2-a]pyridin-5-yl]sulfamoyl]ethyl ester (60 mg, 0.093 mmol, 1 eq) in tetrahydrofuran (3.00 mL) at 0°C and the reaction was stirred at room temperature for 30 minutes.
  • the reaction solution was quenched with sodium sulfate decahydrate at 0°C. Filter and concentrate under reduced pressure.
  • the crude product was purified by HPLC under the following conditions (chromatography column specifications: XBridge BEH Shield RP18 5 ⁇ m, 30mm*150mm; mobile phase A: water (10mmol/L sodium bicarbonate), mobile phase B: acetonitrile; flow rate: 60ml/min; elution gradient: 40%B to 60%B in 10min; detection wavelength: 254nm/220nm; retention time (min): 8.33).
  • triethylamine (740.29 mg, 7.317 mmol, 3 eq) was added to a solution of 5,7-dichloro-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester (600 mg, 2.439 mmol, 1 eq) in tert-butanol (6 mL) at room temperature.
  • 3,4-dimethoxybenzylamine (16.31 mg, 0.097 mmol, 1.2 eq) was added dropwise at room temperature. The mixture was heated to 60°C and stirred for 2 hours. The reaction solution was cooled to room temperature.
  • lithium hydroxide 114.41 mg, 4.776 mmol, 3 eq
  • a solution of 7-chloro-5- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester 600 mg, 1.592 mmol, 1 eq
  • methanol 2 mL
  • tetrahydrofuran (2 mL
  • water 2 mL
  • the temperature was raised to 60°C and stirred for 1 hour.
  • the reaction mixture was acidified with 1N hydrochloric acid solution to a pH of 4. A white solid precipitated, which was filtered and the filter cake was collected to obtain 1 g of crude product.
  • N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate 1.5 g, 5.512 mmol, 4 eq
  • N-methylimidazole 1.1 g, 13.780 mmol, 10 eq
  • 7-chloro-5- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid 500 mg, 1.378 mmol, 1 eq
  • 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine 375.87 mg, 1.654 mmol, 1.2 eq
  • the obtained residue was purified by silica gel column chromatography, petroleum ether/ethyl acetate (3:1) to obtain 7-chloro-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-5- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (500 mg, 60.25%).
  • 6-azaspiro[2.5]octane hydrochloride (309.75 mg, 2.098 mmol, 2 eq) was added in batches to a solution of 7-chloro-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-5- ⁇ [(2,4-dimethoxyphenyl)methyl]amino ⁇ -[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (600 mg, 1.049 mmol, 1 eq) and triethylamine (318.43 mg, 3.147 mmol, 3 eq) in tert-butanol (10 mL) at room temperature.
  • Step 8 Synthesis of ethyl 2-[(7- ⁇ 6-azaspiro[2.5]octane-6-yl ⁇ -8- ⁇ [6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]carbamoyl ⁇ -[1,2,4]triazolo[1,5-a]pyridin-5-yl)sulfamoyl]acetate (Compound 30-11):
  • nitric acid (1.25 mL) was added to a sulfuric acid solution (17 mL) of methyl 4-bromo-2,6-difluorobenzoate (5 g, 20 mmol, 1 eq) at room temperature, and the reaction solution was stirred at room temperature for 1 hour.
  • the reaction mixture was quenched with water at room temperature, extracted with dichloromethane (3 ⁇ 100 mL), the organic phases were combined, backwashed with saturated brine (2 ⁇ 120 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product of methyl 4-bromo-2,6-difluoro-3-nitrobenzoate (6.01 g) was obtained.
  • methylamine (472 mg, 15 mmol, 1.5 eq) was added to a methanol solution (30 mL) of methyl 4-bromo-2,6-difluoro-3-nitrobenzoate (3 g, 10 mmol, 1 eq) at room temperature, and the reaction solution was stirred at 60°C for 16 hours.
  • the reaction solution was cooled to room temperature, quenched with water, and extracted with ethyl acetate (3 ⁇ 80 mL). The organic phases were combined and backwashed with saturated brine (2 ⁇ 80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • 6-azaspiro[2.5]octane hydrochloride (217 mg, 2 mmol, 1.2 eq) and triethylamine (824 mg, 8 mmol, 5 eq) were added to a solution of 4-bromo-6-fluoro-2-methylamino-3-nitrobenzoic acid methyl ester (500 mg, 1.6 mmol, 1 eq) in tert-butyl alcohol (15 mL) at room temperature, and the reaction solution was heated to 100°C and stirred for 16 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate (3 ⁇ 30 mL).
  • lithium hydroxide (31.7 g, 1.3 mmol, 5 eq), distilled water (2 mL) and methanol (2 mL) were added to a tetrahydrofuran solution (2 mL) of 5- ⁇ 6-azaspiro[2.5]octan-6-yl ⁇ -7-bromo-3-methyl-1,3-benzodiazole-4-carboxylic acid methyl ester (100 mg, 0.3 mmol, 1 eq) at room temperature, and the reaction solution was heated to 60°C and stirred for 72 hours.
  • reaction solution was extracted with ethyl acetate (2 ⁇ 10 mL), the aqueous phase was collected, the pH was adjusted to 6 with 1M dilute hydrochloric acid, extracted with ethyl acetate (2 ⁇ 10 mL), the organic phases were combined, backwashed with saturated brine (2 ⁇ 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5- ⁇ 6-azaspiro[2.5]octan-6-yl ⁇ -7-bromo-3-methyl-1,3-benzodiazole-4-carboxylic acid (101 mg, 105%).
  • 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine (112 mg, 0.5 mmol, 3 eq), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (185 mg, 0.7 mmol, 4 eq), and N-methylimidazole (135 mg, 1.7 mmol, 10 eq) were added to a dichloromethane solution (4 mL) of 5- ⁇ 6-azaspiro[2.5]octan-6-yl ⁇ -7-bromo-3-methyl-1,3-benzodiazole-4-carboxylic acid (60 mg, 0.16 mmol, 1 eq) at room temperature, and the reaction solution was heated to 60°C and stirred for 1 hour.
  • reaction solution was cooled to room temperature, extracted with ethyl acetate (3 ⁇ 10 mL), and the organic phases were combined, backwashed with saturated brine (2 ⁇ 10 mL), and dried over anhydrous sodium sulfate.
  • the product was filtered and the filtrate was concentrated under reduced pressure.
  • NCA Imaging-based Nuclear Count Analysis
  • the final tested concentrations of AM-5308 were: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, and 0.5 nM.
  • test concentrations of the test compounds were: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, and 0.5 nM.
  • the cells were cultured in a 37°C, 5% CO 2 incubator for 4 days.
  • Inhibition rate (%) 100-(compound well reading value-low reading control well reading value)/(high reading control well reading value-low reading control well reading value)*100
  • High reading control well cells plus 30nL DMSO; low reading control well: 10 ⁇ M AM-5308.
  • GraphPad Prism 8 software was used to calculate IC 50 (nM) and plot the effect-dose curve of the compound.
  • Signal Ave_PC The average value of the positive control on the reaction plate.
  • Signal Ave_VC The average value of negative control on the reaction plate.
  • IC50 values of the compounds were obtained using GraphPad 8.0 using a nonlinear fitting formula.
  • OVCAR-3 cells (ATCC) were selected for the experiment. 0.1 mL of approximately 5 ⁇ 10 6 OVCAR-3 cells were injected subcutaneously on the right side of female nude mice. According to the tumor volume (average tumor volume was 150 mm 3 ), the animals were randomly divided into 6 groups (vehicle group, compound 9 was divided into three dose groups of 10, 20 or 30 mg/kg, and AMG650 was divided into two dose groups of 15 or 30 mg/kg), with 10 animals in each group, and oral administration once a day starting from the 28th day after tumor inoculation. The tumor volume was measured using an electronic vernier caliper (Chengdu Sanhe Measuring Instrument Co., Ltd.). The tumor volume and animal body weight were measured twice a week (28th day from the start of the study and 46th day from the end of the study), and the tumor growth inhibition rate of the compound was calculated.
  • the formula for calculating tumor volume is: 1/2 ⁇ a ⁇ b 2 , where a and b are the measured length and width of the tumor, respectively.
  • the calculation formula of tumor inhibition rate %TGI was: 1-(TV Tn -TV T0 )/(TV Cn -TV C0 ) ⁇ 100%, TVC was the average tumor volume of the negative control group, and TVT was the average tumor volume of the treatment group.
  • TGIs of the 10, 20, and 30 mg/kg dose groups of compound 9 were 47.35%, 106.60%, and 115.58%, respectively; the TGIs of AMG650 15 and 30 mg/kg were 72.58% and 113.15%, respectively. All dose groups of compound 9 had no significant effect on the changes in animal body weight relative to the vehicle group, and no obvious toxicity was observed.
  • compound 9 in the present invention can induce tumor regression in female nude mouse xenograft tumor models caused by human high serous ovarian cancer OVCAR-3 cells (TP53 mutation, CCNE1 amplification).
  • Compound 9 at doses of 20 and 30 mg/kg can significantly inhibit tumor growth in the subcutaneous transplant tumor model of OVCAR-3 mice, and the inhibitory effect of compound 9 at a dose of 20 mg/kg on subcutaneous transplant tumors in mice is comparable to that of AMG650 30 mg/kg.
  • the tumor-to-blood ratio (ratio of tumor tissue exposure to plasma exposure) of compound 9 is better than that of AMG650, indicating that a higher proportion of the drug enters the tumor tissue to exert its effect.
  • the lower absolute exposure of compound 9 can reduce the potential cumulative toxicity of the drug.

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Abstract

The present invention provides a compound represented by formula (I), a pharmaceutical composition, and a preparation method therefor and use thereof. The compound has a good inhibitory effect on KIF18A, and can be used alone or in a binding complex with a microtubule to regulate the KIF18A protein for the treatment of KIF18A-mediated disorders and/or diseases, such as tumor diseases, and for the preparation of a drug used for such disorders or diseases.

Description

稠环类KIF18A抑制剂化合物、药物组合物及其制备方法和应用Condensed ring KIF18A inhibitor compound, pharmaceutical composition, preparation method and application thereof
本发明要求享有：The present invention claims:
于2022年9月30日向中国国家知识产权局提交的，专利申请号为202211217025.8，名称为“稠环类KIF18A抑制剂化合物、药物组合物及其制备方法和应用”的在先申请的优先权；Priority to the prior application, patent application number 202211217025.8, filed with the State Intellectual Property Office of China on September 30, 2022, entitled “Fused-ring KIF18A inhibitor compounds, pharmaceutical compositions, preparation methods and applications thereof”;
于2022年11月10日向中国国家知识产权局提交的，专利申请号为202211406766.0，名称为“稠环类KIF18A抑制剂化合物、药物组合物及其制备方法和应用”的在先申请的优先权；Priority to the prior application, patent application number 202211406766.0, filed with the State Intellectual Property Office of China on November 10, 2022, entitled “Fused-ring KIF18A inhibitor compounds, pharmaceutical compositions, preparation methods and applications thereof”;
于2023年2月16日向中国国家知识产权局提交的，专利申请号为202310125351.4，名称为“稠环类KIF18A抑制剂化合物、药物组合物及其制备方法和应用”的在先申请的优先权；Priority to the prior application, patent application number 202310125351.4, filed with the State Intellectual Property Office of China on February 16, 2023, entitled “Fused-ring KIF18A inhibitor compounds, pharmaceutical compositions, preparation methods and uses thereof”;
于2023年9月20日向中国国家知识产权局提交的，专利申请号为202311219723.6，名称为“稠环类KIF18A抑制剂化合物、药物组合物及其制备方法和应用”的在先申请的优先权；Priority to the prior application, patent application number 202311219723.6, filed with the State Intellectual Property Office of China on September 20, 2023, entitled “Fused-ring KIF18A inhibitor compounds, pharmaceutical compositions, preparation methods and uses thereof”;
所述在先申请的全文通过引用的方式结合于本发明中。The entire content of said prior application is incorporated herein by reference.
技术领域Technical Field
本发明属于医药领域，具体涉及一种稠环类KIF18A抑制剂化合物、药物组合物及其制备方法和应用。The present invention belongs to the field of medicine, and specifically relates to a condensed-ring KIF18A inhibitor compound, a pharmaceutical composition, and a preparation method and application thereof.
背景技术Background technique
癌症是影响人类健康的最严重的疾病之一，死亡率和发病率常居各种疾病前列。虽然随着医疗技术和药物研发的不断发展和进步，部分患者的生活质量得到了极大的改善，但是在寻求针对不同癌症的有效治疗或治愈的药物的路途中，还有更多的未被满足的临床需求，而更多的新靶点将为未来癌症药物研发提供新的可能。Cancer is one of the most serious diseases affecting human health, with mortality and morbidity often ranking among the highest among all diseases. Although the quality of life of some patients has been greatly improved with the continuous development and progress of medical technology and drug research and development, there are still more unmet clinical needs in the search for effective treatment or cure drugs for different cancers, and more new targets will provide new possibilities for future cancer drug research and development.
由于调控细胞周期的一个或多个基因的损伤或缺失，导致癌细胞出现不受调节的细胞增殖。各种激酶和驱动蛋白已经被鉴定在正常分裂的细胞和癌细胞的细胞周期和有丝分裂调节和进展中起关键作用。Cancer cells experience unregulated cell proliferation due to damage or loss of one or more genes that regulate the cell cycle. Various kinases and kinesins have been identified as playing key roles in cell cycle and mitosis regulation and progression in both normally dividing cells and cancer cells.
驱动蛋白分子是以细胞内微管为轨道的动力蛋白，也称为分子马达，可以将ATP能转变为机械能，在真核细胞与细胞有丝分裂及减数分裂、组织器官的生长发育以及神经元的发育及信号传导等密切相关。驱动蛋白成员共享一个相对保守的马达结构域。根据分子中马达结构域的位置，驱动蛋白家族大致分为三类：N型驱动蛋白，即蛋白质多肽链的氨基(-NH2)末端区域具有一个马达结构域；M型驱动蛋白，即中间区域具有一个马达结构域；C型驱动蛋白，即羧基(-COOH)末端区域具有一个马达结构域。Kinesin molecules are motor proteins that use intracellular microtubules as tracks, also known as molecular motors, which can convert ATP energy into mechanical energy. In eukaryotic cells, they are closely related to cell mitosis and meiosis, the growth and development of tissues and organs, and the development and signal transduction of neurons. Kinesin members share a relatively conserved motor domain. According to the location of the motor domain in the molecule, the kinesin family is roughly divided into three categories: N-type kinesin, that is, the amino (-NH 2 ) terminal region of the protein polypeptide chain has a motor domain; M-type kinesin, that is, the middle region has a motor domain; C-type kinesin, that is, the carboxyl (-COOH) terminal region has a motor domain.
染色体不稳定性是癌症的一个标志，由有丝分裂期间的染色体分离错误导致。靶向染色体不稳定性是药物开发中一种新兴的治疗策略。KIF18A是N型Kinesin-8驱动蛋白家族中的一员，已被证明在维持双极纺锤体的完整性和促进染色体不稳定性癌细胞的生存能力方面发挥作用。有丝分裂是一个有效的干预点，许多抗有丝分裂药物被用于临床治疗人类癌症。应用最广泛的微管蛋白抑制剂，它既可以稳定微管，也可以防止微管组装。目前抗有丝分裂的药物存在治疗窗较窄的局限性，这些问题需要开发新的靶点来解决。Chromosomal instability is a hallmark of cancer and is caused by errors in chromosome segregation during mitosis. Targeting chromosomal instability is an emerging therapeutic strategy in drug development. KIF18A is a member of the N-type Kinesin-8 kinesin family and has been shown to play a role in maintaining the integrity of the bipolar spindle and promoting the viability of cancer cells with chromosomal instability. Mitosis is an effective intervention point, and many anti-mitotic drugs are used in the clinical treatment of human cancers. The most widely used microtubule inhibitor, it can both stabilize microtubules and prevent microtubule assembly. Current anti-mitotic drugs have the limitation of a narrow therapeutic window, and these problems need to be addressed by the development of new targets.
尽管微管蛋白抑制剂被广泛用作治疗多种人类癌症类型的标准治疗方法，但这些药物存在对正常细胞的附带损伤，包括骨髓抑制和神经毒性。由于KIF18A在正常二倍体体细胞中可能不是必须的(KIF18A基因敲除小鼠是可存活的，但在生殖方面存在缺陷，这表明KIF18A不是正常体细胞分裂的必要基因)，因此靶向KIF18A有可能会显著降低其毒性，有利于提升临床中靶向微管蛋白药物的治疗安全窗。Although tubulin inhibitors are widely used as standard treatments for a variety of human cancer types, these drugs have collateral damage to normal cells, including bone marrow suppression and neurotoxicity. Since KIF18A may not be essential in normal diploid somatic cells (KIF18A knockout mice are viable but have reproductive defects, indicating that KIF18A is not an essential gene for normal somatic cell division), targeting KIF18A may significantly reduce its toxicity, which is conducive to improving the therapeutic safety window of tubulin-targeted drugs in the clinic.
KIF18A蛋白在多种肿瘤中均有高表达，包括结肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、膀胱癌、头颈部癌、宫颈癌和卵巢癌。KIF18A在乳腺癌发生、发展和转移过程中起关键作用，其高表达预示患者不良预后。KIF18A是来源于三阴性乳腺癌或结直肠癌的染色体不稳定性细胞增殖所必需的，但在二倍体细胞中不需要KIF18A。敲除KIF18A基因可导致雄性小鼠不育，但雌性小鼠没有受到影响。KIF18A mRNA表达与乳腺癌患者中较高的肿瘤等级和较大的肿瘤显著相关，且KIF18A是乳腺癌淋巴结转移的独立预测因素，风险系数为3.2。此外，抑制KIF18A表达不仅影响KIF18A在细胞有丝分裂中的关键功能，还能够通过稳定前沿微管来减少癌细胞迁移，最终导致PI3K-AKT信号通路失活而诱导细胞凋亡。KIF18A protein is highly expressed in a variety of tumors, including colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer, and ovarian cancer. KIF18A plays a key role in the occurrence, development, and metastasis of breast cancer, and its high expression indicates a poor prognosis in patients. KIF18A is required for the proliferation of chromosomal instability cells derived from triple-negative breast cancer or colorectal cancer, but KIF18A is not required in diploid cells. Knockout of the KIF18A gene can cause infertility in male mice, but female mice are not affected. KIF18A mRNA expression is significantly associated with higher tumor grade and larger tumors in breast cancer patients, and KIF18A is an independent predictor of lymph node metastasis in breast cancer, with a risk coefficient of 3.2. In addition, inhibiting KIF18A expression not only affects the key function of KIF18A in cell mitosis, but also reduces cancer cell migration by stabilizing leading-edge microtubules, ultimately leading to the inactivation of the PI3K-AKT signaling pathway and inducing cell apoptosis.
因此，对KIF18A蛋白抑制剂的开发可能是癌症药物的一个新的突破。Therefore, the development of KIF18A protein inhibitors may be a new breakthrough in cancer drugs.
发明内容Summary of the invention
为改善上述技术问题，本发明提供了一种式(I)所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、药学上可接受的盐或其前药化合物：
In order to improve the above technical problems, the present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound:
其中，A选自无取代或任选被一个、两个或更多个Ra取代的或稠环基团1；所述稠环基团1包含两个、三个或四个彼此独立地选自饱和或部分不饱和的C3-14碳环、C6-14芳环、5-14元杂芳环、3-14元杂环的环；每个Ra相同或不同，彼此独立地选自H、OH、卤素、氰基、NH2、NO2，无取代或任选被一个、两个或更多个Ra1取代的下列基团：C1-12烷基、C1-12烷氧基、C3-12环烷基；或者，连接在同一个环碳原子上的两个Ra与其连接的碳原子一起共同形成饱和或部分不饱和的C3-14碳环；每个Ra1相同或不同，彼此独立地选自H、OH、卤素、氰基、NH2、NO2、C1-12烷基、C1-12烷氧基、C3-12环烷基；wherein A is selected from unsubstituted or optionally substituted by one, two or more Ra or a fused ring group 1; the fused ring group 1 comprises two, three or four rings independently selected from a saturated or partially unsaturated C 3-14 carbocyclic ring, a C 6-14 aromatic ring, a 5-14 membered heteroaromatic ring, or a 3-14 membered heterocyclic ring; each Ra is the same or different and is independently selected from H, OH, halogen, cyano, NH 2 , NO 2 , the following groups which are unsubstituted or optionally substituted by one, two or more Ra1 : C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl; or two Ras attached to the same ring carbon atom together with the carbon atom to which they are attached form a saturated or partially unsaturated C 3-14 carbocyclic ring; each Ra1 is the same or different and is independently selected from H, OH, halogen, cyano, NH 2 , NO 2 , C 1-12 alkyl, C 1-12 alkoxy, or C 3-12 cycloalkyl;
X1、X2、X3相同或不同，彼此独立地选自N或CR0；R0选自H、卤素、氰基、C1-12烷基、卤代C1-12烷基、氰基C1-12烷基、C1-12烷氧基、卤代C1-12烷氧基、氰基C1-12烷氧基； X1 , X2 , X3 are the same or different and are independently selected from N or CR0 ; R0 is selected from H, halogen, cyano, C1-12 alkyl, halogenated C1-12 alkyl, cyano C1-12 alkyl, C1-12 alkoxy, halogenated C1-12 alkoxy, cyano C1-12 alkoxy;
B选自无取代或任选被一个、两个或更多个Rb取代的下列基团：C1-12烷基、卤代C1-12烷基、氰基C1-12烷基、C1-12烷氧基、卤代C1-12烷氧基、氰基C1-12烷氧基、C3-12环烷基、C3-12环烷基氧基、C3-12环烷基硫基、3-14元杂环基；每个Rb相同或不同，彼此独立地选自卤素、氰基、C1-12烷基、卤代C1-12烷基、氰基C1-12烷基、C1- 12烷氧基、卤代C1-12烷氧基、氰基C1-12烷氧基；B is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R b : C 1-12 alkyl, halogenated C 1-12 alkyl, cyano C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, cyano C 1-12 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylthio, 3-14 membered heterocyclyl; each R b is the same or different and is independently selected from halogen, cyano, C 1-12 alkyl, halogenated C 1-12 alkyl, cyano C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, cyano C 1-12 alkoxy ;
环G选自无取代或任选被一个、两个或更多个Rg取代的稠环基团2，所述稠环基团2由环G1和环G2稠合形成；环G1选自C6-14芳环、5-14元杂芳环、3-14元杂环；环G2选自C3-14碳环、C6-14芳环、5-14元杂芳环、3-14元杂环；M和E优选连接在环G1上；每个Rg相同或不同，彼此独立地选自卤素、氰基、C1-12烷基、卤代C1-12烷基、氰基C1-12烷基、C1-12烷氧基、卤代C1-12烷氧基、氰基C1-12烷氧基；Ring G is selected from a fused ring group 2 which is unsubstituted or optionally substituted by one, two or more Rgs , and the fused ring group 2 is formed by condensing ring G1 and ring G2 ; ring G1 is selected from a C6-14 aromatic ring, a 5-14 membered heteroaromatic ring, and a 3-14 membered heterocyclic ring; ring G2 is selected from a C3-14 carbocyclic ring, a C6-14 aromatic ring, a 5-14 membered heteroaromatic ring, and a 3-14 membered heterocyclic ring; M and E are preferably attached to ring G1 ; each Rg is the same or different and is independently selected from halogen, cyano, C1-12 alkyl, halogenated C1-12 alkyl, cyano C1-12 alkyl, C1-12 alkoxy, halogenated C1-12 alkoxy, and cyano C1-12 alkoxy;
E选自无取代或任选被一个、两个或更多个Re取代的下列基团：-NH-S(＝O)2-Re1、-S(＝O)2-NH-Re2、-S(＝O)(＝NH)-Re3、-N(Re4)(Re5)、3-14元杂环基；每个Re相同或不同，彼此独立地选自OH、卤素、氰基、C1-12烷基、C1-12烷氧基、卤代C1-12烷基、卤代C1-12烷氧基、氰基C1-12烷基、氰基C1-12烷氧基、-N(Re6)(Re7)；E is selected from the following groups which are unsubstituted or optionally substituted by one, two or more Re : -NH-S(=O) 2 - Re1 , -S(=O) 2 -NH- Re2 , -S(=O)(=NH) -Re3 , -N( Re4 )( Re5 ), 3-14 membered heterocyclyl; each Re is the same or different and is independently selected from OH, halogen, cyano, C1-12 alkyl, C1-12 alkoxy, halo C1-12 alkyl, halo C1-12 alkoxy, cyano C1-12 alkyl, cyano C1-12 alkoxy, -N( Re6 )( Re7 );
Re1、Re2、Re3、Re4、Re5、Re6、Re7相同或不同，彼此独立地选自H、C1-12烷基、C1-12烷氧基、羟基C1-12烷基、卤代C1-12烷基、卤代C1-12烷氧基、氰基C1-12烷基、氰基C1-12烷氧基、C3-12环烷基、3-14元杂环基、C1- 12烷氧基-C1-12烷基； Re1 , Re2 , Re3 , Re4 , Re5 , Re6 , and Re7 are the same or different and are independently selected from H, C1-12 alkyl, C1-12 alkoxy , hydroxyC1-12 alkyl, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, cyanoC1-12 alkyl, cyanoC1-12 alkoxy, C3-12 cycloalkyl, 3-14 membered heterocyclyl , and C1-12 alkoxy- C1-12 alkyl;
M选自无取代或任选被一个、两个或更多个Rm取代的下列基团：C3-12环烷基、C3-12环烯基、3-14元杂环基；每个Rm相同或不同，彼此独立地选自卤素、氰基、C1-12烷基、卤代C1-12烷基、氰基C1-12烷基、C1-12烷氧基、氰基C1-12烷氧基。M is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R m : C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-14 membered heterocyclyl; each R m is the same or different and independently selected from halogen, cyano, C 1-12 alkyl, halo C 1-12 alkyl, cyano C 1-12 alkyl, C 1-12 alkoxy, cyano C 1-12 alkoxy.
根据一些实施方案，A选自无取代或任选被一个、两个或更多个Ra取代的或稠环基团1；所述稠环基团1包含两个、三个或四个彼此独立地选自饱和或部分不饱和的C3-8碳环、C6-10芳环、5-10元杂芳环、3-8元杂环的环；每个Ra相同或不同，彼此独立地选自H、OH、卤素、氰基、NH2、NO2、C1-6烷基、C1- 6烷氧基、C3-8环烷基、卤代C1-6烷基、卤代C1-6烷氧基、氰基C1-6烷基、氰基C1-6烷氧基、C3-8环烷基-C1-6烷氧基；或者，连接在同一个环碳原子上的两个Ra与其连接的碳原子一起共同形成饱和或部分不饱和的C3-8碳环；According to some embodiments, A is selected from unsubstituted or optionally substituted with one, two or more Ra or a fused ring group 1; the fused ring group 1 comprises two, three or four rings independently selected from a saturated or partially unsaturated C 3-8 carbocyclic ring, a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring, or a 3-8 membered heterocyclic ring; each Ra is the same or different and independently selected from H, OH, halogen, cyano, NH 2 , NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, cyano C 1-6 alkyl, cyano C 1-6 alkoxy , or C 3-8 cycloalkyl -C 1-6 alkoxy; or, two Ras attached to the same ring carbon atom together with the carbon atom to which they are attached form a saturated or partially unsaturated C 3-8 carbocyclic ring;
根据一些实施方案，A选自 According to some embodiments, A is selected from
其中，T选自CH2、CH、NH、NRa或O；wherein T is selected from CH 2 , CH, NH, NR a or O;
Z选自CH2、CH、NH、NRa或O；Z is selected from CH 2 , CH, NH, NR a or O;
X选自N或CH；X is selected from N or CH;
n选自0、1、2、3、4或5；n is selected from 0, 1, 2, 3, 4 or 5;
p、q彼此独立地选自0、1、2、3，且p和q不同时为0；p and q are independently selected from 0, 1, 2, and 3, and p and q are not 0 at the same time;
r、s彼此独立地选自0、1、2、3，且r和s不同时为0。r and s are independently selected from 0, 1, 2, and 3, and r and s are not 0 at the same time.
根据一些实施方案，X1、X2相同或不同，彼此独立地选自N或CR0。According to some embodiments, X 1 and X 2 are the same or different and are independently selected from N or CR 0 .
根据一些实施方案，X1、X2相同或不同，彼此独立地选自N或CH。According to some embodiments, X 1 and X 2 are the same or different and are independently selected from N or CH.
根据一些实施方案，X2、X3不同时为N。According to some embodiments, X 2 and X 3 are not N at the same time.
根据一些实施方案，当X1和X2为N时，X3为CR0；当X1为N或CR0，X2为CR0时，X3为N或CR0；当X1为N或CR0，X2为N时，X3为CR0；R0选自H、卤素、C1-6烷基；According to some embodiments, when X1 and X2 are N, X3 is CR0 ; when X1 is N or CR0 and X2 is CR0 , X3 is N or CR0 ; when X1 is N or CR0 and X2 is N, X3 is CR0 ; R0 is selected from H, halogen, C1-6 alkyl;
根据一些实施方案，当X1和X2为N时，X3为CR0；当X1为N或CH，X2为CH时，X3为N或CR0；当X1为CH，X2为N时，X3为CR0；当X1为N，X2为CR0时，X3为N；R0选自H、C1-6烷基；According to some embodiments, when X1 and X2 are N, X3 is CR0 ; when X1 is N or CH and X2 is CH, X3 is N or CR0 ; when X1 is CH and X2 is N, X3 is CR0 ; when X1 is N and X2 is CR0 , X3 is N; R0 is selected from H, C1-6 alkyl;
根据一些实施方案，B选自C1-6烷基、C3-8环烷基、C3-8环烷基氧基、3-8元杂环基、卤代3-8元杂环基。According to some embodiments, B is selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, 3-8 membered heterocyclyl, halogenated 3-8 membered heterocyclyl.
根据一些实施方案，B选自卤代6元含N杂环基；例如为卤代哌啶基。According to some embodiments, B is selected from a halogenated 6-membered N-containing heterocyclic group; for example, a halogenated piperidinyl group.
根据一些实施方案，B选自 According to some embodiments, B is selected from
根据一些实施方案，A选自无取代或任选被一个、两个或更多个Ra取代的 或稠环基团1；所述稠环基团1由两个、三个、四个或更多个选自苯环、吡啶环、咪唑环、哌嗪环、二氢吡啶环、四氢吡啶环、二氢吡咯环、四氢吡咯环、二氢吡喃环、环丁烯环、环戊烯环、环己烯环、环庚烯环的环稠合而成。According to some embodiments, A is selected from unsubstituted or optionally substituted with one, two or more Ra Or a fused ring group 1; the fused ring group 1 is composed of two, three, four or more rings selected from a benzene ring, a pyridine ring, an imidazole ring, a piperazine ring, a dihydropyridine ring, a tetrahydropyridine ring, a dihydropyrrole ring, a tetrahydropyrrole ring, a dihydropyran ring, a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, and a cycloheptene ring.
根据一些实施方案，A选自无取代或任选被一个、两个或更多个Ra取代的下列基团： According to some embodiments, A is selected from the following groups which are unsubstituted or optionally substituted with one, two or more Ra :
根据一些实施方案，每个Ra相同或不同，彼此独立地选自H、OH、F、Cl、氰基、甲基、乙基、异丙基、甲氧基、乙氧基、三氟甲基、二氟甲氧基、三氟甲氧基、环丙基、环丙基甲氧基；或者，连接在同一个环碳原子上的两个Ra与其连接的碳原子一起共同形成环丙烷环、环丁烷环、环戊烷环、环己烷环、环庚烷环。According to some embodiments, each Ra is the same or different and is independently selected from H, OH, F, Cl, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclopropylmethoxy; or, two Ras attached to the same ring carbon atom together with the carbon atom to which they are attached form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, or a cycloheptane ring.
根据一些实施方案，A选自 According to some embodiments, A is selected from
根据一些实施方案，环G选自无取代或任选被一个、两个或更多个Rg取代的稠环基团2，所述稠环基团2由环G1和环G2稠合形成；环G1选自C6-10芳环、5-10元杂芳环、5-10元杂环；环G2选自C3-10碳环、C6-10芳环、5-10元杂芳环、3-10元杂环；According to some embodiments, ring G is selected from a fused ring group 2 which is unsubstituted or optionally substituted by one, two or more R g , and the fused ring group 2 is formed by condensing ring G 1 and ring G 2 ; ring G 1 is selected from a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring, and a 5-10 membered heterocyclic ring; ring G 2 is selected from a C 3-10 carbocyclic ring, a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring, and a 3-10 membered heterocyclic ring;
根据一些实施方案，环G1选自环戊烯环、环己烯环、二氢呋喃环、二氢吡喃环、咪唑环、三唑环、苯环、吡啶环、二氢吡啶环、吡咯环、吡唑环、呋喃环、噻吩环；优选为苯环或吡啶环。According to some embodiments, ring G1 is selected from a cyclopentene ring, a cyclohexene ring, a dihydrofuran ring, a dihydropyran ring, an imidazole ring, a triazole ring, a benzene ring, a pyridine ring, a dihydropyridine ring, a pyrrole ring, a pyrazole ring, a furan ring, and a thiophene ring; preferably a benzene ring or a pyridine ring.
根据一些实施方案，环G2选自环戊烯环、环己烯环、二氢呋喃环、二氢吡喃环、咪唑环、三唑环、苯环、吡啶环、吡咯环、吡唑环、呋喃环、噻吩环、甲基咪唑环。According to some embodiments, ring G2 is selected from a cyclopentene ring, a cyclohexene ring, a dihydrofuran ring, a dihydropyran ring, an imidazole ring, a triazole ring, a benzene ring, a pyridine ring, a pyrrole ring, a pyrazole ring, a furan ring, a thiophene ring, and a methylimidazole ring.
根据一些实施方案，环G选自 According to some embodiments, ring G is selected from
根据一些实施方案，E选自无取代或任选被一个或两个Re取代的下列基团：-NH-S(＝O)2-Re1、-S(＝O)2-NH-Re2、-S(＝O)(＝NH)-Re3；Re1、Re2、Re3相同或不同，彼此独立地选自H、C1-6烷基、羟基C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基、氰基C1-6烷基、氰基C1-6烷氧基、C3-8环烷基、3-8元杂环基、C1-6烷氧基-C1-6烷基；每个Re相同或不同，彼此独立地选自OH、卤素、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、氰基C1-6烷基、氰基C1-6烷氧基。According to some embodiments, E is selected from the following groups which are unsubstituted or optionally substituted with one or two Re : -NH-S(＝O) 2 - Re1 , -S(＝O) 2 -NH- Re2 , -S(＝O)(＝NH) -Re3 ; Re1 , Re2 , Re3 are the same or different and are independently selected from H, C1-6 alkyl, hydroxyC1-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxy, cyanoC1-6 alkyl, cyanoC1-6 alkoxy, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C1-6 alkoxy- C1-6 alkyl; each Re is the same or different and are independently selected from OH, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, cyanoC1-6 alkyl, cyanoC1-6 alkoxy.
根据一些实施方案，E选自 According to some embodiments, E is selected from
根据一些实施方案，M选自无取代或任选被一个、两个或更多个Rm取代的C3-8环烷基、C3-8环烯基或含氮的3-8元杂环基；每个Rm相同或不同，彼此独立地选自H、卤素、氰基、C1-6烷基、卤代C1-6烷基、氰基C1- 6烷基、C1-6烷氧基、氰基C1-6烷氧基；或者，连接在同一个环碳原子上的两个Rm与其连接的碳原子一起共同形成饱和或部分不饱和的C3-8碳环；According to some embodiments, M is selected from C 3-8 cycloalkyl, C 3-8 cycloalkenyl or nitrogen-containing 3-8 membered heterocyclyl which is unsubstituted or optionally substituted by one, two or more R m ; each R m is the same or different and is independently selected from H, halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy, cyano C 1-6 alkoxy; or, two R m connected to the same ring carbon atom together with the carbon atom to which they are connected form a saturated or partially unsaturated C 3-8 carbocyclic ring;
根据一些实施方案，M选自无取代或任选被一个、两个或更多个Rm取代的 According to some embodiments, M is selected from unsubstituted or optionally substituted with one, two or more R m
根据一些实施方案，式(I)所示化合物选自以下结构：
According to some embodiments, the compound represented by formula (I) is selected from the following structures:
其中，A、M、E、环G、环G1、环G2彼此独立地具有本文中所述的定义，表示碳碳单键或者碳碳双键。wherein A, M, E, Ring G, Ring G 1 , and Ring G 2 are independently defined as described herein, Represents a carbon-carbon single bond or a carbon-carbon double bond.
根据一些实施方案，式(I)所示的化合物具有以下结构：
According to some embodiments, the compound represented by formula (I) has the following structure:
其中，B、M、E、环G、X、Z、T、X1、X2、X3、Ra、n、p、q、r、s彼此独立地具有本文中所述的定义。wherein B, M, E, ring G, X, Z, T, X 1 , X 2 , X 3 , Ra , n, p, q, r, and s are independently defined as described herein.
根据一些实施方案，式(I)所示的化合物具有以下结构：
According to some embodiments, the compound represented by formula (I) has the following structure:
其中，B、环G、X、Z、T、X1、X2、X3、Ra、n、r、s、p、q彼此独立地具有本文中所述的定义。wherein B, Ring G, X, Z, T, X 1 , X 2 , X 3 , Ra , n, r, s, p, q are independently defined as described herein.
根据一些实施方案，式(I)所示的化合物具有以下结构：
According to some embodiments, the compound represented by formula (I) has the following structure:
其中，A、环G1、环G2彼此独立地具有本文中所述的定义。wherein A, ring G 1 and ring G 2 are independently defined as described herein.
根据一些实施方案，式(I)所示的化合物具有以下结构：
According to some embodiments, the compound represented by formula (I) has the following structure:
其中，A、环G2彼此独立地具有本文中所述的定义。wherein A and ring G2 independently have the definitions described herein.
根据一些实施方案，式(I)所示的化合物具有以下结构：
According to some embodiments, the compound represented by formula (I) has the following structure:
其中，B、环G2、X、Z、T、X1、X2、X3、Ra、n、r、s、p、q彼此独立地具有本文中所述的定义。wherein B, Ring G 2 , X, Z, T, X 1 , X 2 , X 3 , Ra , n, r, s, p, q are independently defined as described herein.
根据一些实施方案，式(I)所示的化合物具有以下结构：
According to some embodiments, the compound represented by formula (I) has the following structure:
其中，环G2、X1、X2、X3彼此独立地具有本文中所述的定义。wherein ring G 2 , X 1 , X 2 , and X 3 are independently as defined herein.
根据一些实施方案，式(I)所示化合物选自以下结构：



According to some embodiments, the compound represented by formula (I) is selected from the following structures:



本发明还提供式(I)所示化合物的制备方法，包括以下步骤：
The present invention also provides a method for preparing the compound represented by formula (I), comprising the following steps:
(1)化合物a与化合物A-NH2反应得到化合物b；(1) Compound a reacts with compound A- NH2 to obtain compound b;
(2)化合物b与化合物M-H反应得到化合物c；(2) Compound b reacts with compound M-H to obtain compound c;
(3)化合物c与化合物E-H反应得到式(I)所示化合物；(3) Compound C reacts with compound E-H to obtain a compound represented by formula (I);
其中，A、E、M和环G彼此独立地具有上文所述的定义；L选自卤素，如Cl、Br、I；Q选自卤素，如F、Cl、Br。wherein A, E, M and ring G are independently defined as above; L is selected from halogen, such as Cl, Br, I; and Q is selected from halogen, such as F, Cl, Br.
本发明还提供一种药物组合物，其包含治疗有效量的式(I)所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、药学上可接受的盐或其前药化合物中的至少一种。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.
根据本发明的实施方案，所述药物组合物还包括一种或多种药学上可接受的辅料。According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
根据本发明的实施方案，所述药物组合物还可以进一步含有一种或多种额外的治疗剂。According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.
本发明还提供一种治疗肿瘤疾病的方法，包括给予患者预防或治疗有效量的式(I)所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、药学上可接受的盐或其前药化合物中的至少一种。The present invention also provides a method for treating tumor diseases, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the compounds represented by formula (I), its racemates, stereoisomers, tautomers, isotope-labeled substances, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof.
本发明还提供治疗肿瘤疾病的方法，包括给予患者预防或治疗有效量的上述药物组合物。The present invention also provides a method for treating tumor diseases, comprising administering to a patient an effective amount of the above-mentioned pharmaceutical composition for prevention or treatment.
所述肿瘤疾病包括肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、膀胱癌、头颈部癌、宫颈癌和卵巢癌。The tumor diseases include colorectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer and ovarian cancer.
在一些实施方案中，所述患者包括哺乳动物，优选是人。In some embodiments, the patient comprises a mammal, preferably a human.
本发明还提供用于治疗肿瘤疾病的式(I)所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、药学上可接受的盐或其前药化合物中的至少一种，或其药物组合物。The present invention also provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or at least one of its prodrug compounds for treating tumor diseases, or a pharmaceutical composition thereof.
本发明还提供式(I)所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、药学上可接受的盐或其前药化合物中的至少一种在制备药物中的用途。The present invention also provides the use of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof in the preparation of a drug.
根据本发明的实施方案，所述用途可以为在制备治疗KIF18A介导的病症和/或疾病的药物中的用途，如在制备KIF18A抑制剂药物中的用途。According to an embodiment of the present invention, the use may be use in preparing a medicament for treating KIF18A-mediated disorders and/or diseases, such as use in preparing a KIF18A inhibitor drug.
根据本发明的实施方案，所述疾病例如为癌症，包括肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、膀胱癌、头颈部癌、宫颈癌或卵巢癌。According to an embodiment of the present invention, the disease is, for example, cancer, including colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.
有益效果Beneficial Effects
本发明的化合物具有良好的KIF18A抑制作用，该化合物可以单独地或与微管形成结合复合物来调节KIF18A蛋白，用以治疗KIF18A介导的病症和/或疾病，例如肿瘤疾病，以及制备用于此类病症或疾病的药物。The compound of the present invention has a good KIF18A inhibitory effect. The compound can regulate KIF18A protein alone or by forming a binding complex with microtubules, so as to treat KIF18A-mediated disorders and/or diseases, such as tumor diseases, and to prepare drugs for such disorders or diseases.
本发明通过结构优化，创造性的获得了一类结构新颖的化合物，其不仅具有良好的KIF18A抑制作用和OVCAR-3体外细胞活性，且理化性质(溶解度、渗透性)显著提升，OVCAR-3体内药效显著提升。The present invention creatively obtains a class of novel structural compounds through structural optimization, which not only have good KIF18A inhibitory effect and OVCAR-3 in vitro cell activity, but also have significantly improved physicochemical properties (solubility, permeability), and significantly improved OVCAR-3 in vivo efficacy.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1本发明化合物9对OVCAR-3小鼠异种移植瘤模型小鼠肿瘤体积和体重影响的折线图。FIG1 is a line graph showing the effects of compound 9 of the present invention on tumor volume and body weight of mice in an OVCAR-3 mouse xenograft tumor model.
术语定义与说明Definition and explanation of terms
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当被理解为本申请说明书和/或权利要求书记载的范围内。Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and/or claims of this application.
除非另有说明，本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如，数值范围“1-14”相当于记载了数值范围“1-14”中的每一个整数数值，即1、2、3、4、5、6、7、8、9、10、11、12、13、14。Unless otherwise specified, the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein. For example, the numerical range "1-14" is equivalent to recording each integer value in the numerical range "1-14", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14.
本申请通式定义中的术语“任选的”(或“任选地”、“任选”)意味着被零个、一个或多个取代基所取代的情形，例如“任选被一个、两个或更多个R取代”意味着可以不被R取代(无取代)或可以选择被一个、两个或更多个R取代。 The term "optional" (or "optionally", "optionally") in the general formula definitions of the present application means the situation of being substituted by zero, one or more substituents, for example, "optionally substituted by one, two or more R" means that it may not be substituted by R (unsubstituted) or may be selectively substituted by one, two or more R.
“更多个”表示三个或三个以上。"More" means three or more.
术语“C1-12烷基”应理解为表示具有1～12个碳原子的直链和支链烷基，“C1-8烷基”表示具有1、2、3、4、5、6、7、或8个碳原子的直链和支链烷基，“C1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。The term "C 1-12 alkyl" is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms, "C 1-8 alkyl" means straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and "C 1-6 alkyl" means straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.
术语“C3-12环烷基”应理解为表示饱和的一价单环、二环(如稠环、桥环、螺环)烃环或三环烷烃，其具有3～12个碳原子，优选“C3-10环烷基”，更优选“C3-8环烷基”。术语“C3-12环烷基”应理解为表示饱和的一价单环、双环(如桥环、螺环)烃环或三环烷烃，其具有3、4、5、6、7、8、9、10、11或12个碳原子。所述C3-12环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如龙脑基、吲哚基、六氢吲哚基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基、2,7-二氮杂螺[3,5]壬烷基、2,6-二氮杂螺[3,4]辛烷基，或者是三环烃基如金刚烷基。The term "C 3-12 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, preferably a "C 3-10 cycloalkyl", more preferably a "C 3-8 cycloalkyl". The term "C 3-12 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The C 3-12 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group, such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonanyl, 2,6-diazaspiro[3,4]octanyl, or a tricyclic hydrocarbon group, such as adamantyl.
术语“C3-12环烯基”应理解为表示含有碳碳双键的一价单环、二环(如稠环、桥环、螺环)或三环烯烃，其具有3～12个碳原子，优选“C3-10环烯基”，更优选“C3-8环烯基”，其可以具有3、4、5、6、7、8、9、10、11或12个碳原子。所述C3-12环烯基可以是单环烃基，如环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基、环壬烯基或环癸烯基，或者是二环烃基如螺[2.5]辛-5-烯基、螺[3.5]壬-6-烯基、螺[4.5]癸-7-烯基。The term "C 3-12 cycloalkenyl" is understood to mean a monovalent monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic olefin containing a carbon-carbon double bond, which has 3 to 12 carbon atoms, preferably a "C 3-10 cycloalkenyl", more preferably a "C 3-8 cycloalkenyl", which may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The C 3-12 cycloalkenyl may be a monocyclic hydrocarbon group, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, or a bicyclic hydrocarbon group such as spiro[2.5]oct-5-enyl, spiro[3.5]non-6-enyl, spiro[4.5]dec-7-enyl.
术语“C6-14芳基”应理解为优选表示具有6～14个碳原子的一价芳香性或部分芳香性的单环、二环或三环烃环，其可以是单芳族环或稠合在一起的多芳族环，优选“C6-10芳基”。术语“C6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”)，特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C13芳基”)，例如芴基，或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。当所述C6-20芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。The term "C 6-14 aryl" is understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a single aromatic ring or multiple aromatic rings condensed together, preferably "C 6-10 aryl". The term "C 6-14 aryl" is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 aryl") having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms ("C 6 aryl"), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl"), such as anthracenyl. When the C 6-20 aryl is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, and for example, substitution may be at the ortho, para or meta position.
术语“5-14元杂芳基”应理解为包括这样的一价单环、二环(如稠环、桥环、螺环)或三环芳族环系：其具有5～14个环原子且包含1-5个独立选自N、O和S的杂原子，例如“5-10元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3各独立选自N、O和S的杂原子并且，另外在每一种情况下可为苯并稠合的。“杂芳基”还指其中杂芳族环与一个或多个芳基、脂环族或杂环基环稠合的基团，其中所述连接的根基或点在杂芳族环上。非限制性实例包括1-、2-、3-、5-、6-、7-或8-吲嗪基、1-、3-、4-、5-、6-或7-异吲哚基、2-、3-、4-、5-、6-或7-吲哚基、2-、3-、4-、5-、6-或7-吲唑基、2-、4-、5-、6-、7-或8-嘌呤基、1-、2-、3-、4-、6-、7-、8-或9-喹嗪基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、1-、4-、5-、6-、7-或8-酞嗪基(phthalazinyl)、2-、3-、4-、5-或6-萘啶基、2-、3-、5-、6-、7-或8-喹唑啉基、3-、4-、5-、6-、7-或8-噌啉基、2-、4-、6-或7-蝶啶基、1-、2-、3-、4-、5-、6-、7-或8-4aH咔唑基、1-、2-、3-、4-、5-、6-、7-或8-咔唑基咔唑基、1-、3-、4-、5-、6-、7-、8-或9-咔啉基、1-、2-、3-、4-、6-、7-、8-、9-或10-菲啶基、1-、2-、3-、4-、5-、6-、7-、8-或9-吖啶基、1-、2-、4-、5-、6-、7-、8-或9-啶基、2-、3-、4-、5-、6-、8-、9-或10-菲咯啉基、1-、2-、3-、4-、6-、7-、8-或9-吩嗪基、1-、2-、3-、4-、6-、7-、8-、9-或10-吩噻嗪基、1-、2-、3-、4-、6-、7-、8-、9-或10-吩嗪基、2-、3-、4-、5-、6-或1-、3-、4-、5-、6-、7-、8-、9-或10-苯并异喹啉基、2-、3-、4-或噻吩并[2,3-b]呋喃基、2-、3-、5-、6-、7-、8-、9-、10-或11-7H-吡嗪并[2,3-c]咔唑基、2-、3-、5-、6-或7-2H-呋喃并[3,2-b]-吡喃基、2-、3-、4-、5-、7-或8-5H-吡啶并[2,3-d]-邻-嗪基、1-、3-或5-1H-吡唑并[4,3-d]-唑基、2-、4-或54H-咪唑并[4,5-d]噻唑基、3-、5-或8-吡嗪并[2,3-d]哒嗪基、2-、3-、5-或6-咪唑并[2,1-b]噻唑基、1-、3-、6-、7-、8-或9-呋喃并[3,4-c]噌啉基、1-、2-、3-、4-、5-、6-、8-、9-、10或11-4H-吡啶并[2,3-c]咔唑基、2-、3-、6-或7-咪唑并[1,2-b][1,2,4]三嗪基、7-苯并[b]噻吩基、2-、4-、5-、6-或7-苯并唑基、2-、4-、5-、6-或7-苯并咪唑基、2-、4-、4-、5-、6-或7-苯并噻唑基、1-、2-、4-、5-、6-、7-、8-或9-苯并氧杂基(benzoxapinyl)、2-、4-、5-、6-、7-或8-苯并嗪基、1-、2-、3-、5-、6-、7-、8-、9-、10-或11-4H-吡咯并[1,2-b][2]苯并氮杂基(benzazapinyl)。典型的稠合杂芳基包括但不限于2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、2-、3-、4-、5-、6-或7-吲哚基、2-、3-、4-、5-、6-或7-苯并[b]噻吩基、2-、4-、5-、6-或7-苯并唑基、2-、4-、5-、6-或7-苯并咪唑基和2-、4-、5-、6-或7-苯并噻唑基。当所述5-14元杂芳基与其它基团相连构成本发明的化合物时，可以为5-14元杂芳基环上的碳原子与其它基团相连，也可以为5-14元杂芳基环上的杂原子与其它基团相连。当所述5-14元杂芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为杂芳基环上与碳原子相连的氢被取代，或者杂芳基环上与杂原子相连的氢被取代。The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-10 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, furthermore, may be benzo-fused. "Heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3- , 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolylcarbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-phenanthridinyl, -acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-oxadiazole, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthroline, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl , 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]pyranyl , 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9 -furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4- , 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14 membered heteroaryl group is connected to other groups to form the compound of the present invention, it can be a carbon atom on the 5-14 membered heteroaryl ring connected to other groups, or it can be a heteroatom on the 5-14 membered heteroaryl ring connected to other groups. When the 5-14 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, a hydrogen atom connected to a carbon atom on a heteroaryl ring may be substituted, or a hydrogen atom connected to a heteroatom on a heteroaryl ring may be substituted.
除非另有定义，术语“3-14元杂环基”是指饱和的或不饱和的非芳族的环或环系，例如，其是4-、5-、6-或7-元的单环、7-、8-、9-、10-、11-或12-元的二环(如稠环、桥环、螺环)或者10-、11-、12-、13-或14-元的三环环系，并且含有至少一个，例如1、2、3、4、5个或更多个选自O、S和N的杂原子，其中N和S还可以任选被氧化成各种氧化状态，以形成氮氧化物、-S(O)-或-S(O)2-的状态。优选地，所述杂环基可以选自“3-10元杂环基”。术语“3-10元杂环基”意指饱和的或不饱和的非芳族的环或环系，并且含有至少一个选自O、S和N的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。所述杂环基可以包括稠合的或桥连的环以及螺环的环。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。杂环基可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于二氢呋喃基、二氢吡喃基、2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、1,2,3,5-四氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。所述3-14元杂环基与其它基团相连构成本发明的化合物时，可以为3-14元杂环基上的碳原子与其它基团相连，也可以为3-14元杂环基环上杂环原子与其它基团相连。例如当3-14元杂环基选自哌嗪基时，可以为哌嗪基上的氮原子与其它基团相连。或当3-14元杂环基选自哌啶基时，可以为哌啶基环上的氮原子和其对位上的碳原子与其它基团相连。Unless otherwise defined, the term "3-14 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) 2 -. Preferably, the heterocyclyl may be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group can include, but is not limited to: 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl. Optionally, the heterocyclic group can be benzo-fused. The heterocyclic group can be bicyclic, such as, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta [c] pyrrole -2 (1H) -yl ring, or 5,6-membered bicyclic rings, such as hexahydropyrrolo [1,2-a] pyrazine -2 (1H) -yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl. When the 3-14 membered heterocyclic group is connected with other groups to form the compound of the present invention, the carbon atom on the 3-14 membered heterocyclic group may be connected with other groups, or the heterocyclic atom on the 3-14 membered heterocyclic group may be connected with other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl may be connected with other groups. Or when the 3-14 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom on the para position thereof may be connected with other groups.
术语“螺环”是指两个环共用1个成环原子的环系。The term "spirocyclic" refers to a ring system in which two rings share one ring-forming atom.
术语“稠环”是指两个环共用2个成环原子的环系。The term "fused ring" refers to a ring system in which two rings share two ring atoms.
术语“桥环”是指两个环共用3个以上成环原子的环系。The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.
术语“卤素”表示氟、氯、溴和碘。The term "halogen" refers to fluorine, chlorine, bromine and iodine.
“卤代”指被一个或多个卤素取代。"Halo" means substituted with one or more halogens.
当环G选自等取代基时，其具有3个连接位点，通常而言，其三个连接位点可分别与通式结构中的A、M、E相连接。优选地，以为例，其中连接位置1与A相连，连接位置2与M相连，连接位置3与E相连。环G、环G1选择其他取代基时，均作上述相同的解释。When ring G is selected from When the substituent is substituted with , it has three connection sites. Generally speaking, the three connection sites can be connected to A, M, and E in the general structure respectively. For example, the connection position 1 is connected to A, the connection position 2 is connected to M, and the connection position 3 is connected to E. When other substituents are selected for ring G and ring G1 , the same explanation as above shall apply.
本领域技术人员知晓，当A选自无取代或任选被一个、两个或更多个Ra取代的时，Ra可位于X1所在环上任意位置，例如，当X1为CH时，Ra可以取代X1上的H形成CRa。Those skilled in the art will appreciate that when A is selected from unsubstituted or optionally substituted with one, two or more Ra When X 1 is CH, Ra can be located at any position on the ring where X 1 is located. For example, when X 1 is CH, Ra can replace the H on X 1 to form CR a .
本领域技术人员可以理解，式(I)所示化合物可以以各种药学上可接受的盐的形式存在。如果这些化合物具有碱性中心，则其可以形成酸加成盐；如果这些化合物具有酸性中心，则其可以形成碱加成盐；如果这些化合物既包含酸性中心(例如羧基)又包含碱性中心(例如氨基)，则其还可以形成内盐。It will be appreciated by those skilled in the art that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form a base addition salt; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form an inner salt.
本发明的化合物可以溶剂合物(如水合物)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。The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of the polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.
根据其分子结构，本发明的化合物可以是手性的，因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物涵盖了各手性碳为R或S构型的异构体或其混合物、消旋体。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物，或者以此形式用于合成。在外消旋的胺的情况中，通过与光学活性的拆分试剂反应，从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸，例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物)，也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物，例如，己烷/异丙醇/乙腈。According to its molecular structure, the compounds of the present invention may be chiral, and therefore various enantiomeric forms may exist. Thus, these compounds may exist in racemic form or optically active form. The compounds of the present invention encompass isomers or mixtures, racemates in which each chiral carbon is in R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolution agent. Examples of suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in R and S forms. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane/isopropanol/acetonitrile.
可以根据已知的方法，例如通过萃取、过滤或柱层析来分离相应的稳定异构体。The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.
术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.
术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。The term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition.
具体实施方式Detailed ways
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.
实施例1Example 1
5-{6-氮杂螺[2.5]辛烷-6-基}-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(化合物1)
5-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (Compound 1)
第一步 2-溴-4-氟-5-甲氧基苯甲醛(化合物1-2)的合成：Step 1 Synthesis of 2-bromo-4-fluoro-5-methoxybenzaldehyde (Compound 1-2):
室温下，向4-氟-3-甲氧基苯甲醛(10g,64.876mmol,1eq)的水(20mL)溶液中加入溴化钾(38.60g,324.380mmol,5eq)，随后加入溴单质(9.98mL,194.628mmol,3eq)。室温下继续搅拌15小时。过滤收集沉淀的固体，用水(3×5mL)洗涤。在真空下干燥得到固体2-溴-4-氟-5-甲氧基苯甲醛(15g，99.22％)。At room temperature, potassium bromide (38.60 g, 324.380 mmol, 5 eq) was added to a solution of 4-fluoro-3-methoxybenzaldehyde (10 g, 64.876 mmol, 1 eq) in water (20 mL), followed by bromine (9.98 mL, 194.628 mmol, 3 eq). Stirring was continued at room temperature for 15 hours. The precipitated solid was collected by filtration and washed with water (3×5 mL). Drying under vacuum gave solid 2-bromo-4-fluoro-5-methoxybenzaldehyde (15 g, 99.22%).
1H NMR(400MHz,DMSO-d6)δ10.13(d,J＝0.8Hz,1H),7.83(dd,J＝10.4,1.6Hz,1H),7.57-7.54(dd,J＝10.4,1.6Hz,1H),3.92(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.13 (d, J = 0.8 Hz, 1H), 7.83 (dd, J = 10.4, 1.6 Hz, 1H), 7.57-7.54 (dd, J = 10.4, 1.6 Hz, 1H), 3.92 (s, 3H).
第二步 3-(2-溴-4-氟-5-甲氧基苯基)丙酸(化合物1-4)的合成：Step 2 Synthesis of 3-(2-bromo-4-fluoro-5-methoxyphenyl)propionic acid (Compound 1-4):
氮气保护，室温下向2-溴-4-氟-5-甲氧基苯甲醛(8g,34.329mmol,1eq)的甲酸(10mL)溶液中加入麦氏酸(化合物1-3)(4947.77mg,34.329mmol,1eq)，随后滴加三乙胺(14.32mL,102.987mmol,3eq)。反应液升温至100℃，搅拌10小时。反应结束后，在室温下用水淬灭，乙酸乙酯(3×200mL)萃取，合并有机相，用饱和氯化钠溶液(1×300mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩。残余物通过硅胶柱色谱纯化，用石油醚：乙酸乙酯(1:1)洗脱，得到3-(2-溴-4-氟-5-甲氧基苯基)丙酸(2.8g，29.44％)。Under nitrogen protection, McLaughlin's acid (compound 1-3) (4947.77 mg, 34.329 mmol, 1 eq) was added to a solution of 2-bromo-4-fluoro-5-methoxybenzaldehyde (8 g, 34.329 mmol, 1 eq) in formic acid (10 mL) at room temperature, followed by dropwise addition of triethylamine (14.32 mL, 102.987 mmol, 3 eq). The reaction solution was heated to 100 °C and stirred for 10 hours. After the reaction was completed, it was quenched with water at room temperature, extracted with ethyl acetate (3×200 mL), the organic phases were combined, washed with saturated sodium chloride solution (1×300 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether: ethyl acetate (1:1) to obtain 3-(2-bromo-4-fluoro-5-methoxyphenyl)propionic acid (2.8 g, 29.44%).
MS(ESI,m/z):275.05[M-H]-,RT(min):0.886。MS (ESI, m/z): 275.05 [MH] - , RT (min): 0.886.
第三步 4-溴-6-氟-7-甲氧基-2,3-二氢茚-1-酮(化合物1-5)的合成：Step 3 Synthesis of 4-bromo-6-fluoro-7-methoxy-2,3-dihydroindan-1-one (Compound 1-5):
氮气保护，室温下向3-(2-溴-4-氟-5-甲氧基苯基)丙酸(2.0g,7.218mmol,1eq)的1,2-二氯乙烷(12mL)溶液中，滴加三氟甲磺酸(3.19mL,36.090mmol,5eq)。反应液升温至80℃，微波反应1小时。反应混合物室温下用水淬灭后，用二氯甲烷萃取(3×60mL)，合并有机相，用饱和食盐水反洗(1×60mL)，无水硫酸钠干燥。所得混合物过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(10:1)，得到4-溴-6-氟-7-甲氧基-2,3-二氢茚-1-酮(1.5g,80.22％)。Under nitrogen protection, trifluoromethanesulfonic acid (3.19 mL, 36.090 mmol, 5 eq) was added dropwise to a solution of 3-(2-bromo-4-fluoro-5-methoxyphenyl)propanoic acid (2.0 g, 7.218 mmol, 1 eq) in 1,2-dichloroethane (12 mL) at room temperature. The reaction solution was heated to 80°C and microwaved for 1 hour. The reaction mixture was quenched with water at room temperature, extracted with dichloromethane (3×60 mL), and the organic phases were combined, backwashed with saturated brine (1×60 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (10:1) to obtain 4-bromo-6-fluoro-7-methoxy-2,3-dihydroindane-1-one (1.5 g, 80.22%).
MS(ESI,m/z):259.15[M+H]+,RT(min):1.030。MS (ESI, m/z): 259.15 [M+H] + , RT (min): 1.030.
1H NMR(400MHz,CDCl3-d)δ7.51(d,J＝11.2Hz,1H),4.09(s,3H),2.99-2.96(m,2H),2.77-2.74(m,2H). 1 H NMR (400 MHz, CDCl 3 -d) δ7.51 (d, J=11.2 Hz, 1H), 4.09 (s, 3H), 2.99-2.96 (m, 2H), 2.77-2.74 (m, 2H).
第四步 7-溴-5-氟-4-甲氧基-2,3-二氢-1H-茚(化合物1-6)的合成：Step 4 Synthesis of 7-bromo-5-fluoro-4-methoxy-2,3-dihydro-1H-indene (Compound 1-6):
氮气保护，0℃下向4-溴-6-氟-7-甲氧基-2,3-二氢茚-1-酮(2g,7.720mmol,1eq)的三氟乙酸(8.80mL)溶液中加入三乙基硅烷(3.74mL,23.160mmol,3eq)。随后将反应混合物置于50℃加热搅拌16小时，反应体系用薄层色谱监测。反应混合物室温下用水淬灭。反应混合物用乙酸乙酯萃取(3×60mL)。合并有机相，用饱和食盐水反洗(1×60mL)，无水硫酸钠干燥。所得混合物过滤后，滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(10:1)，得到7-溴-5-氟-4-甲氧基-2,3-二氢-1H-茚(1.5g,79.28％)。Under nitrogen protection, triethylsilane (3.74 mL, 23.160 mmol, 3 eq) was added to a solution of 4-bromo-6-fluoro-7-methoxy-2,3-dihydroindene-1-one (2 g, 7.720 mmol, 1 eq) in trifluoroacetic acid (8.80 mL) at 0 ° C. The reaction mixture was then heated and stirred at 50 ° C for 16 hours, and the reaction system was monitored by thin layer chromatography. The reaction mixture was quenched with water at room temperature. The reaction mixture was extracted with ethyl acetate (3×60 mL). The organic phases were combined, backwashed with saturated brine (1×60 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, petroleum ether/ethyl acetate (10:1) to obtain 7-bromo-5-fluoro-4-methoxy-2,3-dihydro-1H-indene (1.5 g, 79.28%).
1H NMR(400MHz,氘代氯仿)δ7.06(d,J＝10.8Hz,1H),3.91(s,3H),3.03-2.99(m,2H),2.90-2.83(m,2H),2.14-2.07(m,2H). 1 H NMR (400 MHz, deuterated chloroform) δ7.06 (d, J=10.8 Hz, 1H), 3.91 (s, 3H), 3.03-2.99 (m, 2H), 2.90-2.83 (m, 2H), 2.14-2.07 (m, 2H).
第五步 7-溴-5-氟-2,3-二氢-1H-茚-4-醇(化合物1-7)的合成：Step 5 Synthesis of 7-bromo-5-fluoro-2,3-dihydro-1H-indene-4-ol (Compound 1-7):
7-溴-5-氟-4-甲氧基-2,3-二氢-1H-茚(800mg,3.264mmol,1eq)和溴化氢的醋酸溶液(8.00mL)在100℃加热搅拌2小时。反应液冷却至室温，反应混合物用乙酸乙酯(50mL)稀释。反应混合物依次用蒸馏水(1×30mL)，饱和碳酸氢钠(1×30mL)，饱和食盐水(1×30mL)洗涤。有机相用无水硫酸钠干燥，所得混合物过滤后，将滤液减压浓缩，粗品/未进一步纯化，直接投下步。7-Bromo-5-fluoro-4-methoxy-2,3-dihydro-1H-indene (800 mg, 3.264 mmol, 1 eq) and hydrogen bromide in acetic acid (8.00 mL) were heated and stirred at 100 ° C for 2 hours. The reaction solution was cooled to room temperature and the reaction mixture was diluted with ethyl acetate (50 mL). The reaction mixture was washed with distilled water (1×30 mL), saturated sodium bicarbonate (1×30 mL), and saturated brine (1×30 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure, and the crude product was directly used in the next step without further purification.
MS(ESI,m/z):231.05[M-H]-,RT(min):1.041MS (ESI, m/z): 231.05 [MH] - , RT (min): 1.041
第六步 7-溴-5-氟-2,3-二氢-1H-茚-4-基三氟甲磺酸酯(化合物1-9)的合成：Step 6 Synthesis of 7-bromo-5-fluoro-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (Compound 1-9):
氮气保护，0℃下向7-溴-5-氟-2,3-二氢-1H-茚-4-醇(3g,12.983mmol,1eq)的二氯甲烷(30.00mL)溶液中，加入吡啶(1.54g,19.474mmol,1.50eq)，继续搅拌10分钟。然后加入三氟甲磺酸酐(化合物1-8)(3.29mL,19.474mmol,1.50eq)，室温下搅拌过夜。反应液室温下用水淬灭。反应混合物用乙酸乙酯萃取(3×80mL)。合并有机相，用饱和食盐水反洗(1×100mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(10:1)，得到7-溴-5-氟-2,3-二氢-1H-茚-4-基三氟甲磺酸酯(2g,42.42％)。Under nitrogen protection, pyridine (1.54 g, 19.474 mmol, 1.50 eq) was added to a solution of 7-bromo-5-fluoro-2,3-dihydro-1H-indene-4-ol (3 g, 12.983 mmol, 1 eq) in dichloromethane (30.00 mL) at 0 ° C, and stirring was continued for 10 minutes. Then trifluoromethanesulfonic anhydride (compound 1-8) (3.29 mL, 19.474 mmol, 1.50 eq) was added and stirred at room temperature overnight. The reaction solution was quenched with water at room temperature. The reaction mixture was extracted with ethyl acetate (3×80 mL). The organic phases were combined, backwashed with saturated brine (1×100 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (10:1) to give 7-bromo-5-fluoro-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (2 g, 42.42%).
1H NMR(400MHz,氘代氯仿)δ7.23(d,J＝9.2Hz,1H),3.18-3.14(m,2H),2.99-2.95(m,2H),2.23-2.16(m,2H). 1 H NMR (400 MHz, deuterated chloroform) δ7.23 (d, J=9.2 Hz, 1H), 3.18-3.14 (m, 2H), 2.99-2.95 (m, 2H), 2.23-2.16 (m, 2H).
第七步 7-溴-5-氟-2,3-二氢-1H-茚-4-甲酸甲酯(化合物1-10)的合成：Step 7 Synthesis of methyl 7-bromo-5-fluoro-2,3-dihydro-1H-indene-4-carboxylate (Compound 1-10):
氮气保护，室温下向7-溴-5-氟-2,3-二氢-1H-茚-4-基三氟甲磺酸酯(1.2g,3.305mmol,1eq)的二甲基亚砜/甲醇(7.5mL,3/2,v/v)溶液中，依次加入醋酸钯(74.19mg,0.331mmol,0.1eq)，双二苯基膦丁烷(140.94mg,0.331mmol,0.1eq)和三乙胺(1148.39uL,8.263mmol,2.5eq)。反应液升温至80℃，同时通入一氧化碳反应1小时。反应混合物室温下用水淬灭，乙酸乙酯萃取(3×10mL)。合并有机相，用饱和食盐水反洗(1×10mL)，无水硫酸钠干燥。所得混合物过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(10:1)，得到7-溴-5-氟-2,3-二氢-1H-茚-4-甲酸甲酯(400mg,44.32％)。Under nitrogen protection, palladium acetate (74.19 mg, 0.331 mmol, 0.1 eq), bis(diphenylphosphinobutane) (140.94 mg, 0.331 mmol, 0.1 eq) and triethylamine (1148.39 uL, 8.263 mmol, 2.5 eq) were added to a solution of 7-bromo-5-fluoro-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (1.2 g, 3.305 mmol, 1 eq) in dimethyl sulfoxide/methanol (7.5 mL, 3/2, v/v) at room temperature. The reaction solution was heated to 80°C and carbon monoxide was introduced for 1 hour. The reaction mixture was quenched with water at room temperature and extracted with ethyl acetate (3×10 mL). The organic phases were combined, backwashed with saturated brine (1×10 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (10:1) to give methyl 7-bromo-5-fluoro-2,3-dihydro-1H-indene-4-carboxylate (400 mg, 44.32%).
1H NMR(400MHz,氘代氯仿)δ7.14(d,J＝10.0Hz,1H),3.91(s,3H),3.25(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),2.16-2.08(m,2H). 1 H NMR (400 MHz, deuterated chloroform) δ7.14 (d, J = 10.0 Hz, 1H), 3.91 (s, 3H), 3.25 (t, J = 7.6 Hz, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.16-2.08 (m, 2H).
第八步 7-溴-5-氟-2,3-二氢-1H-茚-4-甲酸(化合物1-11)的合成：Step 8 Synthesis of 7-bromo-5-fluoro-2,3-dihydro-1H-indene-4-carboxylic acid (Compound 1-11):
室温下向7-溴-5-氟-2,3-二氢-1H-茚-4-甲酸甲酯(500mg,1.831mmol,1eq)四氢呋喃/水(4mL，3/1，v/v)溶液中加入氢氧化锂(131.54mg,5.493mmol,3eq)。反应液室温搅拌16小时，反应混合物室温下加水稀释，并用1摩尔每升盐酸溶液酸化pH 5～6。反应混合物用乙酸乙酯萃取(3×30mL)。合并有机相，用饱和食盐水反洗(1×40mL)，无水硫酸钠干燥。所得混合物过滤，滤液减压浓缩。粗品/所得混合物未进一步纯化，直接投下步。Lithium hydroxide (131.54 mg, 5.493 mmol, 3 eq) was added to a solution of 7-bromo-5-fluoro-2,3-dihydro-1H-indene-4-carboxylic acid methyl ester (500 mg, 1.831 mmol, 1 eq) in tetrahydrofuran/water (4 mL, 3/1, v/v) at room temperature. The reaction mixture was stirred at room temperature for 16 hours, and the reaction mixture was diluted with water at room temperature and acidified to pH 5-6 with 1 mol/L hydrochloric acid solution. The reaction mixture was extracted with ethyl acetate (3×30 mL). The organic phases were combined, backwashed with saturated brine (1×40 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product/the resulting mixture was not further purified and was directly used in the next step.
MS(ESI,m/z):257.10[M-H]-,RT(min):1.053MS (ESI, m/z): 257.10 [MH] - , RT (min): 1.053
第九步 7-溴-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]-5-氟-2,3-二氢-1H-茚-4-甲酰胺(化合物1-13)的合成：Step 9 Synthesis of 7-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-5-fluoro-2,3-dihydro-1H-indene-4-carboxamide (Compound 1-13):
氮气保护，室温下向7-溴-5-氟-2,3-二氢-1H-茚-4-甲酸(500mg,1.930mmol,1eq)和2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-胺(化合物1-12)(660.76mg,2.895mmol,1.5eq)的二氯甲烷溶液(5mL)中加入四甲基氯甲脒六氟磷酸盐(2166.02mg,7.720mmol,4eq)和N-甲基咪唑(1584.61mg,19.300mmol,10eq)。室温搅拌1小时。反应混合物室温下用水稀释，并用二氯甲烷萃取(3×30mL)。合并有机相，用饱和食盐水反洗(1×10mL)，无水硫酸钠干燥。所得混合物过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(10:1)，得到7-溴-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]-5-氟-2,3-二氢-1H-茚-4-甲酰胺(160mg,17.67％)。Under nitrogen protection, tetramethylchloroformamidine hexafluorophosphate (2166.02 mg, 7.720 mmol, 4 eq) and N-methylimidazole (1584.61 mg, 19.300 mmol, 10 eq) were added to a dichloromethane solution (5 mL) of 7-bromo-5-fluoro-2,3-dihydro-1H-indene-4-carboxylic acid (500 mg, 1.930 mmol, 1 eq) and 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (Compound 1-12) (660.76 mg, 2.895 mmol, 1.5 eq) at room temperature. Stir at room temperature for 1 hour. The reaction mixture was diluted with water at room temperature and extracted with dichloromethane (3×30 mL). The organic phases were combined, backwashed with saturated brine (1×10 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (10:1) to give 7-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-5-fluoro-2,3-dihydro-1H-indene-4-carboxamide (160 mg, 17.67%).
MS(ESI,m/z):469.25[M+H]+,RT(min):1.455.MS (ESI, m/z): 469.25 [M+H] + , RT (min): 1.455.
第十步 5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]-2,3-二氢-1H-茚-4-甲酰胺(化合物1-15)的合成：Step 10 Synthesis of 5-{6-azaspiro[2.5]octane-6-yl}-7-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2,3-dihydro-1H-indene-4-carboxamide (Compound 1-15):
氮气保护，室温下向7-溴-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]-5-氟-2,3-二氢-1H-茚-4-甲酰胺(160mg,0.341mmol,1eq)和6-氮杂螺[2.5]辛烷盐酸盐(化合物1-14)(251.69mg,1.705mmol,5eq)的N,N-二甲基乙酰胺(10mL)溶液中，加入叔丁醇钠(196.59mg,2.046mmol,6eq)。反应液升温至140℃，加热反应3天。反应液冷却至室温，并用水淬灭。反应混合物用乙酸乙酯萃取(3×30mL)。合并有机相，用饱和食盐水反洗(1×30mL),无水硫酸钠干燥。所得混合物过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(10:1)，得到5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]-2,3-二氢-1H-茚-4-甲酰胺(48mg,25.12％)。Under nitrogen protection, sodium tert-butoxide (196.59 mg, 2.046 mmol, 6 eq) was added to a solution of 7-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-5-fluoro-2,3-dihydro-1H-indene-4-carboxamide (160 mg, 0.341 mmol, 1 eq) and 6-azaspiro[2.5]octane hydrochloride (Compound 1-14) (251.69 mg, 1.705 mmol, 5 eq) in N,N-dimethylacetamide (10 mL) at room temperature. The reaction solution was heated to 140°C and heated for 3 days. The reaction solution was cooled to room temperature and quenched with water. The reaction mixture was extracted with ethyl acetate (3×30 mL). The organic phases were combined, backwashed with saturated brine (1×30 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (10:1) to give 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2,3-dihydro-1H-indene-4-carboxamide (48 mg, 25.12%).
MS(ESI,m/z):560.60[M+H]+,RT(min):1.494.MS (ESI, m/z): 560.60 [M+H] +, RT (min): 1.494.
1H NMR(400MHz,氘代氯仿)δ12.69(s,1H),7.46(s,1H),7.27(s,1H),3.99(d,J＝7.2Hz,4H),3.47(t,J＝7.6Hz,2H),3.03(t,J＝5.4Hz,4H),2.93(t,J＝7.6Hz,2H),2.37(s,3H),2.10(q,J＝7.6Hz,2H),1.99(s,4H),1.55(s,4H),0.38(s,4H). 1 H NMR (400 MHz, deuterated chloroform) δ 12.69 (s, 1H), 7.46 (s, 1H), 7.27 (s, 1H), 3.99 (d, J = 7.2 Hz, 4H), 3.47 (t, J = 7.6 Hz, 2H), 3.03 (t, J = 5.4 Hz, 4H), 2.93 (t, J = 7.6 Hz, 2H), 2.37 (s, 3H), 2.10 (q, J = 7.6 Hz, 2H), 1.99 (s, 4H), 1.55 (s, 4H), 0.38 (s, 4H).
第十一步 5-{6-氮杂螺[2.5]辛烷-6-基}-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(化合物1)的合成：Step 11 Synthesis of 5-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (Compound 1):
氮气保护，室温下向5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]-2,3-二氢-1H-茚-4-甲酰胺(45mg,0.080mmol,1eq)的1,4-二氧六环(2mL)溶液中加入二环己基(3-异丙氧基-2',4',6'-三异丙基-[1,1'-联苯基]-2-基)磷烷(Ephos,8.59mg,0.016mmol,0.2eq)，(甲磺酸{双环己基(3-异丙氧-2',4',6'-三异丙基-[1,1'-联苯]-2-基)膦烷}(2'-甲氨基-1,1'-联苯-2-基)钯(II)(Ephos-Pd-G4,7.37mg,0.008mmol,0.1eq)，碳酸铯(78.48mg,0.240mmol,3eq)和2-羟基乙磺酰胺(化合物1-16)(12.06mg,0.096mmol,1.2eq)。反应液升温至100℃，加热1小时。反应液冷却至室温，反应混合物室温下用水淬灭。反应混合物用乙酸乙酯萃取(3×10mL)。合并有机相，用饱和食盐水反洗(1×10mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。粗品通过高效液相纯化，条件如下(层析柱规格:XBridge Prep OBD C18 Column,30*150mm,5μm；流动相A:水(10mmol/L碳酸氢铵)，流动相B:乙腈；流速:60mL/min；洗脱梯度:8min内，48％B至80％B,80％B；检测波长:UV 220nm；保留时间(分钟):7.88)。得到化合物1(21.93mg,44.81％)。To a solution of 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2,3-dihydro-1H-indene-4-carboxamide (45 mg, 0.080 mmol, 1 eq) in 1,4-dioxane (2 mL) was added dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane( Ephos, 8.59 mg, 0.016 mmol, 0.2 eq), (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphine} (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (Ephos-Pd-G4, 7.37 mg, 0.008 mmol, 0.1 eq), cesium carbonate (78.48 mg, 0.240 mmol, 3 eq) and 2-Hydroxyethanesulfonamide (Compound 1-16) (12.06 mg, 0.096 mmol, 1.2 eq). The reaction solution was heated to 100 ° C and heated for 1 hour. The reaction solution was cooled to room temperature and the reaction mixture was quenched with water at room temperature. The reaction mixture was extracted with ethyl acetate (3×10 mL). The organic phases were combined, backwashed with saturated brine (1×10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (chromatographic column specifications: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL/min; elution gradient: 48% B to 80% B, 80% B within 8 min; detection wavelength: UV 220 nm; retention time (minutes): 7.88). Compound 1 (21.93 mg, 44.81%) was obtained.
MS(ES,m/z):605.45[M+H]+,RT(min):1.894.MS (ES, m/z): 605.45 [M+H] + , RT (min): 1.894.
1H NMR:(400MHz,DMSO-d6)δ12.92(s,1H),9.39(s,1H),7.38(s,1H),7.27(s,1H),4.99(s,1H),3.90(s,4H),3.77(t,J＝6.5Hz,2H),3.31(s,2H),3.22(t,J＝7.5Hz,2H),2.94(s,4H),2.85(t,J＝7.5Hz,2H),2.31(s,3H),2.05-1.86(m,6H),1.65(s,4H),0.36(s,4H). 1 H NMR: (400 MHz, DMSO-d 6 ) δ 12.92 (s, 1H), 9.39 (s, 1H), 7.38 (s, 1H), 7.27 (s, 1H), 4.99 (s, 1H), 3.90 (s, 4H), 3.77 (t, J=6.5 Hz, 2H), 3.31 (s, 2H), 3.22 (t, J=7.5 Hz, 2H), 2.94 (s, 4H), 2.85 (t, J=7.5 Hz, 2H), 2.31 (s, 3H), 2.05-1.86 (m, 6H), 1.65 (s, 4H), 0.36 (s, 4H).
实施例2 Example 2
5-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(化合物9)
5-{6-azaspiro[2.5]octan-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (Compound 9)
第一步 7-溴-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-5-氟-2,3-二氢-1H-茚-4-甲酰胺(化合物9-2)的合成：The first step is the synthesis of 7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-5-fluoro-2,3-dihydro-1H-indene-4-carboxamide (compound 9-2):
氮气保护，室温下向6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-胺(197.37mg,0.868mmol,1.5eq)，N,N,N',N'-四甲基氯甲脒六氟磷酸盐(649.81mg,2.316mmol,4eq)和7-溴-5-氟-2,3-二氢-1H-茚-4-甲酸(150mg,0.579mmol,1.00eq)的二氯甲烷(7.5mL)溶液中，加入N-甲基咪唑(475.38mg,5.790mmol,10eq)。反应液升温至60℃，搅拌1小时。反应液冷却至室温，用二氯甲烷萃取(3×50mL)。合并有机相，用饱和食盐水反洗(1×50mL)，无水硫酸钠干燥。所得混合物过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(5:1)，得到7-溴-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-5-氟-2,3-二氢-1H-茚-4-甲酰胺(180mg,66.38％)。Under nitrogen protection, N-methylimidazole (475.38 mg, 5.790 mmol, 10 eq) was added to a solution of 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine (197.37 mg, 0.868 mmol, 1.5 eq), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (649.81 mg, 2.316 mmol, 4 eq) and 7-bromo-5-fluoro-2,3-dihydro-1H-indene-4-carboxylic acid (150 mg, 0.579 mmol, 1.00 eq) in dichloromethane (7.5 mL) at room temperature. The reaction solution was heated to 60°C and stirred for 1 hour. The reaction solution was cooled to room temperature and extracted with dichloromethane (3×50 mL). The organic phases were combined, backwashed with saturated brine (1×50 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (5:1) to give 7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-5-fluoro-2,3-dihydro-1H-indene-4-carboxamide (180 mg, 66.38%).
MS:(ESI,m/z):468.30[M+H]+,RT(min):1.397.MS: (ESI, m/z): 468.30 [M+H] + , RT (min): 1.397.
第二步 5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-2,3-二氢-1H-茚-4-甲酰胺(化合物9-3)的合成：Step 2 Synthesis of 5-{6-azaspiro[2.5]octane-6-yl}-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (Compound 9-3):
氮气保护，室温下向7-溴-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-5-氟-2,3-二氢-1H-茚-4-甲酰胺(80mg,0.171mmol,1eq)和6-氮杂螺[2.5]辛烷盐酸盐(126.11mg,0.855mmol,5eq)的N,N-二甲基乙酰胺(4mL)溶液中，加入叔丁醇钠(82.08mg,0.855mmol,5eq)。反应液升温至140℃，搅拌48小时。反应液冷却至室温，用乙酸乙酯萃取(3×50mL)。合并有机相，用饱和食盐水反洗(3×50mL)，无水硫酸钠干燥。所得混合物过滤，滤液减压浓缩。所得残余物用制备色谱板纯化，石油醚/乙酸乙酯(1:1)，得到5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-2,3-二氢-1H-茚-4-甲酰胺(50mg,52.31％)。Under nitrogen protection, sodium tert-butoxide (82.08 mg, 0.855 mmol, 5 eq) was added to a solution of 7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-5-fluoro-2,3-dihydro-1H-indene-4-carboxamide (80 mg, 0.171 mmol, 1 eq) and 6-azaspiro[2.5]octane hydrochloride (126.11 mg, 0.855 mmol, 5 eq) in N,N-dimethylacetamide (4 mL) at room temperature. The reaction solution was heated to 140°C and stirred for 48 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate (3×50 mL). The organic phases were combined, backwashed with saturated brine (3×50 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative chromatography using petroleum ether/ethyl acetate (1:1) to give 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (50 mg, 52.31%).
MS:(ESI,m/z):559.45[M+H]+,RT(min):1.590.MS: (ESI, m/z): 559.45 [M+H] + , RT (min): 1.590.
第三步 5-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(化合物9)的合成：Step 3 Synthesis of 5-{6-azaspiro[2.5]octan-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (Compound 9):
氮气保护，室温下向5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-2,3-二氢-1H-茚-4-甲酰胺(45mg,0.080mmol,1eq)和2-羟基乙磺酰胺(20.13mg,0.160mmol,2eq)的1,4-二氧六环(4.5mL)溶液中，加入二环己基(3-异丙氧基-2',4',6'-三异丙基-[1,1'-联苯基]-2-基)磷烷(8.6mg,0.016mmol,0.2eq)，(甲磺酸{双环己基(3-异丙氧-2',4',6'-三异丙基-[1,1'-联苯]-2-基)膦烷}(2'-甲氨基-1,1'-联苯-2-基)钯(II)(7.39mg,0.008mmol,0.1eq)和碳酸铯(78.62mg,0.240mmol,3eq)。反应液升温至100℃搅拌1小时。反应液冷却至室温，用乙酸乙酯萃取(3×10mL)。合并有机相，用饱和食盐水反洗(1×10mL)，无水硫酸钠干燥。所得混合物过滤，滤液减压浓缩。粗品通过制备型高效液相纯化得到5-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(8.8mg,17.98％)。Under nitrogen protection, 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (45 mg, 0.080 mmol, 1 eq) and 2-hydroxyethanesulfonamide (20.13 mg, 0.160 mmol, 2 eq) were added to a solution of 1:1, ... , 4-dioxane (4.5 mL) solution, add dicyclohexyl (3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphane (8.6 mg, 0.016 mmol, 0.2 eq), (methanesulfonic acid {dicyclohexyl (3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphane} (2' -methylamino-1,1'-biphenyl-2-yl)palladium(II) (7.39 mg, 0.008 mmol, 0.1 eq) and cesium carbonate (78.62 mg, 0.240 mmol, 3 eq). The reaction solution was heated to 100°C and stirred for 1 hour. The reaction solution was cooled to room temperature and extracted with ethyl acetate (3×10 mL). The organic phases were combined, backwashed with saturated brine (1×10 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid phase to obtain 5-{6-azaspiro[2.5]octan-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (8.8 mg, 17.98%).
MS:(ESI,m/z):604.40[M+H]+,RT(min):1.861.MS: (ESI, m/z): 604.40 [M+H] + , RT (min): 1.861.
1H NMR:(400MHz,DMSO-d6)δ12.16(s,1H),9.31(s,1H),7.46(s,1H),7.22(s,1H),6.53(s,1H),4.96(s,1H),3.77(t,J＝6.5Hz,2H),3.71(t,J＝5.8Hz,4H),3.33(s,1H),3.29(s,1H),3.21(t,J＝7.5Hz,2H),2.94(t,J＝5.3Hz,4H),2.85(t,J＝7.5Hz,2H),2.26(s,3H),2.05-1.88(m,6H),1.63(s,4H),0.34(s,4H). 1 H NMR: (400 MHz, DMSO-d 6 ) δ 12.16 (s, 1H), 9.31 (s, 1H), 7.46 (s, 1H), 7.22 (s, 1H), 6.53 (s, 1H), 4.96 (s, 1H), 3.77 (t, J=6.5 Hz, 2H), 3.71 (t, J=5.8 Hz, 4H), 3.33 (s, 1H), 3.29 (s, 1H), 3.21 (t, J=7.5 Hz, 2H), 2.94 (t, J=5.3 Hz, 4H), 2.85 (t, J=7.5 Hz, 2H), 2.26 (s, 3H), 2.05-1.88 (m, 6H), 1.63 (s, 4H), 0.34 (s, 4H).
实施例3Example 3
5-(6-氮杂螺[2.5]辛烷-6-基)-N-[6-(4,4-二氟哌啶-1-基)吡啶-2-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(化合物8)
5-(6-Azaspiro[2.5]octan-6-yl)-N-[6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (Compound 8)
第一步 5-(6-氮杂螺[2.5]辛烷-6-基)-7-溴-2,3-二氢-1H-茚-4-甲酸(化合物8-1)的合成：Step 1 Synthesis of 5-(6-azaspiro[2.5]octane-6-yl)-7-bromo-2,3-dihydro-1H-indene-4-carboxylic acid (Compound 8-1):
氮气保护，室温下向7-溴-5-氟-2,3-二氢-1H-茚-4-甲酸(50mg,0.161mmol,1eq)的N-甲基吡咯烷酮(1mL)溶液中加入叔丁醇钠(77.50mg,0.805mmol,5eq)，搅拌反应2分后，室温下加入6-氮杂螺[2.5]辛烷盐酸盐(89.66mg,0.805mmol,5eq)。反应体系升温至160℃，反应4小时。反应液冷却至室温，用乙酸乙酯萃取(3×10mL)。合并有机相，用饱和食盐水反洗(1×10mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(3:1)，得到5-(6-氮杂螺[2.5]辛烷-6-基)-7-溴-2,3-二氢-1H-茚-4-甲酸(30mg,53.11％)。Under nitrogen protection, sodium tert-butoxide (77.50 mg, 0.805 mmol, 5 eq) was added to a solution of 7-bromo-5-fluoro-2,3-dihydro-1H-indene-4-carboxylic acid (50 mg, 0.161 mmol, 1 eq) in N-methylpyrrolidone (1 mL) at room temperature. After stirring for 2 minutes, 6-azaspiro[2.5]octane hydrochloride (89.66 mg, 0.805 mmol, 5 eq) was added at room temperature. The reaction system was heated to 160°C and reacted for 4 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate (3×10 mL). The organic phases were combined, backwashed with saturated brine (1×10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (3:1) to give 5-(6-azaspiro[2.5]octan-6-yl)-7-bromo-2,3-dihydro-1H-indene-4-carboxylic acid (30 mg, 53.11%).
MS:(ESI,m/z):377.00[M+H]+,RT(min):0.827MS:(ESI,m/z):377.00[M+H] + ,RT(min):0.827
第二步 5-(6-氮杂螺[2.5]辛烷-6-基)-7-溴-N-[6-(4,4-二氟哌啶-1-基)吡啶-2-基]-2,3-二氢-1H-茚-4-甲酰胺(化合物8-3)的合成：Step 2 Synthesis of 5-(6-azaspiro[2.5]octane-6-yl)-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (Compound 8-3):
氮气保护，室温下向5-(6-氮杂螺[2.5]辛烷-6-基)-7-溴-2,3-二氢-1H-茚-4-甲酸(20mg,0.057mmol,1eq)的二氯甲烷(1mL)溶液中加入6-(4,4-二氟哌啶-1-基)吡啶-2-胺(9.13mg,0.044mmol,1.5eq)，四甲基氯代脲六氟磷酸酯(64.09mg,0.228mmol,4eq)，N-甲基咪唑(46.88mg,0.570mmol,10eq)。反应液升温至80℃反应1小时。反应液冷却至室温，用二氯甲烷萃取(3×10mL)。合并有机相，用饱和食盐水反洗(1×10mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(3:1)，得到5-(6-氮杂螺[2.5]辛烷-6-基)-7-溴-N-[6-(4,4-二氟哌啶-1-基)吡啶-2-基]-2,3-二氢-1H-茚-4-甲酰胺(30mg,96.32％)。Under nitrogen protection, 6-(4,4-difluoropiperidin-1-yl)pyridin-2-amine (9.13 mg, 0.044 mmol, 1.5 eq), tetramethyl chlorouronium hexafluorophosphate (64.09 mg, 0.228 mmol, 4 eq), and N-methylimidazole (46.88 mg, 0.570 mmol, 10 eq) were added to a solution of 5-(6-azaspiro[2.5]octan-6-yl)-7-bromo-2,3-dihydro-1H-indene-4-carboxylic acid (20 mg, 0.057 mmol, 1 eq) in dichloromethane (1 mL) at room temperature. The reaction solution was heated to 80°C for 1 hour. The reaction solution was cooled to room temperature and extracted with dichloromethane (3×10 mL). The organic phases were combined, backwashed with saturated brine (1×10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (3:1) to give 5-(6-azaspiro[2.5]octan-6-yl)-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (30 mg, 96.32%).
MS:(ESI,m/z):365.90[M+H]+,RT(min):1.140MS:(ESI,m/z):365.90[M+H] + ,RT(min):1.140
第三步 5-(6-氮杂螺[2.5]辛烷-6-基)-N-[6-(4,4-二氟哌啶-1-基)吡啶-2-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(化合物8)的合成：Step 3 Synthesis of 5-(6-azaspiro[2.5]octan-6-yl)-N-[6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (Compound 8):
氮气保护，室温下向5-(6-氮杂螺[2.5]辛烷-6-基)-7-溴-N-[6-(4,4-二氟哌啶-1-基)吡啶-2-基]-2,3-二氢-1H-茚-4-甲酰胺(25mg,0.046mmol,1eq)的1,4-二氧六环(1mL,11.804mmol,257.55eq)溶液中加入双环已基(3-异丙氧-2′,4′,6′-三异丙基-[1,1′-联苯]-2-基)膦烷(4.90mg,0.009mmol,0.2eq),(甲磺酸{双环己基(3-异丙氧-2',4′,6′-三异丙基-[1,1′-联苯]-2-基)膦烷}(2'-甲氨基-1,1'-联苯-2-基)钯(II)(4.21mg,0.005mmol,0.1eq)，碳酸铯(44.80mg,0.138mmol,3eq)和2-羟基乙磺酰胺(8.60mg,0.069mmol,1.5eq)。反应液升温至100℃，搅拌1小时。反应液冷却至室温，用乙酸乙酯萃取(3×10mL)。合并有机相，用饱和食盐水反洗(1×10mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。粗品通过高效液相纯化，条件如下(色谱柱kinete 5μm EVO C18，30mm*150mm，流动相A：水(10mmol/L碳酸氢铵)，流动相B:乙腈，流速：60mL/min，洗脱梯度:40％B to 75％B in 8min；254nm；Rt:6.9min)，得到5-(6-氮杂螺[2.5]辛烷-6-基)-N-[6-(4,4-二氟哌啶-1-基)吡啶-2-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(2.79mg,10.29％)。To a solution of 5-(6-azaspiro[2.5]octan-6-yl)-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (25 mg, 0.046 mmol, 1 eq) in 1,4-dioxane (1 mL, 11.804 mmol, 257.55 eq) was added bicyclohexyl (3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-4-carboxamide) (25 mg, 0.046 mmol, 1 eq) at room temperature. ]-2-yl)phosphine (4.90 mg, 0.009 mmol, 0.2 eq), (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine} (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (4.21 mg, 0.005 mmol, 0.1 eq), cesium carbonate (44.80 mg, 0.138 mmol, 3 eq) and 2-hydroxyethanesulfonamide (8.60 mg, 0.069mmol, 1.5eq). The reaction solution was heated to 100°C and stirred for 1 hour. The reaction solution was cooled to room temperature and extracted with ethyl acetate (3×10mL). The organic phases were combined, backwashed with saturated brine (1×10mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (chromatographic column kinete 5μm EVO C18, 30mm*150mm, mobile phase A: water (10mm ol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60mL/min, elution gradient: 40% B to 75% B in 8min; 254nm; Rt: 6.9min), to obtain 5-(6-azaspiro[2.5]octan-6-yl)-N-[6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (2.79mg, 10.29%).
MS:(ESI,m/z):590.05[M+H]+,RT(min):1.874MS:(ESI,m/z):590.05[M+H] + ,RT(min):1.874
1H-NMR:(400MHz,DMSO-d6)δ12.30(s,1H),9.34(s,1H),7.61–7.54(m,2H),7.22(s,1H),6.70–6.63(m,1H),4.99(s,1H),3.77(t,J＝6.5Hz,2H),3.72(t,J＝5.7Hz,4H),3.30(s,2H),3.22(t,J＝7.5Hz,2H),3.03–2.89(m,4H),2.83(t,J＝7.5Hz,2H),2.09–1.90(m,6H),1.64(s,4H),0.35(s,4H). 1 H-NMR: (400 MHz, DMSO-d 6 ) δ 12.30 (s, 1H), 9.34 (s, 1H), 7.61–7.54 (m, 2H), 7.22 (s, 1H), 6.70–6.63 (m, 1H), 4.99 (s, 1H), 3.77 (t, J=6.5 Hz, 2H), 3.72 (t, J=5.7 Hz, 4H), 3.30 (s, 2H), 3.22 (t, J=7.5 Hz, 2H), 3.03–2.89 (m, 4H), 2.83 (t, J=7.5 Hz, 2H), 2.09–1.90 (m, 6H), 1.64 (s, 4H), 0.35 (s, 4H).
实施例4Example 4
5-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)吡嗪-2-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(化合物13)
5-{6-azaspiro[2.5]octan-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (Compound 13)
第一步 5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[6-(4,4-二氟哌啶-1-基)吡嗪-2-基]-2,3-二氢-1H-茚-4-甲酰胺(化合物13-2)的合成：Step 1 Synthesis of 5-{6-azaspiro[2.5]octane-6-yl}-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)pyrazine-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (Compound 13-2):
氮气保护，室温下向5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-2,3-二氢-1H-茚-4-甲酸(25mg,0.071mmol,1eq)和6-(4,4-二氟哌啶-1-基)吡嗪-2-胺(18.35mg,0.085mmol,1.2eq)的二氯甲烷(5mL)溶液中，加入N,N,N,N-四甲基氯甲脒六氟磷酸盐(80.11mg,0.284mmol,4eq)和N-甲基咪唑(58.60mg,0.710mmol,10eq)，反应液升温至80℃，搅拌反应1小时。反应液冷却至室温，反应液用乙酸乙酯萃取(3×5mL)。合并有机相，用饱和食盐水反洗(1×10mL)，无水硫酸钠干燥。过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(3:1)得到5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[6-(4,4-二氟哌啶-1-基)吡嗪-2-基]-2,3-二氢-1H-茚-4-甲酰胺(25mg,39.19％)。Under nitrogen protection, N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (80.11 mg, 0.284 mmol, 4 eq) and N-methylimidazole (58.60 mg, 0.710 mmol, 10 eq) were added to a solution of 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-2,3-dihydro-1H-indene-4-carboxylic acid (25 mg, 0.071 mmol, 1 eq) and 6-(4,4-difluoropiperidin-1-yl)pyrazin-2-amine (18.35 mg, 0.085 mmol, 1.2 eq) in dichloromethane (5 mL) at room temperature. The reaction solution was heated to 80°C and stirred for 1 hour. The reaction solution was cooled to room temperature and extracted with ethyl acetate (3×5 mL). The organic phases were combined, backwashed with saturated brine (1×10 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and petroleum ether/ethyl acetate (3:1) to give 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (25 mg, 39.19%).
MS:(ESI,m/z):548.05[M+H]+,RT(min):1.255MS:(ESI,m/z):548.05[M+H] + ,RT(min):1.255
第二步 5-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)吡嗪-2-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(化合物13)的合成：Step 2 Synthesis of 5-{6-azaspiro[2.5]octan-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (Compound 13):
氮气保护，室温下向5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[6-(4,4-二氟哌啶-1-基)吡嗪-2-基]-2,3-二氢-1H-茚-4-甲酰胺(25mg,0.046mmol,1eq)和2-羟基乙磺酰胺(11.6mg,0.092mmol,2eq)的1,4-二氧六环溶液(5mL)中加入双环已基(3-异丙氧-2′,4′,6′-三异丙基-[1,1′-联苯]-2-基)膦烷(2.45mg,0.005mmol,0.1eq)和甲烷磺酸{双环己基[3-异丙氧-2',4′,6′-三异丙基-(1,1′-联苯)-2-基]膦烷}(2'-甲氨基-1,1'-联苯-2-基)钯(II)(8.40mg,0.009mmol,0.2eq)和碳酸铯(44.72mg,0.138mmol,3eq)，反应液升温至100℃，搅拌反应1小时。反应液冷却至室温，用乙酸乙酯萃取(3×5mL)。合并有机相，用饱和氯化钠溶液反洗(2×5mL)，无水硫酸钠干燥。过滤，滤液减压浓缩。所得残余物用制备型高效液相纯化，条件如下：层析柱规格:Ultimate 5μM XB-C18；流动相A:水(10mmol/L碳酸氢钠),流动相B:乙腈；流速:60ml/min；洗脱梯度:35％B to 60％B in 22min；检测波长:254nm/220nm；保留时间(min):7.55，得到5-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)吡嗪-2-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(2.23mg,8.17％)。To a solution of 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (25 mg, 0.046 mmol, 1 eq) and 2-hydroxyethanesulfonamide (11.6 mg, 0.092 mmol, 2 eq) in 1,4-dioxane (5 mL) was added bicyclohexyl (3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′ -biphenyl]-2-yl)phosphine (2.45mg, 0.005mmol, 0.1eq) and methanesulfonic acid {biscyclohexyl [3-isopropoxy-2', 4', 6'-triisopropyl-(1,1'-biphenyl)-2-yl]phosphine} (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (8.40mg, 0.009mmol, 0.2eq) and cesium carbonate (44.72mg, 0.138mmol, 3eq), the reaction solution was heated to 100°C and stirred for 1 hour. The reaction solution was cooled to room temperature and extracted with ethyl acetate (3×5mL). The organic phases were combined, backwashed with saturated sodium chloride solution (2×5mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC under the following conditions: chromatography column specifications: Ultimate 5μM XB-C18; mobile phase A: water (10mmol/L sodium bicarbonate), mobile phase B: acetonitrile; flow rate: 60ml/min; elution gradient: 35%B to 60%B in 22min; detection wavelength: 254nm/220nm; retention time (min): 7.55, to obtain 5-{6-azaspiro[2.5]octane-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (2.23mg, 8.17%).
MS:(ESI,m/z):591.20[M+H]+,RT(min):1.754MS:(ESI,m/z):591.20[M+H] + ,RT(min):1.754
1H NMR(400MHz,DMSO-d6)δ12.99(s,1H),8.76(s,1H),8.16(s,1H),7.24(s,1H),5.00(s,1H),3.77(d,J＝6.5Hz,6H),3.24(m,4H),2.95(d,J＝5.3Hz,4H),2.80(t,J＝7.6Hz,2H),2.05(m,4H),1.95(m,2H),1.64(s,4H),0.36(s,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 8.76 (s, 1H), 8.16 (s, 1H), 7.24 (s, 1H), 5.00 (s, 1H), 3.77 (d, J=6.5 Hz, 6H), 3.24 (m, 4H), 2.95 (d, J=5.3 Hz, 4H), 2.80 (t, J=7.6 Hz, 2H), 2.05 (m, 4H), 1.95 (m, 2H), 1.64 (s, 4H), 0.36 (s, 4H).
实施例5Example 5
5-(6-氮杂螺[2.5]辛烷-6-基)-N-[2-(4,4-二氟哌啶-1-基)-3-氟吡啶-4-基]-7-(2-羟基乙基磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(化合物27)
5-(6-Azaspiro[2.5]octan-6-yl)-N-[2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-4-yl]-7-(2-hydroxyethylsulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (Compound 27)
第一步 5-(6-氮杂螺[2.5]辛烷-6-基)-7-溴-N-[2-(4,4-二氟哌啶-1-基)-3-氟吡啶-4-基]-2,3-二氢-1H-茚-4-甲酰胺(化合物27-2)的合成：The first step is the synthesis of 5-(6-azaspiro[2.5]octane-6-yl)-7-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-4-yl]-2,3-dihydro-1H-indene-4-carboxamide (compound 27-2):
氮气保护，室温下向5-(6-氮杂螺[2.5]辛烷-6-基)-7-溴-2,3-二氢-1H-茚-4-甲酸(25mg,0.071mmol,1eq)和2-(4,4-二氟哌啶-1-基)-3-氟吡啶-4-胺(18.15mg,0.078mmol,1.1eq)的二氯甲烷(2mL)溶液中，加入N,N,N',N'-四甲基氯甲脒六氟磷酸盐(80.11mg,0.284mmol,4eq)和1-甲基咪唑(58.60mg,0.710mmol,10eq)。升温至60℃搅拌反应1小时。反应混合物用水(10mL)稀释。用二氯甲烷萃取(3×10mL)。合并有机相，用饱和食盐水反洗(1×10mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(10:1)，得到5-(6-氮杂螺[2.5]辛烷-6-基)-7-溴-N-[2-(4,4-二氟哌啶-1-基)-3-氟吡啶-4-基]-2,3-二氢-1H-茚-4-甲酰胺(35mg,85.25％)。Under nitrogen protection, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (80.11 mg, 0.284 mmol, 4 eq) and 1-methylimidazole (58.60 mg, 0.710 mmol, 10 eq) were added to a solution of 5-(6-azaspiro[2.5]octan-6-yl)-7-bromo-2,3-dihydro-1H-indene-4-carboxylic acid (25 mg, 0.071 mmol, 1 eq) and 2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-4-amine (18.15 mg, 0.078 mmol, 1.1 eq) in dichloromethane (2 mL) at room temperature. The mixture was heated to 60°C and stirred for 1 hour. The reaction mixture was diluted with water (10 mL). Extracted with dichloromethane (3×10 mL). The organic phases were combined, backwashed with saturated brine (1×10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, petroleum ether/ethyl acetate (10:1) to obtain 5-(6-azaspiro[2.5]octan-6-yl)-7-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-4-yl]-2,3-dihydro-1H-indene-4-carboxamide (35 mg, 85.25%).
MS:(ESI,m/z):563.15[M+H]+,RT(min):1.184MS:(ESI,m/z):563.15[M+H] + ,RT(min):1.184
第二步 5-(6-氮杂螺[2.5]辛烷-6-基)-N-[2-(4,4-二氟哌啶-1-基)-3-氟吡啶-4-基]-7-(2-羟基乙基磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(化合物27)的合成：Step 2 Synthesis of 5-(6-azaspiro[2.5]octan-6-yl)-N-[2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-4-yl]-7-(2-hydroxyethylsulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (Compound 27):
氮气保护，室温下，向5-(6-氮杂螺[2.5]辛烷-6-基)-7-溴-N-[2-(4,4-二氟哌啶-1-基)-3-氟吡啶-4-基]-2,3-二氢-1H-茚-4-甲酰胺(30mg,0.053mmol,1eq)和2-羟基乙磺酰胺(13.33mg,0.106mmol,2eq)的1,4-二氧六环溶液(2mL)中，加入碳酸铯(52.04mg,0.159mmol,3eq),双环已基(3-异丙氧-2′,4′,6′-三异丙基-[1,1′-联苯]-2-基)膦烷(5.69mg,0.011mmol,0.2eq)和(甲磺酸{双环己基(3-异丙氧-2',4′,6′-三异丙基-[1,1′-联苯]-2-基)膦烷}(2'-甲氨基-1,1'-联苯-2-基)钯(II)(4.89mg,0.005mmol,0.1eq)。加入完毕后体系100℃继续搅拌1小时。反应结束，加入水(10mL)淬灭反应，并用乙酸乙酯萃取(3×10mL)。合并有机相，用饱和食盐水反洗(1×10mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。粗品通过高效液相纯化，条件如下：层析柱规格:XBridge BEH Shield RP18 5μm,30mm*150mm；流动相A:水(10mmol/L碳酸氢铵)，流动相B:乙腈；流速:60mL/min；洗脱梯度:50％B to 75％B in 8min；254nm；Rt:6.9min。得到5-(6-氮杂螺[2.5]辛烷-6-基)-N-[2-(4,4-二氟哌啶-1-基)-3-氟吡啶-4-基]-7-(2-羟基乙基磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(17.1mg,52.75％).Under nitrogen protection, cesium carbonate (52.04 mg, 0.159 mmol, 2 eq) was added to a solution of 5-(6-azaspiro[2.5]octan-6-yl)-7-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-4-yl]-2,3-dihydro-1H-indene-4-carboxamide (30 mg, 0.053 mmol, 1 eq) and 2-hydroxyethanesulfonamide (13.33 mg, 0.106 mmol, 2 eq) in 1,4-dioxane (2 mL) at room temperature. mol, 3eq), bicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (5.69 mg, 0.011 mmol, 0.2eq) and (methanesulfonic acid {bicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine}(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) (4.89 mg, 0.005 mmol, 0.1eq) were added. After completion, the system was stirred at 100°C for 1 hour. After the reaction was completed, water (10 mL) was added to quench the reaction and extracted with ethyl acetate (3×10 mL). The organic phases were combined, backwashed with saturated brine (1×10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions: Chromatography column specifications: XBridge BEH Shield RP18 5μm, 30mm*150mm; Mobile phase A: water (10mm ol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL/min; elution gradient: 50% B to 75% B in 8min; 254nm; Rt: 6.9min. 5-(6-azaspiro[2.5]octan-6-yl)-N-[2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-4-yl]-7-(2-hydroxyethylsulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (17.1mg, 52.75%) was obtained.
MS:(ESI,m/z):608.45[M+H]+,RT(min):1.736MS:(ESI,m/z):608.45[M+H] + ,RT(min):1.736
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),9.33(s,1H),8.00–7.85(m,2H),7.18(s,1H),4.99(s,1H),3.78(t,J＝6.5Hz,2H),3.54(t,J＝5.7Hz,4H),3.30(d,J＝6.4Hz,2H),3.10(t,J＝7.5Hz,2H),2.94(t,J＝5.2Hz,4H),2.85(t,J＝7.5Hz,2H),2.14–2.01(m,4H),2.01–1.91(m,2H),1.46(s,4H),0.32(s,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.50 (s, 1H), 9.33 (s, 1H), 8.00–7.85 (m, 2H), 7.18 (s, 1H), 4.99 (s, 1H), 3.78 (t, J=6.5 Hz, 2H), 3.54 (t, J=5.7 Hz, 4H), 3.30 (d, J=6.4 Hz, 2H), 3.10 (t, J=7.5 Hz, 2H), 2.94 (t, J=5.2 Hz, 4H), 2.85 (t, J=7.5 Hz, 2H), 2.14–2.01 (m, 4H), 2.01–1.91 (m, 2H), 1.46 (s, 4H), 0.32 (s, 4H).
实施例6Example 6
5-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)-5-氟吡啶-2-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(化合物28)
5-{6-azaspiro[2.5]octan-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (Compound 28)
第一步 5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[6-(4,4-二氟哌啶-1-基)-5-氟吡啶-2-基]-2,3-二氢-1H-茚-4-甲酰胺(化合物28-2)的合成：The first step is the synthesis of 5-{6-azaspiro[2.5]octane-6-yl}-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (compound 28-2):
氮气保护，室温下向5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-2,3-二氢-1H-茚-4-甲酸(30mg,0.086mmol,1eq)的二氯甲烷(1mL)溶液中加入6-(4,4-二氟哌啶-1-基)-5-氟吡啶-2-胺(23.77mg,0.103mmol,1.2eq),四甲基氯甲脒六氟磷酸盐(96.13mg,0.344mmol,4eq)和N-甲基咪唑(70.33mg,0.860mmol,10eq)，80℃下搅拌反应1小时。反应液冷却至室温，用乙酸乙酯萃取(3×20mL)。合并有机相，用饱和食盐水反洗(1×20mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(8:1)，得到5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[6-(4,4-二氟哌啶-1-基)-5-氟吡啶-2-基]-2,3-二氢-1H-茚-4-甲酰胺(50mg,91.17％)。Under nitrogen protection, 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-amine (23.77 mg, 0.103 mmol, 1.2 eq), tetramethylchloroformamidine hexafluorophosphate (96.13 mg, 0.344 mmol, 4 eq) and N-methylimidazole (70.33 mg, 0.860 mmol, 10 eq) were added to a solution of 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-2,3-dihydro-1H-indene-4-carboxylic acid (30 mg, 0.086 mmol, 1 eq) in dichloromethane (1 mL) at room temperature, and the mixture was stirred at 80°C for 1 hour. The reaction solution was cooled to room temperature and extracted with ethyl acetate (3×20 mL). The organic phases were combined, backwashed with saturated brine (1×20 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (8:1) to give 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (50 mg, 91.17%).
MS:(ESI,m/z):562.65[M+H]+,RT(min):1.806MS:(ESI,m/z):562.65[M+H] + ,RT(min):1.806
第二步 5-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)-5-氟吡啶-2-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(化合物28)的合成：Step 2 Synthesis of 5-{6-azaspiro[2.5]octan-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (Compound 28):
氮气保护，室温下向5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[6-(4,4-二氟哌啶-1-基)-5-氟吡啶-2-基]-2,3-二氢-1H-茚-4-甲酰胺(50mg,0.089mmol,1eq)的1,4-二氧六环(2mL)溶液中加入(甲磺酸{双环己基(3-异丙氧-2’,4′,6′-三异丙基-[1,1′-联苯]-2-基)膦烷}(2’-甲氨基-1,1’-联苯-2-基)钯(II)(8.15mg,0.009mmol,0.1eq)，双环已基(3-异丙氧-2′,4′,6′-三异丙基-[1,1′-联苯]-2-基)膦烷(9.49mg,0.018mmol,0.2eq)，碳酸铯(86.74mg,0.267mmol,3eq)和2-羟基乙烷-1-磺酰胺(16.66mg,0.134mmol,1.5eq)。反应液升温至100℃，继续搅拌1小时。反应液冷却至室温，用乙酸乙酯萃取(3×10mL)，合并有机相，用饱和食盐水反洗(2×10mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品通过制备型高效液相纯化，条件如下：层析柱规格:YMC Triart C18 EXRs 5μm,30mm*150mm；流动相A:水(0.1％碳酸氢铵)，流动相B:乙腈；流速:60mL/min；洗脱梯度:60％B to 85％B in 8min,；检测波长:220nm；保留时间(min):7.8。得到5-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)-5-氟吡啶-2-基]-7-(2-羟基乙磺酰胺基)-2,3-二氢-1H-茚-4-甲酰胺(10.08mg,18.69％)To a solution of 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl]-2,3-dihydro-1H-indene-4-carboxamide (50 mg, 0.089 mmol, 1 eq) in 1,4-dioxane (2 mL) was added (methanesulfonic acid {bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane} (2' -methylamino-1,1'-biphenyl-2-yl)palladium(II) (8.15 mg, 0.009 mmol, 0.1 eq), bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (9.49 mg, 0.018 mmol, 0.2 eq), cesium carbonate (86.74 mg, 0.267 mmol, 3 eq) and 2-hydroxyethane-1-sulfonamide (16.66 mg, 0.134 mmol, 1.5eq). The reaction solution was heated to 100°C and stirred for 1 hour. The reaction solution was cooled to room temperature, extracted with ethyl acetate (3×10mL), the organic phases were combined, backwashed with saturated brine (2×10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography under the following conditions: Chromatographic column specifications: YMC Triart C18 EXRs 5μm, 30mm*150mm; Mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: water (0.1% ammonium bicarbonate), mobile phase C: water (0.1% ammonium bicarbonate), mobile phase D: water (0.1% ammonium bicarbonate), mobile phase E: water (0.1% ammonium bicarbonate), mobile phase F: water (0.1% ammonium bicarbonate), mobile phase F: water (0.1% ammonium bicarbonate), mobile phase G ... Phase B: acetonitrile; flow rate: 60 mL/min; elution gradient: 60% B to 85% B in 8 min, detection wavelength: 220 nm; retention time (min): 7.8. 5-{6-azaspiro[2.5]octan-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-2,3-dihydro-1H-indene-4-carboxamide (10.08 mg, 18.69%) was obtained.
MS:(ESI,m/z):608.45[M+H]+,RT(min):1.863MS:(ESI,m/z):608.45[M+H] + ,RT(min):1.863
1H NMR:(400MHz,DMSO-d6)δ12.43(s,1H),9.34(s,1H),7.78–7.68(m,1H),7.62–7.52(m,1H),7.23(s,1H),4.97(s,1H),3.77(s,2H),3.64–3.48(m,4H),3.30(s,2H),3.25–3.18(m,2H),3.01–2.89(m,4H),2.88–2.79(m,2H),2.18–2.03(m,4H),2.02–1.91(m,2H),1.63(s,4H),0.35(s,4H). 1 H NMR: (400 MHz, DMSO-d 6 ) δ 12.43 (s, 1H), 9.34 (s, 1H), 7.78–7.68 (m, 1H), 7.62–7.52 (m, 1H), 7.23 (s, 1H), 4.97 (s, 1H), 3.77 (s, 2H), 3.64–3.48 (m, 4H), 3.30 (s, 2H), 3.25–3.18 (m, 2H), 3.01–2.89 (m, 4H), 2.88–2.79 (m, 2H), 2.18–2.03 (m, 4H), 2.02–1.91 (m, 2H), 1.63 (s, 4H), 0.35 (s, 4H).
实施例7Example 7
7-{6-氮杂螺[2.5]辛烷-6-基}-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]-5-(2-羟基乙磺酰胺基)咪唑并[1,2-a]吡啶-8-甲酰胺(化合物29)
7-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-5-(2-hydroxyethanesulfonamido)imidazo[1,2-a]pyridine-8-carboxamide (Compound 29)
第一步 5,7-二氯咪唑并[1,2-a]吡啶-8-甲酸甲酯(化合物29-3)的合成：Step 1 Synthesis of 5,7-dichloroimidazo[1,2-a]pyridine-8-carboxylic acid methyl ester (Compound 29-3):
氮气保护，室温下将2-溴-1,1-二甲氧基乙烷(3.2g,19.001mmol,2.1eq)的氢溴酸(20mL)溶液搅拌反应30分钟后，加乙醇(15mL)，随后向上述体系中加入碳酸氢钠(5.3g,63.336mmol,7eq)和2-氨基-4,6-二氯吡啶-3-甲酸甲酯(2g,9.048mmol,1eq)。反应液升温至60℃，继续搅拌1小时。反应液冷却至室温，加水淬灭，反应混合物用乙酸乙酯萃取(3×80mL)。合并有机相，用饱和食盐水反洗(2×80mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(3:1)，得到5,7-二氯咪唑并[1,2-a]吡啶-8-甲酸甲酯(1.5g,67.65％)Under nitrogen protection, a solution of 2-bromo-1,1-dimethoxyethane (3.2 g, 19.001 mmol, 2.1 eq) in hydrobromic acid (20 mL) was stirred at room temperature for 30 minutes, and then ethanol (15 mL) was added. Then sodium bicarbonate (5.3 g, 63.336 mmol, 7 eq) and methyl 2-amino-4,6-dichloropyridine-3-carboxylate (2 g, 9.048 mmol, 1 eq) were added to the above system. The reaction solution was heated to 60 ° C and stirred for 1 hour. The reaction solution was cooled to room temperature, quenched with water, and the reaction mixture was extracted with ethyl acetate (3×80 mL). The organic phases were combined, backwashed with saturated brine (2×80 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (3:1) to obtain methyl 5,7-dichloroimidazo[1,2-a]pyridine-8-carboxylate (1.5 g, 67.65%)
MS:(ESI,m/z):244.08[M+H]+,RT(min):0.886MS:(ESI,m/z):244.08[M+H] + ,RT(min):0.886
第二步 5,7-二氯咪唑并[1,2-a]吡啶-8-甲酸(化合物29-4)的合成：Step 2 Synthesis of 5,7-dichloroimidazo[1,2-a]pyridine-8-carboxylic acid (Compound 29-4):
室温下向5,7-二氯咪唑并[1,2-a]吡啶-8-甲酸甲酯(680mg,2.775mmol,1eq)的水(5mL)和四氢呋喃(5mL)的混合溶液中加入氢氧化锂(199.37mg,8.325mmol,3eq)，室温搅拌反应16小时。反应混合物用1N盐酸溶液酸化到PH为6。所得混合物浓缩，得到粗品的5,7-二氯咪唑并[1,2-a]吡啶-8-甲酸(1.2g)。Lithium hydroxide (199.37 mg, 8.325 mmol, 3 eq) was added to a mixed solution of 5,7-dichloroimidazo[1,2-a]pyridine-8-carboxylic acid methyl ester (680 mg, 2.775 mmol, 1 eq) in water (5 mL) and tetrahydrofuran (5 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified to pH 6 with 1N hydrochloric acid solution. The resulting mixture was concentrated to give crude 5,7-dichloroimidazo[1,2-a]pyridine-8-carboxylic acid (1.2 g).
MS:(ESI,m/z):230.90[M+H]+,RT(min):0.498MS:(ESI,m/z):230.90[M+H] + ,RT(min):0.498
第三步 5,7-二氯-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]咪唑并[1,2-a]吡啶-8-甲酰胺(化合物29-5)的合成：Step 3 Synthesis of 5,7-dichloro-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]imidazo[1,2-a]pyridine-8-carboxamide (Compound 29-5):
氮气保护，室温下向5,7-二氯咪唑并[1,2-a]吡啶-8-甲酸(800mg,3.463mmol,1eq)的二氯甲烷(4mL)溶液中加入6-(4,4-二氟哌啶-1-基)-4-甲基嘧啶-2-胺(944.33mg,4.156mmol,1.2eq),N,N,N',N'-四甲基氯甲脒六氟磷酸盐(3886.32mg,13.852mmol,4eq)和N-甲基咪唑(2843.13mg,34.630mmol,10eq)。室温搅拌反应2小时。反应混合物用乙酸乙酯萃取(3×50mL)。合并有机相，用饱和食盐水反洗(1×50mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(5:1)，得到5,7-二氯-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]咪唑并[1,2-a]吡啶-8-甲酰胺(350mg,22.91％)。Under nitrogen protection, 6-(4,4-difluoropiperidin-1-yl)-4-methylpyrimidin-2-amine (944.33 mg, 4.156 mmol, 1.2 eq), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (3886.32 mg, 13.852 mmol, 4 eq) and N-methylimidazole (2843.13 mg, 34.630 mmol, 10 eq) were added to a solution of 5,7-dichloroimidazo[1,2-a]pyridine-8-carboxylic acid (800 mg, 3.463 mmol, 1 eq) in dichloromethane (4 mL) at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate (3×50 mL). The organic phases were combined, backwashed with saturated brine (1×50 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (5:1) to give 5,7-dichloro-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]imidazo[1,2-a]pyridine-8-carboxamide (350 mg, 22.91%).
MS:(ESI,m/z):441.25[M+H]+,RT(min):1.198MS:(ESI,m/z):441.25[M+H] + ,RT(min):1.198
第四步 2-[(7-氯-8-{[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]氨基甲酰基}咪唑并[1,2-a]吡啶-5-基)氨磺酰基]乙酸乙酯(化合物29-7)的合成：Step 4 Synthesis of ethyl 2-[(7-chloro-8-{[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]carbamoyl}imidazo[1,2-a]pyridin-5-yl)sulfamoyl]acetate (Compound 29-7):
氮气保护，室温下向5,7-二氯-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]咪唑并[1,2-a]吡啶-8-甲酰胺(300mg,0.680mmol,1eq)的1,4-二氧六环(5mL)溶液中加入2-氨磺酰基乙酸乙酯(170.49mg,1.020mmol,1.5eq),(甲磺酸{双环己基(3-异丙氧-2’,4′,6′-三异丙基-[1,1′-联苯]-2-基)膦烷}(2’-甲氨基-1,1’-联苯-2-基)钯(II)(62.45mg,0.068mmol,0.1eq)，双环已基(3-异丙氧-2′,4′,6′-三异丙基-[1,1′-联苯]-2-基)膦烷(72.72mg,0.136mmol,0.2eq)和碳酸铯(664.54mg,2.040mmol,3eq)。反应液升温至100℃反应1小时。反应液冷却至室温，反应混合物用乙酸乙酯萃取(3×40mL)。合并有机相，用饱和食盐水反洗(1×50mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(5:1)，得到2-[(7-氯-8-{[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]氨基甲酰基}咪唑并[1,2-a]吡啶-5-基)氨磺酰基]乙酸乙酯(150mg,38.57％)。To a solution of 5,7-dichloro-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]imidazo[1,2-a]pyridine-8-carboxamide (300 mg, 0.680 mmol, 1 eq) in 1,4-dioxane (5 mL) was added ethyl 2-sulfamoyl acetate (170.49 mg, 1.020 mmol, 1.5 eq), (methanesulfonic acid {biscyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (62.45 mg, 0.068 mmol, 0.1 eq), bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (62.45 mg, 0.068 mmol, 0.1 eq), and 1,4-dioxane (5 mL) were added. ]-2-yl)phosphine (72.72 mg, 0.136 mmol, 0.2 eq) and cesium carbonate (664.54 mg, 2.040 mmol, 3 eq). The reaction solution was heated to 100 ° C for 1 hour. The reaction solution was cooled to room temperature and the reaction mixture was extracted with ethyl acetate (3×40 mL). The organic phases were combined, backwashed with saturated brine (1×50 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, petroleum ether/ethyl acetate (5:1) to obtain ethyl 2-[(7-chloro-8-{[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]carbamoyl}imidazo[1,2-a]pyridin-5-yl)sulfamoyl]acetate (150 mg, 38.57%).
MS:(ESI,m/z):572.45[M+H]+,RT(min):1.094MS:(ESI,m/z):572.45[M+H] + ,RT(min):1.094
第五步 2-[(7-{6-氮杂螺[2.5]辛烷-6-基}-8-{[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]氨基甲酰基}咪唑并[1,2-a]吡啶-5-基]氨磺酰基]乙酸乙酯(化合物29-8)的合成：Step 5 Synthesis of ethyl 2-[(7-{6-azaspiro[2.5]octane-6-yl}-8-{[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]carbamoyl}imidazo[1,2-a]pyridin-5-yl]sulfamoyl]acetate (Compound 29-8):
氮气保护，室温下向2-[(7-氯-8-{[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]氨基甲酰基}咪唑并[1,2-a]吡啶-5-基)氨磺酰基]乙酸乙酯(120mg,0.210mmol,1eq)的叔丁醇(1mL)溶液中加入6-氮杂螺[2.5]辛烷(34.99mg,0.315mmol,1.5eq)和三乙胺(63.69mg,0.630mmol,3eq),反应液升温至100℃，搅拌反应2天。反应液冷却至室温，反应混合物用乙酸乙酯萃取(3×20mL)。合并有机相，用饱和食盐水反洗(2×20mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(1:1)，得到2-[(7-{6-氮杂螺[2.5]辛烷-6-基}-8-{[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]氨基甲酰基}咪唑并[1,2-a]吡啶-5-基]氨磺酰基]乙酸乙酯(60mg,44.22％)。Under nitrogen protection, 6-azaspiro[2.5]octane (34.99 mg, 0.315 mmol, 1.5 eq) and triethylamine (63.69 mg, 0.630 mmol, 3 eq) were added to a solution of ethyl 2-[(7-chloro-8-{[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]carbamoyl}imidazo[1,2-a]pyridin-5-yl)sulfamoyl]ethyl acetate (120 mg, 0.210 mmol, 1 eq) in tert-butanol (1 mL) at room temperature. The reaction solution was heated to 100°C and stirred for 2 days. The reaction solution was cooled to room temperature and the reaction mixture was extracted with ethyl acetate (3×20 mL). The organic phases were combined, backwashed with saturated brine (2×20 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (1:1) to give ethyl 2-[(7-{6-azaspiro[2.5]octan-6-yl}-8-{[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]carbamoyl}imidazo[1,2-a]pyridin-5-yl]sulfamoyl]acetate (60 mg, 44.22%).
MS:(ESI,m/z):647.45[M+H]+,RT(min):1.240MS:(ESI,m/z):647.45[M+H] + ,RT(min):1.240
第六步 7-{6-氮杂螺[2.5]辛烷-6-基}-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]-5-(2-羟基乙磺酰胺基)咪唑并[1,2-a]吡啶-8-甲酰胺(化合物29)的合成：Step 6 Synthesis of 7-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-5-(2-hydroxyethanesulfonamido)imidazo[1,2-a]pyridine-8-carboxamide (Compound 29):
氮气保护，0℃下向2-[(7-{6-氮杂螺[2.5]辛烷-6-基}-8-{[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]氨基甲酰基}咪唑并[1,2-a]吡啶-5-基]氨磺酰基]乙酸乙酯(60mg,0.093mmol,1eq)的四氢呋喃(3.00mL)溶液中加入氢化铝锂(5.28mg,0.140mmol,1.5eq)，室温下搅拌反应30分钟。反应液在0℃下用十水合硫酸钠淬灭。过滤，减压浓缩。粗品通过高效液相纯化，条件如下(层析柱规格:XBridge BEH Shield RP18 5μm,30mm*150mm；流动相A:水(10mmol/L碳酸氢钠),流动相B:乙腈；流速:60ml/min；洗脱梯度:40％B to 60％B in 10min；检测波长:254nm/220nm；保留时间(min):8.33)。得到7-{6-氮杂螺[2.5]辛烷-6-基}-N-[2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基]-5-(2-羟基乙磺酰胺基)咪唑并[1,2-a]吡啶-8-甲酰胺(1.8mg,3.21％)。Under nitrogen protection, lithium aluminum hydride (5.28 mg, 0.140 mmol, 1.5 eq) was added to a solution of ethyl 2-[(7-{6-azaspiro[2.5]octane-6-yl}-8-{[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]carbamoyl}imidazo[1,2-a]pyridin-5-yl]sulfamoyl]ethyl ester (60 mg, 0.093 mmol, 1 eq) in tetrahydrofuran (3.00 mL) at 0°C and the reaction was stirred at room temperature for 30 minutes. The reaction solution was quenched with sodium sulfate decahydrate at 0°C. Filter and concentrate under reduced pressure. The crude product was purified by HPLC under the following conditions (chromatography column specifications: XBridge BEH Shield RP18 5μm, 30mm*150mm; mobile phase A: water (10mmol/L sodium bicarbonate), mobile phase B: acetonitrile; flow rate: 60ml/min; elution gradient: 40%B to 60%B in 10min; detection wavelength: 254nm/220nm; retention time (min): 8.33). 7-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-5-(2-hydroxyethanesulfonamido)imidazo[1,2-a]pyridine-8-carboxamide (1.8mg, 3.21%) was obtained.
MS:(ES,m/z):605.45[M+H]+,RT(min):1.559.MS: (ES, m/z): 605.45 [M+H] + , RT (min): 1.559.
1H NMR:(400MHz,DMSO-d6)δ12.31(s,1H),11.77(s,1H),7.83(s,1H),7.48-7.28(m,2H),7.11(s,1H),4.15(s,2H),3.98(s,4H),3.70-3.35(m,4H),3.32-3.01(m,4H),2.55(s,2H),2.38(s,3H),1.98(s,4H),0.43(s,4H). 1 H NMR: (400 MHz, DMSO-d 6 ) δ 12.31 (s, 1H), 11.77 (s, 1H), 7.83 (s, 1H), 7.48-7.28 (m, 2H), 7.11 (s, 1H), 4.15 (s, 2H), 3.98 (s, 4H), 3.70-3.35 (m, 4H), 3.32-3.01 (m, 4H), 2.55 (s, 2H), 2.38 (s, 3H), 1.98 (s, 4H), 0.43 (s, 4H).
实施例8Example 8
N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-5-(2-羟基乙磺酰胺基)-7-{6-氮杂螺[2.5]辛烷-6-基}-[1,2,4]三唑并[1,5-a]吡啶-8-甲酰胺(化合物30)
N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-5-(2-hydroxyethanesulfonamido)-7-{6-azaspiro[2.5]octan-6-yl}-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (Compound 30)
第一步 4,6-二氯-2-[[(E)-(羟基氨基)亚甲基]氨基]吡啶-3-甲酸甲酯(化合物30-2)的合成：Step 1 Synthesis of methyl 4,6-dichloro-2-[[(E)-(hydroxyamino)methylene]amino]pyridine-3-carboxylate (Compound 30-2):
氮气保护,室温下向2-氨基-4,6-二氯吡啶-3-甲酸甲酯(3g,13.572mmol,1eq)的异丙醇(60.00mL)溶液中，加入N,N-二甲基甲酰胺二甲基缩醛(2.18mL,16.286mmol,1.20eq),升温至70℃搅拌反应3小时,冷却至室温，向反应液中加入盐酸羟胺(1.13g,16.286mmol,1.2eq)，室温搅拌反应3小时。过滤，收集滤饼并用异丙醇(3×50mL)洗涤。得到产物4,6-二氯-2-[[(E)-(羟基氨基)亚甲基]氨基]吡啶-3-甲酸甲酯(1.5g,41.85％)。Under nitrogen protection, add N,N-dimethylformamide dimethyl acetal (2.18mL, 16.286mmol, 1.20eq) to a solution of 2-amino-4,6-dichloropyridine-3-carboxylic acid methyl ester (3g, 13.572mmol, 1eq) in isopropanol (60.00mL) at room temperature, heat to 70℃ and stir for 3 hours, cool to room temperature, add hydroxylamine hydrochloride (1.13g, 16.286mmol, 1.2eq) to the reaction solution, stir for 3 hours at room temperature. Filter, collect the filter cake and wash with isopropanol (3×50mL). The product 4,6-dichloro-2-[[(E)-(hydroxyamino)methylene]amino]pyridine-3-carboxylic acid methyl ester (1.5g, 41.85%) was obtained.
MS:(ESI,m/z):264.10[M+H]+,RT(miN):0.949.MS: (ESI, m/z): 264.10 [M+H] + , RT (miN): 0.949.
第二步 5,7-二氯-[1,2,4]三唑并[1,5-a]吡啶-8-甲酸甲酯(化合物30-3)的合成：Step 2 Synthesis of 5,7-dichloro-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester (Compound 30-3):
氮气保护，0℃下向4,6-二氯-2-[[(E)-(羟基氨基)亚甲基]氨基]吡啶-3-甲酸甲酯(1.5g,5.681mmol,1eq)的乙腈(10mL)溶液中滴加三氟乙酸酐(1.79g,8.521mmol,1.5eq)的乙腈(5mL)溶液。升温至室温搅拌反应4小时。将反应液减压浓缩。用饱和碳酸氢钠水溶液中和到PH＝7。用二氯甲烷萃取(3×20mL)。合并有机相，用饱和食盐水反洗(1×20mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(1:2)，得到5,7-二氯-[1,2,4]三唑并[1,5-a]吡啶-8-甲酸甲酯(1.1g,77.13％)。Under nitrogen protection, add trifluoroacetic anhydride (1.79 g, 8.521 mmol, 1.5 eq) in acetonitrile (5 mL) to a solution of 4,6-dichloro-2-[[(E)-(hydroxyamino)methylene]amino]pyridine-3-carboxylic acid methyl ester (1.5 g, 5.681 mmol, 1 eq) in acetonitrile (10 mL) at 0 ° C. Heat to room temperature and stir to react for 4 hours. Concentrate the reaction solution under reduced pressure. Neutralize with saturated sodium bicarbonate aqueous solution to pH = 7. Extract with dichloromethane (3×20 mL). Combine the organic phases, backwash with saturated brine (1×20 mL), and dry over anhydrous sodium sulfate. After filtering the resulting mixture, the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography, petroleum ether/ethyl acetate (1:2) to obtain 5,7-dichloro-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester (1.1 g, 77.13%).
MS:(ESI,m/z):246.20[M+H]+,RT(min):0.828.MS: (ESI, m/z): 246.20 [M+H] + , RT (min): 0.828.
第三步 7-氯-5-{[(2,4-二甲氧基苯基)甲基]氨基}-[1,2,4]三唑并[1,5-a]吡啶-8-甲酸甲酯(化合物30-5)的合成：Step 3 Synthesis of 7-chloro-5-{[(2,4-dimethoxyphenyl)methyl]amino}-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester (Compound 30-5):
氮气保护，室温下向5,7-二氯-[1,2,4]三唑并[1,5-a]吡啶-8-甲酸甲酯(600mg,2.439mmol,1eq)的叔丁醇(6mL)溶液中加入三乙胺(740.29mg,7.317mmol,3eq),搅拌反应2分钟后，室温下滴加3，4-二甲氧基苄胺(16.31mg,0.097mmol,1.2eq)。升温至60℃搅拌反应2小时。将反应液冷却至室温。加水(20mL)稀释，用乙酸乙酯萃取(3×20mL)。合并有机相，用饱和食盐水反洗(1×20mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(1:3)，得到7-氯-5-{[(2,4-二甲氧基苯基)甲基]氨基}-[1,2,4]三唑并[1,5-a]吡啶-8-甲酸甲酯(700mg,68.56％)。Under nitrogen protection, triethylamine (740.29 mg, 7.317 mmol, 3 eq) was added to a solution of 5,7-dichloro-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester (600 mg, 2.439 mmol, 1 eq) in tert-butanol (6 mL) at room temperature. After stirring for 2 minutes, 3,4-dimethoxybenzylamine (16.31 mg, 0.097 mmol, 1.2 eq) was added dropwise at room temperature. The mixture was heated to 60°C and stirred for 2 hours. The reaction solution was cooled to room temperature. Diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic phases were combined, backwashed with saturated brine (1×20 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (1:3) to give methyl 7-chloro-5-{[(2,4-dimethoxyphenyl)methyl]amino}-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (700 mg, 68.56%).
MS:(ESI,m/z):377.35[M+H]+,RT(min):1.062.MS: (ESI, m/z): 377.35 [M+H] + , RT (min): 1.062.
第四步 7-氯-5-{[(2,4-二甲氧基苯基)甲基]氨基}-[1,2,4]三唑并[1,5-a]吡啶-8-甲酸(化合物30-6)的合成：Step 4 Synthesis of 7-chloro-5-{[(2,4-dimethoxyphenyl)methyl]amino}-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (Compound 30-6):
在氮气保护下，室温下，向7-氯-5-{[(2,4-二甲氧基苯基)甲基]氨基}-[1,2,4]三唑并[1,5-a]吡啶-8-甲酸甲酯(600mg,1.592mmol,1eq)的甲醇(2mL),四氢呋喃(2mL)和水(2mL)的溶液中，分批加入氢氧化锂(114.41mg,4.776mmol,3eq)。升温至60℃搅拌反应1小时。反应混合物用1N盐酸溶液酸化到PH为4。有白色固体析出，抽滤，收集滤饼，得到粗品1g.Under nitrogen protection, lithium hydroxide (114.41 mg, 4.776 mmol, 3 eq) was added in batches to a solution of 7-chloro-5-{[(2,4-dimethoxyphenyl)methyl]amino}-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester (600 mg, 1.592 mmol, 1 eq) in methanol (2 mL), tetrahydrofuran (2 mL) and water (2 mL) at room temperature. The temperature was raised to 60°C and stirred for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid solution to a pH of 4. A white solid precipitated, which was filtered and the filter cake was collected to obtain 1 g of crude product.
MS:(ESI,m/z):363.60[M+H]+,RT(min):1.000. MS: (ESI, m/z): 363.60 [M+H] + , RT (min): 1.000.
第五步 7-氯-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-5-{[(2,4-二甲氧基苯基)甲基]氨基}-[1,2,4]三唑并[1,5-a]吡啶-8-甲酰胺(化合物30-7)的合成：Step 5 Synthesis of 7-chloro-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-5-{[(2,4-dimethoxyphenyl)methyl]amino}-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (Compound 30-7):
氮气保护下，室温下，向7-氯-5-{[(2,4-二甲氧基苯基)甲基]氨基}-[1,2,4]三唑并[1,5-a]吡啶-8-甲酸(500mg,1.378mmol,1eq)和6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-胺(375.87mg,1.654mmol,1.2eq)的N,N-二甲基甲酰胺(10mL)溶液中，分批加入N,N,N',N'-四甲基氯甲脒六氟磷酸盐(1.5g,5.512mmol,4eq)和N-甲基咪唑(1.1g,13.780mmol,10eq)。升温至60℃，搅拌反应1小时。将反应液冷却至室温，加水(20mL)稀释，用二氯甲烷萃取(3×20mL)。合并有机相，用饱和食盐水反洗(1×20mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(3:1)，得到7-氯-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-5-{[(2,4-二甲氧基苯基)甲基]氨基}-[1,2,4]三唑并[1,5-a]吡啶-8-甲酰胺(500mg,60.25％)。Under nitrogen protection, at room temperature, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.5 g, 5.512 mmol, 4 eq) and N-methylimidazole (1.1 g, 13.780 mmol, 10 eq) were added in batches to a solution of 7-chloro-5-{[(2,4-dimethoxyphenyl)methyl]amino}-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (500 mg, 1.378 mmol, 1 eq) and 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine (375.87 mg, 1.654 mmol, 1.2 eq) in N,N-dimethylformamide (10 mL). The temperature was raised to 60°C and stirred for 1 hour. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (3×20 mL). The organic phases were combined, backwashed with saturated brine (1×20 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, petroleum ether/ethyl acetate (3:1) to obtain 7-chloro-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-5-{[(2,4-dimethoxyphenyl)methyl]amino}-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (500 mg, 60.25%).
MS:(ESI,m/z):572.50[M+H]+,RT(min):1.370.MS: (ESI, m/z): 572.50 [M+H] + , RT (min): 1.370.
第六步 7-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-5-{[(2,4-二甲氧基苯基)甲基]氨基}-[1,2,4]三唑并[1,5-a]吡啶-8-甲酰胺(化合物30-8)的合成：Step 6 Synthesis of 7-{6-azaspiro[2.5]octane-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-5-{[(2,4-dimethoxyphenyl)methyl]amino}-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (Compound 30-8):
在氮气保护下，室温下，向7-氯-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-5-{[(2,4-二甲氧基苯基)甲基]氨基}-[1,2,4]三唑并[1,5-a]吡啶-8-甲酰胺(600mg,1.049mmol,1eq)和三乙胺(318.43mg,3.147mmol,3eq)的叔丁醇(10mL)溶液中，分批加入6-氮杂螺[2.5]辛烷盐酸盐(309.75mg,2.098mmol,2eq)。升温至120℃搅拌反应2小时。将反应液冷却至室温，用水(10mL)稀释。用二氯甲烷萃取(3×10mL)。合并有机相，用饱和食盐水反洗(1×10mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，二氯甲烷/甲醇(10:1)，得到化合物30-8(445mg,62.32％)。Under nitrogen protection, 6-azaspiro[2.5]octane hydrochloride (309.75 mg, 2.098 mmol, 2 eq) was added in batches to a solution of 7-chloro-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-5-{[(2,4-dimethoxyphenyl)methyl]amino}-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (600 mg, 1.049 mmol, 1 eq) and triethylamine (318.43 mg, 3.147 mmol, 3 eq) in tert-butanol (10 mL) at room temperature. The temperature was raised to 120°C and stirred for 2 hours. The reaction solution was cooled to room temperature and diluted with water (10 mL). Extracted with dichloromethane (3×10 mL). The organic phases were combined, backwashed with saturated brine (1×10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with dichloromethane/methanol (10:1) to obtain compound 30-8 (445 mg, 62.32%).
MS:(ESI,m/z):647.60[M+H]+,RT(min):1.172.MS: (ESI, m/z): 647.60 [M+H] + , RT (min): 1.172.
第七步 5-氨基-7-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-[1,2,4]三唑并[1,5-a]吡啶-8-甲酰胺(化合物30-9)的合成：Step 7 Synthesis of 5-amino-7-{6-azaspiro[2.5]octane-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (Compound 30-9):
氮气保护，60℃下，化合物30-8(410mg,0.634mmol,1eq)的三氟乙酸(5mL,67.315mmol,106.18eq)溶液搅拌反应1小时。将反应液冷却至室温，所得残余物减压浓缩。用饱和碳酸氢钠水溶液碱化到pH＝8。用乙酸乙酯萃取(3×20mL)。合并有机相，用饱和食盐水反洗(1×20mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用反相柱层析纯化，条件如下：层析柱规格(C18层析柱)，流动相，水和乙腈，0％到80％梯度10分钟，UV254纳米检测器。得到化合物30-9(310mg,88.63％)。Under nitrogen protection, at 60°C, a solution of compound 30-8 (410 mg, 0.634 mmol, 1 eq) in trifluoroacetic acid (5 mL, 67.315 mmol, 106.18 eq) was stirred for 1 hour. The reaction solution was cooled to room temperature and the residue was concentrated under reduced pressure. Alkalize to pH = 8 with saturated sodium bicarbonate aqueous solution. Extract with ethyl acetate (3×20 mL). Combine the organic phases, backwash with saturated brine (1×20 mL), and dry over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography under the following conditions: chromatography column specifications (C18 chromatography column), mobile phase, water and acetonitrile, 0% to 80% gradient 10 minutes, UV254 nanometer detector. Compound 30-9 (310 mg, 88.63%) was obtained.
MS:(ESI,m/z):497.30[M+H]+,RT(min):1.410.MS: (ESI, m/z): 497.30 [M+H] + , RT (min): 1.410.
第八步 2-[(7-{6-氮杂螺[2.5]辛烷-6-基}-8-{[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]氨基甲酰基}-[1,2,4]三唑并[1,5-a]吡啶-5-基)氨磺酰基]乙酸乙酯(化合物30-11)的合成：Step 8 Synthesis of ethyl 2-[(7-{6-azaspiro[2.5]octane-6-yl}-8-{[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]carbamoyl}-[1,2,4]triazolo[1,5-a]pyridin-5-yl)sulfamoyl]acetate (Compound 30-11):
在氮气保护下，0℃下，向化合物30-9(100mg,0.201mmol,1eq)和三乙胺(61.14mg,0.603mmol,3eq)的二氯甲烷(3mL)溶液中，滴加2-(氯磺酰基)乙酸乙酯(75.16mg,0.402mmol,2eq)。升温至室温搅拌反应2小时。加水(10mL)稀释，用二氯甲烷萃取(3×10mL)。合并有机相，用饱和食盐水反洗(1×10mL),无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用反相柱层析纯化，条件如下：C18层析柱，流动相，水和乙腈，10％到70％梯度10分钟，UV254纳米检测器。得到化合物30-11(80mg,61.43％)。Under nitrogen protection, at 0°C, ethyl 2-(chlorosulfonyl)acetate (75.16 mg, 0.402 mmol, 2 eq) was added dropwise to a solution of compound 30-9 (100 mg, 0.201 mmol, 1 eq) and triethylamine (61.14 mg, 0.603 mmol, 3 eq) in dichloromethane (3 mL). The mixture was heated to room temperature and stirred for 2 hours. It was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The organic phases were combined, backwashed with saturated brine (1×10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography under the following conditions: C18 chromatography column, mobile phase, water and acetonitrile, 10% to 70% gradient for 10 minutes, UV254 nanometer detector. Compound 30-11 (80 mg, 61.43%) was obtained.
MS:(ESI,m/z):647.30[M+H]+,RT(min):1.100.MS: (ESI, m/z): 647.30 [M+H] + , RT (min): 1.100.
第九步 N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-5-(2-羟基乙磺酰胺基)-7-{6-氮杂螺[2.5]辛烷-6-基}-[1,2,4]三唑并[1,5-a]吡啶-8-甲酰胺(化合物30)的合成：Step 9 Synthesis of N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-5-(2-hydroxyethanesulfonamido)-7-{6-azaspiro[2.5]octan-6-yl}-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (Compound 30):
在氮气保护下，0℃下，向化合物30-11(70mg,0.108mmol,1eq)的四氢呋喃(3mL)溶液中，滴加四氢铝锂的四氢呋喃溶液(6.16mg,0.162mmol,1.5eq)，加入完毕后体系0℃下继续搅拌1小时。反应混合物0℃下用冰水淬灭。反应混合物用乙酸乙酯萃取(3×10mL)，合并有机相，用饱和食盐水反洗(1×10mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。粗品通过高效液相纯化，条件如下：层析柱规格:SuNfire C18 5μm,30mm*150mm；流动相A:水(0.05％甲酸)，流动相B:乙腈；流速:60mL/min；洗脱梯度:35％B to 68％B in 8min；254nm/220nm；Rt:7.42min。得到化合物30(23.73mg,35.42％)。Under nitrogen protection, at 0°C, a solution of lithium aluminum tetrahydride in tetrahydrofuran (6.16 mg, 0.162 mmol, 1.5 eq) was added dropwise to a solution of compound 30-11 (70 mg, 0.108 mmol, 1 eq) in tetrahydrofuran (3 mL). After the addition was completed, the system was stirred for 1 hour at 0°C. The reaction mixture was quenched with ice water at 0°C. The reaction mixture was extracted with ethyl acetate (3×10 mL), the organic phases were combined, backwashed with saturated brine (1×10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC under the following conditions: column specifications: SuNfire C18 5μm, 30mm*150mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60mL/min; elution gradient: 35%B to 68%B in 8min; 254nm/220nm; Rt: 7.42min. Compound 30 (23.73mg, 35.42%) was obtained.
MS:(ESI,m/z):605.20[M+H]+,RT(min):1.720. MS: (ESI, m/z): 605.20 [M+H] + , RT (min): 1.720.
1H NMR(400MHz,DMSO-d6)δ14.04(s,1H),11.77(s,1H),8.96(s,1H),7.51(s,1H),6.87(s,1H),6.59(s,1H),4.96(s,1H),3.83(t,J＝6.6Hz,2H),3.72(t,J＝6.1Hz,4H),3.21(t,J＝6.7Hz,2H),3.10(s,4H),2.27(s,3H),1.97(t,J＝15.6Hz,4H),1.72(s,4H),0.39(s,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 14.04 (s, 1H), 11.77 (s, 1H), 8.96 (s, 1H), 7.51 (s, 1H), 6.87 (s, 1H), 6.59 (s, 1H), 4.96 (s, 1H), 3.83 (t, J = 6.6 Hz, 2H), 3.72 (t, J = 6.1 Hz, 4H), 3.21 (t, J = 6.7 Hz, 2H), 3.10 (s, 4H), 2.27 (s, 3H), 1.97 (t, J = 15.6 Hz, 4H), 1.72 (s, 4H), 0.39 (s, 4H).
实施例9Example 9
5-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-7-(2-羟基乙烷磺酰胺基)-3-甲基-1,3-苯并二唑-4-甲酰胺(化合物31)
5-{6-azaspiro[2.5]octan-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-3-methyl-1,3-benzodiazole-4-carboxamide (Compound 31)
第一步 4-溴-2,6-二氟-3-硝基苯甲酸甲酯(化合物31-2)的合成：Step 1 Synthesis of methyl 4-bromo-2,6-difluoro-3-nitrobenzoate (Compound 31-2):
氮气保护，室温下向4-溴-2,6-二氟苯甲酸甲酯(5g,20mmol,1eq)的硫酸溶液(17mL)中加入硝酸(1.25mL)，反应液室温搅拌1小时。反应混合物室温下水淬灭，用二氯甲烷萃取(3×100mL)，合并有机相，并用饱和食盐水反洗(2×120mL)，无水硫酸钠干燥，过滤，滤液减压浓缩。得到4-溴-2,6-二氟-3-硝基苯甲酸甲酯(6.01g)粗品。Under nitrogen protection, nitric acid (1.25 mL) was added to a sulfuric acid solution (17 mL) of methyl 4-bromo-2,6-difluorobenzoate (5 g, 20 mmol, 1 eq) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with water at room temperature, extracted with dichloromethane (3×100 mL), the organic phases were combined, backwashed with saturated brine (2×120 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product of methyl 4-bromo-2,6-difluoro-3-nitrobenzoate (6.01 g) was obtained.
1H NMR:(400MHz,DMSO-d6)δ8.11(dd,J＝9.5,2.1Hz,1H),3.93(s,3H). 1 H NMR: (400 MHz, DMSO-d 6 ) δ 8.11 (dd, J=9.5, 2.1 Hz, 1H), 3.93 (s, 3H).
第二步 4-溴-6-氟-2-甲氨基-3-硝基苯甲酸甲酯(化合物31-3)的合成：Step 2 Synthesis of methyl 4-bromo-6-fluoro-2-methylamino-3-nitrobenzoate (Compound 31-3):
氮气保护,室温下向4-溴-2,6-二氟-3-硝基苯甲酸甲酯(3g,10mmol,1eq)的甲醇溶液中(30mL)，加入甲胺(472mg,15mmol,1.5eq)，反应液60℃下搅拌16小时。反应液冷却至室温，用水淬灭，用乙酸乙酯萃取(3×80mL)。合并有机相，并用饱和食盐水反洗(2×80mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1)，得到4-溴-6-氟-2-甲氨基-3-硝基苯甲酸甲酯(2.21g,71％)。Under nitrogen protection, methylamine (472 mg, 15 mmol, 1.5 eq) was added to a methanol solution (30 mL) of methyl 4-bromo-2,6-difluoro-3-nitrobenzoate (3 g, 10 mmol, 1 eq) at room temperature, and the reaction solution was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature, quenched with water, and extracted with ethyl acetate (3×80 mL). The organic phases were combined and backwashed with saturated brine (2×80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain methyl 4-bromo-6-fluoro-2-methylamino-3-nitrobenzoate (2.21 g, 71%).
MS:(ESI,m/z):306.85[M+H]+,RT(min):1.180MS:(ESI,m/z):306.85[M+H] + ,RT(min):1.180
第三步 6-{6-氮杂螺[2.5]辛烷-6-基}-4-溴-2-甲氨基-3-硝基苯甲酸甲酯(化合物31-4)的合成：Step 3 Synthesis of 6-{6-azaspiro[2.5]octane-6-yl}-4-bromo-2-methylamino-3-nitrobenzoic acid methyl ester (Compound 31-4):
氮气保护，室温下向4-溴-6-氟-2-甲氨基-3-硝基苯甲酸甲酯(500mg,1.6mmol,1eq)的叔丁醇(15mL)溶液中加入6-氮杂螺[2.5]辛烷盐酸盐(217mg,2mmol,1.2eq)，三乙胺(824mg,8mmol,5eq)，反应液升温至100℃搅拌16小时。反应液冷却至室温，用乙酸乙酯萃取(3×30mL)，合并有机相，并用饱和食盐水反洗(2×30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱层析纯化(石油醚：乙酸乙酯＝5:1)，得到6-{6-氮杂螺[2.5]辛烷-6-基}-4-溴-2-甲氨基-3-硝基苯甲酸甲酯(460mg,71％)。Under nitrogen protection, 6-azaspiro[2.5]octane hydrochloride (217 mg, 2 mmol, 1.2 eq) and triethylamine (824 mg, 8 mmol, 5 eq) were added to a solution of 4-bromo-6-fluoro-2-methylamino-3-nitrobenzoic acid methyl ester (500 mg, 1.6 mmol, 1 eq) in tert-butyl alcohol (15 mL) at room temperature, and the reaction solution was heated to 100°C and stirred for 16 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate (3×30 mL). The organic phases were combined and backwashed with saturated brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 6-{6-azaspiro[2.5]octan-6-yl}-4-bromo-2-methylamino-3-nitrobenzoic acid methyl ester (460 mg, 71%).
MS:(ESI,m/z):398.35[M+H]+,RT(min):1.380MS:(ESI,m/z):398.35[M+H] + ,RT(min):1.380
第四步 5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-3-甲基-1,3-苯并二唑-4-甲酸甲酯(化合物31-6)的合成：Step 4 Synthesis of 5-{6-azaspiro[2.5]octane-6-yl}-7-bromo-3-methyl-1,3-benzodiazole-4-carboxylic acid methyl ester (Compound 31-6):
氮气保护，室温下6-{6-氮杂螺[2.5]辛烷-6-基}-4-溴-2-甲氨基-3-硝基苯甲酸甲酯(440mg,1.1mmol,1eq)的乙醇溶液(3mL)中，加入原甲酸三甲酯(3.5g,33mmol,30eq)，锌粉(433mg,6.6mmol,6eq)，溴化锂(115mg,1.3mmol,1.2eq)和甲酸(508mg,11mmol,10eq)，加入完毕后室温反应搅拌1小时。用水淬灭，乙酸乙酯萃取(3×30mL)，合并有机相，并用饱和食盐水反洗(2×30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱层析纯化(石油醚：乙酸乙酯＝5:1)，得到5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-3-甲基-1,3-苯并二唑-4-甲酸甲酯(190mg,45.5％)。Under nitrogen protection, trimethyl orthoformate (3.5 g, 33 mmol, 30 eq), zinc powder (433 mg, 6.6 mmol, 6 eq), lithium bromide (115 mg, 1.3 mmol, 1.2 eq) and formic acid (508 mg, 11 mmol, 10 eq) were added to a solution of methyl 6-{6-azaspiro[2.5]octan-6-yl}-4-bromo-2-methylamino-3-nitrobenzoate (440 mg, 1.1 mmol, 1 eq) in ethanol (3 mL) at room temperature. After the addition was complete, the reaction was stirred at room temperature for 1 hour. The mixture was quenched with water and extracted with ethyl acetate (3×30 mL). The organic phases were combined and backwashed with saturated brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-3-methyl-1,3-benzodiazole-4-carboxylic acid methyl ester (190 mg, 45.5%).
MS:(ESI,m/z):378.30[M+H]+,RT(min):1.193MS:(ESI,m/z):378.30[M+H] + ,RT(min):1.193
第五步 5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-3-甲基-1,3-苯并二唑-4-甲酸(化合物31-7)的合成： Step 5 Synthesis of 5-{6-azaspiro[2.5]octane-6-yl}-7-bromo-3-methyl-1,3-benzodiazole-4-carboxylic acid (Compound 31-7):
氮气保护，室温下向5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-3-甲基-1,3-苯并二唑-4-甲酸甲酯(100mg,0.3mmol,1eq)的四氢呋喃溶液(2mL)中，加入氢氧化锂(31.7g,1.3mmol,5eq)，蒸馏水(2mL)和甲醇(2mL)，反应液升温至60℃搅拌72小时。反应液用乙酸乙酯萃取(2×10mL)，收集水相，用1M稀盐酸将PH调至6，用乙酸乙酯萃取(2×10mL)，合并有机相，并用饱和食盐水反洗(2×10mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-3-甲基-1,3-苯并二唑-4-甲酸(101mg,105％)。Under nitrogen protection, lithium hydroxide (31.7 g, 1.3 mmol, 5 eq), distilled water (2 mL) and methanol (2 mL) were added to a tetrahydrofuran solution (2 mL) of 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-3-methyl-1,3-benzodiazole-4-carboxylic acid methyl ester (100 mg, 0.3 mmol, 1 eq) at room temperature, and the reaction solution was heated to 60°C and stirred for 72 hours. The reaction solution was extracted with ethyl acetate (2×10 mL), the aqueous phase was collected, the pH was adjusted to 6 with 1M dilute hydrochloric acid, extracted with ethyl acetate (2×10 mL), the organic phases were combined, backwashed with saturated brine (2×10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-3-methyl-1,3-benzodiazole-4-carboxylic acid (101 mg, 105%).
MS:(ESI,m/z):364.30[M+H]+,RT(min):0.763MS:(ESI,m/z):364.30[M+H] + ,RT(min):0.763
第六步 5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-3-甲基-1,3-苯并二唑-4-甲酰胺(化合物31-8)的合成：Step 6 Synthesis of 5-{6-azaspiro[2.5]octane-6-yl}-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-3-methyl-1,3-benzodiazole-4-carboxamide (Compound 31-8):
氮气保护下，室温下向5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-3-甲基-1,3-苯并二唑-4-甲酸(60mg,0.16mmol,1eq)的二氯甲烷溶液中(4mL)，加入6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-胺(112mg,0.5mmol,3eq)，N,N,N',N'-四甲基氯甲脒六氟磷酸盐(185mg,0.7mmol,4eq)，N-甲基咪唑(135mg,1.7mmol,10eq)，反应液升温至60℃搅拌1小时。反应液冷却至室温，乙酸乙酯萃取(3×10mL)，合并有机相，并用饱和食盐水反洗(2×10mL)，无水硫酸钠干燥。过滤，滤液减压浓缩，所得残余物用硅胶柱层析纯化(石油醚：乙酸乙酯＝2:1)，得到5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-3-甲基-1,3-苯并二唑-4-甲酰胺(72mg,76％)。Under nitrogen protection, 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine (112 mg, 0.5 mmol, 3 eq), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (185 mg, 0.7 mmol, 4 eq), and N-methylimidazole (135 mg, 1.7 mmol, 10 eq) were added to a dichloromethane solution (4 mL) of 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-3-methyl-1,3-benzodiazole-4-carboxylic acid (60 mg, 0.16 mmol, 1 eq) at room temperature, and the reaction solution was heated to 60°C and stirred for 1 hour. The reaction solution was cooled to room temperature, extracted with ethyl acetate (3×10 mL), and the organic phases were combined, backwashed with saturated brine (2×10 mL), and dried over anhydrous sodium sulfate. The product was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-3-methyl-1,3-benzodiazole-4-carboxamide (72 mg, 76%).
MS:(ESI,m/z):573.30[M+H]+,RT(min):1.392MS:(ESI,m/z):573.30[M+H] + ,RT(min):1.392
第七步 5-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-7-(2-羟基乙烷磺酰胺基)-3-甲基-1,3-苯并二唑-4-甲酰胺(化合物31)的合成：Step 7 Synthesis of 5-{6-azaspiro[2.5]octan-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-3-methyl-1,3-benzodiazole-4-carboxamide (Compound 31):
氮气保护，室温下向5-{6-氮杂螺[2.5]辛烷-6-基}-7-溴-N-[6-(4，4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-3-甲基-1,3-苯并二唑-4-甲酰胺(100mg,0.17mmol,1eq)的1,4-二氧六环溶液(1mL)中，加入2-羟基乙烷磺酰胺(26mg,0.2mmol,1.2eq)，甲烷磺酸{双环己基[3-异丙氧-2',4′,6′-三异丙基-(1,1′-联苯)-2-基]膦烷}(2'-甲氨基-1,1'-联苯-2-基)钯(II)(16.02mg,0.017mmol,0.1eq)，双环已基(3-异丙氧-2′,4′,6′-三异丙基-[1,1′-联苯]-2-基)膦烷(18.65mg,0.035mmol,0.2eq)，碳酸铯(170.44mg,0.522mmol,3eq)，反应液升温至100℃搅拌1小时。反应液冷却至室温，用乙酸乙酯萃取(3×10mL)，合并有机相，并用饱和食盐水反洗(2×10mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物通过制备型高效液相纯化，得到5-{6-氮杂螺[2.5]辛烷-6-基}-N-[6-(4,4-二氟哌啶-1-基)-4-甲基吡啶-2-基]-7-(2-羟基乙烷磺酰胺基)-3-甲基-1,3-苯并二唑-4-甲酰胺(7.08mg,6.3％)。To a solution of 5-{6-azaspiro[2.5]octan-6-yl}-7-bromo-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-3-methyl-1,3-benzotriazole-4-carboxamide (100 mg, 0.17 mmol, 1 eq) in 1,4-dioxane (1 mL) was added 2-hydroxyethanesulfonamide (26 mg, 0.2 mmol, 1.2 eq), methanesulfonic acid {bicyclohexyl[3-isopropoxy-2',4',6'-triisopropyl]-1-[4-(4-fluoropiperidin-1-yl)-4-methylpyridin-2-yl]-3-methyl-1,3-benzotriazole-4-carboxamide (100 mg, 0.17 mmol, 1 eq) at room temperature. Propyl-(1,1′-biphenyl)-2-yl]phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (16.02 mg, 0.017 mmol, 0.1 eq), bicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (18.65 mg, 0.035 mmol, 0.2 eq), cesium carbonate (170.44 mg, 0.522 mmol, 3 eq), the reaction solution was heated to 100°C and stirred for 1 hour. The reaction solution was cooled to room temperature, extracted with ethyl acetate (3×10 mL), the organic phases were combined, backwashed with saturated brine (2×10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 5-{6-azaspiro[2.5]octane-6-yl}-N-[6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl]-7-(2-hydroxyethanesulfonamido)-3-methyl-1,3-benzodiazole-4-carboxamide (7.08 mg, 6.3%).
MS:(ESI,m/z):618.70[M+H]+,RT(min):1.903MS:(ESI,m/z):618.70[M+H] + ,RT(min):1.903
1H NMR:(400MHz,DMSO-d6)δ10.73(s,1H),9.15(s,1H),8.18(s,1H),7.42(s,1H),7.15(s,1H),6.57(s,1H),5.05(s,1H),3.83(d,J＝6.6Hz,2H),3.80(d,J＝3.9Hz,3H),3.69(t,J＝5.5Hz,4H),3.45(t,J＝6.6Hz,2H),2.96(t,J＝5.2Hz,4H),2.29(s,3H),2.05–1.85(m,4H),1.45(s,4H),0.29(s,4H). 1 H NMR: (400 MHz, DMSO-d 6 ) δ 10.73 (s, 1H), 9.15 (s, 1H), 8.18 (s, 1H), 7.42 (s, 1H), 7.15 (s, 1H), 6.57 (s, 1H), 5.05 (s, 1H), 3.83 (d, J = 6.6 Hz, 2H), 3.80 (d, J = 3.9 Hz, 3H), 3.69 (t, J = 5.5 Hz, 4H), 3.45 (t, J = 6.6 Hz, 2H), 2.96 (t, J = 5.2 Hz, 4H), 2.29 (s, 3H), 2.05–1.85 (m, 4H), 1.45 (s, 4H), 0.29 (s, 4H).
生物学评价Biological evaluation
测试例1Test Example 1
测试名称：OVCAR-3细胞中基于成像的核计数分析(NCA)Test Name: Imaging-based Nuclear Count Analysis (NCA) in OVCAR-3 cells
第0天 化合物稀释及处理Day 0 Compound dilution and handling
a)AM-5308最终测试浓度为：10000、3333.3、1111.1、370.3、123.4、41.1、13.7、4.5、1.5、0.5nM。a) The final tested concentrations of AM-5308 were: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, and 0.5 nM.
b)待测试化合物最终测试浓度为：10000、3333.3、1111.1、370.3、123.4、41.1、13.7、4.5、1.5、0.5nM。b) The final test concentrations of the test compounds were: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, and 0.5 nM.
c)细胞在37℃、5％CO2的培养箱中培养4天。c) The cells were cultured in a 37°C, 5% CO 2 incubator for 4 days.
d)DMSO浓度为0.1％。d) The DMSO concentration was 0.1%.
第1天 将细胞接种到384孔细胞培养板中Day 1: Seed cells into 384-well cell culture plates
a)当细胞汇合度达到80％-90％时，处理细胞。a) When the cell confluence reached 80%-90%, cells were processed.
b)将细胞重悬于培养基中，然后以所需的密度对细胞进行计数和稀释。b) Resuspend the cells in culture medium, then count and dilute the cells at the desired density.
c)在384孔板中加入30μL/孔的含有适当细胞的细胞悬液：600个细胞/孔。c) Add 30 μL/well of the cell suspension containing appropriate cells to a 384-well plate: 600 cells/well.
第4天 检测Day 4 Testing
a)加入30μL 8％的固定液(终浓度4％)并在室温下孵育板30分钟。a) Add 30 μL of 8% fixative (final concentration 4%) and incubate the plate at room temperature for 30 minutes.
b)离心板，1000RPM，30s。b) Centrifuge the plate at 1000 RPM for 30 seconds.
c)60μl/孔PBS洗涤两次。c) Wash twice with 60 μl/well PBS.
d)固定后，将细胞透化并在含有2μg/mL Hoechst 33342 DNA染料的60μL洗涤缓冲液中染色(1％BSA、0.2％Triton X-100、1X PBS)。d) After fixation, cells were permeabilized and stained in 60 μL wash buffer (1% BSA, 0.2% Triton X-100, 1X PBS) containing 2 μg/mL Hoechst 33342 DNA dye.
e)将板密封并在室温下避光孵育1小时。e) Seal the plate and incubate at room temperature for 1 hour in the dark.
f)用PBS洗涤3次。 f) Wash 3 times with PBS.
g)加入50μLPBS/孔，并使用HCS扫描板子。g) Add 50 μL PBS/well and scan the plate using HCS.
h)数据采集与检测h) Data collection and detection
数据分析data analysis
抑制率(％)＝100-(化合物孔读值-低读值对照孔读值)/(高读值对照孔读值-低读值对照孔读值)*100Inhibition rate (%) = 100-(compound well reading value-low reading control well reading value)/(high reading control well reading value-low reading control well reading value)*100
高读值对照孔：细胞加30nL DMSO；低读值对照孔：10μM AM-5308。High reading control well: cells plus 30nL DMSO; low reading control well: 10μM AM-5308.
使用GraphPad Prism 8软件计算IC50(nM)并绘制化合物的效果-剂量曲线。GraphPad Prism 8 software was used to calculate IC 50 (nM) and plot the effect-dose curve of the compound.
表1本申请化合物的生物学活性数据
Table 1 Biological activity data of the compounds of the present application
测试例2Test Example 2
测试名称：ADP-GloTM激酶检测Test Name: ADP-Glo TM Kinase Assay
操作步骤：Steps:
1)制备1×反应缓冲液。1) Prepare 1× reaction buffer.
2)用Echo 655向反应板每孔转移100nL稀释好的化合物储液。DMSO的最终浓度为1％。2) Use Echo 655 to transfer 100 nL of the diluted compound stock solution to each well of the reaction plate. The final concentration of DMSO is 1%.
3)用封板膜封住反应板，1000g离心1分钟。3) Seal the reaction plate with a sealing film and centrifuge at 1000 g for 1 minute.
4)用1×反应缓冲液配制2×酶溶液。4) Prepare 2× enzyme solution with 1× reaction buffer.
5)向反应板中每孔加入5μL 2×酶溶液。用封板膜封住板子1000g离心1分钟，室温放置15分钟。5) Add 5 μL 2× enzyme solution to each well of the reaction plate. Seal the plate with a sealing film and centrifuge at 1000 g for 1 minute, then leave at room temperature for 15 minutes.
6)用1×反应缓冲液配制2×ATP溶液。6) Prepare 2× ATP solution using 1× reaction buffer.
7)向反应板中加入5μL 2×ATP溶液，1000g离心1分钟，开始反应。7) Add 5 μL 2× ATP solution to the reaction plate and centrifuge at 1000 g for 1 minute to start the reaction.
8)室温反应60分钟。8) React at room temperature for 60 minutes.
9)加入10μL ADP Glo试剂。1000g离心1分钟，在室温下孵育60分钟。9) Add 10 μL ADP Glo reagent. Centrifuge at 1000 g for 1 minute and incubate at room temperature for 60 minutes.
10)加入20μL激酶检测试剂。1000g离心1分钟，室温下孵育60分钟。10) Add 20 μL of kinase assay reagent, centrifuge at 1000 g for 1 minute, and incubate at room temperature for 60 minutes.
11)1000g离心1分钟。11) Centrifuge at 1000 g for 1 minute.
12)在Envision 2104读取发光信号。12) Read the luminescence signal on Envision 2104.
数据分析：data analysis:
抑制百分率计算如下:
％inhibition＝100-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)×100The inhibition percentage was calculated as follows:
%inhibition＝100-(Signal cmpd -Signal Ave_PC )/(Signal Ave_VC -Signal Ave_PC )×100
Signalcmpd:反应板上测试化合物的平均值。Signal cmpd : Average value of the test compound on the reaction plate.
SignalAve_PC:反应板上阳性对照的平均值。Signal Ave_PC : The average value of the positive control on the reaction plate.
SignalAve_VC:反应板上阴性对照的平均值。Signal Ave_VC : The average value of negative control on the reaction plate.
计算IC50以及拟合化合物量效曲线:Calculate IC50 and fit compound dose-effect curve:
用GraphPad 8.0，利用非线性拟合公式来得到化合物的IC50。The IC50 values of the compounds were obtained using GraphPad 8.0 using a nonlinear fitting formula.
3)质量控制3) Quality Control
Z factor>0.5；S/B>2。Z factor>0.5;S/B>2.
表2本申请化合物的酶活数据
Table 2 Enzyme activity data of the compounds of the present application
测试例3本发明化合物对肿瘤消退的影响Test Example 3 Effect of the Compounds of the Invention on Tumor Regression
为了证明KIF18A抑制剂对肿瘤消退的影响，选择了OVCAR-3细胞(ATCC公司)进行试验。在雌性裸鼠右侧皮下注射0.1mL约5×106个OVCAR-3细胞。根据肿瘤体积(平均肿瘤体积为150mm3)将动物随机分为6组(溶媒组，化合物9分为10、20或30mg/kg三个剂量组，AMG650分为15或30mg/kg两个剂量组)，每组10只动物，从肿瘤接种后第28天开始，每天口服1次。使用电子游标卡尺(成都市三和量具有限公司)测量肿瘤体积。每周测定两次肿瘤体积和动物体重(研究开始第28天，研究结束第46天)，计算化合物肿瘤生长抑制率。In order to demonstrate the effect of KIF18A inhibitor on tumor regression, OVCAR-3 cells (ATCC) were selected for the experiment. 0.1 mL of approximately 5×10 6 OVCAR-3 cells were injected subcutaneously on the right side of female nude mice. According to the tumor volume (average tumor volume was 150 mm 3 ), the animals were randomly divided into 6 groups (vehicle group, compound 9 was divided into three dose groups of 10, 20 or 30 mg/kg, and AMG650 was divided into two dose groups of 15 or 30 mg/kg), with 10 animals in each group, and oral administration once a day starting from the 28th day after tumor inoculation. The tumor volume was measured using an electronic vernier caliper (Chengdu Sanhe Measuring Instrument Co., Ltd.). The tumor volume and animal body weight were measured twice a week (28th day from the start of the study and 46th day from the end of the study), and the tumor growth inhibition rate of the compound was calculated.
肿瘤体积计算公式为：1/2×a×b2，其中a、b分别为肿瘤测量的长和宽。The formula for calculating tumor volume is: 1/2×a×b 2 , where a and b are the measured length and width of the tumor, respectively.
抑瘤率％TGI计算公式为：1-(TVTn-TVT0)/(TVCn-TVC0)×100％，TVC为阴性对照组平均肿瘤体积，TVT为治疗组平均肿瘤体积。The calculation formula of tumor inhibition rate %TGI was: 1-(TV Tn -TV T0 )/(TV Cn -TV C0 )×100%, TVC was the average tumor volume of the negative control group, and TVT was the average tumor volume of the treatment group.
使用GraphPad Prism软件(V9.5.0)绘制数据，肿瘤体积和体重数据表示为平均值正负平均值的标准误差。由图1可见，化合物9剂量组10、20和30mg/kg的TGI分别为47.35％、106.60％和115.58％；AMG650 15和30mg/kg的TGI分别为72.58％和113.15％。化合物9所有剂量组相对于溶媒组动物体重变化无明显影响，没有观察到明显的毒性。Data were plotted using GraphPad Prism software (V9.5.0), and tumor volume and body weight data were expressed as mean values plus or minus standard errors of the mean values. As shown in Figure 1, the TGIs of the 10, 20, and 30 mg/kg dose groups of compound 9 were 47.35%, 106.60%, and 115.58%, respectively; the TGIs of AMG650 15 and 30 mg/kg were 72.58% and 113.15%, respectively. All dose groups of compound 9 had no significant effect on the changes in animal body weight relative to the vehicle group, and no obvious toxicity was observed.
以上结果表明，本发明中的化合物9能够诱导人高浆液性卵巢癌OVCAR-3细胞(TP53突变,CCNE1扩增)导致的雌性裸鼠异种移植瘤模型的肿瘤消退。化合物9在20和30mg/kg剂量下，在携带OVCAR-3小鼠皮下移植瘤模型中能够显著抑制肿瘤生长，化合物9在20mg/kg剂量下的小鼠皮下移植瘤的抑制效果与AMG650 30mg/kg的抑制效果相当。The above results show that compound 9 in the present invention can induce tumor regression in female nude mouse xenograft tumor models caused by human high serous ovarian cancer OVCAR-3 cells (TP53 mutation, CCNE1 amplification). Compound 9 at doses of 20 and 30 mg/kg can significantly inhibit tumor growth in the subcutaneous transplant tumor model of OVCAR-3 mice, and the inhibitory effect of compound 9 at a dose of 20 mg/kg on subcutaneous transplant tumors in mice is comparable to that of AMG650 30 mg/kg.
由表3可见，化合物9的瘤血比(肿瘤组织暴露量与血浆暴露量的比值)优于AMG650，表明更高比例的药物进入肿瘤组织发挥作用。同时与AMG650相比，化合物9较低的绝对暴露量可以降低药物潜在的蓄积毒性。As shown in Table 3, the tumor-to-blood ratio (ratio of tumor tissue exposure to plasma exposure) of compound 9 is better than that of AMG650, indicating that a higher proportion of the drug enters the tumor tissue to exert its effect. At the same time, compared with AMG650, the lower absolute exposure of compound 9 can reduce the potential cumulative toxicity of the drug.
表3.小鼠血浆和肿瘤组织暴露量
Table 3. Exposure in mouse plasma and tumor tissue
以上对本发明技术方案的实施方式进行了示例性的说明。应当理解，本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。 The above is an exemplary description of the implementation of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope of the claims of this application.

Claims (10)

  1. 一种式(I)所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、药学上可接受的盐或其前药化合物： A compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound:
    其中，A选自无取代或任选被一个、两个或更多个Ra取代的或稠环基团1；所述稠环基团1包含两个、三个或四个彼此独立地选自饱和或部分不饱和的C3-14碳环、C6-14芳环、5-14元杂芳环、3-14元杂环的环；每个Ra相同或不同，彼此独立地选自H、OH、卤素、氰基、NH2、NO2，无取代或任选被一个、两个或更多个Ra1取代的下列基团：C1-12烷基、C1-12烷氧基、C3-12环烷基；或者，连接在同一个环碳原子上的两个Ra与其连接的碳原子一起共同形成饱和或部分不饱和的C3-14碳环；每个Ra1相同或不同，彼此独立地选自H、OH、卤素、氰基、NH2、NO2、C1-12烷基、C1-12烷氧基、C3-12环烷基；wherein A is selected from unsubstituted or optionally substituted by one, two or more Ra or a fused ring group 1; the fused ring group 1 comprises two, three or four rings independently selected from a saturated or partially unsaturated C 3-14 carbocyclic ring, a C 6-14 aromatic ring, a 5-14 membered heteroaromatic ring, or a 3-14 membered heterocyclic ring; each Ra is the same or different and is independently selected from H, OH, halogen, cyano, NH 2 , NO 2 , the following groups which are unsubstituted or optionally substituted by one, two or more Ra1 : C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl; or two Ras attached to the same ring carbon atom together with the carbon atom to which they are attached form a saturated or partially unsaturated C 3-14 carbocyclic ring; each Ra1 is the same or different and is independently selected from H, OH, halogen, cyano, NH 2 , NO 2 , C 1-12 alkyl, C 1-12 alkoxy, or C 3-12 cycloalkyl;
    X1、X2、X3相同或不同，彼此独立地选自N或CR0；R0选自H、卤素、氰基、C1-12烷基、卤代C1-12烷基、氰基C1-12烷基、C1-12烷氧基、卤代C1-12烷氧基、氰基C1-12烷氧基； X1 , X2 , X3 are the same or different and are independently selected from N or CR0 ; R0 is selected from H, halogen, cyano, C1-12 alkyl, halogenated C1-12 alkyl, cyano C1-12 alkyl, C1-12 alkoxy, halogenated C1-12 alkoxy, cyano C1-12 alkoxy;
    B选自无取代或任选被一个、两个或更多个Rb取代的下列基团：C1-12烷基、卤代C1-12烷基、氰基C1-12烷基、C1-12烷氧基、卤代C1-12烷氧基、氰基C1-12烷氧基、C3-12环烷基、C3-12环烷基氧基、C3-12环烷基硫基、3-14元杂环基；每个Rb相同或不同，彼此独立地选自卤素、氰基、C1-12烷基、卤代C1-12烷基、氰基C1-12烷基、C1-12烷氧基、卤代C1-12烷氧基、氰基C1-12烷氧基；B is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R b : C 1-12 alkyl, halogenated C 1-12 alkyl, cyano C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, cyano C 1-12 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylthio, 3-14 membered heterocyclyl; each R b is the same or different and is independently selected from halogen, cyano, C 1-12 alkyl, halogenated C 1-12 alkyl, cyano C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, cyano C 1-12 alkoxy;
    环G选自无取代或任选被一个、两个或更多个Rg取代的稠环基团2，所述稠环基团2由环G1和环G2稠合形成；环G1选自C6-14芳环、5-14元杂芳环、3-14元杂环；环G2选自C3-14碳环、C6-14芳环、5-14元杂芳环、3-14元杂环；M和E优选连接在环G1上；每个Rg相同或不同，彼此独立地选自卤素、氰基、C1-12烷基、卤代C1-12烷基、氰基C1-12烷基、C1-12烷氧基、卤代C1-12烷氧基、氰基C1-12烷氧基；Ring G is selected from a fused ring group 2 which is unsubstituted or optionally substituted by one, two or more Rgs , and the fused ring group 2 is formed by condensing ring G1 and ring G2 ; ring G1 is selected from a C6-14 aromatic ring, a 5-14 membered heteroaromatic ring, and a 3-14 membered heterocyclic ring; ring G2 is selected from a C3-14 carbocyclic ring, a C6-14 aromatic ring, a 5-14 membered heteroaromatic ring, and a 3-14 membered heterocyclic ring; M and E are preferably attached to ring G1 ; each Rg is the same or different and is independently selected from halogen, cyano, C1-12 alkyl, halogenated C1-12 alkyl, cyano C1-12 alkyl, C1-12 alkoxy, halogenated C1-12 alkoxy, and cyano C1-12 alkoxy;
    E选自无取代或任选被一个、两个或更多个Re取代的下列基团：-NH-S(＝O)2-Re1、-S(＝O)2-NH-Re2、-S(＝O)(＝NH)-Re3、-N(Re4)(Re5)、3-14元杂环基；每个Re相同或不同，彼此独立地选自OH、卤素、氰基、C1-12烷基、C1-12烷氧基、卤代C1-12烷基、卤代C1-12烷氧基、氰基C1-12烷基、氰基C1-12烷氧基、-N(Re6)(Re7)；E is selected from the following groups which are unsubstituted or optionally substituted by one, two or more Re : -NH-S(=O) 2 - Re1 , -S(=O) 2 -NH- Re2 , -S(=O)(=NH) -Re3 , -N( Re4 )( Re5 ), 3-14 membered heterocyclyl; each Re is the same or different and is independently selected from OH, halogen, cyano, C1-12 alkyl, C1-12 alkoxy, halo C1-12 alkyl, halo C1-12 alkoxy, cyano C1-12 alkyl, cyano C1-12 alkoxy, -N( Re6 )( Re7 );
    Re1、Re2、Re3、Re4、Re5、Re6、Re7相同或不同，彼此独立地选自H、C1-12烷基、C1-12烷氧基、羟基C1-12烷基、卤代C1-12烷基、卤代C1-12烷氧基、氰基C1-12烷基、氰基C1-12烷氧基、C3-12环烷基、3-14元杂环基、C1-12烷氧基-C1-12烷基； Re1 , Re2 , Re3 , Re4 , Re5 , Re6 , and Re7 are the same or different and are independently selected from H, C1-12 alkyl, C1-12 alkoxy, hydroxyC1-12 alkyl, haloC1-12 alkyl, haloC1-12 alkoxy, cyanoC1-12 alkyl, cyanoC1-12 alkoxy, C3-12 cycloalkyl, 3-14 membered heterocyclyl, and C1-12 alkoxy- C1-12 alkyl ;
    M选自无取代或任选被一个、两个或更多个Rm取代的下列基团：C3-12环烷基、C3-12环烯基、3-14元杂环基；每个Rm相同或不同，彼此独立地选自卤素、氰基、C1-12烷基、卤代C1-12烷基、氰基C1-12烷基、C1-12烷氧基、氰基C1-12烷氧基。M is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R m : C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-14 membered heterocyclyl; each R m is the same or different and independently selected from halogen, cyano, C 1-12 alkyl, halo C 1-12 alkyl, cyano C 1-12 alkyl, C 1-12 alkoxy, cyano C 1-12 alkoxy.
  2. 根据权利要求1所述的化合物，其特征在于，A选自无取代或任选被一个、两个或更多个Ra取代的或稠环基团1；所述稠环基团1包含两个、三个或四个彼此独立地选自饱和或部分不饱和的C3-8碳环、C6-10芳环、5-10元杂芳环、3-8元杂环的环；每个Ra相同或不同，彼此独立地选自H、OH、卤素、氰基、NH2、NO2、C1-6烷基、C1-6烷氧基、C3-8环烷基、卤代C1-6烷基、卤代C1-6烷氧基、氰基C1-6烷基、氰基C1-6烷氧基、C3-8环烷基-C1-6烷氧基；或者，连接在同一个环碳原子上的两个Ra与其连接的碳原子一起共同形成饱和或部分不饱和的C3-8碳环；The compound according to claim 1, characterized in that A is selected from unsubstituted or optionally substituted by one, two or more Ra or a fused ring group 1; the fused ring group 1 comprises two, three or four rings independently selected from a saturated or partially unsaturated C 3-8 carbocyclic ring, a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring, or a 3-8 membered heterocyclic ring; each Ra is the same or different and independently selected from H, OH, halogen, cyano, NH 2 , NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, cyano C 1-6 alkyl, cyano C 1-6 alkoxy, or C 3-8 cycloalkyl-C 1-6 alkoxy; or, two Ras attached to the same ring carbon atom together with the carbon atom to which they are attached form a saturated or partially unsaturated C 3-8 carbocyclic ring;
    优选地，A选自 Preferably, A is selected from
    其中，T选自CH2、CH、NH、NRa或O；wherein T is selected from CH 2 , CH, NH, NR a or O;
    Z选自CH2、CH、NH、NRa或O；Z is selected from CH 2 , CH, NH, NR a or O;
    X选自N或CH；X is selected from N or CH;
    n选自0、1、2、3、4或5；n is selected from 0, 1, 2, 3, 4 or 5;
    p、q彼此独立地选自0、1、2、3，且p和q不同时为0；p and q are independently selected from 0, 1, 2, and 3, and p and q are not 0 at the same time;
    r、s彼此独立地选自0、1、2、3，且r和s不同时为0；r and s are independently selected from 0, 1, 2, and 3, and r and s are not 0 at the same time;
    优选地，X1、X2相同或不同，彼此独立地选自N或CR0；Preferably, X 1 and X 2 are the same or different and are independently selected from N or CR 0 ;
    优选地，X1、X2相同或不同，彼此独立地选自N或CH；Preferably, X 1 and X 2 are the same or different and are independently selected from N or CH;
    优选地，X2、X3不同时为N；Preferably, X 2 and X 3 are not N at the same time;
    优选地，当X1和X2为N时，X3为CR0；当X1为N或CR0，X2为CR0时，X3为N或CR0；当X1为N或CR0，X2为N时，X3为CR0；R0选自H、卤素、C1-6烷基；Preferably, when X1 and X2 are N, X3 is CR0 ; when X1 is N or CR0 and X2 is CR0 , X3 is N or CR0 ; when X1 is N or CR0 and X2 is N, X3 is CR0 ; R0 is selected from H, halogen, C1-6 alkyl;
    优选地，当X1和X2为N时，X3为CR0；当X1为N或CH，X2为CH时，X3为N或CR0；当X1为CH，X2为N时，X3为CR0；当X1为N，X2为CR0时，X3为N；R0选自H、C1-6烷基；Preferably, when X1 and X2 are N, X3 is CR0 ; when X1 is N or CH and X2 is CH, X3 is N or CR0 ; when X1 is CH and X2 is N, X3 is CR0 ; when X1 is N and X2 is CR0 , X3 is N; R0 is selected from H, C1-6 alkyl;
    优选地，B选自C1-6烷基、C3-8环烷基、C3-8环烷基氧基、3-8元杂环基、卤代3-8元杂环基；Preferably, B is selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, 3-8 membered heterocyclyl, halogenated 3-8 membered heterocyclyl;
    优选地，B选自卤代6元含N杂环基；例如为卤代哌啶基；Preferably, B is selected from a halogenated 6-membered N-containing heterocyclic group; for example, a halogenated piperidinyl group;
    优选地，B选自 Preferably, B is selected from
    优选地，A选自无取代或任选被一个、两个或更多个Ra取代的 或稠环基团1；所述稠环基团1由两个、三个、四个或更多个选自苯环、吡啶环、咪唑环、哌嗪环、二氢吡啶环、四氢吡啶环、二氢吡咯环、四氢吡咯环、二氢吡喃环、环丁烯环、环戊烯环、环己烯环、环庚烯环的环稠合而成；Preferably, A is selected from unsubstituted or optionally substituted with one, two or more Ra or a fused ring group 1; the fused ring group 1 is formed by the fusion of two, three, four or more rings selected from a benzene ring, a pyridine ring, an imidazole ring, a piperazine ring, a dihydropyridine ring, a tetrahydropyridine ring, a dihydropyrrole ring, a tetrahydropyrrole ring, a dihydropyran ring, a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, and a cycloheptene ring;
    优选地，A选自无取代或任选被一个、两个或更多个Ra取代的下列基团： Preferably, A is selected from the following groups which are unsubstituted or optionally substituted with one, two or more Ra :
    优选地，每个Ra相同或不同，彼此独立地选自H、OH、F、Cl、氰基、甲基、乙基、异丙基、甲氧基、乙氧基、三氟甲基、二氟甲氧基、三氟甲氧基、环丙基、环丙基甲氧基；或者，连接在同一个环碳原子上的两个Ra与其连接的碳原子一起共同形成环丙烷环、环丁烷环、环戊烷环、环己烷环、环庚烷环；Preferably, each Ra is the same or different and is independently selected from H, OH, F, Cl, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclopropylmethoxy; or, two Ras connected to the same ring carbon atom together with the carbon atom to which they are connected form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, or a cycloheptane ring;
    优选地，A选自 Preferably, A is selected from
  3. 根据权利要求1或2所述的化合物，其特征在于，环G选自无取代或任选被一个、两个或更多个Rg取代的稠环基团2，所述稠环基团2由环G1和环G2稠合形成；环G1选自C6-10芳环、5-10元杂芳环、5-10元杂环；环G2选自C3-10碳环、C6-10芳环、5-10元杂芳环、3-10元杂环；The compound according to claim 1 or 2, characterized in that ring G is selected from a fused ring group 2 which is unsubstituted or optionally substituted by one, two or more R g , wherein the fused ring group 2 is formed by condensing ring G 1 and ring G 2 ; ring G 1 is selected from a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring, and a 5-10 membered heterocyclic ring; ring G 2 is selected from a C 3-10 carbocyclic ring, a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring, and a 3-10 membered heterocyclic ring;
    优选地，环G1选自环戊烯环、环己烯环、二氢呋喃环、二氢吡喃环、咪唑环、三唑环、苯环、吡啶环、二氢吡啶环、吡咯环、吡唑环、呋喃环、噻吩环；优选为苯环或吡啶环；Preferably, ring G1 is selected from a cyclopentene ring, a cyclohexene ring, a dihydrofuran ring, a dihydropyran ring, an imidazole ring, a triazole ring, a benzene ring, a pyridine ring, a dihydropyridine ring, a pyrrole ring, a pyrazole ring, a furan ring, and a thiophene ring; preferably a benzene ring or a pyridine ring;
    优选地，环G2选自环戊烯环、环己烯环、二氢呋喃环、二氢吡喃环、咪唑环、三唑环、苯环、吡啶环、吡咯环、吡唑环、呋喃环、噻吩环、甲基咪唑环；Preferably, ring G2 is selected from a cyclopentene ring, a cyclohexene ring, a dihydrofuran ring, a dihydropyran ring, an imidazole ring, a triazole ring, a benzene ring, a pyridine ring, a pyrrole ring, a pyrazole ring, a furan ring, a thiophene ring, and a methylimidazole ring;
    优选地，环G选自 Preferably, ring G is selected from
  4. 根据权利要求1-3任一项所述的化合物，其特征在于，E选自无取代或任选被一个或两个Re取代的下列基团：-NH-S(＝O)2-Re1、-S(＝O)2-NH-Re2、-S(＝O)(＝NH)-Re3；Re1、Re2、Re3相同或不同，彼此独立地选自H、C1-6烷基、羟基C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基、氰基C1-6烷基、氰基C1-6烷氧基、C3-8环烷基、3-8元杂环基、C1-6烷氧基-C1-6烷基；每个Re相同或不同，彼此独立地选自OH、卤素、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、氰基C1-6烷基、氰基C1-6烷氧基；The compound according to any one of claims 1 to 3, characterized in that E is selected from the following groups which are unsubstituted or optionally substituted by one or two Re : -NH-S(=O) 2 - Re1 , -S(=O) 2 -NH- Re2 , -S(=O)(=NH) -Re3 ; Re1 , Re2 , and Re3 are the same or different and are independently selected from H, C1-6 alkyl, hydroxy C1-6 alkyl, halo C1-6 alkyl, halo C1-6 alkoxy, cyano C1-6 alkyl, cyano C1-6 alkoxy, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C1-6 alkoxy- C1-6 alkyl; each Re is the same or different and is independently selected from OH, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, cyano C1-6 alkyl, cyano C1-6 alkoxy, 1-6 alkoxy;
    优选地，E选自 Preferably, E is selected from
  5. 根据权利要求1-4任一项所述的化合物，其特征在于，M选自无取代或任选被一个、两个或更多个Rm取代的C3-8环烷基、C3-8环烯基或含氮的3-8元杂环基；每个Rm相同或不同，彼此独立地选自H、卤素、氰基、C1-6烷基、卤代C1-6烷基、氰基C1-6烷基、C1-6烷氧基、氰基C1-6烷氧基；或者，连接在同一个环碳原子上的两个Rm与其连接的碳原子一起共同形成饱和或部分不饱和的C3-8碳环；The compound according to any one of claims 1 to 4, characterized in that M is selected from a C 3-8 cycloalkyl group, a C 3-8 cycloalkenyl group or a nitrogen-containing 3-8 membered heterocyclic group which is unsubstituted or optionally substituted by one, two or more R m ; each R m is the same or different and is independently selected from H, halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy, cyano C 1-6 alkoxy; or, two R m connected to the same ring carbon atom together with the carbon atom to which they are connected form a saturated or partially unsaturated C 3-8 carbocyclic ring;
    优选地，M选自无取代或任选被一个、两个或更多个Rm取代的 Preferably, M is selected from unsubstituted or optionally substituted by one, two or more R m
  6. 根据权利要求1-5任一项所述的化合物，其特征在于，所述化合物具有以下结构： The compound according to any one of claims 1 to 5, characterized in that the compound has the following structure:
    其中，A、M、E、环G、环G1、环G2彼此独立地具有权利要求1-5任一项所述的定义，表示碳碳单键或者碳碳双键；Wherein, A, M, E, ring G, ring G 1 and ring G 2 are independently defined as in any one of claims 1 to 5, Represents a carbon-carbon single bond or a carbon-carbon double bond;
    优选地，式(I)所示的化合物具有以下结构： Preferably, the compound represented by formula (I) has the following structure:
    其中，B、M、E、环G、X、Z、T、X1、X2、X3、Ra、n、p、q、r、s彼此独立地具有权利要求1-5任一项所述的定义；Wherein, B, M, E, ring G, X, Z, T, X 1 , X 2 , X 3 , Ra , n, p, q, r, s are independently defined as in any one of claims 1 to 5;
    优选地，式(I)所示的化合物具有以下结构： Preferably, the compound represented by formula (I) has the following structure:
    其中，B、环G、X、Z、T、X1、X2、X3、Ra、n、r、s、p、q彼此独立地具有权利要求1-5任一项所述的定义；wherein B, ring G, X, Z, T, X 1 , X 2 , X 3 , Ra , n, r, s, p, q are independently defined as in any one of claims 1 to 5;
    优选地，式(I)所示的化合物具有以下结构： Preferably, the compound represented by formula (I) has the following structure:
    其中，A、环G1、环G2彼此独立地具有权利要求1-5任一项所述的定义；wherein A, ring G 1 , and ring G 2 independently have the definitions in any one of claims 1 to 5;
    优选地，式(I)所示的化合物具有以下结构： Preferably, the compound represented by formula (I) has the following structure:
    其中，A、环G2彼此独立地具有权利要求1-5任一项所述的定义；Wherein, A and ring G2 independently have the definitions as described in any one of claims 1 to 5;
    优选地，式(I)所示的化合物具有以下结构： Preferably, the compound represented by formula (I) has the following structure:
    其中，B、环G2、X、Z、T、X1、X2、X3、Ra、n、r、s、p、q彼此独立地具有权利要求1-5任一项所述的定义；wherein B, ring G 2 , X, Z, T, X 1 , X 2 , X 3 , Ra , n, r, s, p, q are independently defined as in any one of claims 1 to 5;
    优选地，式(I)所示的化合物具有以下结构： Preferably, the compound represented by formula (I) has the following structure:
    其中，环G2、X1、X2、X3彼此独立地具有权利要求1-5任一项所述的定义。Wherein, ring G 2 , X 1 , X 2 , and X 3 are independently defined as in any one of claims 1 to 5 .
  7. 根据权利要求1-6任一项所述的化合物，其特征在于，所述化合物选自以下结构： The compound according to any one of claims 1 to 6, characterized in that the compound is selected from the following structures:
  8. 权利要求1-7任一项所述化合物的制备方法，包括以下步骤： A method for preparing the compound according to any one of claims 1 to 7, comprising the following steps:
    (1)化合物a与化合物A-NH2反应得到化合物b；(1) Compound a reacts with compound A- NH2 to obtain compound b;
    (2)化合物b与化合物M-H反应得到化合物c；(2) Compound b reacts with compound M-H to obtain compound c;
    (3)化合物c与化合物E-H反应得到式(I)所示化合物；(3) Compound C reacts with compound E-H to obtain a compound represented by formula (I);
    其中，A、E、M和环G彼此独立地具有权利要求1-7任一项所述的定义；L选自卤素，如Cl、Br、I；Q选自卤素，如F、Cl、Br。Wherein, A, E, M and ring G are independently defined as in any one of claims 1 to 7; L is selected from halogen, such as Cl, Br, I; Q is selected from halogen, such as F, Cl, Br.
  9. [根据细则26改正 12.10.2023]
    一种药物组合物，其包含治疗有效量的权利要求1-7任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、药学上可接受的盐或其前药化合物中的至少一种。    [Corrected 12.10.2023 in accordance with Rule 26]
    A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound according to any one of claims 1 to 7, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.
  10. 权利要求1-7任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、多晶型物、药学上可接受的盐或其前药化合物中的至少一种在制备药物中的用途；Use of at least one of the compound according to any one of claims 1 to 7, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof in the preparation of a medicament;
    优选地，所述用途可以为在制备治疗KIF18A介导的病症和/或疾病的药物中的用途，如在制备KIF18A抑制剂药物中的用途；Preferably, the use may be for preparing a drug for treating KIF18A-mediated disorders and/or diseases, such as for preparing a KIF18A inhibitor drug;
    优选地，所述疾病例如为癌症，包括肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、膀胱癌、头颈部癌、宫颈癌或卵巢癌。Preferably, the disease is, for example, cancer, including colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.
PCT/CN2023/121929 2022-09-30 2023-09-27 Fused ring kif18a inhibitor compound, pharmaceutical composition, and preparation method therefor and use thereof WO2024067675A1 (en)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020132649A1 (en) * 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2020132651A1 (en) * 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
WO2021026100A1 (en) * 2019-08-02 2021-02-11 Amgen Inc. Pyridine derivatives as kif18a inhibitors
CN113226473A (en) * 2018-12-20 2021-08-06 美国安进公司 KIF18A inhibitors
CN114269731A (en) * 2019-08-02 2022-04-01 美国安进公司 KIF18A inhibitors
CN114302880A (en) * 2019-08-02 2022-04-08 美国安进公司 KIF18A inhibitors
CN116535400A (en) * 2023-04-26 2023-08-04 上海湃隆生物科技有限公司 Azaspiro compounds and uses thereof
WO2023217233A1 (en) * 2022-05-13 2023-11-16 上海湃隆生物科技有限公司 Kinesin kif18a inhibitor and use thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020132649A1 (en) * 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2020132651A1 (en) * 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
CN113226473A (en) * 2018-12-20 2021-08-06 美国安进公司 KIF18A inhibitors
US20220056015A1 (en) * 2018-12-20 2022-02-24 Amgen Inc. Kif18a inhibitors
WO2021026100A1 (en) * 2019-08-02 2021-02-11 Amgen Inc. Pyridine derivatives as kif18a inhibitors
CN114269731A (en) * 2019-08-02 2022-04-01 美国安进公司 KIF18A inhibitors
CN114302880A (en) * 2019-08-02 2022-04-08 美国安进公司 KIF18A inhibitors
WO2023217233A1 (en) * 2022-05-13 2023-11-16 上海湃隆生物科技有限公司 Kinesin kif18a inhibitor and use thereof
CN116535400A (en) * 2023-04-26 2023-08-04 上海湃隆生物科技有限公司 Azaspiro compounds and uses thereof

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