[go: up one dir, main page]

WO2019170055A1 - Composés ayant une activité inhibitrice de kinase cdk4/6, composition pharmaceutique de ceux-ci et utilisation de ceux-ci - Google Patents

Composés ayant une activité inhibitrice de kinase cdk4/6, composition pharmaceutique de ceux-ci et utilisation de ceux-ci Download PDF

Info

Publication number
WO2019170055A1
WO2019170055A1 PCT/CN2019/076864 CN2019076864W WO2019170055A1 WO 2019170055 A1 WO2019170055 A1 WO 2019170055A1 CN 2019076864 W CN2019076864 W CN 2019076864W WO 2019170055 A1 WO2019170055 A1 WO 2019170055A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
optionally substituted
substituted
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2019/076864
Other languages
English (en)
Chinese (zh)
Inventor
查传涛
耿美玉
黄颖
丁健
万惠新
黄敏
富燕
唐帅
叶艳
兰小晶
陈奕
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Shanghai Haihe Pharmaceutical Co Ltd
Original Assignee
Shanghai Institute of Materia Medica of CAS
Shanghai Haihe Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS, Shanghai Haihe Pharmaceutical Co Ltd filed Critical Shanghai Institute of Materia Medica of CAS
Publication of WO2019170055A1 publication Critical patent/WO2019170055A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a compound having kinase inhibitory activity, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystal form, solvate, hydrate or prodrug thereof, and use thereof .
  • the invention also relates to pharmaceutical compositions comprising these compounds and to methods of preventing or treating diseases, particularly those diseases mediated by CDK kinase, in particular CDK4/6 kinase aberrant activity.
  • Cyclin-dependent kinase is a type of serine/threonine kinase that plays a central role in the cell cycle, leading to the initiation and progression of the cell cycle. End.
  • the CDK family is an important signal transduction molecule in the cell, and its CDK-cyclin complex with cyclin is involved in cell growth, proliferation, dormancy and apoptosis.
  • CDK kinase As a therapeutic target for cancer has received extensive attention, such as Flavopiridol (Alvocidib), Seliciclib (CYC202), Dinaciclib (SCH727965) and Milciclib (PHA-848125). Clinical studies at different stages. However, due to the early detection of CDK inhibitors, the inhibition activity of each CDK family subtype is not high, or lack of certain selectivity, or poor absorption in vivo, which limits the clinical application. In recent years, drug discovery in this field has been made by increasing the selectivity of CDK inhibitors for each CDK family subtype or increasing the inhibitory activity of CDK kinase, especially the selective inhibitors targeting CDK4/6. Become a hot spot again.
  • CDK4/6 is overactive in many cancers, leading to uncontrolled cell proliferation.
  • inhibition of CDK4/6 can achieve inhibition of cell proliferation downstream of the signaling pathway.
  • Pfizer's PD0332991 (Palbociclib) and Novartis's LEE-011 (Ribociclib) have been marketed as drugs for the treatment of ER-positive, HER2-negative breast cancer.
  • LY-2835219 (abemaciclib) a similar drug, is expected to be available around 2017, and there are a large number of similar compounds in preclinical and early clinical research stages at different stages of development.
  • problems in these compounds such as poor efficacy of monotherapy, low selectivity to other targets, and resistance to brain metastasis. Therefore, there is an urgent need in the field to research and develop new ones.
  • a novel CDK kinase inhibitor with high efficacy, low toxicity, resistance to drug resistance and clinical application value.
  • the invention provides a compound of formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystalline form, solvate, hydrate thereof or Prodrug,
  • R 1 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 - a C 8 cycloalkyl group, an optionally substituted 4-8 membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from nitrogen, oxygen and sulfur, an optionally substituted carbonyl group, an optionally substituted sulfonyl group, and An optionally substituted sulfinyl group;
  • R 2 is selected from the group consisting of: halogen, -OH, -CN, -NR a R b , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 a -C 8 cycloalkyl group, and an optionally substituted 3-8 membered heterocyclic group;
  • R a and R b are each independently selected from the group consisting of: H, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, and hydroxy substituted C 1 -C 6 alkyl;
  • n is the number of R 2 substituents and is 0, 1, 2 or 3;
  • R 3 is hydrogen or halogen
  • R 4 is an optionally substituted C 1 -C 6 alkyl group
  • R 5 is selected from the group consisting of hydrogen, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted 4-8 membered heterocyclic group, and an optionally substituted C 3 -C 8 cycloalkyl group.
  • the invention provides a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystalline form, solvate thereof, hydrated thereof Or prodrug, characterized in that
  • R 1 is selected from the group consisting of: an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 2 -C 6 alkenyl group, an optionally substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 8 a cycloalkyl group, an optionally substituted 4-8 membered heterocyclic group, an optionally substituted C 1 -C 6 alkylcarbonyl group, an optionally substituted 4-8 membered heterocyclic carbonyl group, an optionally substituted sulfonyl group, and An optionally substituted sulfinyl group; the optional substituent described in R 1 is one or more substituents independently selected from the group consisting of halogen, -OH, -NH 2 , -CN, C 1 -C 3 alkane a hydroxy-substituted C 1 -C 4 alkyl group, a C 1 -C 3 alkoxy group, a -NH(
  • R 2 is selected from the group consisting of: halogen, -OH, -CN, -NR a R b , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted 4- An 8-membered heterocyclic group, and an optionally substituted C 3 -C 7 cycloalkyl group; the optional substituents described in R 2 are one or more substituents independently selected from the group consisting of halogen, -OH, - NH 2 , -CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -NH(C 1 -C 4 alkyl), and -N(C 1 -C 4 alkyl) 2 ;
  • R a and R b are each independently selected from the group consisting of: H, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, and hydroxy-substituted C 1 -C 4 alkyl;
  • n is the number of R 2 substituents and is 0, 1, 2 or 3;
  • R 3 is hydrogen or halogen
  • R 4 is C 1 -C 4 alkyl
  • R 5 is selected from: hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 4 -C 8 heterocyclyl, and optionally substituted C 3 -C 8 cycloalkyl group; R 5 as said optional substituents are one or more substituents independently selected from the group consisting of: halo, -OH, -CN, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl.
  • the invention provides a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystalline form, solvate thereof, hydrated thereof Or prodrug, characterized in that
  • R 1 is selected from the group consisting of: an optionally substituted C 1 -C 4 alkyl group, an optionally substituted C 3 -C 6 cycloalkyl group, an optionally substituted 4-6 membered heterocyclic group, an optionally substituted C 1 -C a 4 -alkylcarbonyl group and an optionally substituted 4-6 membered heterocyclylcarbonyl group;
  • the optional substituents described in R 1 are one or more substituents independently selected from the group consisting of halogen, -OH, -NH 2 , -CN, C 1 -C 3 alkyl, hydroxy substituted C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -NH(C 1 -C 2 alkyl), -N(C 1 - C 2 alkyl) 2 , C 3 -C 6 cycloalkyl and optionally substituted by C 1 -C 2 alkyl, halogenated C 1 -C 3 alkyl or
  • R 1 is selected from the group consisting of R 1a (C 1 -C 4 alkyl), C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic, C 1 -C 2 alkyl substituted 4-6 membered heterocyclic group a hydroxy-substituted C 1 -C 3 alkyl-substituted 4-6 membered heterocyclic group, a halogenated C 1 -C 3 alkyl-substituted 4-6 membered heterocyclic group, a hydroxy-substituted C 1 -C 2 alkane Alkylcarbonyl;
  • R 1a is selected from the group consisting of: halogen, -OH, -NH 2 , -CN, C 1 -C 3 alkoxy, -NH(C 1 -C 2 alkyl), -N(C 1 -C 2 alkane 2 , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C
  • R 1 is selected from the group consisting of R 1a (C 1 -C 4 alkyl), C 3 -C 6 cycloalkyl, hydroxymethyl substituted carbonyl, with
  • R 1a is selected from the group consisting of: F, -OH, -NH 2 , -CN, CF 3 , C 1 -C 3 alkoxy, -NH(C 1 -C 2 alkyl), -N(C 1 -C 2 alkane Base) 2 ,
  • R 1b is selected from the group consisting of methyl, ethyl and hydroxy substituted propyl groups
  • R 1aa is selected from the group consisting of: C 1 -C 2 alkyl.
  • the invention provides a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystalline form, solvate or former thereof Medicament characterized in that R 2 is selected from the group consisting of: halogen, -OH, -NH 2 , -CN, C 1 -C 4 alkyl, m is the number of R 2 substituents, and is 0, 1; preferably, R 2 is selected from the group consisting of: F, Cl, -OH, -NH 2 , -CN, C 1 -C 3 alkyl, m is the number of R 2 substituents, and is 0, 1; more preferably, m is R 2 substituted The number of bases, and is 0.
  • the invention provides a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystalline form, solvate thereof, hydrated thereof Or prodrug, characterized in that R 3 is H or F.
  • the invention provides a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystalline form, solvate thereof, hydrated thereof And a prodrug characterized in that R 4 is a C 1 -C 2 alkyl group; preferably, R 4 is a methyl group.
  • the invention provides a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystalline form, solvate thereof, hydrated thereof Or prodrug, characterized in that
  • R 5 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, and optionally substituted C 3 -C 6 cycloalkyl; the optional substituents described in R 5 are one or two independent a substituent selected from the group consisting of halogen, -OH, -CN, C 1 -C 4 alkyl, and C 3 -C 5 cycloalkyl;
  • R 5 is selected from:
  • R 5 is
  • the invention provides a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystalline form, solvate or former thereof Medicine, characterized in that
  • R 1 is selected from the group consisting of R 1a (C 1 -C 4 alkyl), C 3 -C 6 cycloalkyl, hydroxymethyl substituted carbonyl,
  • R 1a is selected from the group consisting of: F, -OH, -NH 2 , -CN, CF 3 , C 1 -C 3 alkoxy, -NH(C 1 -C 2 alkyl), -N(C 1 -C 2 alkane Base) 2 ,
  • R 1b is selected from the group consisting of methyl, ethyl and hydroxy substituted propyl groups
  • R 1aa is selected from the group consisting of: C 1 -C 2 alkyl
  • n is the number of R 2 substituents and is 0;
  • R 3 is hydrogen or F
  • R 4 is a methyl group
  • the invention provides a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystalline form, solvate or former thereof Medicine, characterized in that
  • R 1 is selected from the group consisting of: R 1a (C 1 -C 4 alkyl),
  • R 1a is selected from the group consisting of: F, -OH, CF 3 , C 1 -C 3 alkoxy, -NH 2 , -N(C 1 -C 2 alkyl) 2 ,
  • R 1b is selected from the group consisting of: methyl, and ethyl
  • R 1aa is selected from the group consisting of: C 1 -C 2 alkyl.
  • the invention provides a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystalline form, solvate thereof, hydrated thereof Or a prodrug, wherein the compound is selected from
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a stereoisomer, geometric isomer, tautomer, pharmacy thereof An acceptable salt, crystal form, solvate, hydrate or prodrug, and a pharmaceutically acceptable excipient.
  • the invention provides a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystalline form, solvate, hydrate thereof or The use of a prodrug for the preparation of a medicament for preventing, treating, or alleviating a disorder or disease caused by abnormal cell proliferation, autoimmunity, inflammation or infection in a patient.
  • the abnormal cell proliferation, autoimmunity, inflammation or infection is caused by a change in a cyclin dependent kinase.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystalline form thereof, Solvates, hydrates or prodrugs, as well as pharmaceutically acceptable carriers.
  • the pharmaceutical composition is formulated for intravenous administration, intramuscular administration, oral administration, rectal administration, inhalation administration, nasal administration, topical administration, ocular administration, or otic administration.
  • the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a solution, an emulsion, an ointment, an eye drop, or an ear drop.
  • Agent in other embodiments of the pharmaceutical composition, it further comprises one or more additional therapeutic agents.
  • the invention provides a compound of formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystal form, solvate, hydrate or prodrug thereof, in the preparation Use in a medicament for preventing, treating, or ameliorating a disorder or disease mediated by one or more abnormal activities of CDK kinase, particularly CDK4/6 kinase.
  • the invention provides a method of preventing, treating, or ameliorating a disorder or disease mediated by one or more abnormal activities of a CDK kinase, particularly a CDK4/6 kinase, comprising administering to an individual in need of such treatment Administration of an effective amount of a compound of formula I, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystal form, solvate, hydrate or prodrug thereof, or a pharmaceutical combination comprising the same Things.
  • the disorder or disease includes, but is not limited to, a cell proliferative disorder, an autoimmune disease, an inflammatory disease, or an infectious disease.
  • the cell proliferative disorder includes, but is not limited to, a malignant tumor, such as melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, cervical cancer. , thyroid cancer, metastasis of secondary sites of primary solid tumors, chronic myeloid leukemia, acute lymphocytic leukemia, other myeloproliferative disorders, papillary thyroid carcinoma, non-small cell lung cancer, and/or mesothelioma .
  • a malignant tumor such as melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, cervical cancer.
  • thyroid cancer metastasis of secondary sites of primary solid tumors, chronic myeloid leukemia, acute lymphocytic leukemia, other myeloproliferative disorders, papillary thyroid carcinoma, non-small cell lung cancer, and/or mesothelioma .
  • the autoimmune disease includes, but is not limited to, rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, hemolytic anemia, or psoriasis.
  • the inflammatory disease includes, but is not limited to, osteoarthritis, gouty arthritis, ulcerative colitis, and/or inflammatory bowel disease, and the like.
  • the infectious disease includes, but is not limited to, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, and/or toxic shock syndrome.
  • alkyl refers to a fully saturated straight or branched hydrocarbon group.
  • the alkyl group preferably contains from 1 to 20 carbon atoms, more preferably from 1 to 16 carbon atoms, from 1 to 10 carbon atoms, from 1 to 6 carbon atoms or from 1 to 4 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl Base, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-decyl, n-decyl and the like.
  • alkenyl refers to a straight or branched hydrocarbon group containing at least one double bond.
  • the alkenyl group preferably contains 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, octenyl, and the like.
  • alkynyl refers to a straight or branched hydrocarbon group containing at least one triple bond.
  • the alkynyl group preferably contains 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms.
  • Representative examples of alkynyl include, but are not limited to, ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, isethynyl, hexynyl, heptynyl, octyne Base.
  • alkoxy refers to an alkyl-O- group, wherein alkyl is as defined above.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy Base, cyclohexyloxy and the like.
  • the alkoxy group contains from about 1 to about 6 or from about 1 to about 4 carbons.
  • the term "carbocycle” refers to a saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon group of 3 to 12 carbon atoms.
  • the carbocyclic ring preferably has from 3 to 8 ring carbon atoms, for example containing 3-7, or 4-7 ring carbon atoms.
  • Exemplary monocyclic carbocycles include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, and the like.
  • Exemplary bicycloalkanes include tetrahydronaphthalene, decahydronaphthalene, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, and the like.
  • Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
  • cycloalkyl refers to a saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon group of 3 to 12 carbon atoms.
  • the cycloalkyl group preferably contains from 3 to 8 ring carbon atoms, for example, contains 3-7, or 4-7 ring carbon atoms.
  • Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.
  • Exemplary bicyclic hydrocarbon groups include borneol, fluorenyl, hexahydroindenyl, 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 and so on.
  • Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
  • aryl is a monocyclic or bicyclic aromatic hydrocarbon group having from 6 to 20 carbon atoms in the ring portion.
  • the aryl group is a C 6 -C 12 aryl group.
  • Non-limiting examples of aryl groups include phenyl, biphenyl, naphthyl or anthryl and the like.
  • heteroaryl refers to a 5-14 membered monocyclic or bicyclic or fused polycyclic aromatic ring containing from 1 to 8 heteroatoms selected from N, O or S.
  • the heteroaryl contains 1-3 heteroatoms selected from N, O or S.
  • the heteroaryl group is preferably a 5-10 membered heteroaryl group, more preferably a 5-6 membered heteroaryl group.
  • the heteroaryl group includes, but is not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, Azolyl, different Azyl, thiazolyl, isothiazolyl, triazolyl, Diazolyl, thiadiazolyl, tetrazolyl, Triazolyl, thiatriazole, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Azinyl, two English, thiazinyl, triazinyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 7H-pyrrolo[2,3-d]pyrimidinyl, imidazo[1 ,2-b]pyridazinyl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazolyl, imidazo[2,1-b][1,3]thiazolyl,
  • heterocycle refers to a fully saturated or unsaturated, aromatic or non-aromatic cyclic group, for example, which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic ring or A 10- to 15-membered tricyclic ring system containing at least one hetero atom on a ring containing at least one carbon atom.
  • Each ring of the hetero atom containing a hetero atom may have 1 to 6, preferably 1, 2 or 3 hetero atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom, wherein the nitrogen and sulfur hetero atoms may also be Optionally oxidized.
  • the heterocyclic ring is a 4- to 7-membered monocyclic heterocyclic ring.
  • Exemplary monocyclic heterocycles include pyrrolidine, pyrrole, pyrazole, oxetane, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, Azole, Oxazolidine Oxazoline Oxazole, thiazole, thiadiazole, thiazolidine, isothiazole, isothiazolidine, furan, tetrahydrofuran, thiophene, Diazole, piperidine, piperazine, 2-oxopiperazine, 2-oxopiperidine, 2-oxopyrrolidine, 2-oxoaza Aza , 4-piperidone, pyridine, pyrazine, pyrimidine, pyridazine, tetrahydropyran, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, 1,3-dioxolane and tetra Hydrogen-1
  • Exemplary bicyclic heterocycles include anthracene, indoline, benzothiazole, benzo Oxazine, benzo Azole, benzothiophene, benzothiazine, quinuclidine, quinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, tetrahydroisoquinoline, decahydroisoquinoline, benzimidazole, benzo Pyran, pyridazine, benzofuran, chromone, coumarin, benzopyran, porphyrin, quinoxaline, oxazole, pyrrolopyridine, furopyridine (eg furo[2,3-c] Pyridine, furo[3,2-b]-pyridine] or furo[2,3-b]pyridine), dihydroisoindole, 1,3-dioxo-1,3-dihydroisoindole Indole-2-, dihydroquinazoline (
  • Exemplary tricyclic heterocycles include carbazole, dibenzoazepine Dithienoazepine Benzopyrene, phenanthroline, acridine, phenanthridine, phenanthrene Oxazine, phenothiazine, xanthene, porphyrin and the like.
  • Heterocyclyl or “heterocycloalkyl” refers to a group formed by the loss of one or more hydrogen atoms from a heterocycle as defined above.
  • the heterocyclic group can be attached at a hetero atom or a carbon atom.
  • the heterocycloalkyl group is a 4-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • Boc means a tert-butoxycarbonyl group.
  • halogen refers to fluoro, chloro, bromo and iodo.
  • a group such as an alkyl group, an alkenyl group, an alkoxy group, a carbocyclic ring, a cycloalkyl group, a heteroaryl group, a heterocyclic group, a heterocyclic group, a carbonyl group, a sulfonyl group, a sulfinyl group or the like may be substituted with a substituent.
  • the substituents include, but are not limited to, OH, Boc, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic ring. a group; NRR', C(O)R, C(O)NRR' or C(O)OR, and each of R and b' is independently selected from the group consisting of: H and a substituted or unsubstituted alkyl group.
  • substitution pattern means that the substitution pattern, event, or circumstance described subsequently may or may not occur, and that the description includes the occurrence of the substitution pattern and The case where the substitution mode does not occur.
  • “optionally substituted alkyl” includes “unsubstituted alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any spatially impractical, chemically incorrect, synthetically infeasible And/or an inherently unstable substitution pattern.
  • substituted or “substituted by” as used herein means that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given group of substituents, conditions. It does not exceed the normal valence of the given atom.
  • two hydrogen atoms on a single atom are replaced by oxygen.
  • a chemically correct and stable compound means that the compound is sufficiently stable to be separated from the reaction mixture and to determine the chemical structure of the compound, and can then be formulated into at least a practically useful formulation.
  • substituted or “substituted by” as used herein, unless the substituent is specifically recited, means that one or more hydrogen atoms on a given atom or group are independently or more, e.g., three or four substituents, the substituents are independently selected from: deuterium (D), halogen, -OH, a mercapto group, a cyano group, -CD 3, -C 1 -C 6 alkyl (preferably -C 1-3 alkyl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl (preferably 3-8 membered cycloalkyl), aryl, heterocyclic (preferably a 3-8 membered heterocyclic group), a heteroaryl group, an aryl-C 1 -C 6 alkyl group, a heteroaryl-C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group
  • the term "pharmaceutically acceptable salt” refers to a salt that retains the biological effects and properties of the compounds of the invention, and which are not biologically or otherwise undesirable.
  • Non-limiting examples of such salts include non-toxic, inorganic or organic base or acid addition salts of the compounds of the invention.
  • the compounds of the invention are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or groups similar thereto.
  • a pharmaceutically acceptable acid addition salt can be formed from a mineral acid and an organic acid.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; ammonium, potassium, sodium, calcium, and magnesium salts are particularly preferred.
  • Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins and the like, especially such as isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound (basic or acidic moiety) by conventional chemical methods.
  • the salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of a suitable base (eg, a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K).
  • a suitable base eg, a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K.
  • the reaction or reaction of the free base form of the compound with a stoichiometric amount of the appropriate acid is usually carried out in water or an organic solvent or a mixed solvent of the two.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred where practicable.
  • suitable salts can be found in Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing Company, Easton, Pa., (1985), which is incorporated herein by reference.
  • pharmaceutically acceptable excipient includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial, antifungal), isotonic agents. , absorption delaying agents, salts, preservatives, pharmaceuticals, pharmaceutical stabilizers, binders, excipients, disintegrating agents, lubricants, sweeteners, flavoring agents, dyes, similar substances, and combinations thereof, It is well known to those of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference. ). Unless any conventional carrier is incompatible with the active ingredient, it can be considered for use in a therapeutic or pharmaceutical composition.
  • solvate means a solvent addition form comprising a stoichiometric or non-stoichiometric solvent. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrate is formed by one or more molecules of water and one molecule of said substance, wherein water retains its molecular state of H 2 O, such a combination can form one or more hydrates, such as hemihydrate, Hydrates and dihydrates.
  • prodrug refers to a chemically modified active or inactive compound which, upon administration to an individual, becomes a compound of the invention by physiological action (eg, hydrolysis, neogeneration, etc.) in the body.
  • physiological action eg, hydrolysis, neogeneration, etc.
  • Adaptability and techniques for making and using prodrugs are well known to those skilled in the art.
  • terapéuticaally effective amount of a compound of the invention refers to an amount of a compound of the invention which can elicit an individual's biological or medical response or ameliorate symptoms, slow or delay the progression of the disease, or prevent disease, and the like.
  • the term "individual” refers to an animal.
  • the animal is a mammal.
  • Individuals also refer to, for example, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.
  • the individual is a human.
  • the term “inhibiting” refers to the alleviation or inhibition of a particular patient, condition or disorder or disease, or a significant decrease in biological activity or process baseline activity.
  • any disease or condition refers to ameliorating a disease or condition (ie, preventing or slowing the progression of a disease or at least one of its clinical symptoms).
  • “treating” refers to ameliorating at least one physical parameter that may not be perceived by a patient.
  • “treating” refers to modulating a disease or condition either physically (eg, to stabilize a detectable condition) or physiologically (eg, to stabilize a parameter of the body) or both.
  • any asymmetric carbon atom in the compounds of the invention may exist in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration.
  • Substituents for unsaturated bond atoms if possible, may exist in cis-(Z)- or trans-(E)- form.
  • the compounds of the invention may exist as one of the possible isomers or as a mixture thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (Enantiomer), racemate or a mixture thereof.
  • Any resulting mixture of isomers can be separated into pure geometric or optical isomers, diastereomers, racemates, for example by chromatography and/or fractional crystallization, depending on the physicochemical differences of the components. .
  • the main advantage of the present invention is that the compounds of the present invention have high selectivity for CDK4/6 kinase, have fewer side effects, and have high resistance to drug resistance (i.e., have high activity against diseases that have been resistant to current kinase inhibitors). It has high bioavailability and high clinical application value, and it has good pharmacokinetic properties, has a good blood-brain distribution, and can cross the blood-brain barrier to inhibit the growth of brain tumors.
  • the experimental instrument description for example, 1 H NMR is recorded by Varian Mercury-300 or Varian Mercury-400 type nuclear magnetic resonance apparatus, and 13 C NMR is performed by Varian Mercury-400 or Varian Mercury-500 or Varian Mercury-600 type nuclear magnetic Resonance recording, chemical shift is expressed in ⁇ (ppm); mass spectrometry is recorded by Finnigan/MAT-95 (EI) and Finnigan LCQ/DECA and Micromass Ultra Q-TOF (ESI) mass spectrometer; 200-300 mesh).
  • 1 H NMR is recorded by Varian Mercury-300 or Varian Mercury-400 type nuclear magnetic resonance apparatus
  • 13 C NMR is performed by Varian Mercury-400 or Varian Mercury-500 or Varian Mercury-600 type nuclear magnetic Resonance recording, chemical shift is expressed in ⁇ (ppm); mass spectrometry is recorded by Finnigan/MAT-95 (EI) and Finnigan LCQ/DECA and Micromass Ultra Q-TOF (ESI) mass spectrometer; 200-300 mesh).
  • iPrOH isopropanol; EtOH: ethanol; DCM: dichloromethane; TFA: trifluoroacetic acid; MeOH: methanol; NaOH: sodium hydroxide; HCl: hydrogen chloride; TEA: triethylamine; Raney Ni: Raney nickel; , 4-dioxane: 1,4-dioxane; NaH: sodium hydride; H 2 O: water; Pd/C: palladium/carbon; H 2 : hydrogen; HATU: 2-(7-oxidized benzotriazine Azole)-N,N,N',N'-tetramethyluron hexafluorophosphate; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; Boc 2 O: di-tert-butyl dicarbonate; NBS : N-bromosuccinimide; NCS: N-chlorosuccinimide; NIS: N-iod
  • Fumaronitrile fumaric acid nitrile; P(nBu) 3 : tri-n-butylphosphine; LDA: lithium diisopropylamide; LiOH: lithium hydroxide; MeI: methyl iodide; EtI: ethyl iodide; (CH 2 O) n : paraformaldehyde; HCO 2 H: formic acid; CH 3 COCl: acetyl chloride; HBTU: O-benzotriazole-tetramethylurea hexafluorophosphate; Pd 2 (dba) 3 : tris (dibenzylidene) Acetone) dipalladium; Xantphos: 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan; DCE: dichloroethane; TLC: thin layer chromatography; DIEA: N, N-II Isopropylethylamine; RT: retention time;
  • the above intermediate amines (1 eq.) are sequentially added to a dry round bottom flask at room temperature, a suitable solvent such as DMF or the like (appropriate amount), a corresponding halogenated product, an epoxy compound or a sulfonic acid ester (1.2 eq.
  • a suitable base such as triethylamine, potassium carbonate, sodium carbonate or the like (1-2 eq.) is allowed to react at room temperature or for 12 hours. Water is added to the reaction mixture, and the mixture is extracted three times with an organic solvent such as dichloromethane or ethyl acetate. The organic phase was combined, dried and filtered, evaporated, evaporated, evaporated, evaporated, evaporated,
  • each of the above intermediate amines (1 eq.), a suitable solvent such as DMF or the like (suitable amount), a condensing agent such as HBTU, HATU (1-2 eq), the corresponding carboxylic acid or activated are sequentially added to a dry round bottom flask at room temperature.
  • the acid material e.g., carboxylic anhydride
  • a suitable organic base such as DIPEA, et 3 N and the like (1-5 eq.
  • Water is added to the reaction mixture, and the mixture is extracted three times with an organic solvent such as dichloromethane or ethyl acetate. The organic phase was combined, dried and filtered, evaporated, evaporated, evaporated, evaporated, or
  • Example 1 (6-(2-(Dimethylamino)ethyl)-N-(5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl) Pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine
  • Example 2 (N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-6-(2 -(pyrrolidin-1-yl)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine)
  • Example 4 (N-(5-Fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-6-(3 -(pyrrolidin-1-yl)propyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine)
  • Example 5-13 The compound of Example 5-13 was prepared in the same manner as in Example 1.
  • Example 8 N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-6-(2, 2,2-trifluoroethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine
  • Example 11 (N-(5-Fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-6-(2 -methoxyethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine)
  • Example 12 2-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)amino) -7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethanol
  • Example 13 N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-6-(2, 2-difluoroethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine
  • Example 14 3-(2-((5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)amino)-7,8 -dihydro-1,6-naphthyridin-6(5H)-yl)propionitrile
  • Example 15 The compound of Example 15 was prepared in the same manner as in Example 14.
  • Example 15 3-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)amino) -7,8-Dihydro-1,6-naphthyridin-6(5H)-yl)propanenitrile
  • Isolated product (1-(2-((5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)amino)-7,8 -Dihydro-1,6-naphthyridin-6(5H)-yl)-2-hydroxyethanone) 38 mg, yellow powder, yield 41.70%.
  • Example 17 The compound of Example 17, 18 was prepared in the same manner as in Example 16.
  • Example 17 2-((5-Fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)amino)-6-(N-A ke-L-prolyl)-5,6,7,8-tetrahydro-1,6-diazepine
  • Example 18 (1-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)amino) )-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-hydroxyethanone)
  • Example 20 The compound of Example 20 was prepared in the same manner as in Example 19.
  • Example 22 1-(2-((5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)amino)-7,8 -dihydro-1,6-naphthyridin-6(5H)-yl)propan-2-ol
  • N-(5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-5,6,7 was added sequentially to the dried sealed tube.
  • 8-tetrahydro-1,6-naphthyridin-2-amine hydrochloride 40 mg, 0.088 mmol
  • water 1 mL
  • anhydrous potassium carbonate 42 mg, 0.3 mmol
  • THF (3 mL) - Methyl oxirane 5 (1 mL).
  • the temperature was raised to 80 ° C for 0.5 hour. After completion of the reaction, the organic phase was separated and concentrated under reduced pressure.
  • Example 23 1-(2-((5-Fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)amino) -7,8-dihydro-1,6-naphthyridin-6(5H)-yl)propan-2-ol
  • Example 24 1-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)amino) -7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-methylpropan-2-ol
  • Example 25 6-(2-ethoxyethyl)-N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl) Pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine
  • Example 26 6-(2,2-Difluoroethyl)-N-(5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidine-2 -yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine
  • Example 27 N-(5-Fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-6-((tetrahydrofuran) -3-yl)methyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine
  • Example 28 N-(5-Fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-6-(3- Methoxypropyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine
  • Example 29 The compound of Example 29, 30 was prepared in the same manner as in Example 19.
  • Example 29 6-Cyclopentyl-N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl) -5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine
  • Example 30 (N-(5-Fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-6-methyl-5,6 ,7,8-tetrahydro-1,6-naphthyridin-2-amine
  • Example 31 The compound of Example 31, 32 was obtained in the same manner as in Example 16.
  • Example 32 2-(Dimethylamino)-1-(2-((5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidine-2) -yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one
  • First step In a 384-well plate, add 5 ⁇ L of enzyme system (50 mM HEPES, 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT and 0.01% Tween 20, 0.1 ⁇ L enzyme), 2.5 ⁇ L of compound, 2.5 ⁇ L of substrate and ATP mix. The solution (final concentration of substrate was 50 nM, final concentration of ATP 100 nM) was incubated at room temperature for 60 min in the dark.
  • enzyme system 50 mM HEPES, 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT and 0.01% Tween 20, 0.1 ⁇ L enzyme
  • Step 2 Add 5 ⁇ L of 1 ⁇ assay buffer diluted EDTA stop solution (final concentration 6 mM) to each well, then add 1 ⁇ assay buffer diluted antibody (final concentration 2 nM) and incubate at room temperature for 1 h in the dark.
  • Step 3 Using PerkinElmer En TRFRET mode board.
  • the fourth step IC50 values were calculated using GraphPad Prism software.
  • A represents an IC 50 of 1 nM to 50 nM
  • the experiments also confirmed that the compounds of the present invention have good selectivity for CDK4 relative to CDK1, i.e., the compounds of the present invention are selective inhibitors of CDK4.
  • the selective inhibition data for exemplary compounds of the invention are shown in Table 2 below.
  • Example compound test for proliferation inhibition activity of different tumor cells (Colo-205, MCF-7, MDA-MB468, LNCAP, K562, U87MG, HepG2, H1975, PANC-1) (CCK-8 or SRB method)
  • the specific steps of the SRB method are as follows: cells in the logarithmic growth phase are inoculated to a 96-well culture plate at a suitable density, 200 ⁇ L per well, and after incubation overnight, different concentrations of the drug are added for 96 hours, and each concentration is set to three replicate wells, and correspondingly Concentration of saline vehicle control and cell-free zeroing. After the end of the action, the adherent cells were decanted, and 10% (w/v) trichloroacetic acid (100 ⁇ L/well) was added and fixed at 4 ° C for 1 h, followed by rinsing with distilled water five times. After drying at room temperature, SRB solution was added to each well.
  • test compound Six male SPF-class SD rats (Shanghai Shipu-Beikai experimental animals) were divided into two groups, and the test compound was configured into a suitable solution or suspension; one group was administered intravenously, and one group was orally administered.
  • Blood was collected by jugular vein puncture, and each sample was collected at about 0.2 mL/time. Heparin sodium was anticoagulated. The time of blood collection was as follows: before, and after 5, 15 and 30 min, 1, 2, 4, 6, and 8 after administration. 24 h; blood samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C), and the collected plasma was stored at -80 ° C before analysis. Plasma samples were analyzed by LC-MS/MS. The time points of blood collection in brain tissue were: 0.5, 2, 6 h (one time point for every 3 animals).
  • blood was collected by cardiac puncture for about 0.50 mL, and then the brain tissue was collected and collected and placed on ice. After the animals are euthanized, brain tissue is collected. The tissue was washed with physiological saline, the filter paper was blotted dry, weighed, and the scissors were cut and placed in an EP test tube.
  • the EP tube was placed in a fully automatic homogenizer, homogenized by adding 50% methanol 50% water according to a corresponding volume of 5 mL/g, and each tissue homogenate was frozen at -20 ° C for testing.
  • the pharmacokinetic parameters ANU 0-t , AUC 0- ⁇ , MRT 0- ⁇ , C max of the test sample were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin5.2. Parameters such as T max , T 1/2 and V d and their mean and standard deviation.
  • the bioavailability (F) will be calculated by the following formula.
  • samples taken prior to reaching C max should be calculated as zero values when calculating the pharmacokinetic parameters. Samples at the sampling point should be incapable of quantification (BLQ) after C max is reached.
  • the representative compound of the present invention (Example 23) has good PK properties in mouse and rat experiments and has a good blood-brain distribution. It is suggested that the compounds of the invention can cross the blood brain barrier to inhibit the growth of brain tumors.
  • test compound is formulated as a suitable solution or suspension; one group is administered intravenously and the other is administered orally.
  • Intravenous group 5, 15 and 30 min, 1, 4, 8 and 24 h before and after administration.
  • Oral administration group before administration and 30 minutes after administration, 1, 2, 4, 6, 8 and 24 hours.
  • Plasma samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C). The collected plasma was stored at -80 °C prior to analysis.
  • Plasma samples were analyzed by LC-MS/MS by the laboratory analysis department. According to the blood drug concentration data of the drug, the pharmacokinetic parameters ANU0-t, AUC0- ⁇ , MRT0- ⁇ , Cmax, Tmax, T1 of the test sample were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin7.0. Parameters such as /2 and Vd and their mean and standard deviation.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions.
  • the nude mice were transplanted subcutaneously with a vernier caliper to measure the diameter of the transplanted tumor.
  • the animals were randomly divided into tumors with an average volume of about 130 mm 3 .
  • the compound of the example administered to the desired concentration with water for injection containing 1% Tween 80
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • V 0 is the measured tumor volume at the time of sub-cage administration (i.e., d 0 )
  • V t is the tumor volume at each measurement.
  • Example 23 was administered orally at a dose of 100 mg/kg and 30 mg/kg once a day for 21 days, which significantly inhibited the growth of subcutaneous xenografts of human colon cancer COLO 205 nude mice. At LY2835219.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés ayant une activité inhibitrice de kinase CDK4/6, une composition pharmaceutique de ceux-ci et une utilisation de ceux-ci. La présente invention concerne en particulier des composés représentés par la formule I, et concerne en outre une composition pharmaceutique comprenant de tels composés et un procédé d'utilisation de tels composés dans la prévention ou le traitement de maladies, en particulier pour une utilisation avec des maladies médiées par une kinase CDK, en particulier par une activité aberrante de kinase CDK4/6.
PCT/CN2019/076864 2018-03-05 2019-03-04 Composés ayant une activité inhibitrice de kinase cdk4/6, composition pharmaceutique de ceux-ci et utilisation de ceux-ci Ceased WO2019170055A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810179402 2018-03-05
CN201810179402.0 2018-03-05

Publications (1)

Publication Number Publication Date
WO2019170055A1 true WO2019170055A1 (fr) 2019-09-12

Family

ID=67845818

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/076864 Ceased WO2019170055A1 (fr) 2018-03-05 2019-03-04 Composés ayant une activité inhibitrice de kinase cdk4/6, composition pharmaceutique de ceux-ci et utilisation de ceux-ci

Country Status (1)

Country Link
WO (1) WO2019170055A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022113003A1 (fr) 2020-11-27 2022-06-02 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk
WO2022149057A1 (fr) 2021-01-05 2022-07-14 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105294683A (zh) * 2014-07-26 2016-02-03 广东东阳光药业有限公司 Cdk类小分子抑制剂的化合物及其用途
CN106188038A (zh) * 2015-06-01 2016-12-07 中国科学院上海药物研究所 一类具有激酶抑制活性的化合物、制备方法和用途
CN106810536A (zh) * 2015-11-30 2017-06-09 甘李药业股份有限公司 一种蛋白激酶抑制剂及其制备方法和医药用途
WO2018121766A1 (fr) * 2016-12-30 2018-07-05 上海医药集团股份有限公司 Composé hétérocyclique fusionné contenant de l'azote, procédé de préparation, intermédiaire, composition et utilisation associés

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105294683A (zh) * 2014-07-26 2016-02-03 广东东阳光药业有限公司 Cdk类小分子抑制剂的化合物及其用途
CN106188038A (zh) * 2015-06-01 2016-12-07 中国科学院上海药物研究所 一类具有激酶抑制活性的化合物、制备方法和用途
CN106810536A (zh) * 2015-11-30 2017-06-09 甘李药业股份有限公司 一种蛋白激酶抑制剂及其制备方法和医药用途
WO2018121766A1 (fr) * 2016-12-30 2018-07-05 上海医药集团股份有限公司 Composé hétérocyclique fusionné contenant de l'azote, procédé de préparation, intermédiaire, composition et utilisation associés

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022113003A1 (fr) 2020-11-27 2022-06-02 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk
WO2022149057A1 (fr) 2021-01-05 2022-07-14 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk

Similar Documents

Publication Publication Date Title
CA3090482C (fr) Derives de tetrahydroquinazoline utiles en tant qu'agents anticancereux
US11248006B2 (en) Macrocyclic derivative of pyrazol[3,4-d]pyrimidin-3-one, pharmaceutical composition and use thereof
RU2622104C2 (ru) Макроциклические ингибиторы киназы lrrk2
ES2775217T3 (es) Inhibidores de bromodominio
JP6609631B2 (ja) 縮合環ヘテロアリール化合物及びｔｒｋ抑制剤としての用途
CN105636953B (zh) 1,4‑二取代的哒嗪衍生物及其用于治疗与smn缺乏相关的病症的用途
WO2021088945A1 (fr) Composé utilisé comme inhibiteur de shp2 et son utilisation
US8841299B2 (en) Substituted pyrrolo[1,2-a]pyrazines as tankyrase inhibitors
US20110059951A1 (en) HETEROCYCLIC DERIVATIVES OF PYRAZOL-4-YL-PYRROLO[2,3-d]PYRIMIDINES AS JANUS KINASE INHIBITORS
TW201910328A (zh) 雜環化合物
CA3085259A1 (fr) Composes heterocycliques bicycliques substitues utilises en tant qu'inhibiteurs de prmt5
JP2018504432A (ja) ユビキチン特異的プロテアーゼ７阻害物質としてのイソチアゾロピリミジノン、ピラゾロピリミジノン及びピロロピリミジノン
WO2017071516A1 (fr) Inhibiteur de kinase et procédé pour sa préparation et utilisation pharmaceutique correspondante
US20230136194A1 (en) Triazolopyridazine derivative, preparation method therefor, pharmaceutical composition thereof, and use thereof
CN106749233A (zh) 一类磺酰胺衍生物及其应用
TW202112784A (zh) 作為磷脂酸肌醇磷酸激酶抑制劑之𠳭唏并嘧啶衍生物
US20220324868A1 (en) Pyrazolone-Fused Pyrimidine Compound, and Preparation Method and Use Therefor
JP2022523477A (ja) ピロロピリミジン誘導体及びこれを有効成分として含有するタンパク質キナーゼ関連疾患の予防又は治療用薬学的組成物
CN117157297A (zh) Prmt5抑制剂
US20150306070A1 (en) Use of maleimide derivatives for preventing and treating leukemia
WO2019170055A1 (fr) Composés ayant une activité inhibitrice de kinase cdk4/6, composition pharmaceutique de ceux-ci et utilisation de ceux-ci
CN114605390B (zh) 具有cdk激酶抑制活性的化合物、其药物组合物和用途
KR20180073681A (ko) 1,4-디카르보닐-피페리딜 유도체
CN116981458A (zh) 具有四氢吲哚-1-甲酰胺作为bcl-2抑制剂的化合物
CN107709312B (zh) 新型抗疟疾药物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19764405

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19764405

Country of ref document: EP

Kind code of ref document: A1