WO2024067675A1 - Composé inhibiteur de kif18a à cycle condensé, composition pharmaceutique, procédé de préparation correspondant et utilisation associée - Google Patents

Composé inhibiteur de kif18a à cycle condensé, composition pharmaceutique, procédé de préparation correspondant et utilisation associée 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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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.

Abstract

La présente invention concerne un composé représenté par la formule (I), une composition pharmaceutique, un procédé de préparation correspondant et une utilisation associée. Le composé a un bon effet inhibiteur sur KIF18A, et peut être utilisé seul ou dans un complexe de liaison avec un microtubule pour réguler la protéine KIF18A pour le traitement de troubles et/ou de maladies à médiation par KIF18A, tels que des maladies tumorales, et pour la préparation d'un médicament utilisé pour de tels troubles ou maladies.
PCT/CN2023/121929 2022-09-30 2023-09-27 Composé inhibiteur de kif18a à cycle condensé, composition pharmaceutique, procédé de préparation correspondant et utilisation associée WO2024067675A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020132651A1 (fr) * 2018-12-20 2020-06-25 Amgen Inc. Inhibiteurs de kif18a
WO2020132649A1 (fr) * 2018-12-20 2020-06-25 Amgen Inc. Amides d'hétéroaryle utiles en tant qu'inhibiteurs de kif18a
WO2021026100A1 (fr) * 2019-08-02 2021-02-11 Amgen Inc. Dérivés de pyridine en tant qu'inhibiteurs de kif18a
CN113226473A (zh) * 2018-12-20 2021-08-06 美国安进公司 Kif18a抑制剂
CN114269731A (zh) * 2019-08-02 2022-04-01 美国安进公司 Kif18a抑制剂
CN114302880A (zh) * 2019-08-02 2022-04-08 美国安进公司 Kif18a抑制剂
CN116535400A (zh) * 2023-04-26 2023-08-04 上海湃隆生物科技有限公司 氮杂螺环化合物及其应用
WO2023217233A1 (fr) * 2022-05-13 2023-11-16 上海湃隆生物科技有限公司 Inhibiteur de kinésine kif18a et son utilisation

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020132651A1 (fr) * 2018-12-20 2020-06-25 Amgen Inc. Inhibiteurs de kif18a
WO2020132649A1 (fr) * 2018-12-20 2020-06-25 Amgen Inc. Amides d'hétéroaryle utiles en tant qu'inhibiteurs de kif18a
CN113226473A (zh) * 2018-12-20 2021-08-06 美国安进公司 Kif18a抑制剂
US20220056015A1 (en) * 2018-12-20 2022-02-24 Amgen Inc. Kif18a inhibitors
WO2021026100A1 (fr) * 2019-08-02 2021-02-11 Amgen Inc. Dérivés de pyridine en tant qu'inhibiteurs de kif18a
CN114269731A (zh) * 2019-08-02 2022-04-01 美国安进公司 Kif18a抑制剂
CN114302880A (zh) * 2019-08-02 2022-04-08 美国安进公司 Kif18a抑制剂
WO2023217233A1 (fr) * 2022-05-13 2023-11-16 上海湃隆生物科技有限公司 Inhibiteur de kinésine kif18a et son utilisation
CN116535400A (zh) * 2023-04-26 2023-08-04 上海湃隆生物科技有限公司 氮杂螺环化合物及其应用

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